6.part I.understanding, Controlling and Preventing Infection Diseases

PART I - Understanding, Controlling, and Preventing Infectious Diseases from Lon...
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Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier
PART I Understanding, Controlling, and Preventing Infectious Diseases
Section A Epidemiology and Control of Infectious Diseases
CHAPTER 1 Principles of Epidemiology and Public Health Benjamin Schwartz, Stacey W. Martin Epidemiology is the study of the distribution and determinants of disease or other health-related states or events in specified populations and the application of this study to control of health problems. [1] The key component of this definition is the link between epidemiology and populations, which distinguishes it from clinical case studies that focus on individuals. Health events can be characterized by their distribution (descriptive epidemiology) and by factors that influence their occurrence (analytic epidemiology). In both descriptive and analytic epidemiology, health-related questions are addressed using quantitative methods to identify patterns or associations from which inferences can be drawn and interventions developed, applied, and assessed. DESCRIPTIVE EPIDEMIOLOGY
Surveillance
The goals of descriptive epidemiology are to define the frequency of health-related events and their distribution by person, place, and time. The foundation of descriptive epidemiology is surveillance, or case detection. Retrospective surveillance identifies health events from existing data, such as clinical or laboratory records, hospital discharge data, and death certificates. Prospective surveillance identifies and collects information about cases as they occur, for example, through ongoing laboratory-based reporting. With passive surveillance, case reports are supplied voluntarily by clinicians, laboratories, health departments, or other sources. The completeness and accuracy of passive reporting are affected by whether reporting is legally mandated, whether a definitive diagnosis can be established, illness severity, interest of the public and the medical community in a condition, and whether a report will elicit a public health response. Because more severe illness is more likely to be diagnosed and reported, the severity and clinical spectrum of passively reported cases are likely to differ from that of all cases of an illness. Passively collected reports of nationally notifiable diseases are tabulated in the Morbidity and Mortality Weekly Report (http://www.cdc.gov/mmwr/ ). In active surveillance, effort is made to ascertain all cases of a condition occurring in a defined population. Active case finding can be prospective, involving routine contacts with reporting sources; retrospective, through record audits; or both. Population-based active surveillance, in which all cases in a defined geographic area are identified and reported, provides the most complete and unbiased ascertainment of disease and is optimal for describing the rate of a disease and its clinical spectrum. By contrast, active surveillance conducted at only one or several participating facilities can yield biased information on disease frequency or spectrum based on the representativeness of the patient population and the size of the sample obtained.
Case Definition
Establishing a standard case definition is an important first step for surveillance and description of the epidemiology of a disease or health event. [2] Formulation of a case definition is particularly important where laboratory diagnostic testing is not definitive. More restrictive case definitions minimize misclassification but may exclude true cases and are most useful when investigating a newly recognized condition, in which the ability to determine etiology, pathogenesis, or risk factors is decreased by inclusion of noncases in the study population. A more inclusive
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definition might be important in an outbreak setting where cases are being detected for further investigation or where preventive interventions can be applied. Multiple research or public health objectives can be addressed by developing a tiered case definition that incorporates varying degrees of diagnostic certainty for definite and probable cases.
Sensitivity, Specificity, and Predictive Value
Sensitivity, specificity, and predictive values can be used to quantify the performance of a case definition or the results of a diagnostic test or algorithm ( Table 1-1 ). Unlike sensitivity and specificity, predictive values vary with the prevalence of a condition within a population. Even with a highly specific diagnostic test, if a disease is uncommon among those tested, a large proportion of positive test results will be false positives, and the positive predictive value will be low ( Table 1-2 ). If the test is applied more selectively, where the proportion of people tested who truly have disease is greater, the test's predictive value will be improved. Thus, sensitivity and specificity are characteristics of the test, whereas predictive values depend on the disease prevalence in the population in which the test is applied. Often, the sensitivity and specificity of a test are inversely related. Selecting the optimal balance of sensitivity and specificity depends on the purpose for which the test is used: a screening test should be highly sensitive, whereas a follow-up confirmatory test should be highly specific. TABLE 1-1 -- Definitions and Formulae for the Calculation of Important Epidemiologic Parameters Measures of Sensitivity: Proportion of A/(A + C) test accuracy true positives (diseased) with a positive test Specificity: Proportion of D/(B + D) true negatives (nondiseased) with a negative test Positive predictive value (PPV): Proportion of positive tests that are true positives Negative predictive value (NPV): Proportion of negative tests that are true negatives Measures of Variance: Statistic data describing variability of dispersion and individuals in a population precision Standard error: Statistic describing the variability of sample-based point estimates (Po) around the true population value being estimated Confidence interval: A range of values that is believed to contain the true value within a defined level of certainty (usually 95%, as shown) Measures of association and risk Relative risk or risk ratio (RR): Risk (probability) of a health event in those with a given exposure divided by the risk in those without the exposure C/(C + D) Odds ratio (OR): Odds of a AD/BC given exposure among those with a health event divided by odds of exposure among Variance A/(A + B)
D/(C + D)
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those without the health event Population attributable fraction: The proportion of disease in a population due to the specific exposure [Pe (RR - 1)]/[1 + Pe (RR - 1)] (Proportion exposed, Pe = (A + B)/(A + B + C + D)
TABLE 1-2 -- Positive and Negative Predictive Values for a Hypothetical Diagnostic Test Having a Sensitivity of 90% and Specificity of 90% Proportion with Condition Positive Predictive Value Negative Predictive Value 1% 10% 20% 50%
Incidence and Prevalence
8% 50% 69% 90%
> 99% 99% 97% 90%
Characterizing disease frequency is one of the most important aspects of descriptive epidemiology. Frequency measures typically include a count of new or existing cases of disease as the numerator and a quantification of the population at risk as the denominator. Cumulative incidence is expressed as a proportion and describes the number of new cases of an illness occurring in a fixed at-risk population over a specified period of time, generally 1 year, unless otherwise stated. Incidence density is defined as the rate of new cases of disease in a dynamic at-risk population; for this measure the denominator is typically expressed as the population-time at-risk (e.g., person-time). Because the occurrence of many infections varies with season, extrapolating annual incidence from cases detected during a short observation period can be inaccurate. In describing the risk of acquiring illness during a disease outbreak, the attack rate, defined as the number of new cases of disease occurring in a specified population and time period, is a useful measure. Prevalence refers to the proportion of the population having a condition at a specific point in time. As such, it is a better measure of disease burden for chronic conditions than is incidence or attack rate, which identify only new (incident) cases. Prevalent cases of disease can be ascertained in a cross-sectional survey, whereas determining incidence requires longitudinal surveillance. When disease prevalence is low and incidence and duration are stable, prevalence is a function of disease incidence multiplied by its average duration.
Describing Illness by Person, Place, and Time
Characterizing disease by person, place, and time is often useful. Demographic variables, including age, sex, socioeconomic status, and race or ethnicity are often associated with the risk of disease. Describing a disease by place can help define risk groups; for example, when an illness is caused by an environmental exposure or is vector-borne, or in an outbreak with a point source exposure. Time, also, is a useful descriptor of disease occurrence. Evaluating long-term (secular) trends provides information that can be used by policy-makers or clinicians to identify emerging health problems or to assess the impact of prevention programs. The timing of illness in outbreaks can be displayed in an epidemic curve and can be useful in defining the mode of transmission of an infection or its incubation period and in assessing the effectiveness of control measures. ANALYTIC EPIDEMIOLOGY
Study Design
The goal of analytic studies is to identify predictors of an outcome. This goal can be addressed in experimental or epidemiologic (observational) studies. Ecological or trend studies can also be used to assess predictors when the frequency or distribution of an outcome has changed over time or differs between populations. In contrast to experimental or observational studies which analyze information about individuals, ecological studies draw inferences from data on a population level. Inferences from ecological studies must be made with caution because populations differ in multiple ways and because relationships observed for groups do not necessarily apply to individuals (known as the ecological fallacy). Because of these drawbacks, ecological studies are best suited to generating hypotheses that can be tested using other study methods. In experimental studies, hypotheses are tested by systematically allocating an exposure of interest to subjects in
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separate groups to achieve the desired comparison. Such studies include randomized, controlled, double-blinded treatment trials, and laboratory experiments. By carefully controlling study variables, investigators can restrict differences among groups, thereby increasing the likelihood that the observed differences are a consequence of the specific factor being studied. Because experiments are prospective, the temporal sequence of exposure and outcome can be clearly established, making it easy to define cause and effect. By contrast, epidemiologic studies test hypotheses using observational methods to assess exposures and outcomes among individuals in populations and identifying statistical associations from which inferences regarding causation are drawn. Although observational studies cannot be controlled to the same degree as experiments, they are practical in circumstances in which exposures or behaviors cannot be assigned. Moreover, the results are more generalizable to a real population having a wide range of attributes. The three basic types of observational studies are cohort studies, cross-sectional studies, and case-control studies ( Table 1-3 ). Hybrid study designs, incorporating components of these three, have also been developed. [3] In planning observational studies care must be taken in the selection of participants to minimize the possibility of bias. Selection bias results when study subjects have differing probabilities of being selected that are related to the risk factors or outcomes under evaluation. TABLE 1-3 -- Types of Observational Studies and Their Advantages and Disadvantages Type of Study Design, Characteristics Advantages Disadvantages Cohort Prospective or retrospective Ideal for outbreak investigations in defined populations Unsuited for rare diseases or those with long latency
Select study group
Prospective design ensures that Expensive exposure preceded disease May require long follow-up periods
Observe for exposures and disease Selection of study group is unbiased by knowledge of disease status
Calculate relative risk (RR) or RR and HR accurately describe Difficult to investigate multiple hazard ratio (HR) of disease given risk given exposure exposures exposure Crosssectional Nondirectional Select study group Determine exposure and disease status Calculate RR for disease given exposure Casecontrol Retrospective Identify cases with disease Rapid, easy to perform, and inexpensive Timing of exposure and disease may be difficult to determine Rapid, easy to perform, and inexpensive Ideal to determine knowledge, attitudes, and behaviors Timing of exposure and disease may be difficult to determine Biases may affect recall of past exposures
Ideal for studying rare diseases, Biases can occur in selecting those with long latency, new cases and controls and diseases determining exposures OR only provides an estimate of the RR if disease is rare
Identify controls without disease Determine exposures in cases and controls Calculate odds ratio (OR) for an exposure given disease
Cohort Studies
In a cohort study, subjects are categorized based on their exposure to a suspected risk factor and are observed for the development of disease. Associations between exposure and disease are expressed by the relative risk of disease in exposed and unexposed groups (see Table 1-1 ). Cohort studies are typically prospective, with exposure being defined before disease occurs. In retrospective cohort studies, in which the cohort is selected after the outcome has occurred, exposures are determined from existing records that preceded the outcome, and, thus, the directionality of
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the exposuredisease relationship is still forward. By characterizing exposures before development of disease, selection bias is minimized and inference of cause and effect is easier. A major disadvantage of cohort studies is that they are impractical for studying rare diseases or conditions with a long latent period between exposure and the onset of clinical illness. Moreover, whereas cohort studies can assess multiple potential outcomes resulting from an exposure, it is difficult to investigate multiple exposures as risk factors for a single outcome. In general, cohort studies are unsuited for investigating risk factors for new or rare diseases or for generating new hypotheses about possible exposuredisease relationships. Cohort studies not only provide data on whether an outcome occurs but, for those experiencing the outcome, on when it occurs. Analysis of time-to-event data for outcomes such as death or illness is a powerful approach to assess or compare the impacts of preventive or therapeutic interventions. The probability of remaining event-free over time can be expressed in a KaplanMeier survival curve where, initially, the event-free probability is 1 and declines in a stepfunction as the outcomes of interest occur ( Figure 1-1A ). Time-to-event data can also be displayed as the cumulative hazard of an event occurring among members of a cohort, increasing from 0 at enrollment ( Figure 11B ). These two approaches are related in that the hazard reflects the incident event rate while survival reflects the cumulative nonoccurrence of that outcome. [4] [5] With time-to-event analysis, the association between exposure and disease is often expressed as a hazard ratio. Like a relative risk, the hazard ratio is a comparative measure of risk between exposed and unexposed groups, the primary difference being the hazard ratio compares event experience over the entire time period, whereas the relative risk compares event occurrence only at the study endpoint. [6]
Figure 1-1 Example of KaplanMeier and cumulative hazard curves. (A) Survival plot for critically ill patients with Streptococcus pneumoniae bacteremia treated with monotherapy or combination therapy. (B) Cumulative hazard of tympanostomy tube placement from 2 months until 45 years of age in children who received pneumococcal conjugate vaccine (PncCRM) or a control vaccine (HBV). (Redrawn from Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004;170:440-444.); (Redrawn from Palmu AAI, Verho J, Jokinen J, et al. The seven-valent pneumococcal conjugate vaccine reduced tympanostomy tube placement in children. Pediatr Infect Dis J 2004;23:732-738.)
Cross-Sectional Studies
In a cross-sectional study, or survey, a sample is selected and at a single point in time exposures and outcome are determined. Outcomes may include disease status or behaviors and beliefs. Unlike cohort studies, multiple exposures can be evaluated as explanations for the outcome. Associations are characterized by the relative risk, as in cohort studies. Because neither exposures nor outcomes are used in selection of the study group, their prevalence is an estimate of that in the overall population from which the sample was drawn. National survey data characterizing health status, behaviors, and medical care are available from the National Center for Health Statistics (http://www.cdc.gov/nchs/express.htm ).
Case-Control Studies
In a case-control study, the investigator identifies a group of people with a disease or outcome of interest (cases) and compares their exposures with those in a selected group of people who do not have disease (controls). Differences between the groups are expressed by an odds ratio, which compares the odds of an exposure in case and control groups (see Table 1-1 ). Case-control studies are retrospective in that disease status is known and serves as the basis for selecting the two comparison groups; exposures are then determined by reviewing available records or by interview. A major advantage of case-control studies is their efficiency in studying uncommon diseases or those with a long latency. Case-control studies can also evaluate multiple exposures that may contribute to a single outcome. They tend to be less costly and more time-efficient than cohort studies because study subjects can be identified from existing
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sources (such as hospital or laboratory records, disease registries, or surveillance reports) and, after identification of suitable control subjects, data on prior exposures can be collected rapidly. Case-control studies also have several drawbacks: bias can be introduced during selection of cases and controls and in retrospectively determining exposures, and inferring causation from statistically significant associations can be complicated by difficulty in determining the temporal sequence of exposure and disease in a retrospective study.
Causal Inference and the Impact of Bias
Care must be taken in the design of all analytic studies, whether experimental or observational; however, concerns about validity and the impact of potential biases are particularly important for observational studies. The validity of a study is the degree to which inferences drawn from a study are warranted. Internal validity refers to the correctness of study conclusions for the population from which the study sample was drawn, whereas external validity refers to the extent to which the study results can be generalized beyond the population sampled. The validity of a study can be affected by bias, or systematic error, in selecting the study participants (sampling), in ascertaining their exposures, or in analyzing and interpreting study data. For errors to result in bias, they must be systematic, or directional. Nonsystematic error (random misclassification) decreases the ability of a study to identify a true association but does not result in detection of a spurious association. Several sources of bias can occur in selection of study participants ( Box 1-1 ). Diagnosis bias results when persons with a given exposure are more likely to be diagnosed as having disease than are people without the exposure; this can occur because diagnostic testing is more likely to be done or because the interpretation of a test may be affected by knowledge of exposure status. For hospital-based studies, differential referral can also bias selection of a study sample. This bias would occur if, for example, the frequency of an exposure varied with socioeconomic status and a hospital predominantly admitted persons from either a high- or low-income group. Bias can also occur when eligible subjects refuse to participate in a study as cases or controls. However, nonresponse, even at high rates, does not result in bias if responders and nonresponders are similar with respect to the exposures of interest. BOX 1-1 Potential Sources of Bias in Observational Studies [a] BIAS IN CASE ASCERTAINMENT AND CASE/CONTROL SELECTION Surveillance bias: differential surveillance or reporting for exposed and unexposed Diagnosis bias: differential use of diagnostic tests in exposed and unexposed Referral bias: differential admission to hospital based on an exposure or a variable associated with exposure Selection bias: differential sampling of cases based on an exposure or a variable associated with exposure Nonresponse bias: differential outcome or exposures of responders and nonresponders Survival bias: differential exposures between those who survive to be included in a study and those who die following an illness Misclassification bias: systematic error in classification of disease status Bias in estimation of exposure Recall bias: differential recall of exposures based on disease status Interviewer bias: differential ascertainment of exposures based on disease status Misclassification bias: systematic errors in measurement or classification of exposure
a A more complete listing is provided by Sackett. [7]
Determining exposures can be affected by several types of bias. Recall of exposures may be different for persons who have had an illness compared with people who were well. This bias occurs in either direction: cases may be more likely to remember an exposure that they associate with their illness (e.g., what was eaten before an episode of diarrhea) or less likely to recall an exposure if a severe illness affected memory. Interviewers can introduce bias by questioning cases and controls differently about their exposures. Misclassification of exposures can result from errors in measurement such as might occur with the use of an inaccurate laboratory test; these errors are often random rather
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than systematic. Even a carefully designed study that minimizes potential biases can make erroneous causal inferences. An exposure can appear falsely to be associated with disease because it is closely linked to the true, but undetermined, risk factor. Race is often found to be associated with the risk of a disease, whereas the true risk factor may be an unmeasured variable that is linked to race, such as socioeconomic status. The risk of making incorrect inferences can be minimized by considering certain general criteria for establishing causation. These include the strength of an association, the presence of a doseresponse effect, a clear temporal sequence of exposure to disease, the consistency of findings with those of other studies, and the biologic plausibility of the hypothesis. [8]
Statistical Analysis Characteristics of Populations and Samples
Whereas epidemiologic analysis seeks to make valid conclusions about populations, the entire population is rarely included in a study. An assumption underlying statistical analysis is that the sample evaluated was selected randomly from the population. Often, this criterion is not met and calls into question the appropriateness and interpretation of statistical analyses. The mean, median, and mode describe a central value for samples and populations. The arithmetic mean is the average, determined by summing individual values and dividing by the sample size. When data are not normally distributed (skewed), calculation of a geometric mean can limit the impact of outlying values. The geometric mean is calculated by taking the n th root of the product of all the individual values, where n is the total number of individual values. For example, immunogenicity of vaccines is usually expressed by the geometric mean titer. The median, or middle value, is another way to describe nonnormally distributed data. The mode, or most commonly occurring value in a sample, is rarely used. Several measures can be used to describe the variability in a sample. The range describes the difference between the highest and lowest value, whereas the interquartile range defines the difference between the 25th and 75th percentiles. Variation among individuals is most often characterized by the variance or standard deviation. The variance is defined as the mean of the squared deviation of each observation from the sample's mean. The standard deviation is the square root of the variance (see Table 1-1 ). For a normally distributed population, 68% of values fall within 1 standard deviation of the mean and 95% of values within 1.96 standard deviations. The standard error represents a type of standard deviation and is used to describe the standard deviation of an estimate (e.g., mean, odds ratio, relative risk). When analyzing a sample, the mean or other statistics describing the sample represent a point estimate of that parameter for the entire population. If another random sample were drawn from the same population, the point estimate for the parameter of interest would likely be different, depending on the variability in the population and the sample size selected. A confidence interval defines a range of values that includes the true population value, within a defined level of certainty. Most often, the 95% confidence interval is presented (see Table 1-1 ).
Measures of Association and Statistical Significance
In a cohort study or survey, the relative risk or risk ratio compares the risk of disease for those with versus those without an exposure (see Table 1-1 ). In case-control studies, association is assessed by the odds ratio, which compares the odds of exposure among those with and without a disease or health outcome; when disease is uncommon (< 10%) in both exposed and unexposed groups, the odds ratio approximates the relative risk. For timeto-event analyses, the comparative risk is expressed as the hazard ratio. Odds ratios, relative risks, and hazard ratios greater than 1 signify increased risk given exposure and values less than 1 suggest that exposure decreases the risk of an outcome. Because observational studies generally do not include all members of a population, the odds ratios, relative risks, and hazard ratios represent an estimate of the true value within the entire population. Statistical analyses can help guide investigators in making causal inferences based on a point estimate of these measures of association.
Statistical Significance
Statistical tests are applied to assess the likelihood that the study results were obtained by chance alone rather than representing a true difference within the population. Most investigators consider a P-value < 0.05 as being statistically significant, indicating a less than 5% risk that the observed association is the result of chance alone (designated a type I error, the probability of which is the alpha level). Although use of this cutoff for significance testing has become conventional, ignoring higher P-values can cause the researcher to miss a real and important association, whereas blind faith in the significance of lower P-values can lead to erroneous conclusions. Statistical
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testing should contribute to, but not replace, criteria for evaluating possible causation. Statistical significance can also be defined based on 95% confidence intervals, which approximately correspond to a P-value of 0.05. An odds ratio, relative risk, or hazard ratio is considered statistically significant if the 95% confidence interval does not include 1. An advantage of using confidence intervals to define statistical significance is that they provide information on whether a finding is statistically significant and on the possible range of values for the point estimate in the population, with 95% certainty. Another pitfall in interpreting statistical significance is ignoring the magnitude of an effect in favor of its significance. A very large study can identify small, perhaps trivial, differences between study groups as significant. Some epidemiologists have proposed that, despite statistical significance, odds ratios less than 2 or 3 in an observational study should not be interpreted because unidentified bias or confounding could have accounted for a difference of this magnitude. [9] Conversely, the relative risk or odds ratio associating an exposure and outcome may be large but, if the exposure is uncommon in both groups, will not explain most cases of illness. The public health importance of an exposure can be described by the population-attributable fraction, or the proportion of the disease in a population that is related to the exposure of interest. Attributable risk can also be calculated among those with a given exposure, quantifying the proportion of their risk of disease due to that specific exposure.
Sample Size
One reason that a study may fail to identify a true risk factor as statistically significant is that the sample size was too small (designated a type II error, the probability of which is the beta level). Statistical power is defined as 1 and is the complement of type II error, that is, the probability of correctly identifying a difference of specified size between groups, if such a difference truly exists. The problem of inadequate sample size in clinical studies was highlighted in an analysis of negative randomized controlled trials reported in three leading medical journals between 1975 and 1990. Of 70 reports, only 16% and 36% had sufficient statistical power (80%) to detect a true 25% or 50% relative difference, respectively, between treatment groups. [10] In calculating sample sizes for testing hypotheses, investigators must select type I and type II errors and define the magnitude of the difference that is deemed clinically important. Often, the type II error is set at 0.2, indicating acceptance of a 20% likelihood that a true difference exists but would not be identified by the study. Sample size calculations can be performed using a range of computer software. The program Epi-Info can be used to perform sample size calculations as well as other statistical functions and is available at no charge from the Centers for Disease Control and Prevention (www.cdc.gov/epiinfo/ ). Ensuring an adequate sample size is particularly important for studies attempting to prove equivalence or noninferiority of a new treatment compared with standard therapy. Food and Drug Administration guidance recommends that noninferiority trials adopt a null hypothesis that a difference exists between treatments; this hypothesis is rejected if the lower 95% confidence limit for the new treatment is within a specified margin of the point estimate for standard therapy. Because the null hypotheses can never be proven or accepted, the failure to reject a null hypothesis of no difference between treatments or exposure does not prove equivalence. The importance of this distinction is illustrated by an analysis of 25 studies claiming equivalence of therapies for pediatric bacterial meningitis. Twenty-three studies claimed equivalence based on a failure to detect a significant difference between treatment groups. However, only 3 of these trials could exclude a 10% difference in mortality, potentially missing a clinically significant difference. [11] In some situations, an investigator would want to detect a significant difference among study groups as soon as possible, for example, when a therapeutic or preventive intervention could be applied once a risk group is identified or when there are concerns about the safety of a drug or vaccine. One approach to this situation is to include in the study design interim analyses after a specified number of subjects are evaluated. Because the likelihood of identifying chance differences as significant increases with the number of analyses, it is recommended that the threshold for defining statistical significance should become more stringent as the number of planned analyses increases. [12] If each interim analysis can lead to stopping the trial, this study design is considered a group sequential method. [13] Another example of a group sequential design is when concordance or discordance in outcome is tabulated for each matched set exposed to alternate treatments. Results for each set are plotted on a graph and data collection continues until a preset threshold for a significant difference between study groups is crossed or no significant difference is detected at a given power. [12]
Statistical Inference
Statistical testing is used to determine the significance of differences between study groups, and, thus, it provides guidance on whether to accept or reject the null hypothesis. Although providing details of specific statistical tests is outside the scope of this chapter, Table 1-4 provides examples of statistical tests that can be applied in analyzing different types of exposure and outcome variables.
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TABLE 1-4 -- Types of Statistical Tests Used to Evaluate the Significance of Associations Among Categorical and Continuous Variables Dependent Variable (Disease, Outcome) Independent Variable (Exposure, Risk Factor) Categorical Dichotomous > 2 categories Continuous Chi-squared test Fisher exact test Chi-squared test Logistic regression Student-test (parametric) Wilcoxon rank sum test (nonparametric) Analysis of variance (parametric) KruskalWallis test (nonparametric) Linear regression Correlation (Pearson: parametric; Spearman: nonparametric) Using appropriate analytic and statistical methods is important in identifying significant predictors of an outcome (i.e., risk factors) correctly. Confounding variables are associated with the disease of interest and with other exposure variables that are associated with the disease and are not part of the causal pathway ( Figure 1-2 ). For example, in a study evaluating the link between childcare attendance and pharyngeal carriage of penicillin-resistant pneumococci, recent antimicrobial use would be a confounder because it is associated with both childcare attendance and carriage of resistant pneumococci. Failure to adjust for recent antimicrobial use as a confounding variable would result in overestimating the relationship between childcare and resistant pneumococcal carriage. Effect modifiers interact with risk factors to affect their impact on outcome but may or may not themselves affect outcome. Frequently, age is an effect modifier, with an exposure associated significantly with an outcome in one age group but not in another. Categorical and Dichotomous Continuous
Figure 1-2 Path diagram illustrating association between confounding variable (C), another risk factor (F), and the disease outcome (D).
There are several approaches to control for confounding variables and effect modifiers. In study design, an extraneous variable can be controlled for by randomization, restricting sampling to one category of the variable or by frequency-matching to obtain similar proportions of cases and controls in each stratum. A more extreme form of matching is to select control subjects who are similar to individual cases for extraneous variables (e.g., age, sex, underlying disease) and to analyze whether exposures are concordant or discordant within matched sets. A newer
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approach to study design is the case-crossover [14] or case series [15] analysis. In this method, the investigator compares exposures occurring in a defined risk period before the outcome with exposures occurring outside the risk window. This approach has been adapted to the study of adverse events after vaccination. If the vaccine causes the event, the rate of the event would be greater within a defined risk window than would be predicted by chance alone based on the expected distribution of the event. [16] The strength of this approach is that each case serves as his or her own control, decreasing confounding. At the analysis stage, the impact of confounding variables and effect modifiers can be limited by performing a stratified analysis or using a multivariable model. In a stratified analysis, the possible association between a risk factor and an outcome is determined separately within different categories, or strata, of the extraneous variable. Stratum-specific estimates can be combined into a single estimate using an appropriate statistical test (e.g., a Mantel Haentzel odds ratio). If a stratification variable is an effect modifier, the relative risk or odds ratio will differ substantially between the strata; for example, an exposure may be a strong risk factor in one age group but not another. In this setting, a summary statistic should not be presented and results for each stratum should be presented separately. When the extraneous variable is a confounder, an unstratified analysis can identify an exposure as a significant risk factor; when the analysis is stratified by the confounder, however, the apparent association with outcome is abolished in each stratum, indicating that the exposure is not an independent risk factor for disease. Because stratified analyses rapidly become confusing as the number of strata increases, techniques of mathematical modeling have been developed that permit the simultaneous control of multiple variables. Significant risk factors determined in a multivariable model are interpreted as each contributing independently and significantly to the outcome, thus controlling for confounding. Effect modification can be taken into account by including terms expressing the interaction between a risk factor and effect modifier in the model. Various multivariable models are appropriate for discrete, continuous, and time-dependent outcomes. A limitation of multivariable modeling is multicollinearity, which occurs when two or more explanatory variables of interest are highly correlated, and can result in inaccurate measures of association and decreased statistical power. The risk of multicollinearity can be reduced by assessing correlations between potential risk factors and selecting which variables to include in the model. Various methods to identify and minimize multicollinearity have been developed. [17] VACCINE EFFICACY STUDIES With advances in vaccine development and the licensure of new vaccines, the ability to interpret results of vaccine efficacy studies becomes increasingly important. Most prelicensure efficacy studies are experimental randomized, double-blind, controlled trials in which vaccine efficacy (VE) is calculated by comparing the attack rates (AR) for disease in the vaccinated and unvaccinated groups (VE (%) = ((AR unvaccinated AR vaccinated)/AR unvaccinated) 100; or (1 RR) 100). After licensure, conducting controlled studies, which requires withholding vaccine from a control group, is no longer ethical. Therefore, further studies of efficacy must be observational rather than experimental, comparing persons who have chosen to be immunized with those who have not. In case-control efficacy studies, investigators identify persons with disease and compare their vaccination status with the vaccination status of healthy controls. The number of vaccinated and unvaccinated cases and controls is included in a two-by-two table, and vaccine efficacy is calculated as 1 minus the odds ratio (VE (%) = (1 OR) 100). When the proportion of cases who have been vaccinated is less than the proportion of vaccinated controls, the odds ratio is < 1 and the point estimate for efficacy indicates that immunization is protective. The precision of the estimate is expressed by the 95% confidence interval. A lower 95% confidence limit that is greater than 0% indicates statistically significant protection; often investigators set power of vaccine efficacy studies so that the lower confidence limit is much greater than zero and consistent with meaningful levels of protection. The most important component of a case-control efficacy study is selecting controls who have the same opportunity for immunization as do cases. If cases had less opportunity to be immunized, results will be biased toward showing protection. Factors such as low socioeconomic status, which may increase the risk of disease and decrease the chance of being immunized, are potential confounding variables and can be controlled for by matching controls to cases for those factors. Cohort studies can also be used to determine vaccine efficacy after licensure. A study design called the indirectcohort method was developed by researchers at the Centers for Disease Control and Prevention to evaluate the efficacy of the pneumococcal polysaccharide vaccine using data collected by disease surveillance. [18] The study cohort included persons identified with invasive pneumococcal infections. The study hypothesis was that, if vaccine was protective, the proportion of vaccinated persons infected with pneumococcal serotypes that are included in the vaccine formulation would be less than the proportion of unvaccinated persons infected with vaccine-type strains. Vaccine efficacy was calculated from the relative serotype distributions overall and for each individual serotype. In a study of pneumococcal polysaccharide vaccine efficacy that utilized this approach, the point estimate of efficacy for preventing invasive infection was 57% (95% confidence interval from 45% to 66%); [19] this estimate is similar to that obtained in a case-control efficacy study. [20]
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DISEASE CONTROL AND PUBLIC HEALTH POLICY

Outbreak Investigations
Outbreak investigations require knowledge of disease transmission and use of descriptive and analytic epidemiologic tools. Possible outbreaks can be identified from surveillance data showing an increased rate of an infection or an unusual clustering in person, place, and time. Comparing the incidence rate of disease with a baseline rate from a previous period is helpful in validating the occurrence of an outbreak. Other explanations for changes in the apparent rate of disease occurrence, such as diagnostic error, seasonal variations, and changes in reporting, must be considered. Using sensitive molecular methods to assess similarity between isolates from cases may be helpful in documenting that an apparent cluster of cases represents an outbreak, because most outbreaks are caused by a single strain. After establishing the presence of an outbreak, the next steps of an investigation are to develop a case definition, identify cases, and characterize the descriptive epidemiology. An epidemic curve depicts number of cases over time and can provide information on possible transmission. In an outbreak with a point source exposure, an index case may be identified, with other cases occurring after an incubation period or at multiples of an incubation period (Figures 1-3 and 1-4 [3] [4]). Plotting the location of cases on a spot map may be helpful in determining possible exposures. Describing host characteristics can be important in identifying at-risk populations for further investigation or targeting control measures, and for developing hypotheses that can be investigated in an analytic study.
Figure 1-3 Example of an epidemic curve for a common source outbreak with continuous exposure. Cases of hepatitis by date of onset, Fayetteville, Arkansas, November to December 1979. (Centers for Disease Control and Prevention, unpublished data.)
Figure 1-4 Example of an epidemic curve for a common source outbreak with continuous exposure. Cases of diarrheal illness in city residents by date of onset and character of stool, Cabool, Missouri, December 1989 to January 1990. (Centers for Disease Control and Prevention, unpublished data.)
Cohort studies are optimal for investigating outbreaks that occur in small, well-defined populations. These include outbreaks in school or childcare, social gatherings, and hospitals. In populations that are not well defined, a case-
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control study is the most feasible approach. It is important to select controls who had an opportunity equal to that of cases for exposure to potential risk factors and developing disease. Neighbors of cases or patients from the same medical-provider practice or hospital as the case are commonly selected as controls. Friends of cases have been used as controls in some investigations, but concerns have been raised about possible overmatching, because friends may be more likely than others to have similar exposures. When the number of cases is relatively small, enrolling multiple controls per case increases the power of the study to find significant risk factors. After a standard questionnaire is administered, significant risk factors are determined by comparing exposures of cases and controls. The results of analyses may lead to inferences of causation and development of prevention and control strategies or to further hypotheses that can be evaluated later. The impact of intervention can be determined by ongoing surveillance and continuing to plot additional cases on the epidemic curve ( Figure 1-4 ).
Impact and Economic Analysis of Disease Prevention
Assessing health and economic impacts of public health interventions is important in developing or supporting policy decisions. Health impacts can be expressed directly as cases of disease, deaths, and sequelae prevented. Vaccine efficacy is a specific example of the prevented fraction (PF), where PF = P (1 RR), with P representing the proportion exposed to an intervention. Secondary measures of health impact include years of potential life lost (YPLLs) or quality-adjusted life-years (QALYs) lost, which quantify the impact of death, or death and disability, respectively, based on the age at which these events occur. [21] A measure of the efficiency of an intervention is the number needed to treat (NNT), which describes how many persons must be exposed to an intervention to avoid one case of adverse health outcome; for example, the number of persons who would need to be immunized to prevent a case or a death, or to be given antibiotic prophylaxis to prevent one case of infection. Because public health resources are limited, it is becoming increasingly important to calculate impact in economic as well as in health terms and to compare an intervention with other potential uses of available resources. Costeffectiveness analyses determine the cost per health outcome achieved, such as the cost per death or complication averted. In a cost-effectiveness formula, costs appear in the numerator and health benefits appear in the denominator. The numerator includes expenditures for the prevention program from which cost savings occurring with disease prevention are subtracted. In addition to direct costs averted (e.g., savings from decreased medical care), indirect costs savings occur from increased productivity of people who do not become ill or miss time from work while receiving care or caring for ill family members. Costutility calculations are similar to cost-effectiveness but assess cost per QALY saved or YPLL averted. Costbenefit analyses differ from cost-effectiveness analyses in that the calculation is made entirely in economic terms. Health benefits are assigned an economic value and expenditures are compared with savings. One problem with this approach lies in the difficulty assigning an economic value to a health effect. For example, the value of a life saved may be quantified as the estimated value of a person's earnings over his or her lifetime, foregone earnings due to premature death, or by a standard amount; both economic and ethical issues may be raised by the choice of approach. Because the parameters used in economic analyses are often uncertain or based on limited data, and because choices made by the investigator (e.g., regarding the value of life) may be influential to the analysis, sensitivity analyses are often performed where parameters are varied across a range of potential values. In addition to defining a range of possible economic outcomes, sensitivity analyses can identify the factors that most influence the results, elucidating where further studies may be important. EVALUATING THE MEDICAL LITERATURE Basic epidemiologic knowledge is important not only in performing research but also in evaluating studies reported in the medical literature. Steps in reviewing published medical research are shown in Box 1-2 . The ability to assess published studies carefully is often limited by the information presented in the report. To improve reporting of randomized controlled trials, a group of investigators and editors developed a Consolidated Standards of Reporting Trials (CONSORT) [23] and later extended these recommendations to reporting of noninferiority and equivalence randomized trials. [24] Although these standards have been adopted by many journals and editorial groups, reporting often does not adhere to the quality standards proposed. [25] [26] Although the guidelines refer to experimental rather than observational studies, most criteria still apply. BOX 1-2 Steps in the Critical Evaluation of Epidemiologic Literature [24] 1. 2. Consider the research hypothesis Consider the study design Type of study
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3.
Selection of study participants Selection and definition of outcome variables Selection and definition of exposure (predictor) variables Sample size and power
Consider the analysis Complete accounting of study subjects and outcomes Appropriateness of statistical tests Potential sources and impact of bias Potential impact of confounding and effect modification
4.
Consider the interpretation of results Magnitude and importance of associations Study limitations Ability to make causal inferences
Assessing the research hypothesis allows readers to determine the relevance of the study to their practice and to judge whether the analyses were done to test the hypothesis or to identify other interesting associations. The ability to make causal inferences from a confirmatory study that tests a single hypothesis is greater than from an exploratory study in which multiple exposures are considered as potential explanations for an outcome. Several components of study design are important to consider. Details should be presented regarding the criteria for selecting a cohort or cases and controls. Exposure and outcome variables should be clearly defined, and the potential for misclassification and its impact should be considered. Quantifying exposure may be important to establish a doseresponse relationship. Finally, sample size estimates should be presented, making clear the magnitude of difference between study groups considered clinically meaningful and the type I and type II error levels. In the analysis, it is important that outcomes for all study subjects are reported, even if that outcome is lost to follow-up. Intent-to-treat analyses consider outcomes for all enrolled subjects, whether or not they completed the therapy (e.g., those who were nonadherent with therapy or who received only part of a vaccination series). The appropriateness of the statistical tests should be assessed; for example, if data are not normally distributed, they can be transformed to a scale that is more normally distributed (e.g., geometric mean titers) or nonparametric statistical tests should be used. In assessing a multivariable model, the reader should critically evaluate the type of model chosen, the variables included, and whether interaction terms were considered. Missing data pose a particular problem in modeling, in that study subjects can only be included if data are available for each variable in the model; thus, the power of a multivariate model may be much less than that predicted in a sample size calculation. Bias can have an important impact on study results and must be carefully considered. Approaches to minimize bias should be clearly described. The direction and potential magnitude of remaining bias should be estimated and its impact on results considered. Potential confounding, the presence of important unmeasured variables, and possible effect modification can have a major impact on the results. Investigators should openly discuss the potential limitations of the investigation and describe the strategies they applied to overcome those limitations. Finally, interpretation of study results includes assessing the magnitude of the associations, their relevance to practice, and the likelihood that the relationships observed are causal. The importance of an exposure in explaining an outcome can be expressed by the attributable proportion. The external validity of the results, however, and the potential impact on one's own patient population must still be assessed. Acknowledgment Thanks to Paul M. Gargiullo, PhD, for assistance. References 1. In: Last JM, ed. A Dictionary of Epidemiology, 2nd ed.. New York: Oxford University Press; 1988:42. 2. Centers for Disease Control and Prevention : Case definitions for public health surveillance. MMWR 1990; 39:143.
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3. Kleinbaum DG, Kupper LL, Morganstern H: Epidemiologic Research: Principles and Quantitative Methods, New York: Van Nostrand Reinhold; 1982:62-95. 4. Bland JM, Altman DG: Survival probabilities (the Kaplan-Meier method). Br Med J 1998; 317:1572. 5. Clark TG, Bradburn MJ, Love SB, et al: Survival analysis part 1: basic concepts and first analyses. Br J Cancer 2003; 89:232-238. 6. Hosmer W, Lemeshow S: Applied Logistic Regression, New York, Wiley, 1989. 7. Sackett DL: Bias in analytic research. J Chronic Dis 1979; 32:51-63. 8. Hill AB: Principles of Medical Statistics, 9th ed.. New York: Oxford University Press; 1971:309-323. 9. Hoffmeister H: Small effects as a main problem in epidemiology. In: Hoffmeister H, Szklo M, Thamm M, ed. Epidemiological Practices in Research on Small Effects, Berlin: Springer-Verlag; 1998:1-4. 10. Moher D, Dulberg CS, Wells GA: Statistical power, sample size, and their reporting in randomized controlled trials. JAMA 1994; 272:122-124. 11. Krysan DJ, Kemper AR: Claims of equivalence in randomized controlled trials of the treatment of bacterial meningitis in children. Pediatr Infect Dis J 2002; 21:753-757. 12. Armitage P, Berry G: Statistical Methods in Medical Research, 2nd ed.. New York, Wiley, 1987. 13. Whitehead J: Sequential methods. In: Redmond CK, Colton T, ed. Biostatistics in Clinical Trials, New York: Wiley; 2001:414-422. 14. Maclure M, Mittleman MA: Should we use a case-crossover design?. Annu Rev Public Health 2000; 21:193221. 15. Farrington CP, Nash J, Miller E: Case series analysis of adverse reactions to vaccines: a comparative evaluation. Am J Epidemiol 1996; 143:1165-1173. 16. Murphy TV, Gargiullo PM, Massoudi MS, et al: Intussuception in recipients of oral, rhesus-based human reassortant rotavirus-tetravalent vaccine (Rotashield). N Engl J Med 2001; 344:564-572. 17. Graham MH: Confronting multicollinearity in ecological multiple regression. Ecology 2003; 84:2809-2815. 18. Broome CV, Facklam RR, Fraser DW: Pneumococcal disease after pneumococcal vaccination: an alternative method to estimate the efficacy of pneumococcal vaccine. N Engl J Med 1980; 303:549-552. 19. Butler JC, Breiman RF, Campbell JF, et al: Pneumococcal polysaccharide vaccine efficacy. JAMA 1993; 270:1826-1831. 20. Shapiro ED, Berg AT, Austrian R: The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325:1453-1460. 21. World Bank : World Development Report 1993: Investing in Health, Oxford, England, Oxford University Press, 1993. 22. Greenberg RS: Medical Epidemiology, Norwalk, CT: Appleton and Lange; 1993:120. 23. Moher D, Schulz KF, Altman DG, CONSORT Group : The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Lancet 2001; 357:1191-1194. 24. Piaggio G, Elbourne DR, Altman DG, et al: Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 2006; 295:1152-1160. 25. Mills EJ, Wu P, Gagnier J, et al: The quality of randomized trial reporting in leading medical journals since the revised CONSORT statement. Contemp Clin Trials 2005; 26:480-487.
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26. Mills E, Wu P, Gagnier J, et al: An analysis of general medical and specialist journals that endorse CONSORT found that reporting was not enforced consistently. J Clin Epidemiol 2005; 58:662-667. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 2 Pediatric Infection Prevention and Control Jane D. Siegel, Leigh Grossman Developing effective prevention strategies for healthcare-associated infections (HAIs) in pediatric patients is a unique science that requires consideration of various host factors, sources of infection, routes of transmission, behaviors associated with care of infants and children, pathogens and their virulence factors, treatments, preventive therapies, and behavioral theory. Although the term nosocomial still applies to infections that are acquired in acute care hospitals, a more general term, healthcare-associated infections (HAIs), is now used since much care of high-risk patients, including those with medical devices (e.g., central venous catheters, ventilators, peritoneal dialysis catheters), has shifted to ambulatory settings, rehabilitation or chronic care facilities, and to the home; thus, often the geographic location of acquisition of the infection cannot be determined. A true nosocomial infection is defined as an infection that was not incubating or present at the time of hospital admission, and that develops 48 hours or more after hospital admission or within 10 days of hospital discharge. In neonates, a transplacental infection is not considered a nosocomial infection. An infection is nosocomial, however, if a mother is not infected at the time of admission but delivers an infected infant more than 48 hours after her admission. The principles of transmission of infectious agents in healthcare settings and prevention are reviewed in the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007. [1] The pediatric host is highly susceptible to common respiratory and gastrointestinal tract viruses (e.g., respiratory syncytial virus (RSV), influenza virus, rotavirus) that may be transmitted in healthcare settings in addition to the usual healthcare-associated bacteria and fungi. HAIs can result in the serious morbidity and mortality that occur in adult patients and in lifetime physical, neurologic, and developmental disabilities. Infection rates between 2% and 13% of admissions or discharges from pediatric units are typical. [2] [3] [4] [5] Intensive care units, oncology services, and gastroenterology services that care for patients with short gut who are dependent on total parenteral nutrition (TPN) have the highest rates of bacterial and fungal infection associated with central venous catheters. Those children who have complex underlying diseases are at greatest risk for prolonged hospitalization, complications, and mortality associated with acquisition of new infections in the hospital. [3] [4] [5] [6] [7] [8] Severely immunosuppressed patients (e.g., allogeneic hematopoietic stem cell transplant (HSCT) recipients, children with leukemia undergoing intensive chemotherapy, solid-organ transplant recipients during the periods of most intense immunosuppression), are at increased risk for invasive aspergillosis and other environmental fungal infections, especially during periods of facility renovation, construction, and water leaks. [9] UNIQUE ASPECTS OF HEALTHCARE-ASSOCIATED INFECTION IN CHILDREN Unique aspects of HAIs in children have been reviewed in detail [5] and are summarized below. Specific risks and pathogens are addressed in multiple other chapters in this textbook.
Host or Intrinsic Factors
Rates of all HAIs as high as 7% to 25% are reported in neonatal intensive care units (NICUs) and are inversely proportional to birthweight. [4] [7] [10] Host, or intrinsic, factors that make children particularly vulnerable to infection are immaturity of the immune system, congenital abnormalities, and congenital or acquired immunodeficiencies. The populations of immunosuppressed children have expanded with the advent of more intense immunosuppressive therapeutic regimens used for oncologic conditions, HSCTs, solid-organ transplants, and rheumatologic conditions and inflammatory bowel disease for which immunosuppressive agents and tumor necrosis factor- inhibitors (infliximab) and other immune modulators are used. Fortunately, the population of children with
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perinatally acquired human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) has dramatically decreased since 1994, but new cases of sexually transmitted HIV infection are diagnosed increasingly in teens who are cared for in children's hospitals. Innate deficiencies of the immune system in prematurely born infants, who may be hospitalized for prolonged periods of time and exposed to intensive monitoring, supportive therapies and invasive procedures, contribute to the high rates of infection in the NICU. All components of the immune system are deficient in neonates and the degree of deficiency is inversely proportional to the gestational age (see Chapter 10 , Immunologic Development and Susceptibility to Infection). Additionally, the underdeveloped skin of the very-low-birthweight infant (< 1000 grams) provides another mode of entry for pathogens. Children with congenital anomalies have a high risk of HAI because they require prolonged and repeated hospitalizations, undergo many complex surgical procedures, and have extended exposure to invasive supportive and monitoring equipment. For example, at the University of Virginia Medical Center, children with myelomeningocele have had an average of 9 hospitalizations (range, 3 to 50) and 6 surgical procedures (range, 2 to 30) by 15 years of age. The source of many HAIs may be the endogenous flora of the patient. [11] [12] An asymptomatic colonizing pathogen can invade an individual patient or be transmitted on the hands of healthcare personnel to other patients. As the rates of colonization with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) at the time of hospital admission have increased, so has transmission of community strains, most often USA 300, within the hospital, [13] making prevention especially challenging. Finally, young infants who have not yet been immunized, or immunosuppressed children who do not respond to vaccines or lose their antibody during treatment (e.g., patients with nephrotic syndrome), have increased susceptibility to infections that would be prevented by vaccines.
Sources or Extrinsic Factors
Important sources of HAIs in infants and children include the mother, invasive monitoring and supportive equipment, blood products, infant formula and human milk, healthcare personnel, and other contacts, including adult and sibling visitors. Maternal infection with Neisseria gonorrhoeae, Treponema pallidum, HIV, hepatitis B virus, parvovirus B19, Mycobacterium tuberculosis, herpes simplex virus, group B streptococcus, or the emerging CA-MRSA pose substantial threats to the neonate. During perinatal care, procedures such as fetal monitoring with scalp electrodes, fetal transfusion and surgery, umbilical cannulation, and circumcision are risk factors for infection. Intrinsically contaminated powdered formulas and infant formulas prepared in contaminated blenders or improperly stored or handled, or both, have resulted in sporadic and epidemic infections in the nursery (e.g., Enterobacter sakazakii). [14] Human milk that has been contaminated by maternal flora or by organisms transmitted through breast pumps has caused isolated serious infections and epidemics. The risks of neonatal hepatitis, cytomegalovirus infection, and HIV infection from contaminated human milk warrant further caution for handling. Rates of central vascular line-associated bloodstream infections (CLA-BSIs) in the pediatric intensive care units (PICUs) and high-risk nurseries (HRN) in the National Nosocomial Infection Surveillance (NNIS) system (now the National Healthcare Safety Network (NHSN)) from 1/2002 to 6/2004 are among the highest for all reporting ICUs, with a mean of 6.6 CLA-BSIs per 1000 catheter-days in the PICUs; this rate is only surpassed in trauma and burn units, with a mean of 7.4 and 7.0 CLA-BSIs per 1000 catheter-days, respectively. [10] Rates of umbilical and CLA infections vary by birthweight category from 3.5 per 1000 catheter-days in the > 2500 gram birthweight group to 9.1 per 1000 catheter-days in the < 1000 gram birthweight group (Tables 2-1 and 2-2 [1] [2]). Medical device-related infections (e.g., CLA-BSIs, ventilator-associated pneumonia (VAP), and surgical site infections (SSIs)) can be prevented by implementing 3 to 5 sets or bundles of evidence-based practices, as defined in the Institute for Healthcare Improvement (IHI) 100,000 lives campaign (www.ihi.org/IHI/Programs/Campaign ). TABLE 2-1 -- National Nosocomial Infection Surveillance Central Line Infection (CLI)-Associated Bloodstream Infection (CLA-BSI) Rates: Intensive Care Units (ICUs) January, 2002 to June, 2004 [a] ICU Type No. of ICUs Reporting Rate/1000 Catheter-Days: Pooled Mean (Median, Range) Trauma Burn Pediatric Medical Respiratory Surgical Neurosurg Coronary Medical-surgical 22 14 54 94 6 99 30 60 7.4 (5.2, 1.911.9) 7.0 (NA) 6.6 (5.2, 0.911.2) 5.0 (3.9, 0.58.8) 4.8 (NA) 4.6 (3.4, 08.7) 4.6 (3.1, 010.6) 3.5 (3.2, 1.09.0)
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Major teaching All others Cardiothoracic

a
100 109 48
4.0 (3.4, 1.77.6) 3.2 (3.1, 0.86.1) 2.7 (1.8, 04.9)
TABLE 2-2 -- National Nosocomial Infection Surveillance Central Line (CLA-BSI)-Associated Bloodstream Infection Rates: Umbilical and Central Catheter Bloodstream Infection Rates: High-Risk Nursery, January, 2002 to June, 2004 [a] Birthweight Group No. of Nurseries Reporting Rate/1000 Catheter Days: Pooled Mean (Median, Range) 1000 grams 10011500 grams 15012500 grams 104 98 97 9.1 (8.5, 1.616.1) 5.4 (4.0, 012.2) 4.1 (3.2, 08.9)
> 2500 grams 94 3.5 (1.9, 07.4) Adapted from the National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470485.
a
Although most work has been done in adult populations, there are modifications for pediatrics and the efficacy of CLA-BSI preventive practices was demonstrated in a 1-year collaborative of children's hospitals sponsored by the Child Health Corporation of America (CHCA) in 2005. Thus, it is likely that rates of device-related infections have been reduced even further since the NNIS report published in December, 2004. Use of more specialized life-saving technologies, such as extracorporeal membrane oxygenation (ECMO), hemodialysis/hemofiltration, pacemakers, and implantable ventricular assist devices (VADs), further increases the risk of infection in the sickest children who require the most intense, invasive support. Many standard infection control procedures for prevention of device-related infections in adults cannot be followed routinely for children. In adults, for example, peripheral intravascular catheters are changed routinely every 3 to 4 days to reduce the risk of catheter colonization and subsequent infection of the bloodstream. Infants, however, may have such limited vascular access that catheters remain in place until they become unnecessary, nonfunctional, or contaminated. Additionally, the specific indications for deep-vein thrombosis and peptic ulcer disease prophylaxis have not been defined for children requiring mechanical ventilator support and there is some evidence suggesting that peptic ulcer disease prophylaxis is associated with an increased risk of necrotizing enterocolitis and candidemia in low-birthweight infants. [15] There are theoretical concerns that infection risk will also increase in association with the innovative practices of cobedding and kangaroo care in the NICU because of increased opportunity for skin-to-skin exposure of multiplegestation infants to each other and to their mothers, respectively. However, the infection risk is reduced with kangaroo care. [16] Finally, exposure to vancomycin and to third-generation cephalosporins contributes substantially to the increase in infections caused by vancomycin-resistant enterococcus (VRE) and multidrug-resistant gramnegative bacilli, including extended-spectrum beta-lactamase (ESBL)-producing organisms, respectively. Exposure to third-generation cephalosporins is also a risk factor for the development of invasive candidiasis in low-birthweight infants in the NICU. [17] [18]
Transmission
The principal modes of transmission of infectious agents are direct and indirect contact, droplet, and airborne. Most infectious agents are transmitted by the contact route via hands of healthcare personnel, but many pathogens can be transmitted by more than one route. Viruses, bacteria, and Candida spp. can be transmitted horizontally. Although the source of most Candida HAIs is the patient's endogenous flora, horizontal transmission, most likely via healthcare personnel hands, has been demonstrated in studies using DNA fingerprinting in the NICU and in a pediatric oncology unit. Transmission of infectious agents by the droplet route requires exposure of mucous membranes to large respiratory droplets (> 5 m) within 1 to 2 meters (3 to 6 feet) of the infected individual, who may be coughing or sneezing. Large respiratory droplets do not remain suspended in the air. Adenovirus, influenza virus, and rhinovirus are primarily transmitted by the droplet route whereas other respiratory viruses (e.g., RSV, parainfluenza) are primarily transmitted by the contact route. Although influenza virus can be transmitted via the airborne route under unusual conditions of reduced air circulation or relative humidity, there is ample evidence that
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transmission of influenza is prevented by droplet precautions and, in the care of infants, the addition of contact precautions under usual conditions. [19] Some agents (e.g., severe acute respiratory syndromecoronavirus (SARS-CoV)) can be transmitted as small-particle aerosols under special circumstances of aerosol-producing procedures (e.g., endotracheal intubation, bronchoscopy); therefore, an N95 or higher respirator is indicated for those in the same airspace when these procedures are performed, but an airborne infection isolation room (AIIR) may not always be required. Roy & Milton proposed a new classification for aerosol transmission when evaluating routes of SARS transmission [20] : (1) obligate: under natural conditions, disease occurs following transmission of the agent only through 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 naturally cause disease through other routes, but under certain environmental conditions can be transmitted via fine-particle aerosols. This conceptual framework may 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 that can cause severe disease and have no known treatment often result in more extreme prevention strategies than may be necessary; therefore, recommended precautions could change as the epidemiology of emerging agents is defined and these controversial issues are resolved. Although transmission of M. tuberculosis can occur rarely from a child with active tuberculosis, the more frequent source is the adult visitor who has not been diagnosed with active pulmonary tuberculosis; thus screening of visiting family members is an important component of control of tuberculosis in pediatric healthcare facilities. [21] Transmission of microbes among children and between children and healthcare personnel is a frequent risk due to the very close contact that occurs during care of infants and young children. Traditionally, multi-bed rooms are crowded with children, parents, and healthcare personnel. However, with the increasing evidence that single-patient rooms provide improved environments for patients that includes reduced risk of transmission of infectious agents and reduced medical errors, the American Institute of Architects' 2006 Guidelines for Design and Construction of Health Care Facilities recommends single-patient rooms for acute medical/surgical and postpartum patients as the standard for all new construction (www.aia.org/aah_gd_hospcons ). Although there are insufficient data at this time to support a definitive recommendation for single-patient rooms in NICUs, there is increasing experience that suggests a benefit to reduce the risk of infection and to improve neurosensory development. [22] Toddlers often share waiting rooms, playrooms, toys, books, and other items and therefore have the potential of transmitting pathogens directly and indirectly to one another. Contaminated bath toys were implicated in an outbreak of multidrug-resistant Pseudomonas aeruginosa in a pediatric oncology unit. [23] Before effective preventive measures were established, [24] 17% of preschool children hospitalized for more than 1 week had a nosocomial viral respiratory tract illness. [25] Infection of pediatric healthcare workers was also common. Since routine care of infants and younger children involves holding, cuddling, wiping noses, feeding, and changing diapers, it is easy to see how RSV and other respiratory tract viral agents can be transmitted in secretions that are then inoculated into the eyes and noses of healthcare workers. RSV infections were more likely in healthy volunteers who held or cuddled infants or handled items that the infants had touched and did not occur in those who were in the patients' rooms but had no direct patient contact and did not touch any items or surfaces. [26] A source of further concern involves healthcare workers with mild symptoms of infection who unknowingly become intermediary hosts and who transmit organisms to susceptible children. Several published studies have shown that infected pediatric healthcare personnel, including resident physicians, transmitted Bordetella pertussis to other patients. [27] Healthcare personnel have been implicated as the source of outbreaks of rotavirus [28] and influenza. [29] Transmission of infectious agents is further facilitated by overcrowding and understaffing. Several studies demonstrated the association of understaffing and overcrowding with increased rates of HAIs in NICUs, PICUs, and general pediatrics units [30] [31] [32] [33] and contributed substantially to the evidence base that supports recommendations to consider staffing levels and composition as important components of an effective infection control program in the 2007 revision of the Healthcare Infection Control Practices Advisory Committee (HICPAC)/Centers for Disease Control and Prevention (CDC) guideline for isolation precautions in healthcare settings. [1] Healthcare personnel are rarely the source of outbreaks of HAIs caused by bacteria and fungi, but when they are, there are usually factors present that increase the risk transmission of infectious agents to others (e.g., sinusitis, draining otitis externa, respiratory tract infections, dermatitis, onychomycosis, wearing of artificial nails). [34] Those individuals with direct patient contact wearing artificial nails have been implicated in outbreaks of Pseudomonas aeruginosa and ESBL-producing Klebsiella pneumoniae in NICUs. [35] [36] These studies contributed to the recommendation to prohibit use of artificial nails or extenders when having direct contact with high-risk patients. [1]
[37]
Pathogens
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While there is no agreed-upon definition for what constitutes an epidemiologically important organism, the following characteristics apply and are presented for guidance to infection control staff in the 2007 revision of the HICPAC/CDC Guideline for Isolation Precautions in Healthcare Settings (www.cdc.gov/ncidod/dhqp/pdf/guidelines/isolation2007.pdf ): 1. A propensity for transmission within healthcare facilities based on published reports and the occurrence of temporal or geographic clusters of > 2 patients (e.g., VRE, MRSA, and methicillin-susceptible Staphylococcus aureus (MSSA), Clostridium difficile, norovirus, 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 postoperatively or in burn units; Legionella sp.; Aspergillus sp.) should trigger an investigation. Antimicrobial resistance (e.g., MRSA, VRE, ESBL-producing gram-negative bacilli, Burkholderia cepacia, Ralstonia spp., Stenotrophomonas maltophilia, and Acinetobacter. Many of the intrinsically resistant gramnegative bacilli also suggest possible water or medication contamination. Association with serious clinical disease, increased morbidity and mortality (e.g., MRSA and MSSA, group A streptococcus). A newly discovered or reemerging pathogen (e.g., vancomycin-insensitive or resistant Staphylococcus aureus (VISA, VRSA), C. difficile).
2.
3. 4.
Pathogens associated with HAIs in hospitalized children differ from those in adults. Viral agents and other respiratory tract pathogens (e.g., Bordetella pertussis) have heightened potential for transmission in pediatric facilities. Gram-negative bacilli, including ESBL and other multidrug-resistant isolates, may be more frequent than MRSA and VRE in many PICUs and NICUs. Patients who are transferred from chronic care facilities may be colonized with resistant gram-negative bacilli at the time of admission to the PICU. [11] Trends in targeted multidrugresistant pathogens that have been tracked in the NNIS (now NHS) ICUs are summarized in Figure 2-1 . Continued increases in MRSA, VRE, and certain resistant gram-negative bacilli are a call to action for all healthcare facilities. The CDC Campaign to prevent antimicrobial resistance and the Guideline for Management of Multi-Drug Resistant Organisms (MDRO) in Healthcare Settings 2006 can be accessed on the following websites, respectively: www.cdc.gov/drugresistance/healthcare ; www.cdc.gov/nciod/dhqp/index.html . Of note, in 2004, rates of healthcare-associated MRSA and VRE appear to have reached a plateau, whereas there are steep increases in the incidence of Klebsiella pneumoniae resistant to third-generation cephalosporins in the ICUs reporting to the current CDC surveillance system, NHSN (formerly NNIS) (www.cdc.gov/ncidod/dhqp/ar_mrsa_data.html ). HAIs caused by MDROs are associated with increased length of stay, increased morbidity and mortality, and increased cost, in part due to the delay in initiating antimicrobial therapy that will be active against the infecting agent. [38] While there is lower prevalence of specific MDROs in pediatric institutions, the same principles of target MDRO identification and control interventions apply to all settings. The emergence of CA-MRSA isolates characterized by the unique Scc mec type IV element was first observed among infants and children and is now being transmitted in hospitals, notably in NICUs, [13] making prevention more complex.
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Figure 2-1 Selected antimicrobial-resistant pathogens associated with nosocomial infections in intensive care unit patients; comparison of resistance rates from January through December 2003 with 1998 through 2002, National Nosocomial Infections Surveillance (NNIS) system. CNS, Coagulase-negative staphylococci; 3rd Ceph, resistance to third-generation cephalosporins (ceftriaxone, cefotaxime, or ceftazidime); Quinolone, resistance to either ciprofloxacin or ofloxacin. *Percent (%) increase in resistance rate of current year (JanuaryDecember 2003) compared with mean rate of resistance over previous 5 years (1998-2003): [(2003 rate previous 5-year mean rate)/previous 5-year mean rate] 100. **Resistance for Escherichia coli or Klebsiella pneumoniae is the rate of nonsusceptibility of these organisms to either 3rd Ceph group or aztreonam. Redrawn from the National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470-485.
The viruses most frequently associated with transmission in a pediatric healthcare facility are RSV, rotavirus, and influenza. However, other respiratory viruses (e.g., parainfluenza, adenovirus) have been implicated in outbreaks in high-risk units. Outbreaks of varicella and measles in pediatric healthcare facilities are rare events now due to consistent uptake during the past decade of vaccines in children and in healthcare personnel. Clinical manifestations with certain pathogens are more severe in infants and young children. RSV and Bordetella pertussis usually cause mild upper respiratory tract infections and cough, respectively, in older children and adults, yet cause severe disease with substantial morbidity and mortality in infants and children, especially those who are immunocompromised or who have underlying cardiac or pulmonary disease. An excessive burden of disease and mortality associated with influenza in infants and young children is also recognized. [39] [40] Candida sp. had been increasing in incidence in most PICUs and NICUs during the 1990s. There is considerable center-to-center variability in both the incidence of invasive candidiasis and the proportion of Candida infections caused by Candida non-albicans sp., most of which are resistant to fluconazole. Risk factors for Candida infections include prolonged length of stay in an ICU, use of CVCs, intralipids, H2-blocking agents, and exposure to thirdgeneration cephalosporins. Gram-negative bacilli and Candida sp. are especially important pathogens for HAIs in patients with short gut who are TPN-dependent and can cause repeated episodes of sepsis. [41] [42] Finally, environmental fungi (e.g., Aspergillus, Fusarium, Scedosporium, Bipolaris, Zygomycetes), are important sources of infection for severely immunocompromised patients, demanding meticulous attention to the conditions of the internal environment of any facility that provides care for severely immunocompromised patients and prevention of possible exposure to construction dust in and around healthcare facilities. [9] [43] With the advent of more effective and less toxic antifungal agents, it is important to identify the infecting agent by obtaining tissue samples and to determine susceptibility to candidate antifungal agents. [43] [44] PREVENTION Prevention remains the mainstay of infection control and requires special considerations in children. The goals of infection control and prevention are to prevent the transmission of infectious agents among individual patients or groups of patients, visitors, and healthcare personnel who care for them. If prevention cannot always be achieved, the next best strategy is early diagnosis, treatment, and prevention of continued transmission. An effective infection control program should improve patient and healthcare personnel safety and decrease short- and long-term morbidity, mortality, and healthcare costs. This chapter describes the unique principles and practice of infection control for the care of children. Specific pathogens and diseases are discussed in detail in chapters dedicated to those topics. Recommended isolation precautions by infectious agent can be found in the Red Book Report of the Committee on Infectious Diseases (COID) of the American Academy of Pediatrics (AAP) and in the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007. [1] In addition, textbooks on healthcare epidemiology and infection control contain chapters devoted to pediatric-specific programs. A series of infection control prevention and control guidelines have been developed and updated by HICPAC/CDC and others to provide evidence-based, rated recommendations for practices that are associated with reduced rates of HAIs, especially those associated with the use of medical devices and surgical procedures ( Box 2-1 ). Bundled practices are groups of three to five evidence-based best practices with respect to a disease process that individually improve care, but when applied together result in substantially greater reduction in infection rates. Adherence to the individual measures within a bundle is readily measured. Bundles for the reduction of CLA-BSIs, surgical site infections (SSIs), and ventilator assocated pneumonia (VAP) established for adults have been adapted to pediatrics (www.ihi.org/IHI/Programs/Campaign ). BOX 2-1 Resources for Infection Control Recommendations CENTERS FOR DISEASE CONTROL AND PREVENTION/HEALTHCARE INFECTION CONTROL PRACTICES COMMITTEE (www.cdc.gov/ncidod/dhqp/index.html ) Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR 2006;55:RR-2
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Guideline for disinfection and sterilization in health-care facilities (in revision) Guideline for prevention of healthcare-associated pneumonia, 2003. MMWR 2004;53(RR-3) Guideline for environmental infection control in health-care facilities, 2003. MMWR 2003;52(RR-10) Guideline for hand hygiene in health-care settings, 2002. MMWR 2002;51(RR-16) Guideline for prevention of intravascular catheter-related infections, 2002. MMWR 2002;51(RR-10) Recommendations for preventing transmission of infections among chronic hemodialysis patients, 2001. MMWR 2001;50(RR-5) Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients, 1999. MMWR 2000;49(RR-10) Guideline for the prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20:247-278 Infection control in health care personnel, 1998. Infect Control Hosp Epidemiol 1998;19:407-463 Guideline for isolation precautions in hospitals in healthcare settings, 2007. www.cdc.gov/neidod/dhqp/pdf/guidelines/isolation2007.pdf Management of multi-drug resistant organisms (MDROs) in healthcare settings, 2006. www.cdc.gov/nciod/dhqp/index.html : posted 10/19/06 Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005. MMWR 2005;54(RR-17) Guideline for prevention of catheter-associated urinary tract infections. Am J Infect Control 1983;11:28-33 AMERICAN ACADEMY OF PEDIATRICS Committee on Infectious Diseases. 2006 Report of the Committee on Infectious Diseases. In: Pickering LK, Baker CJ, Long SS (eds). Red Book, 27th ed. Illinois, American Academy of Pediatries, 2006 OTHER Society for Healthcare Epidemiology of America (SHEA) Position Papers (www.sheaonline.org/PositionPapers.html ) Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines (www.journals.uchicago.edu/IDSA/guidelines ) Association for Professionals in Infection Control and Epidemiology (APIC) Practice. Guidelines and State of the Art Reports (www.apic.org ) Carrico R (ed.) APIC Text of Infection Control and Epidemiology, 2nd ed. Washington, DC, Association for Professionals in Infection, Control and Epidermiology 2005 Saiman L, Siegel JD, and the Cystic Fibrosis Foundation Consensus. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. Infect Control Hosp Epidermial 2003;24(Suppl. 1-62).
Administrative Factors
The importance of certain administrative measures for a successful infection control program has been demonstrated. There is now an adequate evidence base to designate infection control as one component of the institutional culture of safety and to obtain support from the senior leadership of the healthcare organization in order to provide necessary fiscal and human resources for a proactive, successful infection control program. Critical elements requiring
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administrative support include access to appropriately trained healthcare epidemiology and infection control personnel; access to clinical microbiology laboratory services needed to support infection control outbreak investigations and multidisciplinary programs to assure judicious use of antimicrobial agents and control of antimicrobial resistance; delivery of effective educational information to healthcare personnel, patients, families, and visitors; and provision of adequate numbers of well-trained infection control, and bedside nursing staff. [1] [30] [31]
[32] [33]
The Infection Control and Prevention Team
The goals of infection control and prevention are to prevent the transmission of infectious agents among individual patients or groups of patients, visitors, and healthcare personnel who care for them. If prevention cannot always be achieved, the next best strategy is early diagnosis, treatment, and prevention of continued transmission. An effective infection control program should improve patient and healthcare personnel safety and decrease short- and long-term morbidity, mortality, and healthcare costs. [45] This chapter describes the unique principles and practice of infection control for the care of children. Recommended isolation precautions by infectious agent may be found in the Red Book Report of the COID (AAP) and in the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2006. [1] The infection control committee establishes policies and procedures to prevent or reduce the incidence and costs associated with HAIs. The infection control committee should be one of the strongest and most accessible committees in the hospital; committee composition should be carefully considered and limited to active, authoritative participants who have well-defined responsibilities on the committee and who represent major groups within the hospital. The chairperson should be a good communicator with expertise in infection control issues, healthcare epidemiology, and clinical pediatric infectious diseases. An important function of the infection control committee is the regular review of infection control policy and the development of new infection control policies as needed. Annual review is required by the Joint Commission on Accreditation of Healthcare Organizations and can be optimally accomplished by careful review of a few policies each month. With the advent of unannounced inspections, a constant state of readiness is required. If a facility chooses not to have an infection control committee, an alternative strategy is needed to accomplish the above tasks. The infection control and prevention division or team is the working group (including physicians, nurses, microbiologists, and administrators) that performs and coordinates all infection control activities. The hospital epidemiologist or medical director of the infection control division is usually a physician with training in pediatric infectious diseases and a dedicated expertise and interest in healthcare epidemiology. In multidisciplinary medical centers, pediatric infectious disease experts should be consulted for management of pediatric infection control and report to the broader infection control leadership. Infection control and prevention professionals (ICPs) are specialized professionals with advanced training and preferably certification in infection control. Although the majority of ICPs are registered nurses, others, including microbiologists, medical technologists, pharmacists, and epidemiologists, are successful in this position. Pediatric patients should have ICP services provided by someone with expertise and training in the care of children. In a large, general hospital, at least one ICP should be dedicated to infection control services for children. The responsibilities of ICPs have expanded greatly in the last decade and include the following: (1) surveillance and infection prevention in facilities affiliated with the primary acute care hospitals (e.g., ambulatory clinics, day-surgery centers, long-term care facilities, rehabilitation centers, home care) in addition to the primary hospital; (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 and pertussis vaccination, respiratory protection fit testing, administration of other vaccines as indicated during infectious disease crises such as pre-exposure 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, renovation, and other environmental conditions associated with increased infection risk; (6) prevention of transmission of MDROs; (7) evaluation of new products that could be associated with increased infection risk (e.g., intravenous infusion materials), for introduction and assessment of performance after implementation; (8) mandatory public reporting of HAI rates in states as legislation is enacted; (9) increased communication with the public and with local public health departments concerning infection control-related issues; and (10) participation in local and multicenter research projects. Infection control programs must be adequately staffed to perform all of these activities. Thus, the ratio of 1 ICP per 250 beds that was associated with a 30% reduction in the rates of nosocomial infection in the Study on Efficacy of Nosocomial Infection Control (SENIC) study performed in the 1970s [46] is no longer sufficient, as the complexity of patient populations and the responsibilities of infection control professionals have increased. Many experts recommend that a ratio of 1 ICP per 100 beds is more appropriate for the current workload, but no study has been performed to confirm the effectiveness of that ratio. There is no information on the number of individuals required outside acute care, but it is clear that individuals well trained in infection control must be available for all sites where healthcare is delivered. [1]
Surveillance
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Surveillance for HAIs consists of a systematic method of determining the incidence and distribution of infections acquired by hospitalized patients. The CDC recommends the following: (1) prospective surveillance on a regular basis by trained infection control professionals, using standardized definitions; (2) analysis of infection rates using established epidemiologic and statistical methods (e.g., calculation of rates using appropriate denominators that reflect duration of exposure; use of statistical process control charts for trending rates); (3) regular use of data in decision-making; and (4) employment of an effective and trained healthcare epidemiologist who develops infection control strategies and policies and serves as a liaison with the medical community and administration. [47] [48] [49] [50] The CDC has established a set of standard definitions of HAIs that have been validated and accepted widely [51] with updates posted on the CDC website or published in HICPAC/CDC guidelines. Standardization of surveillance methodology has become especially important with the advent of state legislation for mandatory reporting to the public of HAI infection rates. [52] Although various surveillance methods are used, the basic goals and elements are similar and include using standardized definitions of infection, finding and collecting cases of HAIs, tabulating data, using appropriate denominators that reflect duration of risk, analyzing and interpreting the data, reporting important deviations from endemic rates (epidemic, outbreaks) to the bedside care providers and to the facility administrators, implementing appropriate control measures, auditing adherence rates for recommended measures, and assessing efficacy of the control measures. Medical centers can utilize different methods of surveillance, as outlined in Box 2-2 . Most experts agree that a combination of methods enhances surveillance and data reliability and that some combination of clinical chart review and database retrieval is important. [47] [48] [49] [50] Administrative databases created for the purposes of billing should not be used as the sole source to identify HAIs because of both the overestimates and underestimates that result from inaccurate coding of HAIs. [52] Use of software designed specifically for infection control data entry and analysis facilitates real-time tracking of trends and timely intervention when clusters are identified. BOX 2-2 Sources of Data for Surveillance Clinical rounds with physicians and/or nurses Review of: Patient orders Radiology reports/databases Pharmacy reports/databases Operating room diagnoses and procedures Microbiology: bacteriology, virology, mycology, acid-fast bacilli, serology reports autopsy reports data-mining reports Postdischarge surveillance, especially for surgical site infections Public health surveillance Review of: Employee health reports Admission diagnoses Outpatient diagnoses Administrative databases, but should not be used as sole source due to inaccurate coding of healthcare-associated infections The microbiology laboratory can provide online culture information about individual patients, outbreaks of infection, antibiotic susceptibility patterns of pathogens in periodic antibiotic susceptibility summary reports, and employee infection data. This laboratory can also assist with surveillance cultures and facilitation of molecular typing of isolates during outbreak investigations. Rapid diagnostic testing of clinical specimens for identification of viruses and Bordetella pertussis is especially important for pediatric facilities. The infection control division and the microbiology laboratory must communicate daily, because even requests for cultures from physicians (e.g., Mycobacterium tuberculosis, Neisseria meningitidis, Clostridium difficile) can be an early marker for identifying patients who are infected, are at high risk of infection, or require isolation. If microbiology laboratory work is outsourced, it is important to assure that the services needed to support an effective infection control program will be
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available, as described in a policy statement of the Infectious Diseases Society of America on this matter. [53] The pharmacy is an important collaborative member of any multidisciplinary team working on strategies to prevent antimicrobial resistance. Antimicrobial utilization in the hospital should be assessed for appropriateness, efficacy, cost, and association with emergence of resistant organisms. For surveillance purposes, use of specific antimicrobial agents can alert the ICP to potentially infected patients (e.g., tuberculosis). The need to restrict use of antimicrobial agents is a collaborative decision based on review of all of these data. Restriction of new, potent antimicrobial agents is advised to prevent emergence of resistance that occurs with increased exposure to most antimicrobial agents (e.g., extended-spectrum cephalosporins, quinolones, linezolid, daptomycin). [54] [55] [56] Control of unusual infections or outbreaks in the community is generally the responsibility of the local or state public health department; however, the individual facility must be responsible for preventing transmission within that facility. Public health agencies can be particularly helpful in alerting hospitals of community outbreaks so that outpatient and inpatient diagnosis, treatment, necessary isolation, and other preventive measures begin promptly to avoid further spread. Conversely, the responsibility of designated individuals in the hospital is to notify public health department personnel of reportable infections so as to facilitate early diagnosis, treatment, and infection control in the community. Benefits of community or regional collaboratives of individual healthcare facilities and local public health departments for prevention of HAIs, especially those caused by MDROs, have been demonstrated and should be encouraged. [1] ISOLATION PRECAUTIONS Isolation of patients with potentially transmissible infectious diseases is a proven strategy for reducing transmission of infectious agents in healthcare settings. During the past decade, many published studies, including those performed in pediatric settings, have provided a strong evidence base for most recommendations for isolation precautions. However, many controversies still exist concerning the most clinically and cost-effective measures for preventing certain HAIs, especially those associated with MDROs. Since 1970, the guidelines for isolation developed by CDC have responded to the needs of the evolving healthcare systems in the United States. For example, universal precautions became a required standard in response to the HIV epidemic and the need to prevent transmission of bloodborne pathogens (e.g., HIV, hepatitis B and C viruses, rapidly fatal infections such as the viral hemorrhagic fevers). The Occupational Safety and Health Administration (OSHA) published specific requirements [57] in 1991 for universal precautions (now called Standard Precautions) for healthcare personnel who, as a result of their required duties, are at increased risk for skin, eye, mucous membrane, or parenteral contact with blood or other potentially infectious materials. Although all requirements may not have been proven to be clinically or cost-effective, healthcare facilities must enforce these measures. The federal Needlestick Safety and Prevention Act, signed into law in November, 2000, authorized OSHA's revision of its Bloodborne Pathogens Standard more explicitly to require the use of safety-engineered sharp devices (www.osha.gov/SLTC/bloodbornepathogens/index.html ). The 1996 CDC/Hospital Infection Control Advisory Committee Guideline for Isolation Precautions in Hospitals [58] has been updated and published in 2007 as the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings. [1] This guideline affirms standard precautions, a combination of universal precautions and body substance isolation as the foundation of transmission prevention measures. Healthcare personnel are provided with guidance to recognize the importance of body fluids, excretions, and secretions in the transmission of infectious pathogens and to take appropriate protective precautions by using personal protective equipment (e.g., masks, gowns, gloves, face shields, or goggles) and safety devices even if an infection is not suspected or known. In addition, this updated guideline provides recommendations for all settings where healthcare is delivered (acute care hospitals, ambulatory surgical and medical centers, long-term care facilities, and home health agencies). Extensive background discussion and recommendations for the prevention of transmission of multidrugresistant organisms (e.g., MRSA, VRE, VISA, VRSA, and gram-negative bacilli) in various settings are also included and were pre-released on the CDC website in October, 2006 (www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuidelines2006.pdf . The categories of Transmission-based Precautions described previously have been retained: Contact, Droplet, and Airborne Precautions. The characteristics of a protective environment for prevention of environmental fungal infections in HSCT recipients that were introduced in previously published guidelines are summarized. Finally, discussion and recommendations with evidence-based ratings for administrative measures that are necessary for effective prevention of infection in healthcare settings are provided. The isolation information presented in this chapter is based on these 2006 to 2007 isolation recommendations.
Standard Precautions
The term Standard Precautions replaced Universal Precautions and Body Substance Isolation in 1996. Standard Precautions should be used when there is likely to be exposure to: (1) blood; (2) all other body fluids, secretions, and excretions, whether or not they contain visible blood, except sweat; (3) nonintact skin; and (4) mucous membranes.
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Standard Precautions strategy is designed to reduce the risk of transmission of microorganisms from both identified and unidentified sources of infection. The components of Standard Precautions are summarized in Table 2-3 . In the updated isolation guideline, safe injection practices are included as a component of standard precautions, not because new practices are recommended but because recent outbreaks of hepatitis B and C virus infection in ambulatory care settings as a result of failure to follow recommended practices indicate a need to reiterate the established effective practices. [59] There are two new additions to Standard Precautions: (1) respiratory hygiene/cough etiquette for source containment by patients with signs and symptoms of respiratory tract infection; and (2) use of a mask by the individual inserting an epidural anesthesia needle or performing myelograms when prolonged exposure of the puncture site is likely to occur to prevent introduction of respiratory tract microorganisms from the person performing the procedure into the cerebrospinal fluid of the patient and therefore prevent meninigitis. Both new components have a strong evidence base. TABLE 2-3 -- Recommendations for Application of Standard Precautions for the Care of all Patients in all Healthcare Settings Component Recommendations for Performance Hand hygiene After touching blood, body fluids, secretions, excretions, contaminated items; immediately after removing gloves; between patient contacts. Alcohol-containing antiseptic handrubs preferred except when hands are visibly soiled with blood or other proteinaceous materials or if exposure to spores (e.g., Clostridium difficile, Bacillus anthracis) is likely to have occurred For touching blood, body fluids, secretions, excretions, contaminated items; for touching mucous membranes and nonintact skin During procedures and patient care activities when contact of clothing/exposed skin with blood/body fluids, secretions, and excretions is anticipated
Gloves Gown
Mask, [a] eye During procedures and patient care activities likely to generate splashes or sprays of blood, protection (goggles), body fluids, secretions, especially suctioning, endotracheal intubation to protect healthcare face shield personnel. For patient protection, use of a mask by the individual inserting an epidural anesthesia needle or performing myelograms when prolonged exposure of the puncture site is likely to occur Soiled patient-care equipment Environmental control Textiles and laundry Injection practices (use of needles and other sharps) Handle in a manner that prevents transfer of microorganisms to others and to the environment; wear gloves if visibly contaminated; perform hand hygiene Develop procedures for routine care, cleaning, and disinfection of environmental surfaces, especially frequently touched surfaces in patient care areas Handle in a manner that prevents transfer of microorganisms to others and to the environment Do not recap, bend, break, or hand-manipulate used needles; if recapping is required, use a one-handed scoop technique only; use needle-free safety devices when available; place used sharps in a puncture-resistant container. Use a sterile, single-use, disposable needle and syringe for each injection given. Single-dose medication vials are preferred when medications are administered to > 1 patient Use mouthpiece, resuscitation bag, or other ventilation devices to prevent contact with mouth and oral secretions Prioritize for single-patient room if the patient is at increased risk of transmission, is likely to contaminate the environment, does not maintain appropriate hygiene, or is at increased risk of acquiring infection or developing adverse outcome following infection Instruct symptomatic persons to cover mouth/nose when sneezing/coughing; use tissues and dispose in no-touch receptacle; observe hand hygiene after soiling of hands with respiratory secretions; wear surgical mask if tolerated or maintain spatial separation, > 1 meter (3 feet) if possible
Patient resuscitation Patient placement
Respiratory hygiene/cough etiquette [b]
a During aerosol-generating procedures on patients with suspected or proven infections transmitted by aerosols (e.g., severe acute respiratory syndrome), wear a fittested N95 or higher respirator in addition to gloves, gown, and face/eye protection. emergency departments and physician offices).
b Source containment of infectious respiratory secretions in symptomatic patients, beginning at initial point of encounter (e.g., triage and reception areas in
Implementation of Standard Precautions requires critical thinking from all healthcare personnel providing direct patient care and the availability of personal protective equipment in proximity to all patient beds. Healthcare personnel with exudative lesions or weeping dermatitis must avoid direct patient care and handling of patient care equipment. Individuals having direct patient contact should be able to anticipate an exposure to blood or other
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potentially infectious material and to take proper protective precautions. Individuals should also know what to do if a high-risk exposure does occur. Exposures of concern are exposures to blood or other potentially infectious material defined as an injury with a contaminated sharp object (e.g., needlestick, scalpel cut); a spill or splash of blood or other potentially infectious material on to nonintact skin (e.g., cuts, hangnails, dermatitis, abrasions, chapped skin) or on to a mucous membrane (e.g., mouth, nose, eye); or a blood exposure covering a large area of normal skin. Handling food trays or furniture, pushing wheelchairs or stretchers, using restrooms or phones, having personal contact with patients (e.g., giving information, touching intact skin, bathing, giving a back rub, shaking hands), or doing clerical or administrative duties for a patient do not constitute high-risk exposures. If hands or other skin surfaces are exposed to blood or other potentially infectious material, the healthcare worker should immediately wash the area with soap and water for at least 10 seconds and rinse with running water for at least 10 seconds. If an eye, the nose, or mouth is splashed with blood or body fluids, the area should be immediately irrigated with a large volume of water. If a skin cut, puncture, or lesion is exposed to blood or other potentially infectious material, the area should be immediately washed with soap and water for at least 10 seconds and rinsed with 70% isopropyl alcohol. Any exposure incident should be immediately reported to the occupational health department and a determination must be made if blood samples are required from the source patient and the exposed individual and if immediate prophylaxis is indicated. All healthcare personnel should know where to find the exposure control plan that is specific for their place of employment, whom to contact, where to go, and what to do if inadvertently exposed to blood or body fluids. Important resources include the occupational health department, the emergency department, and the infection control/hospital epidemiology division. The most important recommendation in any accidental exposure is to seek advice and intervention immediately, because the efficacy of recommended prophylaxis regimens is improved with shorter intervals after exposure, such as for hepatitis B immune globulin administration after exposure to the hepatitis B virus or for antiretroviral therapy after percutaneous exposure to HIV. Chemoprophylaxis following exposure to HIV-infected material is most effective if initiated within 4 hours of exposure. [60] Additionally, reporting a workrelated exposure is required for subsequent medical care and workers' compensation.
Transmission-Based Precautions
Transmission-based Precautions are designed for patients with documented or suspected infection with pathogens for which additional precautions beyond Standard Precautions are needed to prevent transmission. The three categories of Transmission-based Precautions are Contact Precautions, Droplet Precautions, and Airborne Precautions and are based on the likely routes of transmission of specific infectious agents. They may be combined for infectious agents that have more than one route of transmission. Whether used singly or in combination, they are always used in addition to Standard Precautions. Since the infectious agent is often not known at the time of admission, Transmission-based Precautions are applied based on the clinical presentation and the most likely pathogens socalled Empiric or Syndromic precautions. This approach is especially useful for emerging agents (e.g., SARS-CoV, avian influenza, pandemic influenza), for which information concerning routes of transmission is still evolving. The categories of clinical presentation are as follows: diarrhea, central nervous system, generalized rash/exanthem, respiratory, skin or wound infection. Single-patient rooms are always preferred for children needing Transmissionbased Precautions. If unavailable, cohorting of patients, and in some cases of staff, according to clinical diagnosis is recommended. Table 2-4 lists the three categories of isolation based on routes of transmission and the necessary components. Table 2-5 lists precautions by syndromes, to be used when a patient has an infectious disease and the agent is not yet identified. It should be noted that for infectious agents that are more likely to be transmitted by the droplet route except during an aerosol-producing procedure (e.g., pandemic influenza), N95 or higher respirators are indicated during the procedure, but an AIIR is not necessarily needed (www.pandemicflu.gov/plan/healthcare/maskguidancehc.html ). TABLE 2-4 -- Transmission-Based Precautions [a] Component Contact Hand hygiene Per Standard Precautions Soap and water preferred over alcohol handrub for Clostridium difficile, Bacillus anthracis spores Yes. Don before room entry
Droplet Per Standard Precautions
Airborne Per Standard Precautions
Gown
Per Standard Precautions
Per Standard Precautions and, if infectious, draining skin lesions present Per Standard Precautions
Gloves Mask
Yes. Don before room entry Per Standard Precautions
Per Standard Precautions
Yes. Don before room entry N95 particulate respirator or
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higher Goggles/face shield Per Standard Precautions Per Standard Precautions. Always for SARS, avian influenza N95 or higher respirator When aerosol-producing procedures When aerosol-producing performed for influenza, SARS, procedures performed for VHF influenza, SARS, VHF Single-patient room preferred. Cohort like-infections if single-patient rooms unavailable Per Standard Precautions Always for SARS, avian influenza Yes. Don upon entry
Room placement Single-patient room preferred. Cohort like-infections if singlepatient rooms unavailable
Single-patient room. Negative air pressure; 12 air changes/hour for new construction, 6 air changes/hour for existing rooms Routine
Environmental measures
Increased frequency, especially in the presence of diarrhea. transmission of Clostridium difficile, norovirus Mask patient if coughing. Cover infectious skin lesions
Routine
Transport
Mask patient
Mask patient Cover infectious skin lesions
SARS, severe acute respiratory syndrome; VHF, viral hemorrhagic fever.

a An addition to Standard precautions, use Transmission-based Precautions, use Transmission-based Precautions for patients with highly transmisible or
epidemiologically important pathogens for which additional precautions are needed.
TABLE 2-5 -- Clinical Syndromes or Conditions Warranting Empiric Transmission-Based Precautions in Addition to Standard Precautions Pending Confirmation of Diagnosis [a] Empiric Precautions (Always Includes Clinical Syndrome or Condition [b] Potential Pathogens [c] Standard Precautions) Diarrhea Acute diarrhea with a likely infectious cause in an incontinent or diapered patient Meningitis Enteric pathogens [d] Contact Precautions (pediatrics and adult)
Neisseria meningitidis
Droplet Precautions for first 24 hours of antimicrobial therapy; mask and face protection for intubation Contact Precautions for infants and children Airborne Precautions plus Contact Precautions if potentially infectious draining body fluid present
Enteroviruses
Mycobacterium tuberculosis Airborne Precautions if pulmonary infiltrate
Rash or Exanthems, Generalized, Etiology Unknown Petechial/ecchymotic with fever (general) Neisseria meningitidis Droplet Precautions for first 24 hours of antimicrobial therapy Droplet Precautions plus Contact Precautions, with face/eye protection, emphasizing safety sharps and barrier precautions when blood exposure likely. Use N95 or higher respiratory protection when aerosol-generating procedure performed Airborne plus Contact Precautions.
If traveled in an area with an ongoing Ebola, Lassa, Marburg outbreak of VHF in the 10 days before viruses onset of fever
Vesicular
Varicella-zoster, herpes
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simplex, variola (smallpox), vaccinia viruses Maculopapular with cough, coryza, and Rubeola (measles) virus fever Respiratory Infections
Contact Precautions only if herpes simplex, localized zoster in an immunocompetent host, or vaccinia viruses most likely Airborne Precautions
Cough/fever/upper-lobe pulmonary Mycobacterium tuberculosis, Airborne Precautions plus Contact infiltrate in an HIV-negative patient or respiratory viruses, Precautions a patient at low risk for HIV infection Streptococcus pneumoniae, Staphylococcus aureus (MSSA or MRSA) Cough/fever/pulmonary infiltrate in any lung location in an HIV-infected patient or a patient at high risk for HIV infection Mycobacterium tuberculosis, respiratory viruses, Streptococcus pneumoniae, Staphylococcus aureus (MSSA or MRSA) Airborne Precautions plus Contact Precautions Use eye/face protection if aerosolgenerating procedure performed or contact with respiratory secretions anticipated. If tuberculosis is unlikely and there are no AIIRs and/or respirators available, use Droplet Precautions instead of airborne precautions. Tuberculosis more likely in HIV-infected than in HIV-negative individuals Cough/fever/pulmonary infiltrate in any lung location in a patient with a history of recent travel (1021 days) to country with outbreak of SARS, avian influenza Mycobacterium tuberculosis, severe acute respiratory syndrome viruscoronavirus (SARS-CoV), avian influenza Airborne plus Contact Precautions plus eye protection. If SARS and tuberculosis unlikely, use Droplet Precautions instead of Airborne Precautions Contact Precautions plus Droplet Precautions; Droplet Precautions may be discontinued when adenovirus and influenza have been ruled out. Contact Precautions Add droplet precautions for the first 24 hours of appropriate antimicrobial therapy if invasive group A streptococcal disease is suspected
Respiratory infections, particularly Respiratory syncytial virus, bronchiolitis and pneumonia, in infants parainfluenza virus, and young children adenovirus, influenza virus, human metapneumovirus Skin or Wound Infection Abscess or draining wound that cannot Staphylococcus aureus be covered (MSSA or MRSA), group A streptococcus
AIIR, airborne infection isolation room; HIV, human immunodeficiency virus; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; VHF, viral hemorrhagic fever.
a Infection control professionals should modify or adapt this table according to local conditions. To ensure that appropriate empiric precautions are always
implemented, hospitals must have systems in place to evaluate patients routinely according to these criteria as part of their preadmission and admission care.
b Patients with the syndromes or conditions listed may have 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 udgment. of specific conditions in the community, as well as clinical judgment. etiologic agents that require additional precautions beyond standard precautions until they can be ruled out.
c The organisms listed under the column Potential Pathogens are not intended to represent the complete, or even most likely, diagnoses, but rather possible d
These pathogens include enterohemorrhagic Escherichia coli O157:H7, Shigella spp., hepatitis A virus, noroviruses, rotavirus, Clostridium difficile.
ENVIRONMENTAL MEASURES Contaminated environmental surfaces and noncritical medical items have been implicated in transmission of several healthcare-associated pathogens, including VRE, C. difficile, Acinetobacter sp., MRSA, and RSV. [1] [9] [61] Pathogens on surfaces are transferred to the hands of healthcare personnel and then transferred to other patients or items. Pathogens with a gastrointestinal tract reservoir, including MRSA, are especially likely to contaminate surfaces when the patient has diarrhea; surfaces surrounding such patients may need to be cleaned and disinfected repeatedly. Frequently touched surfaces and those closest to the patient are most likely to be contaminated (e.g., bedrails, bedside tables, commodes, doorknobs, sinks, surfaces, and equipment in close proximity to the patient). Most often, the failure to follow recommended procedures for cleaning and disinfection contributes more than the
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specific agent to the environmental reservoir of pathogens during outbreaks. In an educational and observational intervention that targeted a defined group of housekeeping personnel, there was a persistent decrease in the acquisition of VRE in a medical ICU; therefore, monitoring for adherence to recommended environmental cleaning practices is an important determinant of success in controlling transmission of MDROs and other environmental pathogens. [62] Certain infectious agents (e.g., rotavirus, noroviruses, C. difficile) may be resistant to some routinely used hospital disinfectants; thus, when there is ongoing transmission and cleaning procedures have been observed to be appropriate, a 1:10 dilution of 5.25% sodium hypochlorite (household bleach) or other special disinfectants may be indicated. [9] Pediatric facilities should use disinfectants active against rotavirus. [63] VISITATION POLICIES Since acquisition of a seemingly innocuous viral infection in neonates and in children with underlying diseases can result in unnecessary evaluation and empirical therapy for septicemia as well as serious life-threatening disease, special visitation policies are required in pediatric units, especially the high-risk units. All visitors with signs or symptoms of respiratory or gastrointestinal tract infection should be restricted from visiting patients in healthcare facilities. During the influenza season, it is preferred for all visitors to have received influenza vaccine. Increased restrictions may be needed in the midst of a community outbreak (e.g., SARS, influenza). For patients requiring Contact Precautions, the use of personal protective equipment by visitors is determined by the nature of the interaction with the patient and the likelihood that the visitor will frequent common areas on the patient unit or interact with other patients and their family members. Although most pediatricians encourage visits by siblings in inpatient areas, the medical risk must not outweigh the psychosocial benefit. Studies demonstrate that parents favorably regard sibling visitation [64] and that bacterial colonization [65] ,66 or subsequent infection 67 does not increase in the neonate or older child who has been visited by siblings, but these studies are limited by small numbers. Strict guidelines for sibling visitation should be established and enforced in an effort to maximize visitation opportunities and minimize risks of transmission of infectious agents. The following recommendations regarding visitation may guide policy development: 1. Sibling visitation is encouraged in the well-child nursery and NICU, as well as in areas for care of older children. 2. Before visitation, parents should be interviewed by a trained staff nurse concerning the current health status of the sibling. Siblings who are visiting should have received all vaccines recommended for age. Children with fever or symptoms of an acute illness such as upper respiratory tract infection, gastroenteritis, or dermatitis should not be allowed to visit. Siblings who have been exposed to a known infectious disease and are still within the incubation period should not be allowed to visit. After the interview, the physician or nurse should place a written consent for sibling visitation in the permanent patient record and a name tag indicating that the sibling has been approved for visitation for that day. Asymptomatic siblings who have been recently exposed to varicella but have been previously immunized can be assumed to be immune. The visiting sibling should visit only his or her sibling and not be allowed in playrooms with groups of patients. Visitation should be limited to periods of time that ensure adequate screening, observation, and monitoring of visitors by medical and nursing staffs. Children should observe hand hygiene before and after contact with the patient. During the entire visit, sibling activity should be supervised by parents or another responsible adult.
3. 4. 5. 6. 7. PETS
Many zoonoses and infections are attributable to animal exposure. Most of these infections result from inoculation of animal flora through a bite or scratch or self-inoculation after contact with the animal, animal secretions or excretions, or contaminated environment. No universal guidelines for hospital pet visitation have been developed because there are no controlled experiences upon which evidence-based recommendations can be made. This topic is reviewed in the Guidelines for Environmental Infection Control in Health-Care Facilities and recommendations are provided to guide institutional policies. [9] Pets can be of significant clinical benefit to the child hospitalized for prolonged periods, and many centers have created their own pet visitation guidelines. Prudent visitation policies should include limiting visitation to animals that meet the following requirements: (1) they are domesticated; (2) they do not require a water environment; (3) they do not bite or scratch; (4) they can be brought to the hospital in a carrier or easily walked on a leash; (5) they are trained to defecate and urinate outside or in appropriate litter boxes; (6) they can be bathed before visitation; and (7) they are known to be free of respiratory, dermatologic, and gastrointestinal tract disease. Reptiles should be excluded due to the risk of transmission of
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Salmonella sp. and development of severe invasive disease in young infants 68 and exotic animals that are imported should be excluded because of unpredictable behavior and the potential for transmission of unusual pathogens (e.g., monkeypox 69 Visitation should be limited to short periods of time and confined to designated areas. Visiting pets should have a certificate of immunization from a licensed veterinarian. Children should observe hand hygiene after contact with pets. Most pediatric facilities restrict pet interaction with severely immunosuppressed patients and those in ICUs. DISINFECTION, STERILIZATION, AND REMOVAL OF INFECTIOUS WASTE The topic of disinfection and sterilization as it relates to infection prevention and control has been reviewed. 70,71 Cleaning is the removal of all foreign material from surfaces and objects. This process is accomplished using soap and enzymatic products. Failure to remove all organic material from items before disinfection and sterilization will reduce the effectiveness of those processes. Disinfection is a process that eliminates all forms of microbial life except the endospore. Disinfection usually requires liquid chemicals. The ability of an inanimate surface or object to be disinfected can be adversely affected by the presence of organic matter; a high level of microbial contamination; too dilute germicide; inadequate disinfection time; an object that can harbor microbes in protected cracks, crevices, and hinges; and pH and temperature. Sterilization is the eradication of all forms of microbial life, including fungal and bacterial spores. Sterilization is achieved by physical and chemical processes such as steam under pressure, dry heat, ethylene oxide, and liquid chemicals. Patient care equipment was originally categorized by Spaulding 72 and subsequently by the CDC 71 as critical, semicritical, and noncritical items with regard to sterilization and disinfection. Critical items require sterilization because they enter sterile body tissues and would have a high risk of causing infection if contaminated; semicritical objects require disinfection because they may contact mucous membranes and nonintact skin; and noncritical items require routine cleaning because they only come in contact with intact skin. If noncritical items used on patients requiring Transmission-based Precautions, especially Contact Precautions, must be shared, these items should be disinfected after use on a patient who is under isolation precautions. Guidelines for specific objects and specific disinfectants are published and updated by the CDC. Multiple published reports and manufacturers similarly recommend the use and reuse of objects with appropriate sterilization, disinfection, or cleaning recommendations. Recommendations in guidelines for reprocessing endoscopes focus on training of personnel, meticulous manual cleaning, high-level disinfection followed by rinsing, air-drying, and proper storage to avoid contamination. 73 Medical devices that are designed for single use (e.g., specialized catheters, electrodes, biopsy needles) must be reprocessed by third parties or hospitals according to the guidance issued by the Food and Drug Administration (FDA) in August, 2000 with amendments in September, 2006; such reprocessors will be considered manufacturers and will be regulated in the same manner. Available data show that single-use devices reprocessed according to the ). FDA regulatory requirements are as safe and effective as new devices (www.fda.gov/cdrh/reprocessing Healthcare facility waste is all biologic or nonbiologic waste that is discarded and not intended for further use. Medical waste is the material generated as a result of use with a patient, such as for diagnosis, immunization, or treatment, and includes soiled dressings and intravenous tubing. Infectious waste is that portion of medical waste that could potentially transmit an infectious disease. Microbiologic waste, pathologic waste, contaminated animal carcasses, blood, and sharps are all examples of the estimated infectious waste discarded in the United States each day. Methods of effective disposal of infectious waste include incineration, steam sterilization, drainage to a sanitary sewer, mechanical disinfection, chemical disinfection, and microwave. State regulations guide the treatment and disposal of regulated medical waste. Recommendations for developing and maintaining a program within a facility for safe management of medical waste can be found in the Guidelines for Environmental Infection Control in HealthCare Facilities. [9] OCCUPATIONAL HEALTH Occupational health and student health collaboration with the infection control division of a hospital is required by OSHA [57] and is important for a successful infection control program. The occupational health program is of paramount importance in hospitals caring for children because healthcare personnel are at increased risk of infection for various reasons, including the following: (1) children have a high incidence of infectious diseases; (2) personnel may be susceptible to many of the infecting pathogens; (3) pediatric care requires close contact; (4) children lack good personal hygiene; (5) infected children may be asymptomatic; and (6) healthcare personnel are exposed to multiple family members who may also be infected. The occupational health department should be an educational resource for information on infectious pathogens in the healthcare workplace. Occupational health, in concert with the infection control service, should provide preemployment education and respirator fit testing; annual retraining for all employees regarding routine health maintenance, available vaccines, standard precautions and isolation categories, and exposure plans; and screening for tuberculosis at regular intervals, as determined by the facility's risk assessment 74 With new pathogens being isolated,
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new diseases and their transmission described, and new prophylactic regimens and treatment available, it is mandatory that personnel have an up-to-date working knowledge of infection control and know where and what the available services, equipment, and therapies are for the healthcare worker. Many educational resources are available to assist with employee education 75 All healthcare personnel should be screened by history or serologic testing, or both, to document their immune status to specific agents, and immunization should be provided for the following for all employees who are nonimmune and who do not have contraindications to receiving the vaccine: diphtheria, tetanus, hepatitis B virus, influenza (yearly), mumps, poliomyelitis, rubella, rubeola, and varicella. Providing vaccines at no cost to healthcare personnel increases acceptance. Recognition of the importance of raising influenza vaccination rates among healthcare personnel to protect the individuals, their patients, and their family members led to the publication of evidence-based recommendations in 2006 76 After licensure of the adolescent/adult pertussis (Tdap) vaccine in 2005, the Advisory Committee on Immunization Practices and the AAP recommend administration of a single dose of Tdap to all healthcare personnel in whom > 2 years have elapsed since the most recent Td booster in order to prevent pertussis in the vaccine recipient and to prevent transmission of pertussis to high-risk patients 77
Special Concerns of Healthcare Personnel
Healthcare personnel who have underlying medical conditions (e.g., hypertension, diabetes, obesity, tobacco use) should be able to obtain general information on wellness and screening when needed from the occupational health service. Healthcare providers with direct patient contact who have infants younger than 1 year of age at home are concerned about acquiring infectious agents from patients and transmitting them to their susceptible children. An immune healthcare worker who is exposed to varicella does not become a silent carrier of this pathogen. However, pathogens to which the healthcare worker is partially immune or nonimmune can cause a severe, mild, or asymptomatic infection in the employee that can be transmitted to family members. Examples include influenza, pertussis, RSV, rotavirus, and tuberculosis. Important preventive procedures for healthcare workers with infants at home are: (1) consistent observance of Standard Precautions, Transmission-based Precautions, and hand hygiene according to published recommendations [1] [37] ; (2) annual influenza immunization; (3) routine tuberculosis screening; (4) assurance of immunity or immunization against poliomyelitis, measles, mumps, hepatitis B, rubella, and pertussis (Tdap); (5) early medical evaluation for infectious illnesses; (6) routine, on-time immunization of infants; and (7) prompt initiation of prophylaxis or therapy following exposure or certain infections. The healthcare worker who is, could be, or anticipates becoming pregnant should feel comfortable working in the healthcare workplace. In fact, with Standard Precautions and appropriate adherence to environmental cleaning and isolation precautions, the vigilant healthcare worker can be at less risk than a preschool teacher, childcare provider, or mother of children with many playmates in the home. Pathogens of potential concern to the pregnant healthcare worker include cytomegalovirus, hepatitis B virus, influenza, measles, mumps, parvovirus B19, rubella, varicellazoster virus, and Mycobacterium tuberculosis. Important preventive procedures include documentation of immunity or immunization before pregnancy for rubella, mumps, measles, poliomyelitis, and hepatitis B virus; annual influenza vaccine; routine tuberculosis screening; early medical evaluation for infectious illnesses; and prompt prophylaxis or therapy if exposed to or infected with certain pathogens. It is important to note that pregnancy is an indication for influenza vaccine to prevent the increased risk of serious disease and hospitalization that occurs in second- and thirdtrimester women who develop influenza infection. Pregnant workers should assume that all patients are potentially infected with cytomegalovirus and other silent pathogens and should use gloves (followed by hand hygiene) when handling body fluids, secretions, and excretions. Table 2-6 summarizes the information about infectious agents that are relevant to the pregnant woman and a comprehensive review has been published 78 TABLE 2-6 -- The Pregnant Healthcare Worker: Guide to Management of Occupational Exposure to Selected Infectious Agents [a] Potential Rate of Effect on the Perinatal Maternal Agent In-Hospital Source Fetus Transmission Screening Prevention Bioweapons Agents, Category A Smallpox (vaccinia) Respiratory secretions, contents of pustulovesicular lesions Fetal vaccinia, Limited data premature delivery, spontaneous abortion, and perinatal death History of successful vaccination with take within previous 5 years Pre-event vaccination contraindicated during pregnancy. Vaccine and vaccinia-immune globulin (VIG) after exposure; pre-
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exposure vaccine only if smallpox present in the community and exposure to patients with smallpox likely. Airborne plus Contact Precautions Cytomegalovirus (CMV) Urine, blood, semen, Classic disease vaginal secretion, [b] (510%); immunosuppressed, hearing loss (1015%) transplant, dialysis, day care Primary infection (25 50%); recurrent infection (52%); symptomatic (< 515%) Routine screening not recommended; antibody is incompletely protective Efficacy of CMV immune globulin not established. No vaccine available. Standard Precautions
Hepatitis A (HAV)
Feces (most common), blood (rare)
No fetal Unknown transmission described; transmission can occur at the time of delivery if mother still in the infectious phase and can cause hepatitis in the infant Hepatitis, early-onset hepatocellular carcinoma HBeAg - and HBsAg + (10%) HBeAg + and HbsAg + (90%) 5% (025%)
Routine screening not recommended
Vaccine is a killed viral vaccine and can safely be used in pregnancy. Contact Precautions during acute phase
Hepatitis B (HBV)
Blood, bodily fluids, vaginal secretions, semen
Routine HBsAg HBV vaccine during testing advised pregnancy if indications exist. Neonate: HBIG plus vaccine at birth. Standard Precautions Routine screening not recommended No vaccine or immune globulin available; postexposure treatment with antiviral agents investigational. Standard Precautions Chemoprophylaxis at 36 weeks decreases shedding. Standard precautions. Contact Precautions for patients with mucocutaneous lesions Antiretroviral chemoprophylaxis for exposures; intrapartum postnatal chemoprophylaxis for HIV+ mothers and their infants indicated to prevent perienatal transmission. Standard Precautions
Hepatitis C (HCV)
Blood, vaginal secretions, semen
Hepatitis
Herpes simplex virus (HSV)
Vesicular fluid, oropharyngeal and vaginal secretions
Sepsis, encephalitis, meningitis, mucocutaneous lesions, congenital malformation (rare) No congenital syndrome. If fetus infected, AIDS in 24 years
Primary genital (33 50%) Recurrent genital (12%)
Antibody testing minimally useful. Genital inspection for lesions if in labor Routine maternal screening advised. If exposed, testing every 3 months
Human Blood, bodily fluids, immunodeficiency vaginal secretions, virus (HIV) semen
Depends on HIV viral load and use of antiretroviral agents during pregnancy, labor and postnatally in the infant If viral load <
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1000 (rate 2%) If viral load 10 000 (rate up to 25%) Influenza Sneezing and No congenital coughing, respiratory syndrome tract secretions (influenza in mother could cause hypoxia in fetus) Rare None Trivalent inactivated vaccine (TIV) for all pregnant women during influenza season to decrease risk of hospitalizations for cardiopulmonary complications in mother. No risk if exposed to individuals who received live attenuated influenza vaccine (LAIV). Droplet Precautions. Add Contact Precautions for young infants Vaccine. Airborne Precautions
Rubeola (measles) Respiratory secretions, coughing
Prematurity, spontaneous abortion; no congenital syndrome
Rare
Antibody test, MDdocumented disease, or 2 doses of measles containing vaccine at or > 12 months of age
Parvovirus B19
Respiratory secretion, blood, immunocompromised patients
Fetal hydrops, stillbirth; no congenital syndrome
Approximately No routine 25%; fetal screening. B19 death < 10% DNA can be detected in serum, leukocytes, respiratory secretions, urine, tissue specimens 90% in first trimester; 40 50% overall Routine rubella IgG testing in pregnancy. Preconceptional screening recommended
No vaccine. Defer care of immunocompromised patients with chronic anemia when possible. Droplet Precautions
Rubella
Respiratory secretions
Congenital syndrome
Vacccine. No congenital rubella syndrome described for vaccine. Droplet Precautions Contact Precautions for patients with congenital rubella Postexposure prophylaxis with penicillin. Standard Precautions; wear gloves when handling infant or caring for patients with primary syphilis with mucocutaneous lesions until
Treponemia pallidum (syphilis)
Blood, lesion, fluid, amniotic fluid
Congenital syndrome
Variable 10 VDRL, RPR 90%; depends FTA-ABS upon stage of maternal disease and trimester of the infection
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completion of 24 hours of treatment. Mycobacterium tuberculosis Sputum, skin lesions Neonatal tuberculosis; liver most frequently infected Rare Skin test: PPD Chest radiograph Varies with PPD reaction size and chest radiograph result; therapy for active disease during pregnancy. Airborne Precautions Contact Precautions if draining skin lesions Vaccine [c] ; VariZIG within 96 hours of exposure if susceptible. Airborne plus Contact Precautions
Varicella-zoster virus [d]
Respiratory secretion, Malformations, Congenital vesicle fluid skin, limb, syndrome central nervous (2%) system, eye. Disseminated or localized disease
Varicella IgG serology; history 90% correct
AIDS, acquired immunodeficiency syndrome; FTA-ABS, fluorescent treponemal antigen-antibody test; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immune globulin; HBsAg, hepatitis B surface antigen; IgG, immunoglobulin G; PPD, purified protein derivative; RPR, rapid plasma reagin test; VDRL, Venereal Disease Research Laboratory test.
a Employment, prepregnancy screening/vaccination is primary prevention for certain agents. Annual immunization for influenza is primary prevention. b Congenital syndrome: varying combinations of jaundice, hepatosplenomegaly, microcephaly, thrombocytopenia, anemia, retinopathy, skin, and bone lesions. c Live virus vaccine given before or after pregnancy. d See Chapter 205 , Varicella-zoster Virus.
INFECTION CONTROL IN THE AMBULATORY SETTING Because most patient visits are in the ambulatory setting and more patients who were formerly admitted to acute care hospitals are being cared for in these settings, it becomes important to establish and maintain rigorous infection control practices in the outpatient environment. The risk of HAIs in ambulatory settings has been reviewed 79,80 and has been associated with lack of adherence to routine infection control practices and procedures, especially recommended safe injection practices. [59] Respiratory viral agents and M. tuberculosis are among the infectious agents transmitted in ambulatory settings. Crowded waiting rooms, toys, furniture, lack of isolation of children undiagnosed and waiting to be seen, contaminated hands, contaminated secretions, and susceptible healthcare workers are only some of the factors that result in sporadic and epidemic illness in outpatient settings. 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 of that clinic indicates the potential for transmission in this setting 81 Patient-to-patient transmission of Burkholderia species and Pseudomonas aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed and prevented by implementing recommended infection control practices. 82,83 Outpatient infection control guidelines and policies for pediatricians' offices have been published and are being updated 84 Prevention strategies include definition of policies, education, and strict adherence to guidelines. References 1. Siegel JD, Rhinehart E, Jackson M, et al. Guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings, 2007. wwwcdc.gov/ncidod/dhqp/pdf/guidelines/Isolation2007.pdf 2. Welliver RC, McLaughlin S: Unique epidemiology of nosocomial infections in a children's hospital. Am J Dis Child 1984; 138:131-135. 3. Ford-Jones EL, Mindorff CM, Langley JM, et al: Epidemiologic study of 4684 hospital-acquired infections in pediatric patients. Pediatr Infect Dis J 1989; 8:668-675. 4. Jarvis WR, Robles B: Nosocomial infections in pediatric patients. Adv Pediatr Infect Dis 1996; 12:243-959.
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5. Jarvis WR, Edwards JR, Culver DH, et al: Nosocomial infection rates in adult and pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Am J Med 1991; 91(suppl. 3B):185S-191S. 6. Yogaraj JS, Elward AM, Fraser VJ: Rate, risk factors, and outcomes of nosocomial primary bloodstream infection in pediatric intensive care unit patients. Pediatrics 2002; 110:481-485. 7. Sohn AH, Garrett DO, Sinkowitz-Cochran RL, et al: Prevalence of nosocomial infections in neonatal intensive care unit patients: results from the first national point-prevalence survey. J Pediatr 2001; 139:821-827. 8. Grohskopf LA, Sinkowitz-Cochran RL, Garrett DO, et al: A national point- prevalence survey of pediatric intensive care unit-acquired infections in the United States. J Pediatr 2002; 140:432-438. 9. CDC : Guidelines for Environmental Infection Control in Health-Care Facilities. Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR 2003; 52(RR-10):1-42. 10. NNIS : National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004; 32:470-485. 11. Toltzis P, Blumer JL: Nosocomial acquisition and transmission of antibiotic- resistant gram-negative organisms in the pediatric intensive care unit. Pediatr Infect Dis J 2001; 20:612-618. 12. Sarginson RE, Taylor N, Reilly N, et al: Infection in prolonged pediatric critical illness: a prospective four-year study based on knowledge of the carrier state. Crit Care Med 2004; 32:839-847. 13. Otter JA, French GL: Nosocomial transmission of community-associated methicillin-resistant Staphylococcus auresus: an emerging threat. Lancet Infect Dis 2006; 6:735-755. 14. Drudy D, Mullane NR, Quinn T, et al: Enterobacter sakazakii : an emerging pathogen in powdered infant formula. Clin Infect Dis 2006; 43:322. 15. Guillet R, Stoll BJ, Cotten CM, et al: Association of H 2 -blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117:e137-e142. 16. Conde-Agudelo A, Diaz-Rossello JL, Belizan JM: Kangaroo mother care to reduce morbidity and mortality in low birthweight infants. Cochrane Database Syst Rev 2003;CD002771 17. Linkin DR, Fishman NO, Patel JB, et al: Risk factors for extended-spectrum beta-lactamase-producing Enterobacteriaceae in a neonatal intensive care unit. Infect Control Hosp Epidemiol 2004; 25:781-783. 18. Cotton CM, McDonald S, Stoll B, et al: The association of third-generation cephalosporin use and invasive candidiasis in extremely low birth-weight infants. Pediatrics 2006; 118:717-722. 19. Bridges CB, Kuehnert MJ, Hall CB: Transmission of influenza: implications for control in health care settings. Clin Infect Dis 2003; 37:1094-1101. 20. Roy CJ, Milton DK: Airborne transmission of communicable infection - the elusive pathway. N Engl J Med 2004; 350:1710-1712. 21. Munoz FM, Seavy D, Medina D, et al: Tuberculosis among adult visitors of children with suspected tuberculosis and employees at a children's hospital. Infect Control Hosp Epidemiol 2002; 23:568-572. 22. White RD: Individual patient rooms in the NICU - an evolving concept. J Perinatol 2003; 23(suppl. 1):S22-S24. 23. Buttery JP, Alabaster SJ, Heine RG, et al: Multiresistant Pseudomonas aeruginosa outbreak in a pediatric oncology ward related to bath toys. Pediatr Infect Dis J 1998; 17:509-513. 24. Hall CB: Nosocomial respiratory syncytial virus infections: the Cold War has not ended. Clin Infect Dis 2000; 31:590-596. 25. Wenzel RP, Deal EC, Hendley JO: Hospital-acquired viral respiratory illness on a pediatric ward. Pediatrics 1977; 60:367-371.
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26. Hall CB, Douglas Jr RG: Modes of transmission of respiratory syncytial virus. J Pediatr 1981; 99:100-103. 27. Bryant KA, Humbaugh K, Brothers K, et al: Measures to control an outbreak of pertussis in a neonatal intermediate care nursery after exposure to a healthcare worker. Infect Control Hosp Epidemiol 2006; 27:541-545. 28. Barnes GL, Callaghan SL, Kirkwood CD, et al: Excretion of serotype G1 rotavirus strains by asymptomatic staff: a possible source of nosocomial infection. J Pediatr 2003; 142:722-725. 29. Maltezou HC, Drancourt M: Nosocomial influenza in children. J Hosp Infect 2003; 55:83-91. 30. Jackson M, Chiarello LA, Gaynes RP, et al: Nurse staffing and health care- associated infections: proceedings from a working group meeting. Am J Infect Control 2002; 30:199-206. 31. Haley RW, Cushion NB, Tenover FC, et al: Eradication of endemic methicillin- resistant Staphylococcus aureus infections from a neonatal intensive care unit. J Infect Dis 1995; 171:614-624. 32. Archibald LK, Manning ML, Bell LM, et al: Patient density, nurse-to-patient ratio and nosocomial infection risk in a pediatric cardiac intensive care unit. Pediatr Infect Dis J 1997; 16:1045-1048. 33. Stegenga J, Bell E, Matlow A: The role of nurse understaffing in nosocomial viral gastrointestinal infections on a general pediatrics ward. Infect Control Hosp Epidemiol 2002; 23:133-136. 34. Vonberg R, Stamm-Balderjahn S, Hansen S, et al: How often do asymptomatic healthcare workers cause methicillin-resistant Staphylococcus aureus outbreaks? A systematic evaluation. Infect Control Hosp Epidemiol 2006; 27:1123-1127. 35. Foca M, Jakob K, Whittier S, et al: Endemic Pseudomonas aeruginosa infection in a neonatal intensive care unit. N Engl J Med 2000; 343:695-700. 36. Gupta A, Della-Latta P, Todd B, et al: Outbreak of extended-spectrum beta- lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit linked to artificial nails. Infect Control Hosp Epidemiol 2004; 25:210215. 37. CDC : Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/ SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR 2002; 51(RR-16):1-44. 38. Harbarth S, Nobre V, Pittet D: Does antibiotic selection impact patient outcome?. Clin Infect Dis 2007; 44:8793. 39. Poehling KA, Edwards KM, Weinberg GA, et al: The underrecognized burden of influenza in young children. N Engl J Med 2006; 355:31-40. 40. Bhat N, Wright JG, Broder KR, et al: Influenza-associated deaths among children in the United States, 20032004. N Engl J Med 2005; 353:2559-2567. 41. Long SS, Stevenson DK: Reducing Candida infections during neonatal intensive care: management choices, infection control, and fluconazole prophylaxis. J Pediatr 2005; 147:135-141. 42. Charlier C, Hart E, Lefort A, et al: Fluconazole for the management of invasive candidiasis: where do we stand after 15 years?. J Antimicrob Chemother 2006; 57:384-410. 43. Pfaller MA: Invasive fungal pathogens: current epidemiological trends. Clin Infect Dis 2006; 43:S3-S14. 44. Spanakis EK, Aperis G, Mylonakis E: New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006; 43:1060-1068. 45. Burke JP: Patient safety: infection control - a problem for patient safety. N Engl J Med 2003; 348:651-656. 46. Haley RW, Culver DH, White JW, et al: The efficacy of infection surveillance and control programs in preventing nosocomial infections in US. hospitals. Am J Epidemiol 1985; 121:182-205.
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47. Pottinger JM, Herwaldt LA, Perl TM: Basics of surveillance - an overview. Infect Control Hosp Epidemiol 1997; 18:513-527. 48. Haley RW: The scientific basis for using surveillance and risk factor data to reduce nosocomial infection rates. J Hosp Infect 1995; 30(suppl.):3-14. 49. Gaynes R, Richards C, Edwards J, et al: Feeding back surveillance data to prevent hospital-acquired infections. Emerg Infect Dis 2001; 7:295-298. 50. Benneyan JC, Lloyd RC, Plsek PE: Statistical process control as a tool for research and healthcare improvement. Qual Safe Health Care 2003; 12:458-464. 51. Garner JS, Jarvis WR, Emori TG, et al: CDC definitions for nosocomial infections 1988. Am J Infect Control 1988; 16:128-140. 52. McKibben L, Horan TC, Tokars JI, et al: Guidance on public reporting of healthcare- associated infections: recommendations of the Healthcare Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol 2005; 26:580-587. 53. Peterson LR, Hamilton JD, Baron EJ, et al: Role of clinical microbiology laboratories in the management and control of infectious diseases and the delivery of health care. Clin Infect Dis 2001; 32:605-611. 54. Sabol K, Patterson JE, Lewis 2nd JS, et al: Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 2005; 49:1664-1665. 55. Pillai SK, Sakoulas G, Wennersten C, et al: Linezolid resistance in Staphylococcus aureus: characterization and stability of resistant phenotype. J Infect Dis 2002; 186:1603-1607. 56. Zaoutis TE, Goyal M, Chu JH, et al: Risk factors for and outcomes of bloodstream infection caused by extendedspectrum beta lactamase-producing Escherichia coli and Klebsiella sp. in children. Pediatrics 2005; 115:942-949. 57. US Department of Labor : Occupational Safety and Health Administration. Occupational exposure to bloodborne pathogens; final rule. Fed Reg 1991; 56:64175-64182. 58. Garner JS: Guideline for isolation precautions in hospitals. Infect Control Hosp Epidemiol 1996; 17:53-80. 59. Williams IT, Perz JF, Bell BP: Viral hepatitis transmission in ambulatory health care settings. Clin Infect Dis 2004; 38:1592-1598. 60. CDC : Updated US. Public Health Service guidelines for the management of occupational exposures to HIV and recommendations for postexposure prophylaxis. MMWR 2005; 54(RR-9):1-17. 61. Hota B: Contamination, disinfection, and cross-colonization: are hospital surfaces reservoirs for nosocomial infection?. Clin Infect Dis 2004; 39:1182-1189. 62. Hayden MK, Bonten MJ, Blom DW, et al: Reduction in acquisition of vancomycin- resistant enerococcus after enforcement if routine environmental cleaning measures. Clin Infect Dis 2006; 42:1552-1560. 63. Ansari SA, Springthorpe VS, Sattar SA: Survival and vehicular spread of human rotaviruses: possible relation to seasonality of outbreaks. Rev Infect Dis 1991; 13:448-461. 64. Renaud MT: Parental response to family centered maternity care and the implementation of sibling visit. Mil Med 1981; 146:850-852. 65. Wranesh BL: The effect of sibling visitation on bacterial colonization rate in neonates. JOGN Nurse 1982; 11:211-213. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
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Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 3 Infections Associated with Group Childcare Andi L. Shane, Larry K. Pickering On average 11.6 million (63%) children 5 years of age or younger and 53% of children 5 to 14 years of age were in some form of group childcare on a regular basis in the winter of 2002 (National Child Care Information Center Child Care Bureau. http://nccic.org ). [1] Aggregation of young children potentiates transmission of organisms that can produce disease in other children, adult care providers, parents, and community contacts. Group childcare settings may potentiate increased frequency of certain diseases, the occurrence of outbreaks of illness ( Table 3-1 ), greater severity of illness, an increase in antibiotic use to permit earlier return to care, which results in the potential for emergence of resistant organisms, and an increased economic burden to individuals and society. [2] [3] [4] The extent of illness resulting from interaction of children and adults in group childcare depends on the age and immune status of children and adults involved, season, environmental characteristics of the childcare facility, and inoculum size and virulence potential of microbes. Children newly entered into a childcare program are at especially high risk of enteric and respiratory tract infections, [5] [6] [7] [8] [9] [10] but as a consequence of these infections may be protected against respiratory tract viral infections and reactive airway diseases during subsequent years. [11] Children who are exposed to infectious pathogens of siblings and contacts in group care and often manifest clinical symptoms of frequent infections early in life may be protected against developing atopic disease in later childhood. [12] TABLE 3-1 -- Association of Infectious Diseases with Group Childcare Settings Disease or Infection Risk Factors and Association with Outbreaks Enteric Viral Rotaviruses, enteric adenoviruses, astroviruses, noroviruses, hepatitis A virus (HAV) Bacterial Shigella, Escherichia coli O157:H7 Campylobacter spp., Salmonella spp., Clostridium difficile Parasitic Giardia lamblia, Cryptosporidium parvum Respiratory tract (acute upper and lower respiratory tract infections and invasive disease) Bacterial Haemophilus influenzae type b (Hib) Streptococcus pneumoniae Group A streptococcus Neisseria meningitidis Bordetella pertussis Mycobacterium tuberculosis Few outbreaks; Hib is vaccine-preventable Few outbreaks; invasive Streptococcus pneumoniae caused by serotypes in vaccine is vaccine- preventable Few outbreaks and low risk of secondary cases Few outbreaks; N. meningitidis caused by serogroups in vaccine is vaccine-preventable in persons over 2 years of age Increasingly associated with outbreaks in childcare centers and schools; vaccine-preventable Occasional outbreaks, usually as a result of contact with an infectious adult care provider Commonly associated with outbreaks Aerosolization and respiratory droplets, person-to-person contact, suboptimal hand hygiene Commonly associated with outbreaks Less commonly associated with outbreaks Commonly associated with outbreaks HAV and rotavirus are vaccine-preventable Close person-to-person contact, fecal-oral contact, food preparation practices, and suboptimal hand hygiene
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Kingella kingae Viral Rhinoviruses, parainfluenza, influenza, respiratory syncytial virus (RSV), respiratory adenoviruses, influenza, metapneumoviruses Multiple organ systems Cytomegalovirus Parvovirus B19 Varicella-zoster virus (VZV)
Outbreaks rare; oropharynx usual habitat; usually manifest as arthritis and osteomyelitis Disease usually caused by same organisms circulating in the community; influenza is vaccine- preventable in children 6 months of age Prevalent asymptomatic excretion with transmission from children to providers Outbreaks reported; risk to susceptible pregnant women and immunocompromised Outbreaks in childcare centers occur. VZV is vaccine-preventable in children 12 months of age. Zoster lesions present low risk of infection Low risk of transmission from active lesions and oral secretions Rarely occurs in childcare centers; vaccine-preventable No documented cases of transmission in the childcare setting No documented cases of transmission in the childcare setting Close person-to-person contact Transmission increased by close person-to-person contact with lesions; outbreaks less likely with decreased incidence of varicella infections; methicillin-resistant Staphylococcus aureus (MRSA) disease increasing Outbreaks in group childcare reported Common in children attending group childcare Tinea corporis and T. capitis outbreaks associated with childcare Outbreaks in group childcare reported with both bacterial and viral etiologies
Herpes simplex virus (HSV) Hepatitis B virus Hepatitis C virus Human immunodeficiency virus (HIV) Skin Staphylococcal and streptococcal impetigo
Scabies Pediculosis Ringworm Conjunctiva
TYPES OF GROUP CHILDCARE The United States Census Bureau classifies regular preschool childcare arrangements by provider (relative of a child in care versus nonrelative) and location of care. Of the 63% of preschool children in a regular childcare arrangement in the winter of 2002, 40% regularly received care by a relative, 37% by nonrelatives, and 11% by both relatives and nonrelatives. The remaining 12% were not classified as receiving a form of childcare regularly. Nonrelative care can be further divided into provision of care in an organized care facility or childcare center (23%), by a nonrelative in the child's home (4%) or in the provider's home (10%). [1] Types of facilities can also be classified by size of enrollment, age of enrollees, and environmental characteristics of the facility. Grouping of children by age varies by setting but in organized care facilities usually children are separated as infants (6 weeks to 12 months), toddlers (13 to 35 months), preschool (36 months to 59 months), and school-aged children (5 to 12 years). The classification of group childcare settings has relevance to infectious disease epidemiology with regard to regulation and monitoring. Most nonrelative care provided in an organized care facility is subject to state licensing and regulation, whereas relative care in a child or provider's home may not be subject to state regulations and monitoring. EPIDEMIOLOGY AND ETIOLOGY OF INFECTIONS Although almost any infectious disease has the propensity to propagate in the childcare setting, diseases shown in Table 3-1 are commonly associated with outbreaks. Organisms that infect enrollees and providers may do so with a predilection for nonimmune persons of specific ages.
Enteric Infections
Outbreaks of diarrhea occur at a rate of approximately 3 per year per childcare center and are most frequently associated with organisms that result in infection after ingestion of a low inoculum. These organisms generally are transmitted from person to person [13] [14] and include rotavirus, sapovirus, norovirus, astrovirus, enteric adenovirus, Giardia lamblia, Cryptosporidium, Aeromonas, Shigella, Escherichia coli O157:H7, E. coli O114, enteropathogenic
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E. coli, and Clostridium difficile. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] These fecal coliforms [27] [28] and enteric viruses contaminate the environment; [29] contamination rates are highest during outbreaks of diarrhea. The attack rates and frequency of asymptomatic excretion of these organisms in children in childcare are shown in Table 3-2 . Reported attack rates depend on several factors, including methods used for organism detection. [22] [23] TABLE 3-2 -- Outbreaks of Diarrhea by Organism Attack Rate Secondary Attack Rate (Family Organism (Enrollees) (%) Members) (%) Rotavirus Astrovirus Calicivirus Giardia lamblia Cryptosporidium Shigella Escherichia coli O157:H7 O114:NM O111:K58 Clostridium difficile 29, 34 67 56, 94 32 Unknown Unknown Unknown Unknown Uncommon Uncommon Uncommon Common 50 5090 50 1754 3374 3373 1580 Unknown Unknown Unknown 1550 2560 2550 Enteric adenovirus 40
Asymptomatic Excretion (Enrollees) Common Common Common Common Common Common Uncommon
Enteric viruses are the predominant etiology of diarrheal syndromes among children in group care, with impact by season. In a prospective study of children enrolled in childcare in Denmark during 6 months of winter, rotavirus was the predominant organism identified in 40% of cases with a confirmed etiology, sapoviruses in 18%, and astroviruses in 7%. [30] Organisms generally associated with foodborne outbreaks, such as Salmonella and Campylobacter jejuni, are infrequently associated with diarrhea in the childcare setting. How ever, a report of an outbreak of diarrhea in 14 of 67 (21%) exposed children and adult care providers associated with ingestion of fried rice contaminated with Bacillus cereus [31] highlights the fact that foodborne outbreaks can occur in the childcare setting, especially when food is prepared and served at the center. Bacterial pathogens that have the potential to cause severe systemic infections, including E. coli O157:H7, have been associated with fecaloral transmission in group childcare settings. An outbreak of this pathogen in a childcare center in Alberta, Canada in June 2002 likely began following introduction of the organism by a 3-year-old enrollee with farm animal contact who developed hemolyticuremic syndrome. A diarrheal attack rate of 23% was noted among enrollees, which is comparable with attack rates of E. coli O157:H7 reported during previous childcare-associated outbreaks. Prolonged asymptomatic shedding and subclinical cases in concert with poor hygiene and toileting practices likely contributed to propagation of the outbreak. [32] Shigella sonnei has been responsible for periodic multicommunity outbreaks in group childcare. A multicommunity outbreak of over 1600 culture-confirmed cases in the greater metropolitan area of Cincinnati, Ohio from May to September, 2001 had an overall mean attack rate of 10% among childcare center enrollees, with highest attack rates occurring among newly or incompletely toilet-trained enrollees and lowest attack rates occurring among diapered children. Attack rate was 6% among staff. An epidemiologic investigation revealed that a single negative stool culture may be sufficient to confirm the clearance of S. sonnei in convalescent, treated enrollees. Secondary transmission was facilitated by poor hygiene practices, including inaccessible handwashing supplies and incomplete diaper disposal practices, as well as recreational activities involving water. [33] A prolonged multistate increase in shigellosis with similar biochemical and genetic profiles occurred in the south and mid-Atlantic areas from June 2001 to March 2003. A significant proportion of cases were associated with group childcare, emphasizing the ongoing public health challenge of management and control. [34] Spread of microbes that cause diarrhea from the childcare setting into families has been reported for many enteropathogens (see Table 3-2 ). The secondary attack rates range from 15% to 80% depending on the enteropathogen, mode of transmission, and length of time in the household. Children in group childcare are generally the index cases within households. A retrospective evaluation of transmission of infectious gastroenteritis (80% due to rotavirus) in 936 households in northern California revealed a secondary household attack rate of 8.8% (95% confidence interval (CI) 7.9-9.7). Older children in the households had a two- to eightfold greater risk of secondary
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infection than adults in the household. Clinical illness in secondary household cases usually was less severe and of decreased duration, compared with illness in the index case. [35] During outbreaks of diarrhea in childcare centers, asymptomatic excretion of enteropathogens is frequent [14] [22] [23] [36] [37] [38] [39] (see Table 3-2 ). During outbreaks associated with enteric viruses and G. lamblia in children younger than 3 years of age, asymptomatic infection occurs in up to 50% of infected children. In one longitudinal study of diarrhea in 82 children younger than 2 years of age in a childcare center, more than 2700 stool specimens were collected on a weekly basis. [39] Using enzyme immunoassays, 21 of 27 (78%) children infected with G. lamblia were found to be asymptomatic and 19 of 37 (51%) children infected with rotavirus were asymptomatic. The role that asymptomatic excretion of enteropathogens plays in spread of disease is unknown. Acute infectious diarrhea is two to three times more common in children in childcare than in age-matched children cared for in their homes. [5] [40] [41] Approximately 20% of clinic visits for acute diarrheal illness among children younger than 3 years of age have been shown to be attributable to childcare attendance. [5] In addition, diarrheal illness is threefold higher among children in their first month in out-of-home childcare than in children cared for at home. [5] [6] Several factors have been reported to be associated with occurrence of diarrhea among children in group settings. Although diarrhea occurs 17 times more frequently in diapered children than in children not wearing diapers, [42] it is unclear whether diapering is a confounding factor, risk factor, or protective factor in group childcare infections. Children who are diapered are more likely to be younger than children who are not; therefore, higher attack rates may merely represent exposure of a younger, nonimmune cohort. In a multicommunity group childcare outbreak of Shigella sonnei, the highest attack rates were noted in rooms where both toilet-trained and diapered children were combined (14%) compared with rooms with toilet-trained children only (9%) and rooms with only diapered children (5%), despite comparable availability of sinks and toilets. [33] A study evaluating costs associated with office visits for diarrhea in children younger than 36 months of age showed that the average cost for each episode of diarrhea was $289 in 1991, with 21% of the total cost for diarrhea in this 1year study attributable to rotavirus diarrhea. [43] A 3-year study analyzing medical claims data for the period from 1993 to 1996 showed that the median cost (in 1998 constant dollars) of a diarrhea-associated hospitalization was $2307, and the median cost of a diarrhea-associated outpatient visit was $47. [44]
Rotavirus
Rotaviruses are the most common etiology of significant symptomatic diarrhea in children less than 2 years of age. Most symptomatic infections occur in infants and children between 4 and 24 months of age and are manifest by profuse, watery diarrhea, preceded by emesis and fever. Infections are primarily transmitted from person to person by the fecaloral route, and are facilitated by interpersonal contact. Rotavirus can be isolated from human stools for approximately 21 days after illness begins and rotavirus RNA has been detected on toys and surfaces in childcare centers. [29] The highest attack rates of rotaviral infections occur in infants and children who may be enrolled in group childcare, with notable transmission rates from infected contacts and significant rates of hospitalization. In one study, children in childcare centers developed predominantly homotypic antibody responses after infection with rotavirus, but as the number of rotavirus infections increased, children developed heterotypic antibody responses to G types at levels that correlate with broad protection against rotavirus infection and illness. [45] In another study, infections with rotavirus were associated with lower concentrations of antirotavirus-specific fecal immunoglobulin A (IgA), indicating a protective role for higher titers of antirotavirus-specific fecal IgA. [46] Prevention of transmission of rotavirus infections in persons involved in group childcare includes meticulous hand hygiene and disinfection of potentially contaminated surfaces, with processing of soiled diapers and clothing in areas that are inaccessible to mobile children. Primary prevention of rotavirus may be accomplished with administration of two rotaviral vaccines licensed in 2005: a pentavalent bovinehuman reassortant vaccine licensed in the United States, or a monovalent human G1 rotavirus vaccine licensed in several countries outside the United States. Large trials of both products have demonstrated both efficacy and safety, and neither vaccine appears to have an association with intussusception in vaccine recipients but this will be monitored closely [47] [48] ,48a (see Chapter 216 , Rotaviruses).
Hepatitis A Virus
Hepatitis A virus (HAV) infections usually are mild or asymptomatic in children. Less than 5% of children younger than 3 years of age and less than 10% of children between 4 and 6 years of age with HAV infection develop jaundice. The first outbreak of HAV in a childcare center was reported in 1973 in North Carolina; [49] since then, outbreaks have been recognized throughout the United States. [50] Peak viral titers in stool and greatest infectivity occur during
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the 2 weeks before onset of symptoms. Outbreaks in childcare centers generally are not recognized until illness becomes apparent in older children or adults. [50] Prior to availability of hepatitis A vaccine in the United States, approximately 15% of episodes of HAV infection were estimated to be associated with childcare centers. HAV infections are transmitted in the childcare setting by the fecaloral route and occur more frequently in settings that include diapered children, although large size and long hours of operation are also risk factors for outbreaks of HAV infection. [51] The mainstays for prevention of HAV infection include general measures such as maintenance of personal hygiene, hand hygiene, and disinfecting procedures. Universal administration of two doses of hepatitis A vaccine to all children, beginning at 1 year (12 to 23 months) of age, the two doses administered at least 6 months apart, [52] is recommended by the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP). [53] Administration of immune globulin during outbreaks for postexposure prophylaxis to unimmunized contacts may be indicated [54] (see Chapter 64 , Acute Hepatitis; Chapter 238 , Hepatitis A Virus). A case-control study to evaluate the effectiveness of a hepatitis A vaccination program targeted at childcare attendees between 2 and 5 years of age found that individuals with direct contact with a childcare center were protected against disease. Furthermore, the 6 times greater risk of hepatitis A that occurred in persons who had contact with a childcare center prior to implementation of the hepatitis A immunization program in Maricopa County, Arizona was not found in the postvaccination case-control study. [55] Education and training of staff regarding appropriate hygienic practices, as well as modes of transmission of HAV and other enteric diseases, and frequent monitoring of hygienic practices by center directors are essential components of any preventive plan.
Respiratory Tract Infections
Children younger than 2 years of age attending childcare centers have an increased number of upper and lower respiratory tract illnesses compared with age-matched children cared for at home. [5] [7] [56] [57] Studies have shown that approximately 10% to 17% of respiratory tract illnesses in United States children younger than 5 years of age are attributable to childcare attendance. [58] [59] Another prospective cohort study found that 89% of disease episodes among children attending a childcare center are respiratory tract infections. [60] In a retrospective cohort study of 2568 children from 1 to 7 years of age, 1-year-old children in childcare centers had an increased risk of the common cold (relative risk (RR), 1.7; 95% CI, 1.4 to 2.0), otitis media (RR, 2.0; 95% CI, 1.6 to 2.5), and pneumonia (RR, 9.7; 95% CI, 2.3 to 40.6). [56] Attendance in family childcare did not increase risk. In a prospective cohort study in France comparing the risk of upper respiratory tract illnesses (URTIs) in children in three settings family, small center and large center demonstrated increased risk of 5 URTIs in small center enrollers (OR2.2; 95% CI, 1.4-3.4) and modestly increased risk in large center enrollers (OR1.2; 95% CI, 0.8-1.8). In this study, the risk for children attending large childcare centers was intermediate between children in family childcare homes and smaller childcare centers, probably as a result of segregation of children in large centers into small classrooms. Respiratory tract infections that have been studied in the childcare setting include pharyngitis, sinusitis, otitis media, common cold, bronchiolitis, and pneumonia. [7] [56] [57] [58] [60] Organisms responsible for illness in children in childcare settings are similar to organisms that circulate in the community and include respiratory syncytial virus, parainfluenza viruses, adenovirus, rhinovirus, coronavirus, influenza viruses, parvovirus B19, and Streptococcus pneumoniae. Infections due to Bordetella pertussis in the United States have experienced a dramatic increase, with 8296 cases of pertussis reported in 2002 and 25,827 cases reported in 2004. [61] [62] [63] Incompletely immunized infants under 12 months of age experience significant clinical disease, whereas adolescents and adults remain mildly to moderately symptomatic and infectious, accounting for a significant proportion of cases. In many group childcare arrangements adolescents and adults may be the index case for pertussis infections. In 2005, the AAP and ACIP recommended use of the two Food and Drug Administration (FDA) licensed Tdap vaccines in people, one for adolescents 10 through 18 years of age, the other for people 11 through 64 years of age. [62] [63] These vaccines may impact disease in people who receive them as well as in susceptible contacts. An adult or adolescent source may also be the index case for Mycobacterium tuberculosis infections in a group childcare setting, with child-to-child transmission occurring infrequently. [64] [65] An outbreak of tuberculosis (TB) associated with a private-home childcare facility in San Francisco, California occurred between 2002 and 2004. Of 11 outbreak cases, 9 (82%) occurred in children less than 7 years of age; all had extensive contact with the privatehome childcare facility, where the adult index patient spent significant time. Two children presented with clinical illness, 3 were identified by contact investigation, and 4 were identified by primary care providers during routine TB screening evaluations. Isolates from 4 of the pediatric patients and 2 of the adult patients shared identical molecular patterns. Thirty-six additional children and adult contacts had latent TB infections. [66] High transmissibility of TB among residents of adult daycare centers has also been demonstrated. [67] Person-to-person transmission of Chlamydophila pneumoniae among children in the childcare setting has been
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reported without occurrence of disease. [68] Kingella kingae colonizes the oropharynx and respiratory tracts of young children and has been associated with invasive disease. [69] The first reported outbreak of invasive K. kingae osteomyelitis/septic arthritis occurred in a childcare center in 2003. Fifteen (13%) children older than 16 months of age were found to be colonized, with 9 children (45%) in the same class as the 2 children with invasive disease. Matching pulse field gel electrophoresis (PFGE) patterns supported child-to-child transmission. [70] A retrospective review of osteoarticular infectious etiologies from 1999 to 2002 of 406 hospitalized children in Paris, France demonstrated that K. kingae was isolated from 14% of clinical specimens. This pathogen was isolated more frequently from children younger than 36 months of age and was the second most common bacterial isolate in this population. Awareness of the clinical manifestations, laboratory requirements for growth, and risk factors for acquisition in childcare may account for the increasing incidence of K. kingae infections. [71] Group A streptococcal infection among children and adult staff in the childcare setting is not a common problem, but outbreaks have been reported. [72] [73] [74] In a study of prevalence of group A streptococcus conducted in a childcare center after a fatal case of invasive disease, 25% of 258 children and 8% of 25 providers had group A streptococci isolated from throat cultures. [72] Risk of carriage was increased in children who shared the room of the index case (odds ratio (OR), 2.7; 95% CI, 0.8 to 9.4). In a study in childcare centers in Israel, the prevalence of group A streptococcus was 3% in infants and 8% in toddlers. Pharyngeal carriage was not associated with respiratory tract symptoms. [75] Group A streptococcal perianal infection and infection associated with varicella have also been reported. [69] [70] The risk of acute otitis media is significantly increased in children in childcare, especially in children younger than 2 years of age. [60] [58] [76] [77] [78] In one study, the incidence rate ratio for otitis media was 1.5 in children in childcare compared with that in children in home care. [58] Otitis media is responsible for most antibiotic use in children younger than 3 years of age in the childcare setting. However, implementation of the 2004 acute otitis media treatment guidelines developed by the AAP [79] may reduce use of prescription antibiotics for acute otitis media in children enrolled in group childcare. Childcare attendance has also been associated with risk of developing recurrent otitis media (more than 6 episodes in 1 year), as well as chronic otitis media with effusion persisting for more than 6 months. [80] The size of the childcare center was an important variable in the occurrence of frequent otitis media in children younger than 12 months of age, varying from 16% in small care groups to 36% in large care groups. [77] Genotypically similar strains of nontypable Haemophilus influenzae were isolated from throats of 127 children attending 16 childcare centers in Michigan. Rates of colonization were greater among attendees of childcare centers with > 5 classrooms, and when suboptimal hand hygiene was performed by staff and children. Colonized children who were recipients of a course of antibiotics at the time of culturing were more likely to be colonized with a betalactamase-producing nontypable H. influenzae strain. [81] Handwashing decreases the frequency of acute respiratory tract diseases in childcare. [82] [83] A cluster, randomized, controlled trial of an infection control intervention including training of childcare staff regarding handwashing, transmission modes of infection, and aseptic techniques related to nose-wiping demonstrated a significant reduction in respiratory tract illnesses among enrollees less than 24 months of age over 311 child-years of surveillance. [84] Because most infectious agents are communicable for a few days before and after clinical illness, exclusion from childcare of children with symptoms of upper respiratory tract infections will probably not decrease spread. Exclusion should occur when illness limits the child's participation in activities or when the child's needs exceed the capacity for provision of care.
Influenza
Although influenza is responsible for disease among persons of all ages, rates of infection are highest among children less than 2 years of age and rates of complications of influenza infection are greatest among children of all ages with predisposing or underlying medical conditions. Influenza viruses are spread from person to person primarily through transmission of large respiratory tract droplets, either directly or by secondary contact with objects that are contaminated with infectious droplets. Children can shed virus for several days prior to onset of clinical symptoms and may be considered to be infectious for > 10 days following symptom onset. Transmission of infections may be increased by close contact among children who are not able to contain their secretions. Complications of influenza, including febrile seizures, encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, pericarditis, and death, can occur in children of preschool age. Among preschool-aged children with influenza infections, hospitalization rates range from 100 to 500/100,000 children, with highest hospitalization rates among children aged 0 to 1 year of age. [85] Deaths from influenza uncommonly occur among both children with and without predisposing medical conditions. Reports of 153 laboratory-confirmed influenza-related pediatric deaths from 40 states during the 2003 to 2004 influenza season indicated that 61 (40%) were < 2 years of age and, of 92 children 2 to 17 years of age, 64 (70%) did not have an underlying medical condition traditionally considered to place a person at risk for influenza-related complications.
[86]
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Annual vaccination against influenza is the primary method for preventing influenza infection, and reducing transmission of infection among children in the childcare setting and among childcare providers. Influenza vaccine is recommended for all children 6 to 59 months of age, care providers of children 0 to 59 months of age in the childcare setting, and children and adolescents > 59 months of age with underlying medical conditions predisposing them to complications from influenza infection. [85] A single-blind randomized controlled trial conducted during the 1996 to 1997 influenza season in 10 childcare centers in San Diego, California revealed that vaccinating children against influenza reduced influenza-related illness among their household contacts. [87] In addition to preventing respiratory tract illness, several studies have shown the effectiveness of influenza vaccine in preventing otitis media among children in childcare. [83] [84] [88] In one study of children 6 to 30 months of age in childcare centers, OR for acute otitis media was 0.69 and the 95% CI was 0.49 to 0.98 for those who received influenza immunization. [88] Routine use of intranasal influenza vaccine among healthy children may be cost-effective and may be maximized by using group-based vaccination approaches. A prospective 2-year efficacy trial of intranasal influenza vaccine in healthy children 15 to 71 months of age demonstrated clinical efficacy as well as economic efficacy associated with focusing vaccination efforts on children in group settings. [89] Vaccinating children has been associated with protection of older persons as well. [90] [91] Effective secondary prevention of transmission of influenza can be achieved with frequent hand hygiene using either soap and water or alcohol-based hand rubs, by both childcare enrollees and providers. Respiratory etiquette with disposal of tissues and cleansing of hands after contact with secretions should be observed. Frequently touched surfaces, toys, and commonly shared items should be cleaned at least daily and when visibly soiled. Children with signs and symptoms of respiratory tract illness should be cohorted, if possible, and excluded from group childcare if their symptoms prevent participation in activities or if their illness requires a level of care that exceeds a level that can be provided by the care provider. Ill childcare providers should be discouraged from providing care or having contact with children in group childcare. Vaccination of both child attendees and adult providers should be encouraged and both children and providers should receive frequent reminders regarding hand hygiene and respiratory etiquette to reduce influenza infections in group childcare settings.
Invasive Bacterial Infection
Studies conducted before routine use of Haemophilus influenzae type b (Hib) vaccine in the United States have shown that the risk of developing primary invasive infection due to H. influenzae type b was higher among children attending childcare centers than in children cared for at home, independent of other possible risk factors. [92] [93] Risk of subsequent or secondary H. influenzae type b disease in the childcare setting was less convincing. [91] Incorporation of conjugated Hib vaccines into the routine immunization schedule of children in the United States has dramatically reduced the frequency of invasive disease due to H. influenzae type b. Risk of disease due to Neisseria meningitidis may be increased in children in group childcare. Using spacetime cluster analysis of invasive infections during 9 years of surveillance, from 1993 to 2001, in the Netherlands, researchers noted that clustering beyond chance occurred at a rate of 3% (95% CI 2% to 4%), and concluded that this rate was likely the result of direct transmission. Childcare center attendance was reported as the likely exposure for 8/40 (20%) of clusters, accounting for 13/82 (16%) cases of invasive disease with multiple serosubtypes. [93] Childcare attendees who develop clinical disease while enrolled in group care prompt heightened community awareness and often result in distribution of prophylaxis to family and childcare contacts. [94] The risks of developing primary invasive disease due to Streptococcus pneumoniae, of nasopharyngeal carriage of S. pneumoniae, and carriage of antibiotic-resistant strains are increased for children in childcare centers [96] [97] [98] [99] [100] [101] [102] [103] and childcare homes. [97] In Finland, an increased risk of invasive pneumococcal disease in children younger than 2 years of age was associated with childcare attendance (OR, 36; 95% CI, 5.7 to 233), family childcare (OR, 4.4; 95% CI, 1.7 to 112), and history of frequent otitis media (OR, 8.8; 95% CI, 2.5 to 31). [97] Resistance significantly decreased with a reduction in antibiotic use. Acute otitis media is the most common manifestation of pneumococcal infection and the source of most antibiotic prescriptions for children. [103] Secondary spread of S. pneumoniae in the childcare setting has been reported, but the exact risks are not known. [103] [105] [106] [107] Colonization with S. pneumoniae in a childcare center was found in 32 of 54 (59%) children 2 to 24 months of age; 75% of the strains were penicillin-nonsusceptible. [98] In an evaluation of the childcare cohort of an 11-month enrollee with multidrug-resistant S. pneumoniae in southwest Georgia, S. pneumoniae was isolated from 19 (90%) of the 21 nasopharyngeal cultures; 10 (53%) were serotype 14 and matched the susceptibility pattern of the strain from the index child; 4 of the 10 children with index-strain carriage had shared a childcare room with the index child, suggesting person-to-person transmission. [107] Incorporation of a conjugated pneumococcal vaccine into the routine childhood immunization schedule of children in the United States in August of 2000 has resulted in a dramatic reduction in the frequency of invasive disease. [108]
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The impact of vaccination on acute otitis media and reduction of penicillin-nonsusceptible pneumococcal infection is less dramatic and more variable, with evidence of increasing nasopharyngeal colonization and respiratory tract infections caused by nonvaccine serotypes and nontypable strains of pneumococcus. [109] [110] [111] [112]
Methicillin-Resistant Staphylococcus aureus
Infections due to methicillin-resistant Staphylococcus aureus (MRSA) were reported infrequently in the group childcare setting before 2000. [113] [114] [115] However, with emergence of a community-acquired MRSA, the incidence of infection and its predisposition for affecting individuals in crowded conditions, where sharing of fomites exists, where skin-to-skin contact occurs, and hygiene is compromised place children in group care at risk.
Echovirus
During an outbreak of echovirus 30 infection in children and care providers in a childcare center, and in exposed parents, infection occurred in 75% of children and 60% of adults, but aseptic meningitis was more frequent in infected adults (12 in 65, 18%) than in children (2 in 79, 3%). [115] A retrospective cohort study of childcare center attendees, employees, and household contacts in Germany revealed that 42% of childcare attendees, 13% of their household contacts, 5% of childcare center employees, and 2% of their household contacts were ill over a 31-day period. Thirteen percent (12/92) of childcare attendees had meningitis. This outbreak likely began among children enrolled in group childcare centers, with secondary cases occurring among their household contacts. [116]
Cytomegalovirus
Young childcare attendees shed cytomegalovirus (CMV) chronically after acquisition and often transmit virus to other children and adults with whom they have close daily contact. [118] [119] [120] Transmission is thought to occur through direct person-to-person contact and from contaminated toys, hands of childcare providers, or classroom surfaces. [120] Prevalence studies have shown that 10% to 70% of children younger than 3 years of age (peak, 13 to 24 months) in childcare settings have CMV detected in urine or saliva. [118] [120] [122] CMV-infected children can transmit the virus to women, with rates from 8% to 20% for their childcare providers and 20% of their mothers per year ( Table 3-3 ) [119] [122] [123] [124] compared with rates of 1% to 3% per year in women whose toddlers are not infected. TABLE 3-3 -- Acquisition of Cytomegalovirus by Childcare Center Providers and Others Study Number of Seronegative Persons Annual Rate of Seroconversion (%) Childcare providers (Alabama) [122] 202 Hospital employees (Alabama) [122] 229 Childcare providers (Virginia) [118] 82 Hospital employees (Virginia) [118] 300 Childcare providers (Iowa) [123] Childcare providers (Toronto) [121]
Bloodborne Viral Pathogens
11 2 20 2 8 13
82 68
Concern has arisen about the potential for spread of bloodborne organisms in the childcare setting: hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). [125] [126] [127] [128] The highest concentrations of HBV in infected persons are found in blood and blood-derived body fluids. The most common and efficient routes of transmission are percutaneous blood exposure, sexual exposure, and, perinatally, from mothers to offspring at the time of delivery (see Chapter 109 , Epidemiology and Prevention of HIV Infection in Children and Adolescents; Chapter 111 , Diagnosis and Clinical Manifestations of HIV Infection). Other recognized but less efficient modes of transmission include bites and mucous membrane exposure to blood or other body fluids. [129] [130] Two case reports and a larger study have demonstrated possible transmission of HBV among children in the childcare setting. [130] [131] [132] Other investigators have failed to demonstrate transmission in childcare, despite long-term exposure to children positive for hepatitis B surface antigen (HBsAg). [132] Because of the small number of studies, the risk of HBV transmission in childcare cannot be quantified precisely. If a known HBsAg carrier bites and breaks the skin of an unimmunized child, hepatitis B immune globulin and the HBV vaccine series should be administered. [125] With implementation of universal immunization of infants with HBV vaccine beginning in 1991, horizontal HBV transmission in the childcare setting has been reduced to negligible. As the seroprevalence of HCV infection in children under 12 years of age is estimated to be 0.2% and most acute infections are asymptomatic, the transmission risk of HCV infection in childcare settings is unknown. The general
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risk of HCV infection from percutaneous exposure to infected blood is estimated to be 10 times greater than HIV but less than HBV. Areas of concern regarding attendance of an HIV-infected child in group care include the child's potential risk of transmitting HIV and of acquisition of infectious agents. [124] No cases of HIV infection are known to have resulted from transmission of the virus in out-of-home childcare. Children with HIV infection in the childcare setting should be monitored for exposure to infectious diseases, and their health and immune status should be evaluated frequently. The risk of transmission of HIV by percutaneous body fluid exposure, such as biting, is low. Complete evaluation of the source and extent of exposure should be undertaken to assess the risks and benefits of postexposure prophylaxis. [125] An infectious disease physician with expertise in HIV care can be contacted for guidance. Precautions for the prevention of HBV, HCV, and HIV infection should be directed toward preventing transfer of blood or exudate fluids from person to person. Childcare providers should be educated about modes of transmission of bloodborne diseases and their prevention, and each center should have written policies for managing illnesses and common injuries such as bite wounds. Standard precautions for handling blood and blood-containing body fluids should be practiced in all childcare settings. [125] Children infected with HIV or HCV or children who are HBsAg carriers should not be excluded from childcare. Decisions regarding attendance at childcare and the optimal type of childcare must be made by parents and the child's physician after considering the possible risks and benefits.
Skin Infection and Infestation
The magnitude of skin infections or infestations and the rates of occurrence in children in group childcare compared with rates in age-matched children not in group childcare are not known. The most frequently recognized nonvaccine-preventable conditions are impetigo or cellulitis (due to Staphylococcus aureus or group A streptococcus), pediculosis, and scabies. [73] [83] [134] Other conditions with skin manifestations that occur in children in childcare include herpes simplex virus (HSV) infection, varicella, ringworm, and molluscum contagiosum. [73] [135] [136] [137] [138] Unimmunized children in childcare facilities are susceptible to varicella infection; most reported cases occur in children younger than 10 years of age. [73] [136] An outbreak of varicella was reported when a child with zoster attended a childcare center. [134] Although the lesions were covered, the child continuously scratched and showed others the lesions, indicating the potential difficulties with this policy. Infection with group A streptococcus is a known complication of varicella. [73] Although universal immunization with varicella vaccine has reduced cases of both varicella infection and its associated streptococcal complications among children in group childcare, [52] several outbreaks of varicella have been reported among childcare attendees in the postlicensure era. [74] [139] [140] An outbreak of varicella in a childcare center in New Hampshire in 2000 with a vaccination coverage rate of 66% resulted in clinical disease in 25 of 88 (28%) children. This outbreak demonstrated poor protection against overall varicella disease. However vaccination was shown to be protective against moderate or severe clinical varicella. [74] An active surveillance evaluation for vaccine effectiveness in Israel revealed 8 childcare-associated outbreaks in a 6month time period from January to June, 2003 involving 116 children with clinical disease from 3 to 6 years of age. A vaccine coverage rate of 37% was noted among this cohort. In concordance with findings from vaccine postlicensure outbreaks in the United States, 94% of children with breakthrough varicella and 14% with natural varicella had mild disease. [138] A varicella outbreak occurring among elementary school attendees in Maine in December to January 2003 was due to failure to vaccinate. The vaccination rates were notable for a decrease from 90% of kindergarten attendees to 60% of third-grade enrollees. Vaccine effectiveness in this cohort of 296 students was 89% against all varicella disease and 96% against moderate to severe disease. This outbreak illustrates the importance of vaccination of susceptible older children and adolescents to decrease the incidence of severe disease in unvaccinated children. [139] As evidenced by these outbreaks, varicella incidence is highest in children 1 to 6 years of age. Therefore implementation of varicella vaccination requirements for childcare and elementary school attendees without evidence of immunity as recommended by the ACIP [140] would reduce the susceptible population, consequently reducing the frequency of varicella outbreaks in group care settings. Primary HSV infection results in gingivostomatitis, most often in children 1 to 4 years of age. [137] [138] In two studies, clusters of primary infections occurred in children in childcare, most frequently manifesting as gingivostomatitis. [137] [138] In one study, restriction endonuclease analysis of DNA of isolated HSV revealed that a single strain of HSV-1 had been transmitted among children. [137] Molluscum contagiosum is a benign, usually asymptomatic viral infection of the skin; humans are the only source. Virus is spread by direct contact or by fomites. Infectivity is low, but outbreaks have been reported. The frequency of occurrence in the childcare setting is unknown. People with atopic dermatitis or immunocompromised hosts, including people with acquired immunodeficiency syndrome (AIDS), have increased risk for acquiring infection or for having more extensive clinical manifestations. The incidence of pediculosis capitis (head lice) among children in childcare facilities in Seattle was 0.02/100 childweeks [141] and 0.03/child-year in San Diego. [142] Treatment of infested children and their contacts with pediculicides that are used as directed may be considered as control measures.
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Parvovirus B19
Parvovirus B19, the agent of erythema infectiosum (fifth disease), can cause arthropathy, transient aplastic crisis, persistent anemia in immunocompromised hosts, and nonimmune fetal hydrops (see Chapter 214 , Human Parvoviruses). Serologic evidence of past infection has been reported to be 30% to 60% in adults, 15% to 60% in school-aged children, and 2% to 15% in preschool children. [143] The virus is endemic among young children and has caused outbreaks of disease in the childcare setting. [145] [146] Parvovirus B19 spreads by the respiratory route or through contact with oropharyngeal secretions. In an outbreak during which more than 571 school and childcare personnel were tested serologically, the overall attack rate among susceptible individuals was 19%, with the highest rate (31%) occurring in childcare personnel. [144] A cross-sectional study of 477 childcare staff revealed a seroprevalence for parvovirus B19 IgG antibodies of 70%. Seropositivity was associated with age, and among staff less than 40 years of age, with length of group childcare contact. [146] The greatest concern is that an infected pregnant woman could transmit the virus transplacentally, leading to fetal hydrops; neonatal illness and congenital malformations have not been linked to prenatal parvovirus B19 infection. Estimates of the risk of fetal loss when a pregnant woman of unknown antibody status is exposed are 2.5% for fetal death after household exposure and 1.5% after occupational exposure in a school. [147] VACCINE-PREVENTABLE DISEASES In the United States, there are 16 diseases against which all children should be immunized, unless there are contraindications: (1) diphtheria; (2) tetanus; (3) pertussis; (4) Haemophilus influenzae type b; (5) measles; (6) mumps; (7) rubella; (8) poliomyelitis; (9) HBV; (10) varicella; (11) Streptococcus pneumoniae; (12) HAV; (13) influenza; (14) rotavirus; (15) human papillomavirus; and (16) meningococcal disease. [52] Immunization of children and their care providers should be high priority ( Table 3-4 ) and immunization is especially likely to benefit children in childcare settings. [148] High levels of immunization exist among children in licensed childcare facilities, [149] partially because laws requiring age-appropriate immunizations of children attending licensed childcare programs exist in almost all United States states, including vaccine mandates for childcare for HBV in 37 (74%) states as of April 2004, hepatitis A in 9 (18%) states as of August 2005, and varicella in 42 (84%) states as of August 2005. [150] In a study of exemptions to immunizations, children of childcare age (3 to 5 years) with exemptions to immunizations were 66 times more likely to acquire measles and 17 times more likely to acquire pertussis than were age-matched immunized children. [151] TABLE 3-4 -- Vaccine-Preventable Infections Immunization Indicated Organism Diphtheria, pertussis, tetanus Haemophilus influenzae type b (Hib) Hepatitis A Childcare Attendee As part of the 5-dose DTaP series As part of the 34-dose series, depending on vaccine used 2-dose series beginning at 1 year (12 to 23 months) of age Childcare Provider Tdap booster as adolescent/young adult; then Tdap every 10 years Not indicated
2-dose series recommended for adults at high risk for hepatitis A virus infection; not routinely recommended for childcare providers 3-dose series recommended for hepatitis B virus infection; not routinely recommended for childcare providers
Hepatitis B
3-dose series beginning at birth
Influenza A and B Annual immunization for all children 6 to 59 months of Annual immunization with trivalent age and high-risk children 59 months of age; 2 doses if inactivated or live attenuated first influenza immunization and 8 years of age influenza vaccine Measles, mumps, rubella Meningococcal disease 2-dose series starting at 12 months of age Booster immunization if only one dose received
Polysaccharide vaccine for children 2 to 10 years of age Conjugate vaccine recommended for in high-risk groups. Conjugate vaccine if 11 to 19 years adults 20 to 55 years of age at of age increased risk (polysaccharide is an acceptable alternative) 4 doses of heptavalent conjugate vaccine for all children Pneumococcal polysaccharide
Pneumococcal
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disease
2 to 23 months of age; 1 dose of conjugate vaccine for vaccine for high-risk groups certain children 24 to 59 months of age. Polysaccharide vaccine in addition to conjugate vaccine for certain highrisk groups 2 to 18 years of age 4-dose series Most adults are immune; inactivated poliovirus vaccine may be indicated in select populations Not indicated
Poliomyelitis
Rotavirus Varicella Human papillomavirus
3-dose series beginning at 2 months of age and completed by 32 weeks of age
2 doses, one at 12 to 18 months of age and the second at 2 doses for susceptible persons 13 4 to 6 years of age years of age 3 doses for females 9 years through 26 years of age 3 doses for females through 26 years of age
INFECTIONS ASSOCIATED WITH ANIMALS Human interactions with animals may be beneficial components of an educational or developmental curriculum in group childcare. However, animal exposure has been associated with sporadic zoonotic infections as well as outbreaks, injuries, and allergies, most notably in children less than 5 years of age. The increased prevalence of infections in this age group is likely due to compromised hand hygiene resulting in transmission of pathogens from animal to child. Animal interaction may occur in locations where childcare is provided, with a resident pet or visiting animal display, or in public venues where children visit, including petting zoos, aquariums, county fairs, parks, carnivals, circuses, or farms. Guidelines to reduce opportunities for transmission and infection have been developed to prevent disease transmission in many of these settings. [152] Infections with enteric organisms pose the greatest risk for human disease from animals. A retrospective review of clinical and agricultural databases from 1966 through 2000 identified 11 published outbreaks of zoonotic disease associated with humananimal contact. A concomitant survey of state public health veterinarians revealed 16 additional outbreaks as well as a paucity of formal guidelines for the prevention of disease and injury from animal contact in the public setting. [153] A subsequent review of the years 1991 to 2005 yielded reports of more than 55 outbreaks of infectious diseases among visitors to public animal exhibits. [153a] The predominant infection was enteric, resulting from direct or indirect fecaloral contact. Inadequate hand hygiene, suboptimal supervision of children's activities following animal contact, and hand-to-mouth activities following animal contact were risk factors for infection. Humananimal contact on public farms with inadequate hand hygiene was responsible for two Escherichia coli O157:H7 outbreaks in 2000. The median age of the 51 ill persons in one of these outbreaks that occurred in Pennsylvania was 4 years; 8 (16%) children developed hemolyticuremic syndrome. Identical E. coli O157:H7 isolates were noted in case patients, farm animals, and the farm environment, [154] suggesting transmission of organisms to children resulting in clinical disease. During 2004 to 2005, three outbreaks of E. coli O157:H7 infections occurred among petting zoo visitors in North Carolina, Florida, and Arizona. A total of 173 cases, including 22 cases of hemolyticuremic syndrome, were reported from the three states; children who visited petting zoos were predominantly affected. Both direct and indirect animal contact, including exposure in a play area contaminated with petting zoo drainage, was associated with infections. Restriction of entry into open-interaction areas of petting zoos by young children was proposed to reduce disease transmission and prevent additional outbreaks. [155] Salmonella enteritica serotype Typhimurium, Cryptosporidium parvum, Campylobacter jejuni, Shiga toxinproducing E. coli (STEC), and Giardia have also been associated with infections with direct and indirect contact with zoo exhibits, farm day camps, and petting zoos. [152] In addition to enteric infections, animal exposure can result in transmission of ecto- and endoparasites, Mycobacterium tuberculosis in certain settings, and local or systemic infections as a consequence of bites, scratches, stings, and other injuries. Food products produced by farm animals as demonstrations should not be consumed by children unless the food has undergone appropriate pasteurization and sterilization. Contact with animals within the childcare environment should occur where controls are established to reduce the risk of injuries and disease. Guidelines to reduce disease associated with animal contact outside and within the childcare facility have been developed and include education of staff, operators, and visitors; specialized design of exhibits where humans and animals will interface; guide to hand hygiene instructions, agents, and stations; cleansing of facilities; and use of facilities for nonanimal events. Specific recommendations for group childcare settings include close supervision of children during animal contact, strict hand hygiene after direct animal contact or contact with animal products or environment, designation of areas for animal contact that are separate from areas in which food or drink are consumed, disinfection and cleaning of all animal areas with supervision of children over 5 years of age
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who may be participating in this task. Animals that visit or live in childcare facilities should be certified by veterinarians and should receive routine preventive health maintenance, including appropriate rabies immunization. Humananimal contact, especially for children less than 5 years of age, should always be supervised. Amphibians, reptiles, and weasels (ferrets and mink) should be housed in a cage and not handled by children. Wild or exotic animals, nonhuman primates, mammals with a high risk of transmitting rabies, wolfdog hybirds, aggressive wild or domestic animals, stray animals, venomous or toxin-producing spiders, and insects should not be permitted in the group childcare setting. [153] [158] ANTIBIOTIC USE AND RESISTANCE PATTERNS Several studies have demonstrated the more frequent use of antimicrobial agents in children in childcare centers. [157] During an 8-week period of observation of 270 children, antimicrobial agents were used by 36% of children in childcare centers compared with 7% and 8% of children in childcare homes or in home care, respectively (P < 0.001). The mean duration of antibiotic therapy prescribed for children in childcare centers (20 days) differed significantly (P < 0.001) from children in childcare homes (4 days) and children in home care (5 days). [108] The estimated annual rates of antibiotic treatment ranged from 2.4 to 3.6 times higher for children in group care when compared with children in home care. [157] Multiple studies have documented an association of childcare center attendance and colonization or infection due to resistant bacteria, including outbreaks of illness due to resistant Streptococcus pneumoniae [96] [98] [100] [101] [102] [107] and Shigella sonnei, [21] [160] as well as colonization due to resistant H. influenzae, [159] E. coli, [162] [163] and MRSA. [114] [115] INFECTIOUS DISEASES IN ADULTS Parents of children who attend a childcare facility and persons who provide care to these children have increased risk of acquiring infections such as CMV, [119] [122] [123] [124] [148] [161] parvovirus B19, [145] [146] HAV, [148] [164] and diarrhea. [33] [42] Childcare providers experience annual rates of CMV seroconversion ranging between 8 and 20%, compared with hospital employees who experience annual rates of seroconversion of 2%. [119] [122] [123] [124] During community outbreaks of erythema infectiosum, childcare providers were found to be among the most affected occupational groups, with seroconversion rates ranging from 9% to 31%. [145] [146] In a prevalence study of hepatitis A antibodies among childcare providers employed in 37 randomly selected childcare centers in Israel during 1997, 90% (402 of 446) of the childcare providers had antibodies to hepatitis A; the authors postulated a twofold risk of acquiring hepatitis A among providers. [162] During outbreaks of diarrhea in childcare centers, 40% of care providers developed diarrhea. [42] During a multicommunity outbreak of shigellosis, the overall median attack rate among employed staff of childcare centers was 6%, with a range of 0% to 17%. [33] In outbreaks of group A streptococcal infection and echovirus 30 infection [115] in childcare centers, adult providers and parents were affected. Childcare providers compared with nonproviders have a significantly higher annual risk of at least one infectious disease and lose more work days due to infectious diseases. [148] [165] Childcare providers should have all immunizations routinely recommended for adults, as shown on the adult immunization schedule (see Table 3-4 ) (www.cdc.gov/nip ). ECONOMIC IMPACT OF GROUP CHILDCARE ILLNESS The economic burden of illness associated with group childcare was estimated at $1.5 billion annually adjusted to 2005 United States dollars. [164] Precise mechanisms for estimating illness burden and for evaluating effectiveness of infection control interventions are rare due to multiple challenges associated with performing such assessments. [165] Attributing an outbreak to group childcare is challenging, because although these settings may promote transmission of infection, childcare attendees and staff interact with household contacts external to the childcare arrangement, thus facilitating secondary spread. For example, an economic assessment of an Escherichia coli O157:H7 outbreak in 1994 in rural Edinburgh, Scotland involved 71 persons with a median age range of 5 years and 7 months. In all cases children had consumed milk with increased coliform counts from a local dairy in the 2 weeks prior to illness onset. Although there was not a specific group childcare association to this outbreak, children of group childcare age were affected disproportionately. Investigating and containing the outbreak cost the community the equivalent of $296,660. [166] In the United States, hepatitis A infections in children less than 18 years of age were estimated to range between $433 and $1492 per case. Between 11% and 16% of hepatitis A infections have been linked to the group childcare setting, although this estimate did not require a strict epidemiologic link of a case patient to the group childcare setting. [167] However, since many hepatitis A infections in young children are asymptomatic, estimates of illness burden are primarily extrapolated from the fewer children who experience more significant complications from hepatitis A infections. In addition to economic analyses of vaccine-preventable infections, an economic analysis of a childcare-associated outbreak of Shigella sonnei in southwestern Ohio in 2001 incurred an overall cost of $821,725
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to contain the outbreak of over 1600 infections, which was the equivalent of $514 per culture-confirmed case. [168] A prospective evaluation of 208 families with at least one childcare enrollee, conducted from November 2000 to May 2001 in the Boston area, documented 2072 viral illnesses over 105,352 person-days. Among the 834 subjects, 1683 upper respiratory infections (URI) and 389 gastrointestinal (GI) illnesses were reported during the study period, with a total mean cost of $49 per URI and $56 per GI episode. Decreased parental productivity during missed days of work to care for a child who was not in childcare accounted for a significant proportion of the nonmedical costs. [164] Future investigations of outbreaks of illness associated with group childcare could utilize recently developed computerized models and paradigms to assess the economic impact of outbreaks. In an era of limited funding, an understanding of expenses and allocation of resources will be important information to justify utility of interventions. PREVENTION Specific standards should be established for personal hygiene, especially hand hygiene, maintenance of current immunization records of children and providers, exclusion policies, targeting frequently contaminated areas for environmental cleaning, and appropriate handling of food and medication. In studies in which improved infection control measures were implemented and monitored, both upper respiratory tract illness and diarrhea were reduced in intervention centers. [82] [171] In addition, in children at intervention centers, 24% fewer antibiotic prescriptions were given and fewer absences from work on the part of parents occurred. [83] Educational sessions on health topics by healthcare professionals was found to be the most efficacious means of promoting health education in simultaneous surveys of licensed childcare center directors, parents, and health providers in Boston, Massachusetts. [170] A crosssectional survey conducted in 2000 of childcare providers, parents, and pediatricians in Baltimore, Maryland revealed deficits of knowledge among all groups. Compared with national guidelines on exclusion for 12 symptoms, childcare providers and parents were overexclusive and pediatricians were underexclusive. More childcare providers and parents than pediatricians felt that exclusion would reduce transmission of disease. [171] As asymptomatic excretion and potential for transmission precede the onset of clinical symptoms in many childcareassociated infectious diseases, strategies that involve prevention would likely be most efficacious in reducing incidence. In addition to traditional handwashing, the use of alcohol-based hand-sanitizing hand gels in healthcare and other settings is an efficacious means of achieving hand hygiene. [171] In support of this preventive strategy, a cluster randomized, controlled trial was conducted in the homes of 292 families with children who were enrolled in out-of-home childcare centers. A multifactorial intervention emphasizing alcohol-based hand sanitizer use in the home reduced transmission of GI illnesses within families. The effect on reduction of respiratory tract illness transmission in this evaluation was less pronounced and may relate to the use of hand-sanitizing gel following toileting activities but not following sneezing, coughing, or blowing/wiping of nasal secretions. [172] Molecular techniques, including DNA probes, could be used as surrogate markers to study transmission of enteric pathogens in childcare centers and from centers to children's homes. [173] Further evaluations of molecular techniques during outbreak investigations, hand hygiene strategies, and educational interventions could assist with allocation of resources to the most effective prevention regimens. Written policies should be available, followed, and reviewed regularly for the following areas: managing child and employee illness, including exclusion policies; maintaining health, including immunizations; diaper-changing procedures; hand hygiene; personal hygiene policies for staff and children; environmental sanitation policies and procedures; handling, serving, and preparation of food; dissemination of information about illness; and handling of animals. Local health authorities should be notified about cases of communicable diseases involving children or care providers in the childcare setting. The AAP and the American Public Health Association jointly published the National Health and Safety Performance Standards: Guidelines for Out-of-Home Childcare Programs. [174] This comprehensive manual provides guidelines regarding infectious diseases and other health-related matters pertinent to out-of-home childcare. References 1. Overturf Johnson J. Who's Minding the Kids? Child Care Arrangements: Winter 2002. Current Population Reports, P70-101. Washington, DC, US Census Bureau, 2005. 2. Osterholm MT, Reves RR, Murph JR, et al: Infectious diseases and child day care. Pediatr Infect Dis J 1992; 11 (suppl):31. 3. Pickering LK, Morrow AL: Contagious diseases of child day care (editorial). Infection 1991; 19:61-63. 4. Carabin H, Gyorkos TW, Soto JC, et al: Estimation of direct and indirect costs because of common infections in toddlers attending day care centers. Pediatrics 1999; 103:556-564.
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147. Pickering LK, Reves RR: Occupational risks for child care providers and teachers. JAMA 1990; 15:1096-1097. 148. Clements DA, Moreira SP, Caplan PM, et al: Post-licensure study of varicella vaccine effectiveness in a day care setting. Pediatr Infect Dis J 1999; 18:1047-1050. 149. Centers for Disease Control and Prevention : Vaccination coverage among children enrolled in Head Start programs and licensed child care centers and entering school United States and selected reporting areas, 19992000 school year. MMWR 2001; 39:847-855. 150. Immunization Action Coalition. State mandates on immunization and vaccine- preventable disease. Available at www.immunize.org/laws , accessed February 26, 2006. 151. Feiken DR, Lezotte DC, Hamman RF, et al: Individual and community risks of measles and pertussis associated with personal exemptions to immunization. JAMA 2000; 284:3145-3150. 152. Centers for Disease Control and Prevention : Compendium of measures to prevent disease associated with animals in public settings, 2005. MMWR 2005; 54(RR-4):1-13. 153. Bender JB, Shulman SA, the Animals in Public Contact Subcommittee of the National Association of State Public Health Veternarians : Reports of zoonotic outbreaks associated with animal exhibits and availability of recommendations for preventing zoonotic disease transmission from animals to people in such settings. J Am Vet Med Assoc 2004; 224:1105-1109. 153a. Steinmuller N, Demma L, Bender JB, et al: Outbreaks of enteric disease associated with animal contact. Not just a foodborne problem anymore. Clin Infect Dis 2006; 43:1596-1602. 154. Crump JA, Sulka AC, Langer AJ, et al: An outbreak of Escherichia coli O157:H7 infections among visitors to a dairy farm. N Engl J Med 2002; 347:555-560. 155. Centers for Disease Control and Prevention : Outbreaks of Escherichia coli O157:H7 associated with petting zoos North Carolina, Florida, and Arizona, 2004 and 2005. MMWR 2005; 54:1277-1280. 156. Centers for Disease Control and Prevention : Healthy Pets, Healthy People. Available at http://www.cdc.gov/healthyoets/resources/websites.htm">www.cdc.gov/healthyoets/resources/websites.htm 157. Reves RR, Jones JA: Antibiotic use and resistance patterns in day care centers. Semin Pediatr Infect Dis 1990; 1:212-221. 158. Centers for Disease Control and Prevention : Multiply resistant shigellosis in a day care center in Texas. MMWR 1986; 35:753-755. 159. Scheifele DW, Fussell SJ: Ampicillin-resistant Haemophilus influenzae colonizing ambulatory children. Am J Dis Child 1981; 135:406-409. 160. Reves RR, Fong M, Pickering LK, et al: Risk factors for fecal colonization with trimethoprim and multiresistant Escherichia coli among children in day care centers in Houston. Antimicrob Agents Chemother 1990; 34:1429-1434. 161. Fornasini M, Reves RR, Murray BE, et al: Trimethoprim-resistant Escherichia coli in households of children attending day care centers. J Infect Dis 1992; 166:326. 162. Peled T, Ashkenazi S, Chodick G, et al: Risk of exposure to hepatitis A virus among day-care workers in Israel: implications for preventive measures. Arch Environ Health 2002; 57:332-336. 163. Reves RR, Pickering LK: Impact of childcare on infectious diseases in adults. Infect Dis Clin N Amer 1999; 6:239. 164. Bourgeois F, Goldman D, Ross-Degnan D, et al: The economic burden of daycare- associated illness. Presented at PAS 2006, E-PAS 2006; 59:2325.4. 165. Duff SB, Mafilios MS, Ackerman SJ: Economic evaluation of infection control practices in day care and the home: methodologic challenges and proposed solutions. Pediatr Infect Dis J 2000; 19:S125-S128.
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166. Roberts JA, Upon PA, Azene G: Escherichia coli O157:H7; and economic assessment of an outbreak. J Public Health Med 2000; 22:99-107. 167. Centers for Disease Control and Prevention : Prevention of hepatitis A through active or passive immunization. MMWR 1999; 48(RR-12):1-37. 168. Shane AL, Mintz ED, Painter JA. Cost-effective management strategies for multicommunity outbreaks of Shigellosis. Unpublished data, 2003. 169. Roberts L, Jorm L, Patel M, et al: Effect of infection control measures on the frequency of diarrheal episodes in child care: a randomized, controlled trial. Pediatrics 2000; 105:743-746. 170. Gupta RA, Shuman S, Taveras EM, et al: Opportunities for health promotion education in child care. Pediatrics 2005; 116:e499-e505. 171. Centers for Disease Control and Prevention : Guideline for hand hygiene in healthcare settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR 2002; 51(RR-16):1-45. 172. Sandora TJ, Taveras EM, Shih M-C, et al: A randomized, controlled trial of a multifaceted intervention including alcohol-based hand sanitizer and hand-hygiene education to reduce illness transmission in the home. Pediatrics 2005; 116:587-594. 173. Jiang X, Dai X, Goldblatt S, et al: Pathogen transmission in child care settings studied by using a cauliflower virus DNA as a surrogate marker. J Infect Dis 1998; 177:881-888. 174. American Academy of Pediatrics/American Public Health Association. Caring for Our Children. National Health and Safety Performance Standards: Guidelines for Out-of-Home Child Care Programs, 2nd ed. Available at http://nrc.uchsc.edu/CFOC/index.html .
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Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 4 Infectious Diseases in Refugee and Internationally Adopted Children Mary Allen Staat Each year thousands of immigrant children come to the United States to begin a new life. In this chapter, the infectious disease issues of two groups of immigrants will be discussed: refugees and internationally adopted children. Refugees are noncitizen immigrants who are unable or unwilling to return to their country of origin because of persecution or a fear of persecution. [1] In addition to refugees, there are other categories of noncitizen people in the United States. These noncitizens may be immigrants or nonimmigrants. Immigrants include refugees, licensed permanent residents, asylees, and parolees. Nonimmigrants include people who are undocumented, students, tourists, or visitors on business. Internationally adopted children are immigrants that are classified as orphans. Most of these children however are not truly orphaned, but instead have been abandoned by or separated from both parents. In most cases these children will be given United States citizenship as they arrive in the United States with their new families. In 2005, there were a total of 53 813 refugees who arrived in the United States. [1] Of these, 38% were < 18 years of age. Nearly 80% of these refugees came from just eight countries: Somalia (19%), Laos (16%), Cuba (12%), Russia (11%), Liberia (8%), the Ukraine (5%), the Sudan (4%), and Vietnam (4%). Refugees come to the United States from all around the world, with the exception of northern Europe, Australia, New Zealand, and Canada. [2] Over the past decade, international adoption has become an increasingly popular way to build families. More than
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175,000 children have been internationally adopted in the United States since 1996. [3] In 2005 alone, 22,728 children were adopted coming from more than 20 countries, with 83% of these children coming from just five countries: China (35%), Russia (20%), Guatemala (17%), Korea (7%) and the Ukraine (4%). [3] Although there has been little variation in the countries of origin over the past 10 years, in 1990, there were very few children arriving from the current top three countries of China, Russia, and Guatemala. [3] The majority of children are adopted as infants and toddlers. With the exception of Korea and Guatemala, where most children are in foster care, children from the other countries have generally resided in orphanages prior to coming to the United States. Because refugees and internationally adopted children come from resource-poor countries, physicians and other healthcare providers should be cognizant of the global prevalence of other infectious diseases that are seen less commonly in native-born North Americans. Both groups are at increased risk for common infectious diseases such as tuberculosis, intestinal parasites, dermatologic infections, and infestations. Hepatitis B, hepatitis C, human immunodeficiency virus (HIV), and syphilis, although seen in the United States, are far more prevalent in the countries of immigrants where there are few resources for screening and prevention. Although there are a number of similarities in refugees and internationally adopted children, there are also important differences. Refugee children and internationally adopted children differ in terms of the general medical screening they receive before arrival in the United States. Most refugees are subjected to organized screening evaluations before emigration visas are issued. [4] For children > 15 years of age, predeparture screening includes serologic testing for HIV and syphilis and a chest radiograph to assess for evidence of tuberculosis. A physical examination is performed on children of all ages. [4] In contrast, no organized screening procedure is required for internationally adopted children. Second, because medical screening for refugees usually is sponsored by responsible medical organizations, results of such testing are typically accurate. In internationally adopted children, medical testing is often incomplete or done shortly after birth. Generally, HIV and syphilis serology and hepatitis B surface antigen test results are provided with the referral information. Although the reliability of this testing has been a concern in the past, in recent years testing done in the child's country of origin has proven to be accurate when repeated in the United States. Third, preventive measures such as immunizations, vitamin supplementation, and dental care are undertaken in most refugee children while still in the camps; in adoptees, there are inconsistencies in the receipt of these measures. Last, differences in the types of infectious diseases may also distinguish refugees from adopted children. Although both populations are susceptible to a variety of infectious agents, because the countries of origin and the living conditions differ, refugee children are more likely to have been exposed to infections such as typhoid fever, malaria, filariasis, flukes, or schistosomiasis, which occur uncommonly in internationally adopted children. As these immigrants join our community, healthcare professionals will inevitably have the opportunity to provide care for these children and should therefore be knowledgeable of the infectious disease issues they may encounter and the need for screening for infectious diseases in these populations. GUIDELINES FOR EVALUATION Because of the predominance of infectious diseases in developing nations, recommendations for screening tests are weighted toward infectious disease processes, but aspects of general health, including vision, hearing, dental, and developmental examinations, also should be included. [5] [6] [7] Despite the healthy appearance of many immigrant children, children should be evaluated by a healthcare professional within 2 weeks after arrival to assure that they are screened properly and receive preventive healthcare services. Table 4-1 outlines the recommended infectious disease screening for refugees and internationally adopted children. TABLE 4-1 -- Recommended Tests for Refugee and Internationally Adopted Children Internationally Adopted Test Refugee Children Children Tuberculin skin test (TST) Hepatitis B Virus Serologic Testing Hepatitis B surface antigen (HBsAg) Hepatitis B surface antibody (anti-HBs) Hepatitis B core antibody (anti-HBc) Hepatitis C virus serologic testing Human immunodefiency virus 1 and 2 serologic testing Syphilis Serologic Testing Nontreponemal test (RPR, VDRL, or ART) 15 years of age All Some 15 years of age Some [a] All [a] All All All [a] All [a]
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Treponemal test (TPPA, MHA-TP, or FTA-ABS) Stool Examination
Not recommended
All
Microscopic evaluation for ova and parasites (3 specimens) All Giardia lamblia and Cryptosporidium antigen (1 specimen) Complete blood count Urinalysis All All All
All All All Not recommended
ART, automated reagin test; FTA-ABS, fluorescent treponemal antibody absorption; MHA-TP, microhemagglutination-Treponema pallidum; RPR, rapid plasma reagin; TPPA, Treponema pallidum particle agglutination; VDRL, Venereal Disease Research Laboratory.
a Consider reassessing 6 months after arrival.
Hepatitis A
Virtually all inhabitants of resource-poor countries have contracted hepatitis A by early adulthood and have immunoglobulin (Ig) G antibodies. In the past, screening for hepatitis A was recommended only in children with chronic hepatitis B infection to determine the need for hepatitis A immunization. Healthcare providers in some states where hepatitis A vaccine was recommended for routine use also may have been screened for hepatitis A. Now that hepatitis A vaccine is recommended for all children 12 months of age, [8] IgG antibody testing in children > 1 year of age may be useful for all immigrants to determine who should be immunized. Age- and country-specific prevalence data are needed for both internationally adopted and refugee children to develop cost-effective screening strategies. Testing will likely be most cost-effective in older children. Screening for IgM antibodies is only useful in the diagnosis of acute infection and therefore is not used routinely for screening. Infection with hepatitis A is anicteric in up to 90% of children < 6 years of age, 50% to 60% in older children and 20% to 30% in adults. [8] Symptoms such as vomiting and loss of appetite, when accompanied by fever and an enlarged, tender liver, should prompt evaluation for viral hepatitis in recently arrived immigrants or adoptees, even in the absence of jaundice. [8]
Hepatitis B
In contrast to hepatitis A testing, routine screening for hepatitis B virus infection is recommended for all refugees and internationally adopted children. [5] [6] [7] Early identification of hepatitis B infection is important so that appropriate management can be initiated and household contacts and caregivers can be vaccinated. The prevalence of hepatitis B infection is 2% to 7% in Asia, Africa, and Central and South America, in contrast to 0.5% in the United States. [9] In many published studies, refugee and internationally adopted children from these countries mirror these rates of infection and typically acquire the virus by vertical transmission, although bloodborne infection and horizontal transmission also have been implicated. [10] [11] [12] [13] [14] [15] [16] [17] [18] In international adoptees, rates were the highest in Romanian adoptees from the early 1990s, where 53% had evidence of past or present infection and 20% had active infection. [15] Studies consistently have shown a prevalence of 3% to 5%. [16] [17] [18] Hepatitis B screening tests, including the hepatitis B surface antigen (HBsAg) and antibodies to surface (anti-HBs) and core (anti-HBc) antigens, are recommended in the medical evaluation of internationally adopted children and refugees. [5] [6] [7] All three tests should be done to determine whether the child is immune due to immunization, recovered from infection, or has acute or chronic hepatitis B. Common patterns of hepatitis B serology profile are shown in Chapter 213 , Hepatitis B and Delta Virus. In a child who is found to be HBsAg-positive, repeat testing should be done 6 months later; if HBsAg persists for > 6 months, the child has chronic hepatitis B infection. If the child no longer has HBsAg and has developed anti-HBs, then the child had acute infection and has recovered and is no longer able to transmit the virus to others. Children with acute or chronic hepatitis B (positive HBsAg) can transmit hepatitis B to others. Children with acute or chronic hepatitis B should have additional testing done, including testing for HBeAg, HBeAb, and serum hepatic enzyme levels. HBsAg-positive children should be followed carefully by a hepatologist for management. In children with hepatitis B infection who are from countries in which delta hepatitis coexists with hepatitis B, such as in southern Italy, parts of Eastern Europe, South America, Africa, and the Middle East, testing for antibodies to the delta hepatitis virus could be done, but generally is not recommended because a positive test would not change clinical management. [5] In children who initially test negative, some experts recommend repeat testing for hepatitis B approximately 6 months after arrival to insure the child was not infected just prior to arrival to the United States. [5] Vaccination of household contacts of children with acute or chronic hepatitis B (HBsAg-positive) must occur promptly. Epidemiologic studies have demonstrated that up to 20% of unvaccinated household contacts become
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HBsAg-positive within > 5 years or more of exposure within the home [19] [20] and transmission of hepatitis B from newly adopted children to their parents has been documented. [19] [20] [21]
Hepatitis C
Until more is known regarding the incidence and prevalence of hepatitis C in refugee and internationally adopted children, screening for this virus is not recommended routinely. However, in both populations, if there is a history of specific risk factors such as current or former injection drug use, receipt of blood products, or residence in settings with a documented high prevalence of hepatitis C, then testing should be done. [22] These risk factors are difficult to ascertain in either group of children. In one study, the prevalence of hepatitis C antibody in internationally adopted children was shown to be < 1%. [18] Until additional data are available, it is recommended that children from China, Russia, Eastern Europe, and Southeast Asia should be screened for hepatitis C infection. [5] In addition, children from other countries should be screened if there is a history of receipt of blood products, maternal drug use, or a high prevalence of infection in the child's birth country. [5] Antibody testing is done initially and if the antibody is positive, polymerase chain reaction (PCR) is performed to confirm infection. Children found to have hepatitis C infection should be immunized for hepatitis A and B and should be referred to a hepatologist for further management.
Human Immunodeficiency Virus-1 and Human Immunodeficiency Virus-2 Infection
Refugees 15 years of age are tested routinely for HIV prior to coming to the United States. [4] Children < 15 years of age are not tested unless they are in a high-risk situation. Otherwise, for children not tested abroad, routine testing is not recommended for refugees unless indicated clinically. In contrast, most internationally adopted children have been tested for antibodies to HIV-1 by enzyme immunoassay (EIA) in their birth country and routine screening by EIA is recommended for all internationally adopted children upon arrival to the United States. [5] Reports of HIV infection in internationally adopted children are rare. In the early 1990s there were two case reports of Romanian adoptees with HIV infection. [23] In recent case series, there have been no reports of HIV infection in adoptees. [14] [17] [18] Positive or indeterminate results should be resolved with use of HIV DNA PCR to detect HIV-1 virus (see Chapter 111 , Diagnosis and Clinical Manifestations of HIV-1 Infection). If there is a clinical suspicion for HIV infection, HIV DNA PCR testing should be considered if the antibody testing by EIA is negative. Retesting > 6 months after arrival to the United States should be considered. Preadoptive testing for HIV-2 infection is not performed routinely. HIV-2 infection is prevalent in some African nations and is now recognized on several other continents; perinatal transmission appears to be limited. Symptoms suggestive of HIV infection with negative EIA results for HIV-1 should prompt testing for HIV-2.
Tuberculosis
Tuberculosis is highly prevalent in the countries of origin for both refugees and internationally adopted children and therefore screening upon arrival to the United States is recommended for both groups. [5] [6] [7] In 2003, 53% of all tuberculosis cases were among foreign-born people in the United States. [24] Even though the overall incidence of tuberculosis decreased in the United States from 1993 to 2003, there was no change in the incidence in foreign-born people. In a study examining trends in the epidemiology of tuberculosis disease in children in the United States, 22% of cases were foreign-born, with case rates of 12.2/100,000 in foreign-born compared with 1.1/100,000 in United States-born children. [25] Refugees 15 years of age and children < 15 years of age with concern about tuberculosis exposure or disease are screened with a chest radiograph prior to arriving in the United States. If the chest radiograph is abnormal, microscopic evaluation of sputum or gastric aspirate for acid-fast bacilli is performed. [4] Sputum-positive people are banned from entry until sputum smears are negative. Several studies in the past have found a high proportion of immigrants and refugees with latent tuberculosis infection (LTBI) in Minnesota (49%), [26] San Francisco (40%), [27] Buffalo (20%), [28] and Maine (35%). [29] A study in San Diego county found that 7% of immigrants screened had active pulmonary tuberculosis and 76% had LTBI. [30] In adoptees, screening in the country of origin is inconsistently done and generally is documented only in older children. After arrival, the proportion of internationally adopted children with LTBI appears to be lower than that seen in refugees. This is likely due to the younger age and lower risk of living conditions of internationally adopted children. LTBI is still prevalent in adoptees. In the most recent study in which all tuberculin skin tests were evaluated by a healthcare professional, 19% of international adoptees had LTBI, with the highest proportion in Russian and Eastern European adoptees (29%) and the lowest in Chinese adoptees (10%). [18] Tuberculosis disease in international adoptees is reported rarely. [31] [32] In the first series of Korean adoptees, although the overall prevalence was < 1%, the two children with tuberculosis disease had nonreactive skin tests. One child had pneumonia due to Mycobacterium tuberculosis and recovered. [31] The other child died from tuberculosis meningitis. [31] These cases illustrate the importance of considering tuberculosis in the differential diagnosis even with negative tuberculin
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skin tests. In the second case report, [32] an adoptee from the Marshall Islands with tuberculosis infected his female guardian and 20% of the contacts identified. Upon arrival in the United States, he had a TST done which was never read. It wasn't until his guardian developed tuberculosis that he was diagnosed with cavitary tuberculosis. For both refugees and internationally adopted children, screening for tuberculosis should be done at the initial assessment by placement of a tuberculin skin test (5 TU purified protein derivative). [5] [6] [7] [24] The test should be read 48 to 72 hours later by a healthcare professional. A reading of 10 mm of induration is considered positive for both refugees and internationally adopted children. A reading of 5 mm or more is considered positive if there is a known contact with a person with active tuberculosis, an abnormal chest radiograph finding, signs or symptoms suggestive of tuberculosis, or evidence of immunosuppression. Children with positive TST should have a thorough physical examination and chest radiograph performed to assess for M. tuberculosis disease. If the chest radiograph and physical examination are normal and the skin test is 10 mm, the diagnosis of LTBI is made and treatment with a 9-month course of isoniazid is begun. Similarly, a child with a 5 mm to 9 mm reaction who has known exposure to someone with active tuberculosis or who is receiving immunosuppressive therapy or has an immunosuppressive condition, including HIV, with no evidence of disease, should receive isoniazid therapy. Retesting of skin testnegative children 6 months after arrival should be considered, especially if there is concern that the child was malnourished or may have been exposed just prior to coming to the United States. While most refugees and internationally adopted children with M. tuberculosis infection have LTBI, disease should be considered in children with pneumonia or nonspecific symptoms such as fever, malaise, growth delay, weight loss, cough, night sweats, and chills. Pulmonary tuberculosis is the most common site of infection in children, accounting for 77% of cases, followed by lymphatic tuberculosis in 16% of children. [25] Chest radiographs may reveal adenopathy, segmental or lobar infiltrates, or pleural effusion. Cavitary lesions and miliary disease are less common. Extrapulmonary manifestations of the central nervous system, middle ear and mastoids, lymph nodes, bone, joints, and skin can be seen. Recovery of the responsible organism is paramount, because many children arrive from countries in which drug-resistant M. tuberculosis is common. Gastric aspirates or bronchoscopy, or both, can be useful adjuncts in a child too young or too ill to expectorate sputum. Initial management of tuberculous disease in refugees or internationally adopted children should include treatment with isoniazid, rifampin, pyrazinamide, and at least one other agent to ensure bactericidal coverage while culture results and susceptibility testing are pending (see Chapters 134 , Mycobacterium tuberculosis and 292 , Antimicrobial Agents). It is important to consider the most recent resistant patterns from the child's country of origin when making treatment decisions. Vaccination with Calmette-Gurin bacillus (BCG) is common in most resource-poor countries, but is not a contraindication to the placement of a tuberculin skin test. [5] Previous studies have demonstrated that placement of a tuberculin skin test after BCG vaccination fails to elicit induration of 10 mm or greater, and thus history of BCG does not affect the interpretation of purified protein derivative. [33] [34] BCG vaccination can be recognized by a 2- to 4-mm scarification, typically on the left deltoid. Occasional complications include enlargement of the regional lymph nodes or nodularity or ulceration at the vaccination site. The granuloma typically is located in the deltoid region and may or may not be draining. Culture of the drainage yields Mycobacterium bovis. There is no consensus regarding the management of this condition. Some lesions resolve without treatment, whereas other lesions require excision or treatment with isoniazid, erythromycin, or clarithromycin, or can be associated with regional or distant sites of infection. [35] [36]
Intestinal Pathogens and Enteric Infections
Intestinal parasites are common in both refugee and internationally adopted children but rates of infection vary by age and country of origin. Most children will not have had testing prior to coming to the United States. A wide variety of parasites, both pathogenic and nonpathogenic ( Table 4-2 ), can be seen in both groups of immigrants. However, refugees are more likely to have nematodes and trematodes compared with internationally adopted children. In internationally adopted children, the prevalence of intestinal parasites varies from 9% to 51%, depending on the age of the child and country of origin, with an increased risk in older children and children originating from countries other than Korea. [14] [15] [16] [17] [18] Giardia lamblia is the most commonly identified pathogen in all studies, with as many as 19% of children infected. [18] Helminthic infections are identified less frequently and include Hymenolepsis species, Ascaris lumbricoides, and Trichuris trichiura. [18] In contrast, in a study of refugees, 17% were found to have Giardia, and 19% had helminths, mainly hookworms. [37] TABLE 4-2 -- Pathogenic and Nonpathogenic Intestinal Parasites Parasite Type Pathogens Protozoa Giardia lamblia
Nonpathogens Endolimax nana
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Entamoeba histolytica Dientamoeba fragilis Balantidium coli Blastocystis hominis [a] Isospora belli Cryptosporidium parvum Cyclospora cayentensis Microsporidium species
Entamoeba coli Entamoeba gingivalis Entamoeba hartmanni Entamoeba polecki Iodamoeba butschlii Chilomastix mesnili Enteromonas hominis Retortamonas intestinalis Trichomonas hominis Trichomonas tenax
Helminths Nematodes (roundworms) Ascaris lumbricoides (roundworm) Trichuris trichiura (whipworm) Strongyloides stercoralis (threadworm) Enterobius vermicularis (pinworm) Necator americanus (hookworm) Ancyclostoma duodenale (hookworm) Cestodes (tapeworms) Hymenolepsis species Taenia saginata (beef tapeworm) Taenia solium (pork tapeworm) Schistosoma species
a Controversy exists regarding the pathogenicity of this organism.
Both refugees and adoptees should be screened for intestinal parasites upon arrival to the United States. [5] [6] [7] The diagnosis of most intestinal parasites is done by examination of stool preserved in formalin and polyvinyl alcohol or sodium-acetate formalin for ova and parasite testing. Testing multiple stool specimens increases the sensitivity of microscopic examination for ova and parasites. [38] [39] In one study, the sensitivity was 76% using one specimen and 92% in two specimens and a third specimen identified parasites in an additional 8% of children. [39] Examination by an experienced technologist is critical in identifying intestinal parasites. One stool specimen should also be evaluated for G. lamblia and Cryptosporidium parvum using antigen testing. [5] [6] [7] Repeat stool samples are essential to assess the effectiveness of treatment for the identified parasite or to determine the presence of new (or newly found) pathogens. If the child remains persistently symptomatic, additional stool sample examinations are warranted and testing for other parasites such as Cyclospora and Strongyloides stercoralis should be considered. In adoptees, screening for parasitosis with eosinophil counts is not indicated because most infections are due to protozoa (e.g., G. lamblia) and nonmigrating nematodes (pinworms) and therefore do not elicit peripheral blood eosinophilia. [7] However, in refugees, eosinophilia may be a useful screening tool since refugees are more likely to have migrating nematodes. In contrast to intestinal parasites, bacterial enteric pathogens appear to be less common in immigrants and adoptees; however, most studies have not assessed systematically for bacterial causes. Children with bloody diarrhea or diarrhea associated with high fever should have stool examined for bacterial enteropathogens (e.g., Salmonella, Shigella, Yersinia, Campylobacter) as part of the initial evaluation. [5]
Syphilis
Refugees 15 years of age routinely are screened for syphilis before resettlement. [4] Although refugees are not screened routinely upon arrival to the United States, refugees of any age should be tested if there is clinical suspicion for syphilis or there is evidence or concern for sexual exposure. Most internationally adopted children will have documentation of syphilis screening in their birth country. Serologic status for syphilis is determined accurately in many foreign countries; as a result, most children with positive tests are
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identified before emigration. Syphilis rarely has been reported in case series of adoptees. [14] [15] [16] [17] [18] Unfortunately, in those children with a history of syphilis, it is difficult to determine when the birth mother contracted syphilis and if she was treated and followed appropriately. In addition, in children with suspected syphilis exposure, details of the evaluation and prescribed treatment regimens are often incomplete or incorrect. Most frequently, documentation of treatment for congenital syphilis is insufficient, often only stating that penicillin has been given. For internationally adopted children, screening with both a nontreponemal test (rapid plasma reagin, Venereal Disease Research Laboratory, automated reagin test) and a treponemal test (microhemagglutinationTreponema pallidum, fluorescent treponemal antibody absorption, or Treponema pallidum particle agglutination) is recommended [5] (see Chapter 182 , Treponema pallidum (Syphilis)). A positive treponemal test result warrants a complete and thorough evaluation to document the extent of the disease and to insure adequate treatment.
Other Testing
A complete blood count is recommended for refugees and internationally adopted children. [5] [6] [7] The hemoglobin and red blood cell indices may identify children with anemia, iron deficiency, hemoglobinopathies, or malaria. Low white blood cell counts and lymphopenia may indicate HIV infection or malnutrition. Eosinophilia is common among refugees and suggests parasitic infection. [7] For refugees, a urinalysis is recommended to assess for hematuria and pyuria. Hematuria may indicate schistosomiasis and pyuria may reflect a urinary tract infection or renal tuberculosis. In refugees, routine screening for malaria is not recommended, but malaria should always be considered in children with fever who come from endemic areas. [7] Elevated blood lead levels have been reported in internationally adopted children. All international adoptees are recommended to have lead testing done as part of their initial evaluation. [40] Exposure is felt to be from leaded gasoline engine exhaust, ceramic ware, lead-based paint, and industrial waste. There is no formal recommendation for refugees; however, it is likely that they could benefit from this screening as well.
Other Common Infections Dermatologic Infections
Lice, scabies, and molluscum contagiosum are common in both refugees and internationally adopted children. The incidence of these conditions has not been well documented. The physical examination should include careful evaluation for these entities so that appropriate treatment is given (see Chapter 202 , Poxviridae (Molluscum Contagiosum)).
Upper Respiratory Tract Infections
Upper respiratory tract infections, including fever, coryza, and otitis media, occur in a large percentage of adopted children within the first month of arrival; one retrospective study placed their incidence at 40%. [41] Since the past history of otitis media is often unknown and since many children have language delays, referral to an otolaryn gologist for hearing test evaluation should be considered for children with otitis media and language delays. PREVENTIVE MEASURES
Immunizations
Making immunization recommendations can be a challenge for clinicians providing care for immigrant children. Most refugees arrive in the United States without immunization records whereas most international adoptees have some documentation of receipt of immunizations. The recommended approach for these two groups of immigrants differs. For refugees, if immunization documents exist, they should be reviewed and may be accepted as valid if the immunizations were provided at ages and intervals acceptable to United States standards. [42] A disease history is only acceptable as proof of immunity for varicella. Refugees who have no records or have incomplete immunizations should receive vaccines at their first visit. Guidelines for routine and catch-up immunizations should be followed. [5] [43] There are few data on verifying immunization status by antibody testing in refugees. In one study in refugees, screening for varicella was more cost-effective than providing immediate vaccine for individuals 5 years of age.
[44]
There have been several studies examining antibody testing to verify the immunization status of internationally adopted children. [45] [46] [47] [48] [49] Unfortunately, results of studies differ; some studies show inadequate protection whereas others show good protection. Differences in study design and laboratory methods likely account for the different results. With a lack of consensus, there currently are two acceptable approaches recommended to insure that internationally adopted children are protected against vaccine-preventable diseases. [5] [43] The first
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approach is to reinitiate immunizations regardless of documentation; the second approach is to use serologic testing to determine which immunizations are needed. Because antibody testing for one vaccine may not be predictive for others, a combination of reimmunization and antibody testing could be utilized. Serologic testing is available for most vaccine antigens ( Table 4-3 ). For children 5 months of age, testing for diphtheria and tetanus toxoid, polio, and hepatitis B antibodies can be done. Testing for measles, mumps, rubella, varicella, and hepatitis A should only be done in children 12 months of age because of the possible presence of maternal antibody. For varicella, testing can be done to verify whether the child had varicella disease since varicella immunization is not available in countries from which children are adopted. TABLE 4-3 -- Serologic Testing Available for Verifying Immunization Status Children 5 Months of Age Children 12 Months of Age Diphtheria IgG EIA Tetanus IgG EIA Hepatitis B surface antibody Diphtheria IgG EIA Tetanus IgG EIA Hepatitis B surface antibody Rubeola (measles) antibody Mumps antibody Rubella antibody Varicella antibody Hepatitis A antibody EIA, enzyme immunoassay; IgG, immunoglobulin G.
Poliovirus serotypes 13 neutralizing antibody Poliovirus serotypes 13 neutralizing antibody
Providing care for new immigrants can be rewarding. Application of directed screening tests upon arrival yields incalculable dividends for prevention and for the welfare of adoptees, refugees, and their families. References 1. Jefferys K. Refugees and asylees: 2005. Office of Immigration Statistics. Annual Flow Report, May 2005. Available online at:http://www.dhs.gov/immigrationstatistics. Accessed July 25, 2006. 2. Office of Refugee Resettlement. State letter #02-28. Table 6. Available online at:http://www.acf.hhs.gov/programs/orr/policy. Accessed July 25, 2006. 3. United States Department of State. Immigrant visas issued to orphans coming into the United States. Available Accessed July 11, 2006. online at:http://travel.state.gov/family/adoption/stats/stats_451.htm" 4. Centers for Disease Control and Prevention. Instructions to panel physicians for completing new US Department of State medical examination for immigrant or refugee application. Available online at:http://www.cdc.ov/ncidod/dq/technica.htm. Accessed July 25, 2006. 5. American Academy of Pediatrics. : Medical evaluation of internationally adopted children for infectious diseases. In: Pickering LK, Baker CJ, Long SS, et al ed. 2006 Red Book: Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village: IL, American Academy of Pediatrics; 2006:182-188. 6. American Academy of Pediatrics, Committee on Community Health Services. : Providing care for immigrant, homeless and migrant children. Pediatrics 2005; 115:1095-1100. 7. Barnett ED: Infectious disease screening for refugees resettled in the United States. Clin Infect Dis 2004; 39:833841. 8. Centers for Disease Control and Prevention. : Preventive of hepatitis A through active or passive immunization: recommendations of Advisory Committee of Immunization Practices (ACIP). MMWR 2006; 55(RR-7):1-23. 9. Centers for Disease Control and Prevention. Traveler's health: yellow book. health information for international travel, 20052006; hepatitis, viral, type b. Available online at: www2.ncid.cdc.gov/travel/yb/utils/ybGet.asp? section=dis&obj=hbv.htm&cssNar=browseoyb.
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10. Catanzaro A, Moser RJ: Health status of refugees from Vietnam, Laos, and Cambodia. JAMA 1982; 247:13031308. 11. Walker PF, Jaranson J: Refugee and immigrant health care. Med Clin North Am 1999; 83:1103-1120. 12. Lange WR, Warnock-Eckhart E: Selected infectious disease risks in international adoptees. Pediatr Infect Dis J 1987; 6:447-450. 13. Hershow RC, Hadler SC, Kane MA: Adoption of children from countries with endemic hepatitis B: transmission risks and medical issues. Pediatr Infect Dis J 1987; 6:431-437. 14. Hostetter MK, Iverson S, Thomas WE, et al: Prospective medical evaluation of internationally adopted children. N Engl J Med 1991; 325:479-485. 15. Johnson DE, Miller LC, Iverson S, et al: The health of children adopted from Romania. JAMA 1992; 268:34463451. 16. Albers LH, Johnson DE, Hostetter MK, et al: Health of children adopted from the former Soviet Union and Eastern Europe: comparison with preadoptive medical records. JAMA 1997; 278:922-924. 17. Miller LC: Hendrie NW: Health of children adopted from China. Pediatrics 2000; 105:e76. 18. Saiman L, Aronson J, Zhou J, et al: Prevalence of infectious diseases among internationally adopted children. Pediatrics 2001; 108:608-612. 19. Friede A, Harris JR, Kobayashi JM, et al: Transmission of hepatitis B virus from adopted Asian children to their American families. Am J Public Health 1988; 78:26-29. 20. Hershow RC, Hadler SC, Kane MA: Adoption of children from countries with endemic hepatitis B: transmission risks and medical issues. Pediatr Infect Dis J 1987; 6:431-437. 21. Sokal EM, Van Cullie O, Buts JP: Horizontal transmission of hepatitis B from children to adoptive parents [letter]. Arch Dis Child 1995; 72:191. 22. Centers for Disease Control and Prevention. : Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998; 47(RR-19):20-26. 23. Kurtz J: HIV infection and hepatitis B in adopted Romanian children [letter]. Br Med J 1991; 13:741-749. 24. Centers for Disease Control and Prevention. : Controlling tuberculosis in the United States: recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of American. MMWR 2005; 54(RR12):1-82. 25. Nelson LJ, Schneider E, Wells CD, et al: Epidemiology of childhood tuberculosis in the United States, 1993 2001; the need for continued vigilance. Pediatrics 2004; 114:333-341. 26. Lifson AR, Thai D, O'Fallon A, et al: Prevalence of tuberculosis, hepatitis B virus, and intestinal parasitic infections among refugees to Minnesota. Public Health Rep 2002; 117:69-77. 27. DeRiemer K, Chin DP, Schecter GF, et al: Tuberculosis among immigrants and refugees. Arch Intern Med 1998; 158:753-760. 28. Meropol SB: Health status of pediatric refugees in Buffalo, NY. Arch Pediatr Adolesc Med 1995; 149:887-892. 29. Hayes EB, Talbot SB, Matheson ES, et al: Health status of pediatric refugees in Portland, ME. Arch Pediatr Adolesc Med 1998; 152:564-568. 30. LoBue PH, Moser KS: Screening of immigrants and refugees for pulmonary tuberculosis in San Diego County, California. Chest 2004; 126:1777-1782. 31. Lange WR, Warnock-Eckhart E, Bean ME: Mycobacterium tuberculosis infection in foreign born adoptees. Pediatr Infect Dis J 1989; 8:625-629.
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32. Curtis AB, Ridzon R, Vogel R, et al: Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999; 341:1491-1495. 33. Lifschitz M: The value of the tuberculin skin test as a screening test for tuberculosis among BCG-vaccinated children. Pediatrics 1965; 36:624-627. 34. Santiago EM, Lawson E, Gillenwater K, et al: A prospective study of bacillus Calmette-Guerin scar formation and tuberculin skin test reactivity in infants in Lima, Peru. Pediatrics 2003; 112:298-302. 35. Torres-Rojas JR, Rondon-Lugo A, Vidal R: Short course of clarithromycin in an immunocompetent patient with BCG-induced regional complicatons. Dermatol On- line J 2002; 8:6.Available online Accessed Jul 25, 2006. at:http://dermatology.cdlib.org;DOJvol8num2/casereports/BCG/Torres.html. 36. FitzGerald JM: Management of adverse reactions to bacille Calmette-Guerin vaccine. Clin Infect Dis 2000; 31 (Suppl 3):S75-S76. 37. Benzeguir AK, Capraru T, Aust-Kettis A, et al: High frequency of gastrointestinal parasites in refugees and asylum seekers upon arrival in Sweden. Scand J Infect Dis 1999; 31:79-82. 38. Hiatt RA, Markell EK, Ng E: How many stool examinations are necessary to detect pathogenic intestinal protozoa?. Am J Trop Med Hyg 1995; 53:36-39. 39. Cartwright CP: Utility of multiple-stool-specimen ova and parasite examinations in a high-prevalence setting. J Clin Microbiol 1999; 37:2408-2411. 40. Centers for Disease Control and Prevention. : Elevated blood lead levels among internationally adopted children United States. MMWR 1998; 49:97-100. 41. Jenista JA, Chapman D: Medical problems of foreign-born adopted children. Am J Dis Child 1987; 141:298302. 42. American Academy of Pediatrics. : Immunization in special clinical circumstances: refugees and immigrants. In: Pickering LK, Baker CJ, Long SS, et al ed. 2006 Red Book: Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village: IL, American Academy of Pediatrics; 2006:96-98. 43. Kroger AT, Atkinson WL, Marcuse E, et al: General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physicians (AAFP). MMWR 2006; 55(RR-15):1-48. 44. Figueira M, Christiansen D, Barnett ED: Cost-effectiveness of sero-testing compared with universal immunization for varicella in refugee children from 6 geographic regions. J Travel Med 2003; 10:203-213. 45. Hostetter MK, Johnson DE: Immunization status of adoptees from China, Russia, and Eastern Europe [abstract]. Pediatr Res 1998; 43:147A. 46. Schulpen TW, van Seventer AH, Rumke HC, et al: Immunization status of children adopted from China [letter]. Lancet 2001; 358:2131-2132. 47. Miller LC, Comfort K, Kely N: Immunization status of internationally adopted children [letter]. Pediatrics 2001; 108:1050-1051. 48. Staat MA, Daniels D: Immunization verification in internationally adopted children [abstract]. Pediatr Res 2001; 49:468A. 49. Schulte JM, Maloney S, Aronson J, et al: Evaluating acceptability and completeness of overseas immunization record of internationally adopted children. Pediatrics 2002; 109:e22-e26. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
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Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 5 Bioterrorism Julia A. McMillan This chapter provides information concerning agents that might be used in a biological attack by groups or individuals with two objectives: causing illness and death, and inciting widespread fear and the public chaos that ensues. The illness that results from biological agents introduced through terrorism does not differ significantly from the signs and symptoms of naturally acquired infection with the same agent. Those clinical aspects of infection are discussed elsewhere in this text. Rather, it is the epidemiology of disease due to bioterrorism that warrants special attention. And, although it is appropriate to consider epidemiologic characteristics of biological terrorism in a pediatric infectious diseases textbook, many of those characteristics are also typical of illness brought on by acts of chemical terrorism. Airborne release and contamination of water or food are the most likely methods for initial dispersal of biological or chemical agents. Medical providers, public health agencies, and first responders (fire fighters, police, and emergency medical services) must be prepared to suspect disease due to acts of terrorism, whatever the causal agent. Infectious diseases that can be spread person to person, e.g., smallpox or salmonellosis, enhance the likelihood of widespread disease. BACKGROUND Infectious agents have been used as agents of terrorism for centuries. Plague-infested cadavers were used as weapons by the Tartars during the Middle Ages, and clothing contaminated by smallpox was used by Spaniards in their conquest of South American peoples. During the past century a variety of microbes were used as weapons, both as agents of war and by small groups whose goal was apparently to terrorize, rather than to kill. Clostridium botulinum and plague were employed by the Japanese and the Chinese, respectively, during World War II. In domestic attacks in the United States, followers of the Bhagwan Shree Rajneesh used Salmonella typhimurium to contaminate 10 restaurant salad bars in 1984, resulting in 751 cases of gastroenteritis, and Aum Shinrikyo followers in Tokyo are reported to have attempted bioterrorism using anthrax and botulinum toxin before their successful sarin gas attack on the Tokyo subway in 1995. During World War II the United States, as well as the United Kingdom, Canada, Japan, and the USSR had active bioweapons research programs involving many of the infectious agents that are now feared as possible weapons of terrorism, including Bacillus anthracis, Francisella tularensis, botulinum toxin, and staphylococcal enterotoxin. By 1969 international efforts at bioweapons disarmament had begun, and the United States had destroyed its offensive bioweapons arsenals by 1973. The Biological Weapons Convention (BWC), more formally known as The Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction, became effective in 1975 and is the first multilateral disarmament treaty involving bioweapons. Though 150 nations have signed and ratified this treaty, there is no established mechanism for monitoring compliance. Noncompliance on the part of at least one signatory nation, the USSR, was detected during investigation of the accidental release of B. anthracis spores from a Soviet military facility in Sverdlovsk, Russia, in 1979, which resulted in the death of 69 people. Public concern for the risk of bioterrorism in the United States was raised following the September, 2001 attacks on the World Trade Center and the Pentagon. These attacks were closely followed by covert terrorism employing the United States Postal Service for distribution of anthrax, resulting in 22 proven or suspected infections and 5 deaths. LIKELY AGENTS OF BIOTERRORISM Bioterrorism involves the intentional, malevolent use of disease-causing biological agent(s) to cause sickness, death, destruction, or panic. The harm caused by bioterrorism may involve human beings, animals, or agriculture, and its goal is political or social gain. Theoretically, there are many biological agents that could be used for these purposes. The United States Centers for Disease Control and Prevention (CDC) has identified and categorized the biological agents most likely to be used in an attack by terrorists ( Table 5-1 ). [1] Category A agents have been assigned the highest priority for defensive preparation because they can be easily disseminated from person to person, they have the potential to cause high mortality, public panic and social disruption, and they require special public health preparedness. The Category A agents include the organisms that cause anthrax (B. anthracis), smallpox, plague (Yersinia pestis), botulism (toxin of C. botulinum), and viral hemorrhagic fevers (Ebola, Marburg, Lassa, and others). Category B includes Coxiella burnetii (Q fever), Brucella species (brucellosis), Burkholderia mallei (glanders), alphaviruses (Venezuelan encephalomyelitis, eastern and western equine encephalomyelitis), ricin toxin (from Ricinus communis, found in castor beans), epsilon toxin (from Clostridium perfringens), and enterotoxin B from
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Staphylococcus, as well as food- and water-borne pathogens, including Salmonella species, Shigella dysenteriae, enterohemorrhagic Escherichia coli, Vibrio cholerae, and Cryptosporidium parvum. The category B agents are somewhat more difficult to disseminate and cause moderate morbidity and low mortality, but their identification requires enhanced diagnostic capacity and disease surveillance. Finally, emerging agents that could be engineered for mass dissemination and may be attractive as weapons because of their associated high morbidity, mortality, and potential public health impact are listed in category C. These include Nipah virus, hantavirus, tickborne hemorrhagic fever viruses, tickborne encephalitis viruses, yellow fever virus, and multidrug-resistant tuberculosis. TABLE 5-1 -- Categories of Potential Agents of Bioterrorism as Determined by the Centers for Disease Control and Prevention Category A Agents Category B Agents Category C Agents Bacillus anthracis (anthrax) Smallpox Yersinia pestis (plague) Francisella tularensis (tuleremia) Clostridium botulinum toxin (botulism) Viral hemorrhagic fevers (Ebola, Marburg, Lassa, others) Coxiella burnetii (Q fever) Brucella species (brucellosis) Burkholderia mallei (glanders) Alphaviruses (including Venezuelan encephalomyelitis, eastern and western equine encephalomyelitis) Ricinus communis toxin (ricin) (from castor beans) Clostridium perfringens epsilon toxin Staphylococcus enterotoxin B Salmonella species Shigella dysenteriae Enterohemorrhagic Escherichia coli Vibrio cholerae Cryptosporidium parvum EPIDEMIOLOGY OF DISEASE CAUSED BY TERRORISM In some instances a single case of recognizable illness should alert the clinician that terrorism is likely. For instance, if a single case of smallpox, a disease that was declared to have been eradicated in 1980, were suspected anywhere in the world, terrorism would be the likely explanation. Similarly, a diagnosis of plague made in the northeastern part of the United States should raise concern for terrorism. Disease presenting in unusual numbers, in an age group that is uncharacteristic for a given pathogen, in a more severe form than usually expected, or among individuals with a common opportunity for exposure, e.g., who attended the same function, should provoke suspicion for terrorism. A more complete list of epidemiologic clues that should suggest bioterrorism is provided in Box 5-1 . BOX 5-1 Epidemiologic Clues That Should Suggest Bioterrorism Single case of disease caused by an uncommon agent Unusual illness in a particular age group Disease with an unusual geographic or seasonal distribution Large number of ill persons with similar disease or syndrome Unusual route of exposure for a particular pathogen, e.g., inhalational anthrax Disease usually transmitted by a vector not found in the region, e.g., plague in an individual who lives in the northeastern United States Higher morbidity and mortality than expected with a common disease or syndrome Failure of a common disease to respond to usual therapy Multiple unusual or unexplained disease entities coexisting in the same patient without other explanation Nipah virus Hantavirus Tickborne hemorrhagic fever viruses Tickborne encephalitis viruses Yellow fever virus Multidrug-resistant Mycobacterium tuberculosis
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Multiple atypical presentations of disease agents Similar genetic type, organism variant, or antimicrobial pattern among agents isolated from temporally or spatially distinct sources Unusual, atypical, genetically engineered, or antiquated strain of agent Endemic disease with unexplained increase in incidence Simultaneous clusters of similar illness in noncontiguous areas, domestic or foreign Atypical aerosol, food, or water transmission Ill people presenting near the same time Death or illness among animals that precedes or accompanies illness or death in humans No illness in people not exposed to common ventilation systems, but illness among those people in proximity to the systems
Adapted from Buehler JW, Berkelman RL, Hartley DM, et al. Syndromic surveillance and bioterrorism-related epidemics. Emerg Infect Dis 2003 October. Available from URL: http://www.cdc.gov/ncidod/EID/vol9no10/030231.htm . [1] CHILDREN AND BIOTERRORISM There is scant historical evidence on which to base predictions regarding particular risks of infants and children in the face of a biological attack, but there are some physiological and behavioral characteristics of children that suggest their disproportionate vulnerability [2] ( Box 5-2 ). The respiratory rate of children is more rapid than that of adults, their intake of air on a per-weight basis is greater, and their skin is more permeable. These characteristics may allow enhanced absorption of toxins. The higher skin-to-mass ratio and reduced fluid reserves of children increase their susceptibility to the dehydrating effects of gastrointestinal losses. The immaturity of the immune system in infants and children may enhance their susceptibility to severe disease if infected with some microbes or toxins. Children may be less physically able to escape a biological threat, and their dependence upon adult caretakers, who may suffer illness or death or be quarantined, could allow them to become secondary victims, even if they were not directly affected by infection or intoxication. In addition, facilities, equipment, pharmaceutical products, and training of emergency response personnel designed to accommodate the needs of infants and children are often not readily available. Finally, children are less able and less likely to verbalize the postevent distress they may feel after witnessing or being a victim of an act of terrorism. BOX 5-2 Physiological and Behavioral Vulnerabilities of Infants and Children in the Face of a Bioterrorist Attack Increased inhalation of air per weight Increased skin permeability Higher skin-to-mass ratio and reduced fluid reserve, leading to greater susceptibility to dehydration Immature immune system Dependence on adult caretakers who may become ill, die, or be quarantined Inability to verbalize exposure or symptoms Lack of availability of equipment, expertise, medications, and personnel appropriate for infants and children Inability to express postevent anxiety and distress
Adapted from American Academy of Pediatrics Committee on Environmental Health and Committee on Infectious Diseases. Chemical-biological terrorism and its impact on children. Pediatrics 2006;118:1267-1278. [2] RECOGNITION OF DISEASE DUE TO BIOTERRORISM Recognition of a bioterrorist event depends upon both system-wide detection of increased numbers of patients presenting with similar manifestations of illness, and upon individual clinicians who are knowledgeable about the signs and symptoms produced by agents likely to be used in such an event. Development of systems to enhance detection of outbreaks, termed syndromic surveillance, has been emphasized as an important component of the national effort to recognize public health emergencies, whether due to terrorism or to naturally occurring disease.
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Automated syndromic surveillance mechanisms are now being used in some parts of the country. Equally important is the role of the astute clinician who recognizes that something about the presentation of an individual patient suggests disease potentially caused by intentional exposure to an agent of bioterrorism. Table 5-2 lists the likely manifestations of illness following exposure to the agents identified by the CDC as likely weapons of bioterrorism. Because of the similarity of these signs and symptoms to those associated with common community-acquired illnesses, and because many of the agents anticipated to be used by terrorists are also causes of community-acquired infection, recognition that an individual patient has been exposed to an agent of biological terrorism early in the course of the illness is unlikely. More pathognomonic findings associated with likely agents of bioterrorism may become apparent later in the course. Those findings that are more likely to raise suspicion for a specific agent are listed in Table 5-3 . TABLE 5-2 -- Clinical Manifestations Associated with Likely Agents of Bioterrorism Clinical Manifestations Agents/Disease Respiratory Symptoms Influenza-like illness with or without atypical pneumonia and cough Purulent conjunctivitis with preauricular or cervical lymphadenopathy Exudative pharyngitis and cervical lymphadenopathy Dermatologic Disease Vesicular rash Smallpox Painless ulceration progressing to Cutaneous anthrax black eschar Ulcer plus painful regional lymphadenopathy Petechiae Shock Hematologic Disease Thrombocytopenia Neutropenia Hemorrhage Disseminated intravascular coagulation Neurologic Findings Flaccid paralysis Encephalitis Meningitis Gastrointestinal Disease Diarrhea Vomiting, abdominal pain, gastrointestinal bleeding Renal Disease Hemolyticuremic syndrome, thrombotic thrombocytopenic purpura Renal failure Escherichia coli O157:H7 Salmonella spp., Shigella dysenteriae, Escherichia coli O15:H7, Vibrio cholerae, Cryptosporidium parvum Gastrointestinal anthrax Botulism Alphavirus (Venezuelan, eastern, and western encephalitis) Inhalational anthrax, septicemic and pneumonic plague, alphavirus (Venezuelan, eastern, and western encephalitis) Brucellosis, viral hemorrhagic fever, hantavirus Viral hemorrhagic fever, alphavirus (Venezuelan, eastern, and western encephalitis) Viral hemorrhagic fever Viral hemorrhagic fever Ulceroglandular tularemia Viral hemorrhagic fever Inhalational anthrax, ricin, viral hemorrhagic fever Tularemia, brucellosis, Q fever, alphavirus (Venezuelan, eastern, and western encephalitis), inhalational anthrax, pneumonic plague, inhalational tularemia, ricin, aerosol exposure to staphylococcal enterotoxin B, hantavirus Oculoglandular tularemia
Oropharyngeal tularemia
Viral hemorrhagic fever, hantavirus
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Painful lymphadenopathy Bubonic plague Adapted from American Academy of Pediatrics. Recommendations for care of children in special circumstances: biological terrorism. In: Pickering LK (ed) Red Book: 2006 Report of the Committee on Infectious Diseases, 26th ed. Elk Grove Village, IL, American Academy of Pediatrics; 2003:100101.
TABLE 5-3 -- Distinctive Findings Associated with Some Likely Agents of Bioterrorism Biological Agent Pathognomonic (Classical) Findings Inhalational anthrax Hemoptysis, with chest radiograph demonstrating widened mediastinum Cutaneous anthrax Botulism Vesicular lesion that develops into necrotic ulceration with black eschar Descending flaccid paralysis that begins with dysphagia, dysarthria, diplopia, dysphonia, and ptosis
Plague, inhalational Fever, cough, hemoptysis, chest pain, with chest radiograph showing bronchopneumonia exposure Plague, cutaneous exposure Q fever Smallpox Swollen regional lymph nodes Fever, chills, headache, weakness, and sweating with elevated serum hepatic enzyme levels Fever, headache, backache, abdominal pain, malaise, followed by a rash that begins on the face and progresses in a centrifugal fashion to involve extremities and then trunk. The lesions evolve from papules to firm vesicles, and then deep-seated, hard pustules Abrupt onset of nausea, abdominal cramps, vomiting, and prostration, often accompanied by diarrhea Nonproductive cough, retrosternal chest pain, dyspnea, and fever, usually without evidence of pulmonary involvement on chest radiograph
Staphyloccal enterotoxin, ingestion Staphyloccal enterotoxin, inhalation
Tularemia, Systemic illness, with painful regional lymphadenopathy, with or without cutaneous ulcers cutaneous exposure Tularemia, ocular exposure Ricin, ingestion Ricin, inhalation Ricin, injection Purulent conjunctivitis, with chemosis, periorbital edema, and conjunctival nodules or ulceration, and accompanying preauricular or cervical lymphadenopathy Vomiting, hemorrhagic gastroenteritis, shock, and cardiovascular collapse Respiratory distress, with necrotizing pneumonitis Rapid onset of shock and cardiovascular collapse
Viral hemorrhagic Fever, myalgia, prostration, petechiae, progressing to shock, mucous membrane hemorrhage, fevers with or without renal involvement Adapted from American Academy of Pediatrics. Recommendations for care of children in special circumstances: biological terrorism. In: Pickering LK (ed) Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006:107111. DIAGNOSIS AND MANAGEMENT OF SUSPECTED BIOTERRORISM EVENT Accurate diagnosis is important in the management of any infectious disease; if bioterrorism is suspected, identification and isolation of the causative organism are critical to further investigation and to subsequent public health efforts. Collection of appropriate diagnostic specimens, prior to treatment with antimicrobial agents if possible, will allow targeted treatment, appropriate preventive measures for contacts, effective infection control, and a more rapid and effective public health effort. Table 5-4 lists recommended microbiologic diagnostic procedures, treatment options, postexposure prophylaxis recommendations, and appropriate isolation precautions for the CDC's list of likely agents of bioterrorism. [3] If bioterrorism is suspected, however, affected patients should be isolated using contact precautions and airborne infection isolation, as well as standard precautions, until test results are available and transmissibility of the illness can be determined. TABLE 5-4 -- Biological Weapons: Recommended Diagnostic Procedures, Isolation, and Treatment of Children
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Agent Alphaviruses (Venezuelan encephalomyelitis, eastern and western equine encephalitis)
Diagnostic Sample(s)
Treatment Options
Prophylaxis
[a]
Isolation Precautions Comments
CSF for virus Supportive isolation and antibody testing; acute and convalescent serum for antibody testing Gram stain of buffy coat, CSF, pleural fluid, swab of skin lesion; culture of blood, CSF, pleural fluid, skin biopsy Ciprofloxacin [b] or doxycycline [c] ; combine with 1 or 2 additional antimicrobial agents for inhalational, gastrointestinal, or oropharyngeal disease [d] Supportive care; mechanical ventilation and parenteral nutrition may be required. Equine botulism antitoxin given as soon as possible (CDC) [f]
Protection Standard; from mosquito respiratory precautions vectors for western equine encephalitis virus Ciprofloxacin Standard; or contact for doxycycline skin lesions [c] or amoxicillin [e] ; anthrax vaccine Additional antimicrobial agents to be used for inhalational, gastrointestinal, or oropharyngeal disease include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin Type-specific antitoxin should be administered when possible; antitoxin prevents additional nerve damage but does not reverse existing paralysis
Anthrax
Botulism
Serum, stool, enema fluid, gastric fluid or vomitus, suspected food samples for toxin detection; culture of stool or gastric secretions; nerve conduction testing Culture of blood or bone marrow; acute and convalescent serum for antibody testing Culture or FA staining of blood, sputum, lymph node aspirate [g]
Standard
Brucellosis
Doxycycline [c] and Doxycycline rifampin; if < 8 [c] and years use rifampin trimethoprimsulfamethoxazole (TMP-SMX) Streptomycin or gentamicin; doxycycline [c] or tetracycline [c]
Standard; contact for draining skin lesions
TMP-SMX; TMP-SMX may substitute for rifampin with doxycycline
Plague
Doxycycline Droplet [c] ; tetracycline [c]
TMP-SMX is alternative to chloramphenicol for meningitis
Q fever
Acute and Doxycycline [c] or convalescent tetracycline [c] serum for antibody testing Serum and/or respiratory secretions for EIA detection Swab of pharyngeal secretions or skin lesions. to be sent to the CDC for
Doxycycline Standard [c] or tetracycline [c] Standard
Chloramphenicol is an alternative for treatment/prophylaxis
Ricin
Supportive care; Protective gastric lavage and mask cathartics if toxin is ingested Supportive care Vaccine if administered within 4 days
Smallpox
Airborne, contact
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isolation of virus [g] Staphylococcal enterotoxin B Serum, urine, Supportive care and respiratory secretions for toxin testing; acute and convalescent serum for antibody testing Gastric aspirate, Gentamicin sputum, pharyngeal exudates, conjunctival exudates, lymph node aspirate, swab from ulcer, and blood for culture [g] , direct fluorescent antibody staining, and PCR testing. Blood for antibody testing None available Standard
Tularemia
Doxycycline
[c]
Standard
Doxycycline [c] , ciprofloxacin [b] , and chloramphenicol are alternatives for treatment
Culture and/or IV ribavirin for Standard, antigen Lassa fever; plasma droplet, and detection of from convalescent contact [i] blood and other patients for body tissues [h] ; Argentine serum for acute hemorrhagic fever; and supportive care convalescent antibody testing Adapted from American Academy of Pediatrics. Recommendations for care of children in special circumstances: biological terrorism. In: Pickering LK (ed). Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006:107111. CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FA, fluorescent antibody; IV, intravenous; PCR, polymerase chain reaction.
a Prophylaxis should only be administered after consultation with public health officials in situations in which exposure is highl y likely. The duration of prophylaxis
has not been determined for most agents.
Viral hemorrhagic fevers
b If susceptibility testing is unknown or indicates resistance to other agents. Ciprofloxacin is licensed by the United States Food and Drug Administration (FDA) for
use in people younger than 18 years of age for treatment of or prophylaxis against anthrax, but it is not licensed for those younger than 18 years for treatment of tularemia. Treatment with ciprofloxacin is warranted for those less than 18 years for selected serious infections.
c Tetracyclines, including doxycycline, are not FDA-approved and are usually contraindicated for children younger than 8 years of age, but treatment is warranted
for selected serious infections.
d Treatment should initially be administered parenterally but may be changed to oral therapy for cutaneous infection without dissemination. e Amoxicillin may only be used as prophylaxis if the organism is known to be susceptible. f Botulism antitoxin must be obtained from the Centers for Disease Control and Prevention Drug Service, 404/639-3670 (weekdays, 84:30) or 404/639-2888
(weekends, nights, holidays).
g The microbiology laboratory should be notified of suspected pathogen so that appropriate safety precautions can be undertaken. h Isolation should only be attempted under biosafety level-4 conditions. i
Because of the risk of nosocomial transmission the state health department and the Centers for Disease Control and Prevention should be contacted for specific advice about management and diagnosis of suspected cases.
NOTIFICATION OF PUBLIC HEALTH AUTHORITIES
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Local public health authorities should be notified as soon as an illness associated with terrorism is suspected. Local authorities may initiate investigation, but they also will likely involve the state agency and the CDC. State health department and state epidemiologists are listed on the websites provided below. References 1. Buehler JW, Berkelman RL, Hartley DM, et al., Syndromic surveillance and bioterrorism-related epidemics. Emerg Infect Dis 2003 October. Available from URL:http://www.cdc.gov/ncidod/EID/vol9no10/03-0231.htm. 2. American Academy of Pediatrics Committee on Environmental Health and Committee on Infectious Diseases. : Chemical-biological terrorism and its impact on children. Pediatrics 2006; 118:1267-1278. 3. American Academy of Pediatrics. : Recommendations for care of children in special circumstances: biological terrorism. In: Pickering LK, ed. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village, IL: American Academy of Pediatrics; 2006:105-111. 4. Arnon SS, Schechter R, Inglesby TV, et al: Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001; 285:1059-1070. 5. Borio L, Inglesby T, Peters CJ, et al: Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA 2002; 287:2391-2405. 6. Dennis DT, Inglesby TV, Henderson DA, et al: Tularemia as a biological weapon: medical and public health management. JAMA 2001; 285:2763-2773. 7. Franz DR, Jahrling PB, Friedlander AM, et al: Clinical recognition and management of patients exposed to biological warfare agents. JAMA 1997; 278:399-411. 8. Henderson DA, Inglesby TV, Bartlett JG, et al: Smallpox as a biological weapon: medical and public health management. JAMA 1999; 281:2127-2137. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier Section B Prevention of Infectious Diseases
CHAPTER 6 Passive Immunization David C. Goldman Passive immunization provides individuals with preformed antibodies that can prevent or treat infectious diseases. Over a century ago, hyperimmune animal sera were produced to treat specific infections. After human plasma fractionation was developed (during World War II), immune globulin (human) (IG) became available for passive immunization. Although this was an enormous breakthrough, intravenous (IV) infusion of the product was found to evoke a variety of severe adverse reactions. Therefore, this route of administration was precluded, and IG was largely limited to intramuscular (IM) injection. For some indications, this was not a disadvantage. However, for treatment of primary immunodeficiency, it became clear that the volume (and hence the amount of immunoglobulin G (IgG)) that could be administered was suboptimal. In 1981, the first (United States-licensed) (human) IGIV was approved by the Food and Drug Administration. It dramatically changed immunoglobulin therapy. Using IGIV enabled clinicians to give large doses of IgG with minimal discomfort and to produce an immediate rise in both total plasma IgG and titers of specific antibodies.
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The products available for passive immunization can be grouped as follows: (1) IG; (2) specific IGs for IM use; (3) IGIV; and (4) specific IGs for IV administration ( Table 6-1 ). In addition, two antitoxins of animal origin are still available for limited distribution, and there is now a licensed humanized monoclonal antibody. Passive immunization can be used for a variety of clinical indications, including: (1) treatment of primary and, in certain cases, secondary immunodeficiency or its sequelae; and (2) prophylaxis against infections due to specific organisms. In general, treatment of established infections has been less successful, even when the specific organism or toxin can be identified. However, the use of IGIV for the treatment of various conditions that involve immune dysregulation, such as immune thrombocytopenic purpura (ITP) and Kawasaki disease, has become routine and has stimulated much investigation of immunomodulation. In the following sections, the various products and their uses are discussed. An effort has been made to use nonproprietary product names exactly as they appear in the labeling, but for brevity, there is liberal use of abbreviations. Emphasis is placed on the approved indications (i.e., those that appear in the product package inserts). In the case of IGIV, not all products have been approved or studied for all indications ( Table 6-2 ). Moreover, in contrast to IGs for IM administration, IGIV products undergo a variety of manufacturing processes, utilize a number of different stabilizers and excipients, are formulated in various concentrations or physical states, and may differ in subtle ways (e.g., IgA content). Compounding this variety is the fact that licensed manufacturers are constantly studying process changes in order to improve the products, and additional manufacturers have products undergoing clinical trials in the hope of bringing them to market. The clinician should always consult the current package insert for the specific IGIV product being used in addition to more general sources of information. TABLE 6-1 -- Immune Globulins Prepared from Human Plasma Nonproprietary Name Abbreviation For Intramuscular Administration Immune globulin (human) Hepatitis B immune globulin (human) Rabies immune globulin (human) [a] Tetanus immune globulin (human) Varicella-zoster immune globulin (human) [b] For Intravenous Administration Immune globulin intravenous (human) Botulism immune globulin intravenous (human) Vaccinia immune globulin intravenous (human)
a
As much of the dose as possible should be instilled around the wound.
IG HBIG RIG TIG VZIG/VariZIG IGIV BIG-IGIV VIG-IGIV
Cytomegalovirus immune globulin intravenous (human) CMV-IGIV
b See text.
TABLE 6-2 -- Available Immune Globulin Intravenous Products in the United States Product Registered Name Manufacturer FDA-Approved Indication Carimune NF Vivaglobulin Gammar-P IV Flebogamma (previously Venoglobulin-S) Gammagard Liquid Gammagard S/D (powder: phasing out) Iveegam EN Gamunex Octagam ZLB Behring ZLB Behring (subcutaneous) ZLB Behring Griflos USA Baxter Baxter Baxter Talecris Biotherapeutics (previously Bayer) Octapharma USA ITP, PID PID PID PID PID CLL, ITP, KD, PID KD, PID ITP, PID PID
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WinRho SDF
Baxter
Chronic or acute ITP and HIV-immune related conditions
CLL, chronic lymphocytic leukemia; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; ITP, immune thrombocytopenia purpura; KD, Kawasaki disease; PID, primary immunodeficiency.
IMMUNE GLOBULIN (HUMAN) IG is prepared by cold alcohol fractionation of pooled human plasma. It is formulated as a 16.5% protein solution. At least 96% of the total protein is IgG; small quantities of IgM and IgA are present. Each lot of product must represent the pooled plasma of at least 1000 donors so as to provide a wide diversity of antibodies. In practice, however, each lot represents many more donors (up to 60,000). Individual donations of the plasma, like those used as the source for all human plasma derivatives, are screened for markers of a variety of viruses (hepatitis B, hepatitis C, human immunodeficiency) to minimize the potential for transmission of infections. Other steps taken to minimize such transmission are noted at the end of this chapter. A major use of IG is for postexposure prophylaxis of hepatitis A. When injected deep into a large muscle mass within 14 days of exposure, IG can prevent symptomatic infection. The usual dose is 0.02 mL/kg, given as soon as possible after exposure. If re-exposure is likely and the patient is at least 2 years old, hepatitis A vaccine should be administered concomitantly, in a separate site with a separate syringe. IG is also effective for pre-exposure prophylaxis of hepatitis A in travelers to areas where hepatitis A is prevalent. However, for travelers who are at least 1 year old and whose departure is not imminent, hepatitis A vaccine has largely replaced IG. If IG is to be used, the dose depends on the circumstances. For a child younger than 1 year, the dose is 0.02 mL/kg if the anticipated stay is 3 months or less and 0.06 mL/kg if it is longer. In older persons whose departure is imminent, the dose of IG is 0.02 mL/kg, concomitant with the vaccine, for a stay of up to 5 months; and 0.06 mL/kg, concomitant with vaccine, for a longer stay. As in the case of postexposure prophylaxis, if IG and hepatitis A vaccine are given simultaneously, separate sites and separate syringes should be used. Vaccination is, by far, the major strategy for achieving protection against measles. It is highly effective. Nonetheless, prophylaxis for measles remains an important indication for IG in children younger than 1 year, in older children who have not been vaccinated, and in immunocompromised children who are not receiving routine immunoglobulin replacement therapy. Prophylaxis is indicated for susceptible household or hospital contacts. A single dose of 0.25 mL/kg given as soon as possible (and within 6 days) after exposure in high-risk, susceptible individuals prevents or modifies infection. Immunocompromised children should receive 0.50 mL/kg. (In either case, no more than 15 mL should be injected, and small children should be given no more than 3 mL in any single site.) A child who is receiving routine IgG replacement therapy is already protected, and no further dosage is indicated. Once an appropriate period has elapsed, every immunocompetent child who is at least 1 year old should be vaccinated. SPECIFIC IMMUNE GLOBULINS Specific IGs for IM use are IgG preparations produced from plasma that is selected by screening donations or collected from donors who have been deliberately immunized or given immune booster therapy. Either approach can ensure the presence of high levels of antibody directed against one or more specific antigens. The manufacturing process is essentially the same as that used to prepare IG. The protein concentration differs for individual products; it can be found in the Description section of the package insert. Specific products available for IM administration are listed in Table 6-1 . They are used to prevent hepatitis B, rabies, tetanus, and varicella-zoster.
Hepatitis B Immune Globulin
Used in conjunction with hepatitis B vaccine, hepatitis B IG (human) (HBIG) has proved to be very effective in preventing disease and subsequent chronic infection in infants of mothers who are chronic carriers of hepatitis B virus (HBV). All pregnant women should be tested for circulating hepatitis B surface antigen (HBsAg). If the mother is positive for HBsAg, the infant should receive 0.5 mL of HBIG as soon as possible after birth. Active immunization with the vaccine should begin at once (with the use of a separate site and a separate syringe), and subsequent doses of vaccine should be given according to the recommended schedule. In general, HBIG is not recommended if the mother's HBsAg status is not known, but the vaccination series should begin at once. Ideally, in such a case, the mother should be tested as soon as possible after delivery. If the test results are positive, the infant should receive 0.5 mL of HBIG as soon as possible and within 7 days of birth, and the vaccination series should be completed according to schedule. Preterm infants (< 2 kg) constitute a special class. If the mother's HBsAg status is unknown and cannot be determined rapidly, the child should be given 0.5 mL of HBIG as well as vaccine, because the premature infant's immune system may have a suboptimal response to the vaccine.
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HBIG is also used (concomitantly with vaccine) if an unimmunized or inadequately immunized child is exposed to blood or another body fluid from a person known or suspected to be acutely infected with hepatitis B. Such exposure could be percutaneous or permucosal; it could occur, for example, through a bite or by sexual contact. In such cases, the dose is 0.06 mL/kg.
Rabies Immune Globulin
Rabies IG (human) (RIG) is always used in association with rabies vaccine. Its sole indication is for postexposure prophylaxis. In general, such prophylaxis is recommended whenever the skin is broken and the child is exposed by bite, scratch, or other means to fluid from a wild animal or a domestic animal known or thought to be rabid. However, the decision to immunize should be made after consultation with local health authorities. If immunization is indicated, RIG should be given concomitantly with the first dose of vaccine, and dosage of the latter should be continued according to the postexposure schedule. The dose of RIG is 20 IU/kg. The current recommendation is that as much of the product as possible should be instilled around the cleaned wound. (If, for example, there are multiple bite sites, the dose should be divided among them.) Any of the dose that cannot be administered by this route should be given IM with a new syringe. Likewise, the first dose of vaccine should be given in a different part of the body and with a separate syringe. RIG is supplied in 2-mL (300-IU) and 10-mL (1500-IU) vials. Thus, the contents of a 2-mL vial can be used to treat a child of up to 15 kg; for larger children, additional vials are required. A 10-mL vial is sufficient to treat a 75-kg adult, making it less suitable for pediatric use. However, if the smaller vials are not available, an appropriate portion can be withdrawn to treat a child who is in need of immediate prophylaxis. The product contains no preservative; once a vial has been entered, the contents should be administered promptly, and the remainder discarded.
Tetanus Immune Globulin
Tetanus IG (human) (TIG) is the oldest of the specific IGs; it is still recommended for the treatment of tetanus and for prophylaxis in certain circumstances. Tetanus is so rare in persons whose immunization history includes at least three doses of tetanus toxoid that TIG is not recommended for such individuals. On the other hand, if a child who has received fewer than three doses of the toxoid (or whose tetanus immunization history is unknown) sustains a wound other than a clean, minor wound, TIG is indicated. The dose is 250 U, that is, the entire contents of a single container (vial or prefilled syringe), given IM. At the same time, the tetanus toxoid-containing vaccine that is appropriate for the age of the child should be administered at a separate site with a separate syringe. Arrangements should be made to complete the active immunization series. TIG is also recommended as part of the therapeutic regimen (including wound cleaning and debridement, antibiotics, and supportive care) for treatment of tetanus. The recommended dose for treatment is 3000 to 6000 U, that is, the contents of 12 to 24 containers. Little information is available that permits a choice between these extremes. Moreover, doses of TIG as low as 500 U (the contents of two containers) have been reported to be effective, for example, in tetanus neonatorum. [2]
Varicella-Zoster Immune Globulin
Postexposure prophylaxis should be targeted toward exposed, susceptible individuals (i.e., without a history of disease or age-appropriate immunization) who are at high risk for the development of severe varicella. Such individuals include: (1) immunocompromised children; (2) pregnant women; (3) neonates whose mothers have signs and symptoms of varicella within 5 days before delivery or within 48 hours after delivery; (4) premature infants > 28 weeks' gestation who are exposed in the neonatal period and whose mothers do not have evidence of immunity; (5) premature infants born at < 28 weeks' gestation or who weigh < 1000 g at birth and are exposed during the neonatal period regardless of maternal history of varicella disease or vaccination. Significant exposure can occur through residence in the same household, close contact with a playmate, proximity to a contagious patient, or contact with a contagious visitor or hospital staff member. In the past, varicella-zoster IG (human) (VZIG) was used routinely in the postexposure prophylaxis following varicella exposure in certain situations. The only manufacturer of VZIG discontinued production in 2004 and for relevant supplies were depleted by 2006. Physicians should access www.cdc.gov/nip/home-hcp.htm recommendations. In February 2006, an investigational VZIG product, VariZIG (Cangene Corporation, Winnipeg, Canada) became available under an investigational new drug application to the Food and Drug Administration (FDA). [3] Similar to VZIG, VariZIG is a purified human IG preparation made from plasma containing high levels of antivaricella IgG antibodies. This product is lyophilized, and after reconstitution is administered IM within 96 hours of exposure. The dose is 125 U (1 vial)/10 kg body weight up to a maximum of 625 U (5 vials). The minimum dose is 125 U. If obtainable in < 96 hours postexposure, VariZIG is preferred to IGIV or acyclovir. It is distributed by FFF Enterprises (Temecula, California: 24-hour telephone, 800-843-7477) under expanded access protocol. Pharmacists
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and healthcare providers who expect to need VariZIG can participate in a program that permits acquisition of an inventory in advance. If VariZIG cannot be obtained within 96 hours postexposure, IGIV can be given at a dose of 400 mg/kg. Although licensed IGIV preparations are known to contain antivaricella antibody, titer in any specific lot is uncertain. An alternative to postexposure prophylaxis with IGIV is oral acyclovir, which should be started 7 to 10 days after exposure and continued for a total of 7 days. This approach can be immunocompetent considered in immunocompetent, seronegative adults with significant exposure. The dose for adults is 800 mg given 4 times a day. If a child requires acyclovir pre-emptively, the dose is 40 to 80 mg/kg per day, divided in four doses. (See Chapter 205 , Varicella-Zoster Virus.) Generally, exposed immunocompetent children should be given varicella vaccine within 96 hours of exposure if they have not previously received vaccine and have no contraindication. IMMUNE GLOBULIN INTRAVENOUS (HUMAN) Like IG, IGIV is prepared from large pools of plasma that can represent as many as 60,000 donors. The early steps in its manufacture are similar to those used for preparing IG. Further processing of individual products is done by a variety of techniques, including steps such as polyethylene glycol precipitation, ion exchange, and exposure to low pH. This variety reflects, in part, the lack of consensus on the optimal procedure for preparing IgG on a commercial scale in a form that is safe for IV administration. There is a diversity of final formulations (e.g., freeze-dried or in solution, different protein concentrations of the latter, different pH, and various stabilizers and other excipients that can be used in a number of different combinations). This variety and the dynamic state of the industry render any compilation of manufacturing methods or formulations rapidly obsolete. The clinician who intends to use a particular product should therefore consult the Description section of the package insert for a brief synopsis of the product's preparation and properties. Although each lot of IGIV must contain at least minimal levels of antibodies to certain infectious organisms or toxoids (measles, polio, and diphtheria), these levels were established to ensure lot-to-lot consistency rather than to match the clinical indications for individual products. Even though the use of large plasma pools enhances this consistency, IGIV products differ in sources of plasma as well as processing methods. As a result, antibody titers to other bacterial and viral pathogens can vary significantly among preparations and lots. [4] [5] In addition, processing steps can alter functional capabilities of IgG or change the relative distribution of immunoglobulin subclasses. These changes may or may not be reflected in antibody titers measured by routine laboratory tests. Moreover, most individual products have undergone clinical trials for only a certain subset of indications. In addition, even when many IGIV products carry the same indication, direct comparisons of the efficacy of multiple products in a single clinical trial are rare. For all of these reasons, IGIV cannot be considered a uniform generic product. Available products in the United States (2006) are shown in Table 6-2 . Certain physiologic properties intrinsic to IGIV preparations (and variable among products) should be considered in all individuals for whom administration is considered and especially in those who have underlying conditions. These include high volume load, sodium content and osmolality, especially in neonates and young children as well as those with cardiac disease, renal impairment or thromboembolic risk; 2% to 10% carbohydrate content, in those with diabetes or renal impairment; low pH in neonates; and average IgA content (< 2 to 720 g/mL) in those with anti-IgA antibodies.
Approved Indications
There are currently 6 FDA approved indications for IGIV: (1) replacement therapy for primary immunodeficiency; (2) treatment of idiopathic thrombocytopenic purpura; (3) prevention of infection and graft-versus-host disease in adult bone marrow transplant recipients; (4) treatment of Kawasaki disease; (5) prevention of infection in children with HIV; and (6) replacement therapy in individuals with chronic B-cell lymphocytic leukemia ( Table 6-3 ). TABLE 6-3 -- Approved Indications for Immune Globulin Intravenous Therapy Indications Dosage Comments Replacement Therapy Primary immunodeficiency Chronic lymphocytic leukemia Bone marrow transplantation Human immunodeficiency virus infection in children Immune Modulation 400 mg/kg q4 weeks (average dose) 400 mg/kg q34 weeks 500 mg/kg q1 week 400 mg/kg q24 weeks Adjust dose according to individual response Cost-effectiveness questioned Other anti-infective therapies also effective Useful in selected symptomatic patients
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Idiopathic thrombocytopenic purpura 400 mg/kg daily for 5 days or 1 Useful in acute and chronic immune (ITP) g/kg, single dose thrombocytopenia purpura Kawasaki disease
Primary Immune Deficiencies
2 g/kg, single dose
Treat before 10 days of fever
During the past 20 years, IGIV has become the drug of choice for replacement therapy in primary immunodeficiency and all IGIV products carry this indication. [6] Although most of the subjects enrolled in IGIV efficacy trials have had the more common primary immunodeficiencies, clinical experience with IGIV in a wide variety of these conditions has been favorable. Patients with the following primary immunodeficiencies have associated hypogammaglobulinemia and may benefit from replacement IGIV therapy: X-linked agammaglobulinemia, common variable immunodeficiency, severe combined immunodeficiency and hyper-IgM syndrome. As clinical experience has grown, physicians have learned to tailor dosage to the individual patient. The objective is to determine the dose and regimen that will achieve and maintain freedom from serious infections. Monitoring the trough levels of IgG in parallel with the patient's clinical course has been helpful in accomplishing this objective. As could be expected, a range of effective doses, dosing schedules, and trough levels has been observed. However, the usual schedule for IV infusion is once every 3 or 4 weeks, and typical doses have been approximately 400 mg/kg with a dosing range of 300 to 800 mg/kg. Trough concentrations of IgG should be maintained in the range of 400 to 500 mg/dL. [7] In 2006, the United States FDA approved IG subcutaneous (Vivaglobulin, ZLB Behring) for people with primary immunodeficiency. It is the first subcutaneous IG approved that can be self-administered weekly (158 mg/kg) using a portable pump.
Secondary Immune Deficiencies
Chronic lymphocytic leukemia (CLL) and the immune suppression that occurs in patients undergoing bone marrow transplantation (BMT) result in quantitative and/or qualitative humoral immunodeficiency. One IGIV product has been studied and approved for treatment of CLL, and another for patients undergoing BMT. However, although IGIV reduces infections in these conditions, selection of patients most likely to benefit, optimal timing and duration of administration, and the relative effectiveness of IGIV and other anti-infective therapies are unresolved issues. Infection with human immunodeficiency virus (HIV) causes dysregulation of humoral immunity with impaired functional antibody activity. One IGIV product is approved for use in HIV-infected children. Such children were shown to have fewer respiratory infections while receiving IGIV; hence, it may benefit selected patients. [8] [9] In these studies, a benefit was observed, for children with CD4 counts higher than 200/mm 3 . Antimicrobial prophylaxis (e.g., trimethoprim-sulfamethoxazole) is an alternative approach to IGIV for preventing bacterial infections and is effective in preventing Pneumocystis carinii pneumonia. [10]
Immunomodulation
Mechanism of immunomodulation by IGIV and its use in treatment of inflammatory and autoimmune diseases have been reviewed recently. [11] Potential anti-inflammatory mechanisms include: neutralization of pathologic autoantibodies, enhanced clearance of autoantibodies, inhibition of phagocytosis by effector cells, altered complement deposition, altered cytokine expression, neutralization of superantigens and modulation of lymphocyte function (reviewed in Knezevic-Maramica & Kruskall [12] ). Because immunomodulation does not appear as a separate category in the labeling of IGIV, the labeled indications that belong to this category are considered individually in this discussion.
Immune Thrombocytopenic Purpura.
ITP often follows viral infections. Antibodies that are specific for or that crossreact with platelet surface antigens coat the cell surface and promote greater clearance of platelets by the spleen. In patients with ITP, IGIV can affect a rapid increase in platelet counts (often within 24 hours of infusion) and thereby can avert life-threatening bleeding. The prevailing hypothesis is that IgG in IGIV interacts with phagocytic Fc receptors, blocking clearance of platelets and allowing them to enter or remain in the circulation. [13] However, the mechanism may be more complex, involving induction of receptor expression. [14] Many different IGIV products have been shown to be effective for treatment of ITP, although few direct comparisons of effectiveness have been made. Compounding the lack of data is the fact that no laboratory tests can predict efficacy in ITP, either of individual products or in individual patients. IGIV has been studied in acute and chronic ITP in both adults and children. Not all cases respond; however, in general, children show response more frequently than do adults, and the increase in platelet count is more prolonged in children treated for acute ITP. (A B-
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lymphocyte-suppressive effect may account for prolonged decrease in antiplatelet antibodies.) Because acute ITP can resolve spontaneously, especially in young children, it is important to obtain the consultation of an experienced hematologist during the planning of the therapeutic approach. [15] Initially, the dosage of IGIV employed for treatment of ITP was 400 mg/kg daily for 5 consecutive days. [13] This regimen is still in use, but monitoring of the platelet count may indicate that dosage can be stopped after the second, third, or fourth day. On the other hand, some IGIV products have been shown to raise the platelet count adequately when a single dose of 1 g/kg is infused. If the rise is insufficient, this dose can be repeated the next day or on alternate days, depending on the product used. In all cases, it is important: (1) not to exceed the rate of administration recommended in the package insert for the particular IGIV product; and (2) to avoid the higher dose in patients with expanded fluid volume.
Kawasaki Disease.
Immune dysregulation may play a role in diseases for which a specific etiology has not been identified. Kawasaki disease is an acute inflammatory condition with multisystem vasculitis that can result in arterial aneurysms, particularly of the coronary vessels. Several IGIV preparations have been studied for the treatment of this condition. IGIV given concurrently with oral aspirin rapidly downregulates the inflammatory response. Its use is associated with a lower incidence of coronary artery aneurysms. [16] [17] Treatment with IGIV is effective when begun early (preferably within 10 days); a single dose of 2 g/kg infused over 10 to 12 hours zis recommended (http://aappolicy.aappublications.org/ ). [16] The initial dosage of aspirin is usually 80 to 100 mg/kg daily, divided among 4 doses, although lower dosage may be equally effective. [18] [19] When fever has subsided and remains under control, 3 to 5 mg/kg given as a single daily dose is adequate. Children who have persistent or recrudescent symptoms can be treated with a second IGIV dose of 2 g/kg. Inasmuch as the etiology of Kawasaki disease is unknown, it is possible that not all IGIV preparations (or all lots) are equally effective, even among products that carry this indication. Moreover, some clinicians recommend oral prednisolone for retreatment when the response to IGIV is inadequate. [20] (See Chapter 199 , Kawasaki Disease, for specific recommendations.)
Bone Marrow Transplantation.
As noted previously, IGIV can reduce the risk of infection in recipients of bone marrow transplants. In addition, several studies have reported IVIG to lower the incidence of acute graft-versus-host disease, but in one of the studies this result was only observed in patients who were older than 20 years. [21] [22]
Other Uses
The number of clinical conditions for which IGIV has been tried greatly exceeds that of its approved indications. The reasons for this are many. The simplest is the obvious fact that clinical research necessarily precedes the compilation of data by the manufacturer, submission of the data to regulatory authorities, and review and approval by the latter. Thus, in principle, a manufacturer might simply choose not to request approval of a particular indication if it offers no market advantage. Other reasons are more complex. A well-received, concisely written paper published in the medical literature might present positive results but might not include all of the less common adverse effects or might not address statistical nuances or subtleties of trial design that raise concerns. Alternatively, widespread use (indeed, commonly accepted treatment) for a particular condition can be generated by the enthusiastic endorsement of a respected clinician. In practice, such use may or may not be confirmed by appropriately controlled and adequately powered studies. The growing off-label use of IGIV has been implicated in shortages of IGIV (see below). This section includes some of the better-known off-label uses of IGIV, but no attempt has been made to include all or even most of them. IGIV has been used an adjuvant for the treatment of toxic shock syndrome associated with staphylococci and invasive streptococcal disease. IGIV typically contains antibodies against superantigen toxins produced by both these organisms. Furthermore, the anti-inflammatory properties of IGIV may help ameliorate the exaggerated cytokine response induced by superantigens. Both animal studies and case reports suggest the utility of IGIV as adjuvant therapy for the treatment of toxic shock syndrome secondary to staphylococcal toxin and streptococcal infection. [23] [24] Typical dose of IGIV for this purpose is 1 g/kg, though a range of doses has been used. Because of the high morbidity and mortality rates in preterm infants, the effects of IGIV in this population have been studied extensively. [25] Despite enthusiasm and the apparent logic of replacing missing antibodies, many studies have shown minimal benefit. [25] [26] [27] One prospective, randomized trial was conducted with preterm (gestational age < 33 weeks) infants whose IgG levels at birth were 400 mg/dL. Those who received IGIV had no fewer infectious episodes and no lower mortality rate than those who received an albumin placebo. [28]
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Parvovirus B19 infection can be prolonged in patients with a variety of immunodeficiencies, including: primary immunodeficiencies, HIV infection, sickle-cell disease, organ transplantation, and cytotoxic therapies. In such patients, parvovirus B19 causes chronic, severe anemia. IGIV (400 mg/kg daily for 5 days) has been reported to reduce the viral load and to restore erythropoiesis in selected patients. [29] [30] Anemia, hydrops, and persistent neonatal infection can also occur with intrauterine infection. In conjunction with intrauterine transfusions of red blood cells, IGIV may be helpful in ameliorating anemia associated with congenital parvovirus B19 infection. [31] Patients with a variety of immune-mediated cytopenias, including anemia and neutropenia, have been treated with IGIV, apparently with some success. [32] Published reports support the use of IGIV in HIV-infected individuals with ITP, although none of the licensed IGIV products carries this specific indication. [33] [34] GuillainBarr syndrome, an acute immune-mediated inflammatory polyneuropathy, may respond to IGIV therapy. Plasma exchange was first shown to decrease morbidity and improve outcome of affected patients. [35] [36] Highdose IGIV (1 g/kg on 2 consecutive days) is apparently as effective as plasma exchange and has been reported to have fewer complications. [37] The use of IGIV for management of acute disseminated encephalomyelitis is not established. SPECIFIC IMMUNE GLOBULINS FOR INTRAVENOUS ADMINISTRATION Currently four specific, plasma-derived immunoglobulin products for IV administration are approved for prophylaxis or therapy of infectious disease (see Table 6-1 ).
Cytomegalovirus Immune Globulin
Cytomegalovirus (CMV) IGIV (human) is indicated for the prophylaxis of CMV disease associated with organ transplantation. [38] [39] [40] Dosage is initiated at a level of 150 mg/kg within 72 hours of organ transplantation and then tapered over 6 additional biweekly doses to either 50 mg/kg (for kidney transplants) or 100 mg/kg (for liver, lung, pancreas, or heart transplants). The use of CMV-IGIV for the prophylaxis of CMV disease varies among transplant centers. Factors that influence the susceptibility of transplant recipients to CMV disease include: organ type, immunosuppressive regimen, and donor/recipient CMV status. CMV-negative transplant recipients who receive an organ from a CMV-positive donor are at highest risk for CMV disease and typically receive some form of CMV prophylaxis. This can include ganciclovir (using a prophylactic or pre-emptive strategy) alone, CMV-IGIV alone, or CMV-IGIV in combination with ganciclovir therapy.
Respiratory Syncytial Virus Immune Globulin
Respiratory syncytial virus (RSV) IGIV (human), shown to be beneficial in reducing RSV infections in high-risk infants, [41] is no longer available. Palivizumab, a humanized (95% human, 5% murine) monoclonal antibody to the A epitope of the F protein of RSV, has replaced RSV-IGIV. In one study, monthly doses of 15 mg/kg decreased the number of hospital admissions as well as the rate of admission to intensive care, both in infants with chronic lung disease (bronchopulmonary dysplasia) and in premature infants without this condition. [42] Palivizumab is given IM and does not interfere with immunization by live-virus vaccines. [43] Palivizumab can be given to neonates with hemodynamically significant congenital heart disease (RSV-IGIV could not be). [44] Because of the high cost of palivizumab, guidelines for use have been recommended (see Chapter 225 , Respiratory Syncytial Virus). [45]
Botulism Immune Globulin
Botulism IGIV (human) (BIG-IV) was approved by the FDA in 2003 under the orphan drug program. It is indicated in infants less than 1 year of age for the treatment of botulism suspected to be caused by either toxin type A or B. It is available under the trade name BabyBIG, only through the California Department of Health Services (510-231-7600, all days/hours). BIG-IV has been shown to reduce the hospitalization time of affected infants significantly if used within 3 days of admission. [46] [47] The recommended dose is 50 mg/kg. A trivalent equine antitoxin is indicated for use in foodborne botulism (see Chapter 189 , Clostridium botulinum (Botulism)).
Vaccinia Immune Globulin
Vaccinia IG (human) (VIG) was developed in the 1960s for the purpose of ameliorating side effects associated with vaccinia immunization, including eczema vaccinatum, generalized, and progressive vaccinia. [48] The original preparation contained a high proportion of protein aggregates and thus was administered IM. The use of VIG has become extremely limited since the eradication of smallpox. It is considered valuable insurance, to be held in reserve if a patient is receiving an experimental vaccine that involves a vaccinia carrier virus, or to prevent or manage complications of smallpox vaccination should such be required for a bioterrorism threat. Recently, a preparation of VIG suitable for IV use (VIG-IGIV) has gained FDA approval. In the event that VIG is required, it can be obtained
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through the Centers for Disease Control and Prevention (CDC: www.bt.cdc.gov/agent/smallpox/ IMMUNOGLOBULIN PRODUCTS PREPARED FROM ANIMAL PLASMA
).
In the past, there existed an array of approved animal-derived immunoglobulin products specific for various infectious agents or their toxins. Few are in use currently, most having been supplanted by analogues of human origin (e.g., RIG, TIG) or by other therapeutic modalities. (There are approved animal-derived products for the treatment of venomous bites and digoxin intoxication and for prevention of organ rejection; these are beyond the scope of this chapter.) The only available products in this category are botulism antitoxin (see Chapter 189 , Clostridium botulinum (Botulism)) and diphtheria antitoxin (see Chapter 130 , Corynebacterium diphtheriae (Diphtheria)). They can be obtained from the CDC for emergency use in the treatment of foodborne botulism and diphtheria, respectively. These equine immunoglobulin products are only provided when specifically indicated. Because immediate anaphylaxis and delayed serum sickness are possible adverse reactions, these products should only be used when their life-saving potential clearly outweighs the risk. Procedures for skin testing and desensitization are readily available and the physician should always be prepared to treat any adverse event. [49] ADVERSE REACTIONS TO IMMUNE GLOBULINS PREPARED FROM HUMAN PLASMA The most common adverse reaction to IM-administered IGs is pain at the injection site. Local or facial flushing can occur, as can headache, chills, or nausea, but these symptoms are less common. Severe systemic reactions are rare.
Infusion-Related Reactions
Adverse events after IV administration of IGs are common ( Box 6-1 ). Severe reactions to IGIV occur infrequently, but mild side effects have been associated with up to 20% of infusions. [50] The Adverse Reactions section of the package insert for an individual product provides the rates of adverse reactions obtained during studies of individual products. However, in view of the fact that few comparative trials of different products have been conducted, these numbers cannot be compared directly and should only be used for general guidance. BOX 6-1 Adverse Effects of Immune Globulin Intravenous Therapy MINOR SYSTEMIC REACTIONS Headache, back or hip pain, fever, dizziness or lightheadedness, nausea, flushing PYROGENIC REACTIONS High fever and systemic symptoms VASOMOTOR/CARDIOVASCULAR MANIFESTATIONS Changes in blood pressure and heart rate INFREQUENT, SERIOUS REACTIONS Aseptic meningitis [a] Acute renal failure Hypersensitivity reactions [b] Anaphylaxis
a Aseptic meningitis may be more common in adults or children with specific underlying conditions. b Reaction reports are more common for products that contain sucrose.
The bases for these side effects are poorly understood. As knowledge of the products has grown, it has become possible to minimize some sources of adverse reactions. For example, although the precise mechanisms remain controversial, the association between adverse reactions and aggregated forms of IgG was repeatedly observed. Accordingly, manufacturers sought procedures to eliminate such aggregates, minimize their formation, or both. Similarly, intermediates of the contact activation system, such as prekallikrein activator, could elicit a variety of
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reactions but largely could be avoided by suitable manufacturing strategies. Nonetheless, even with these advances, the classic constellation of side effects continues to be observed. Apparently, patients with certain conditions (e.g., primary immunodeficiency) are more vulnerable to the side effects of IGIV. Furthermore, among patients who receive IGIV repeatedly, some respond adversely more frequently than do others. The incidence of adverse events is particularly affected by the rate of infusion. For this reason, the instructions in the Dosage and Administration sections of package inserts for individual products should be carefully followed. These generally provide a starting rate (usually as flow rate per kilogram of body mass), a schedule for increasing the rate, and a maximum rate. Experience with the individual patient and product is of paramount importance. Most reactions subside when the rate of infusion is decreased. However, if reactions occur repeatedly, corticosteroid given IV, 30 min prior to the infusion, may alleviate symptoms. Some clinicians prefer to use oral antihistamine or analgesic medications. Severe, migraine-like headaches and aseptic meningitis have been reported in children. [51] [52] In one clinical trial in which adults received high-dose IGIV (2 g/kg), aseptic meningitis developed in 4 of 8 patients with a history of migraine headaches. [53] By contrast, the incidence in patients without such a history was 4% (2 of 46). Several large controlled trials in children with Kawasaki disease and preterm neonates have not documented IGIV-induced aseptic meningitis. However, this condition has been observed in children as well as adults being treated for ITP. [54] [55] Symptoms of meningitis (fever, headache, photophobia, and nuchal rigidity) can appear during the infusion or up to 48 hours later; cerebrospinal fluid pleocytosis in case reports ranges from < 100 to > 1000 neutrophils/mm 3 . Although the mechanism is not fully understood, cerebrospinal fluid levels of protein, including IgG, are often elevated. [53] [56] Severe hypersensitivity reactions and anaphylaxis are rare; if they occur, IgA deficiency should be considered. [57] For individuals with IgA deficiency and hypersensitivity reactions, IGIV with an extremely low IgA content is available (Baxter Healthcare Corporation). Routine screening for IgA deficiency is not recommended. Other rare events reported to be associated with IGIV infusion are Coombs-positive hemolytic anemia and accelerated serum sickness (upon repeated exposure) as well as thromboembolic events. [50] [58] Two relatively rare adverse reactions to IGIV, that is, acute renal failure and renal insufficiency, deserve special attention. The mechanism underlying these reactions is unclear, but strong associations with both the nature of products and conditions of the patient have been observed. [50] [59] Patients 65 years or older, patients receiving concomitant treatment with nephrotoxic agents, and patients with diabetes mellitus, pre-existing renal disease, hypovolemia, or sepsis appear particularly vulnerable. [59] Most, but not all, reports of adverse renal events have involved IGIV products that contain sucrose. Patients with renal impairment (clinical or subclinical) should be observed during and after IGIV infusion for exacerbation of the condition. Adequate hydration (but not overhydration) should be maintained, and the rates of administration recommended in the package insert for the individual product should be carefully followed.
Interference with Active Immunization
Antibodies present in IGs can interfere with the response to the corresponding vaccines. This is rarely a problem when the vaccine is a substance such as a toxoid, a polysaccharide, or a killed virus preparation, even when it is given simultaneously with the IG, provided that the two products are administered with separate syringes at different sites. However, these antibodies can interfere with replication after administration of live-virus vaccines and, thus, prevent successful immunization. The effect on measles immunization has been studied in detail, but in principle, similar interference could occur with any live-virus vaccine. Measles, mumps, and rubella vaccine should not be given in the 2 weeks before or 3 months after an individual receives any IgG preparation. Because high doses of IGIV can inhibit the response to measles vaccine for extended periods, longer intervals are required as the dose is increased (up to 11 months after 2 g/kg IGIV as for Kawasaki disease) to provide sufficient time for passively acquired antibodies to dissipate. [1] [18]
Transmission of Infectious Agents
Although IGs prepared from human plasma are biologic products and, hence, must always be considered to carry a theoretical risk for transmission of viruses, they have a remarkable record of safety. Even IGIV, which is administered directly into the bloodstream, often in large quantities, has been extremely safe. The many investigations conducted have revealed no documented case of transmission of hepatitis by United States-licensed IGs for IM use. Similarly, there is no evidence of transmission of HIV by United States-licensed IGs for either IM or IV administration. [60] Several cases of non-A, non-B hepatitis were associated with IGIV administration between 1983 and 1987. [61] [62] These cases involved sources of IGIV that were not commercial lots available in the United States. In February 1994,
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however, a worldwide recall of United States-licensed IGIV products manufactured by Baxter Healthcare Corporation was initiated because of hepatitis C virus (HCV) transmissions. [63] Cases of hepatitis C occurred in several countries, including the United States, among individuals who received these products between April 1, 1993, and February 23, 1994 (when they were removed from the market). The reason for these transmissions of hepatitis illustrates the complex relationships that underlie the production of IGs and all human plasma derivatives. These products had initially been licensed in February 1986 and, like other United States-licensed IGIV products, had an impeccable safety record. In 1990, the first test for antibody to HCV a single-antigen anti-HCV test became commercially available. In 1992, a more sensitive test (a multiantigen antiHCV test) came into use. Although using these tests to screen donors of blood and blood components (e.g., red blood cells, platelets) was of obvious benefit, application of the more sensitive test for screening of donors of plasma for fractionation had a paradoxical effect; that is, although withholding units of plasma that gave a positive test result meant that fewer infectious donors were represented in the plasma pools, these pools were also depleted with respect to beneficial anti-HCV antibodies that had cocirculated with the antibodies detected by the test. These beneficial antibodies had served two functions: (1) neutralization of viruses; and (2) complexing with viruses so as to partition them away from the protein fraction that became the final product. As a consequence, many lots of IGIV manufactured by Baxter Healthcare Corporation from plasma collected from donors who had been tested by the more sensitive test contained infectious (i.e., nonneutralized, noncomplexed) virus. [64] [65] By contrast, IGIV made by other manufacturers from plasma collected from donors who had undergone the same type of testing did not transmit hepatitis C. [63] [64] [65] This finding showed that the margin of safety had differed among individual IGIV products. Concerns about the potential transmission of prion disease by IG products have been raised. These concerns are highlighted by the lack of serologic assays to screen blood products for prions. The findings of several studies suggest that the likelihood of prion transmission via plasma products is exceedingly small. This includes the observations that very low levels of prions are found in the plasma of affected individuals and that the processing of plasma for the production of IGs typically inactivates prions. [66] [67] [68] [69] To date, no case of prion disease has been linked to IG therapy. Studies performed on a laboratory scale have shown that many manufacturing steps that are intrinsic to the process for preparing IgG greatly lower viral and prion burden. For example, alcohol fractionation of plasma partitions virus and prions away from the IgG fraction. [67] [70] If the alcohol concentration at a particular manufacturing step is sufficiently high and the virus is sufficiently labile (e.g., HIV), alcohol is viricidal. [70] Other precipitating agents, such as polyethylene glycol, can achieve similar partitioning of viruses. Incubation at low pH, either in the presence or in the absence of enzymes, has a strong antiviral effect. [71] [72] Solvent-detergent treatment is one step that has been deliberately introduced to achieve viral inactivation in various IGs. This treatment destroys enveloped viruses such as HBV, HCV, and HIV. [73] It is used in the manufacturing of numerous IGs for IM and IV use (including current IGIV products made by Baxter Healthcare Corporation). Another deliberate viral inactivation used for some products is heat treatment, which can be performed in the presence of stabilizers to prevent denaturation of the IgG. [74] The process for making some IG products now includes so-called nanofiltration, that is, filtration of the product through membranes with pore dimensions that permit the passage of proteins but not viruses. Brief summaries of these procedures as well as of the experiments demonstrating inactivation and removal of specific viruses are generally provided in the Description sections of the package inserts for the individual products. PRODUCT SHORTAGES There have been periodic shortages of certain IG products. The reasons for this are multiple. In some cases, there have been specific production problems. In others, demand is a major factor. For example, use of IGIV in the United States has steadily increased by approximately 10% each year, and production has not always kept pace. Off-label use of IGIV contributes importantly to shortage. A study of 12 academic health centers revealed that 52% of IGIV prescribed was used for off-label indications. [75] In response to these shortages, some hospitals have developed committees to review and restrict usage of IGIV. It is incumbent on clinicians to employ IGs appropriately so that products will be available for use in conditions for which they have proven benefit. THE FUTURE In the immediate future, we may anticipate additional IG products for IV administration. Some of these are likely to be specific IGs directed against known infectious agents. In the future, additional specific monoclonal antibody (mAb) products also may become available. mAb technology enables the production of large amounts of purified antibody with defined specificity and isotype that may not be present in standard IG preparations. This approach
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makes it possible rapidly to provide patients with a defined amount of protective antibody. Furthermore, advances in molecular biology have made possible the humanization of murine mAb, whereby the murine sequences are limited to the variable region of the antibody. This process leads to decreased antigenicity, improved pharmacokinetics, and presumably produces fewer side effects. In the last 10 years, a number of mAbs have been licensed for use, including those for: (1) organ transplantation (via inhibition of cytokine activity or depletion of lymphocyte subsets); (2) treatment of malignancies (i.e., lymphoma, colon and breast cancer); and (3) immunologic modulation (i.e., asthma and Crohn disease). Early attempts to utilize mAb against endotoxin in the treatment of gram-negative bacillary septicemia were not successful. [76] [77] A variety of mAbs for the treatment and prevention of infectious diseases are in clinical development related to the following pathogens: Cryptococcus neoformans, Staphylococcus aureus, HIV, RSV and Candida albicans. The advantages provided by mAbs have led some to hope that these reagents will be helpful in dealing with the problems of drug-resistant pathogens and potential bioterrorism attacks. [78] In parallel with continuing product development, it is reasonable to expect improvements in the design and conduct of clinical trials. One example might be streamlining the design of trials involving well-known products (e.g., IGIV) used to treat well-understood conditions such as primary immunodeficiency. Another, one hopes, is the conduct of trials that are sufficiently powered to permit major off-label uses to be either approved or abandoned. Acknowledgment The author thanks John S. Finlayson for significant use of material from the second edition of Principles and Practices of Pediatric Infectious Diseases. References 1. American Academy of Pediatrics. : Hepatitis. In: Pickering LK, ed. Redbook; 2006 Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village IL: American Academy of Pediatrics; 2006:419-429. 2. McCracken Jr GH, Dowell DL, Marshall FN: Double-blind trial of equine antitoxin and human immune globulin in tetanus neonatorum. Lancet 1971; 1:1146-1149. 3. Centers for Disease Control and Prevention. : A new product (VariZIG TM ) for postexposure prophylaxis of varicella under an investigational new drug application expanded access protocol. Morbid Mortal Wkly Rep MMWR 2006; 55:209-210. 4. Weisman LE, Cruess DF, Fischer GW: Opsonic activity of commercially available standard intravenous immunoglobulin preparations. Pediatr Infect Dis J 1994; 13:1122-1125. 5. Fischer GW, Cieslak TJ, Wilson SR, et al: Opsonic antibodies to Staphylococcus epidermidis: in vitro and in vivo studies using human intravenous immune globulin. J Infect Dis 1994; 169:324-329. 6. Haeney M: Intravenous immune globulin in primary immunodeficiency. Clin Exp Immunol 1994; 97(Suppl 1):11-15. 7. Eijkhout HW, Der Meer JW, Kallenberg CG, et al: The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med 2001; 135:165-174. 8. The National Institute of Child Health and Human Developments Intravenous Immunoglobulin Study Group. : Intravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection. N Engl J Med 1991; 325:73-80. 9. Mofenson LM, Moye J, Korelitz J, et al: Crossover of placebo patients to intravenous immunoglobulin confirms efficacy for prophylaxis of bacterial infections and reduction of hospitalizations in human immunodeficiency virusinfected children. Pediatr Infect Dis J 1994; 13:477-484. 10. Spector SA, Gelber RD, McGrath N, et al: A controlled trial of intravenous immune globulin for the prevention of serious bacterial infections in children receiving zidovudine for advanced human immunodeficiency virus infection. Pediatric AIDS Clinical Trials Group. N Engl J Med 1994; 31:1181-1187. 11. Kazatchkine MD, Kaveri SV: Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001; 345:747-755.
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12. Knezevic-Maramica I, Kruskall MS: Intravenous immune globulins: an update for clinicians. Transfusion 2003; 43:1460-1480. 13. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 1982; 306:1254-1258. 14. Samuelsson A, Towers TL, Ravetch JV: Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291:484-486. 15. Dickerhoff R, von Ruecker A: The clinical course of immune thrombocytopenic purpura in children who did not receive intravenous immunoglobulins or sustained prednisone treatment. J Pediatr 2000; 137:629-632. 16. Newburger JW, Takahashi M, Beiser AS, et al: A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991; 324:1633-1639. 17. Leung DY: Immunomodulation by intravenous immune globulin in Kawasaki disease. J Allergy Clin Immunol 1989; 84:588-593. 18. Kawasaki syndrome. : In: Pickering LK, ed. 2003 Red Book: Report of the Committee on Infectious Diseases, Elk Grove: American Academy of Pediatrics,; 2003:392-395. 19. Durongpisitkul K, Gururaj VJ, Park JM, et al: The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995; 96:1057-1061. 20. Dale RC, Saleem MA, Daw S, et al: Treatment of severe complicated Kawasaki disease with oral prednisolone and aspirin. J Pediatr 2000; 137:723-726. 21. Sullivan KM, Kopecky KJ, Jocom J, et al: Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. N Engl J Med 1990; 323:705-712. 22. Winston DJ, Ho WG, Bartoni K, et al: Intravenous immunoglobulin and CMV- seronegative blood products for prevention of CMV infection and disease in bone marrow transplant recipients. Bone Marrow Transplant 1993; 12:283-288. 23. Barry W, Hudgins L, Donta ST, et al: Intravenous immunoglobulin therapy for toxic shock syndrome. JAMA 1992; 267:3315-3316. 24. Perez CM, Kubak BM, Cryer HG, et al: Adjunctive treatment of streptococcal toxic shock syndrome using intravenous immunoglobulin: case report and review. Am J Med 1997; 102:111-113. 25. Lacy JB, Ohlsson A: Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: meta-analyses. Arch Dis Child Fetal Neonatal Ed 1995; 72:F151-F155. 26. Haque KN, Zaidi MH, Haque SK, et al: Intravenous immunoglobulin for prevention of sepsis in preterm and low birth weight infants. Pediatr Infect Dis 1986; 5:622-625. 27. Chirico G, Rondini G, Plebani A, et al: Intravenous gammaglobulin therapy for prophylaxis of infection in highrisk neonates. J Pediatr 1987; 110:437-442. 28. Sandberg K, Fasth A, Berger A, et al: Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G. J Pediatr 2000; 137:623-628. 29. Frickhofen N, Abkowitz JL, Safford M, et al: Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): a treatable cause of anemia in AIDS. Ann Intern Med 1990; 113:926-933. 30. Naides SJ, Howard EJ, Swack NS, et al: Parvovirus B19 infection in human immunodeficiency virus type 1infected persons failing or intolerant to zidovudine therapy. J Infect Dis 1993; 168:101-105. 31. Heegaard ED, Hasle H, Skibsted L, et al: Congenital anemia caused by parvovirus B19 infection. Pediatr Infect Dis J 2000; 19:1216-1218. 32. Hanada T, Saito K, Nagasawa T, et al: Intravenous gammaglobulin therapy for thromboneutropenic neonates of
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mothers with systemic lupus erythematosus. Eur J Haematol 1987; 38:400-404. 33. Tertian G, Risler N, Le Bras P, et al: Intravenous gammaglobulin treatment for thrombocytopenic purpura in patients with human immunodeficiency virus (HIV) infection. Eur J Haematol 1987; 39:180-181. 34. Bussel JB, Cunningham-Rundles C: Intravenous usage of gammaglobulin: humoral immunodeficiency, immune thrombocytopenic purpura, and newer indications. Cancer Invest 1985; 3:361-366. 35. French Cooperative Group on Plasma Exchange in GuillainBarr syndrome. : Efficiency of plasma exchange in GuillainBarr syndrome: role of replacement fluids. Ann Neurol 1987; 22:753-761. 36. The GuillainBarr Syndrome Study Group. : Plasmapheresis and acute GuillainBarr syndrome. Neurology 1985; 35:1096-1104. 37. Vajsar J, Sloane A, Wood E, et al: Plasmapheresis vs intravenous immunoglobulin treatment in childhood GuillainBarr syndrome. Arch Pediatr Adolesc Med 1994; 148:1210-1212. 38. Snydman DR, Werner BG, Heinze-Lacey B, et al: Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med 1987; 317:1049-1054. 39. Snydman DR, Werner BG, Tilney NL, et al: Final analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus-immune globulin: comparison of the randomized and open-label trials. Transplant Proc 1991; 23:1357-1360. 40. Snydman DR, Werner BG, Dougherty NN, et al: Cytomegalovirus immune globulin prophylaxis in liver transplantation. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1993; 119:984-991. 41. Groothuis JR, Simoes EA, Levin MJ, et al: Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group. N Engl J Med 1993; 329:1524-1530. 42. The IMpact-RSV Study Group. : Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102:531-537. 43. American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. : Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102:1211-1216. 44. Meissner HC, Long SS: Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003; 112:1447-1452. 45. American Academy of Pediatrics. : Respiratory syncytial virus. In: Pickering LK, ed. 2006 Red Book: Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village IL: American Academy of Pediatrics; 2006:560566. 46. Thompson JA, Filloux FM, Van Orman CB, et al: Infant botulism in the age of botulism immune globulin. Neurology 2005; 64:2029-2032. 47. Arnon SS, Schechter R, Maslanka SE, et al: Human botulism immune globulin for the treatment of infant botulism. N Engl J Med 2006; 354:462-471. 48. Barbero GJ, Gray A, Scott TF, et al: Vaccinia gangrenosa treated with hyperimmune vaccinal gamma globulin. Pediatrics 1955; 16:609-618. 49. American Academy of Pediatrics. : Antibodies of animal origin. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases, Elk Grove, IL: American Academy of Pediatrics; 2003:60-63. 50. Duhem C, Dicato MA, Ries F: Side-effects of intravenous immune globulins. Clin Exp Immunol 1994; 97 (Suppl. 1):79-83. 51. Watson JD, Gibson J, Joshua DE, et al: Aseptic meningitis associated with high dose intravenous immunoglobulin therapy. J Neurol Neurosurg Psychiatry 1991; 54:275-276.
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52. Vera-Ramirez M, Charlet M, Parry GJ: Recurrent aseptic meningitis complicating intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyradiculoneuropathy. Neurology 1992; 42:1636-1637. 53. Sekul EA, Cupler EJ, Dalakas MC: Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994; 121:259-262. 54. Pallares DE, Marshall GS: Acute aseptic meningitis associated with administration of intravenous immune globulin. Am J Pediatr Hematol Oncol 1992; 14:279. 55. Kressebuch H, Schaad UB, Hirt A, et al: Cerebrospinal fluid inflammation induced by intravenous immunoglobulins. Pediatr Infect Dis J 1992; 11:894-895. 56. Scribner CL, Kapit RM, Phillips ET, et al: Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med 1994; 121:305-306. 57. Burks AW, Sampson HA, Buckley RH: Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. Detection of IgE antibodies to IgA. N Engl J Med 1986; 314:560-564. 58. Wolberg AS, Kon RH, Monroe DM, et al: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30-34. 59. Epstein JS, Gaines A, Kapit R, et al: Important drug information: immune globulin intravenous (human). Int J Trauma Nurs 1999; 5:139-140. 60. Center for Disease Control and Prevention. : Safety of therapeutic immune globulin preparations with respect to transmission of human T-lymphotropic virus type III/lymphadenopathy-associated virus infection. MMWR Morb Mortal Wkly Rep 1986; 35:231-233. 61. Lever AM, Webster AD, Brown D, et al: Non-A, non-B hepatitis occurring in agammaglobulinaemic patients after intravenous immunoglobulin. Lancet 1984; 2:1062-1064. 62. Weiland O, Mattsson L, Glaumann H: Non-A, non-B hepatitis after intravenous gammaglobulin. Lancet 1986; 1:976-977. 63. Center for Disease Control and Prevention. : Outbreak of hepatitis C associated with intravenous immunoglobulin administration United States, October 1993June 1994. MMWR Morb Mortal Wkly Rep 1994; 43:505-509. 64. Yu MW, Mason BL, Guo ZP, et al: Hepatitis C transmission associated with intravenous immunoglobulins. Lancet 1995; 345:1173-1174. 65. Bresee JS, Mast EE, Coleman PJ, et al: Hepatitis C virus infection associated with administration of intravenous immune globulin. A cohort study. JAMA 1996; 276:1563-1567. 66. Brown P, Cervenakova L, McShane LM, et al: Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit CreutzfeldtJakob disease in humans. Transfusion 1999; 39:1169-1178. 67. Reichl HE, Foster PR, Welch AG, et al: Studies on the removal of a bovine spongiform encephalopathy-derived agent by processes used in the manufacture of human immunoglobulin. Vox Sang 2002; 83:137-145. 68. Van Holten RW, Autenrieth S, Boose JA, et al: Removal of prion challenge from an immune globulin preparation by use of a size-exclusion filter. Transfusion 2002; 42:999-1004. 69. Stenland CJ, Lee DC, Brown P, et al: Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002; 42:1497-1500. 70. Wells MA, Wittek AE, Epstein JS, et al: Inactivation and partition of human T-cell lymphotrophic virus, type III, during ethanol fractionation of plasma. Transfusion 1986; 26:210-213. 71. Kempf C, Jentsch P, Poirier B, et al: Virus inactivation during production of intravenous immunoglobulin. Transfusion 1991; 31:423-427.
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72. Louie RE, Galloway CJ, Dumas ML, et al: Inactivation of hepatitis C virus in low pH intravenous immunoglobulin. Biologicals 1994; 22:13-19. 73. Edwards CA, Piet MP, Chin S, et al: Tri(n-butyl) phosphate/detergent treatment of licensed therapeutic and experimental blood derivatives. Vox Sang 1987; 521:53-59. 74. Chandra S, Cavanaugh JE, Lin CM, et al: Virus reduction in the preparation of intravenous immune globulin: in vitro experiments. Transfusion 1999; 39:249-257. 75. Chen C, Danekas LH, Ratko TA, et al: A multicenter drug use surveillance of intravenous immunoglobulin utilization in US academic health centers. Ann Pharmacother 2000; 34:295-299. 76. Angus DC, Birmingham MC, Balk RA, et al: E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. JAMA 2000; 283:1723-1730. 77. Derkx B, Wittes J, McCloskey R: Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Clin Infect Dis 1999; 28:770-777. 78. Casadevall A, Dadachova E, Pirofski LA: Passive antibody therapy for infectious diseases. Nat Rev Microbiol 2004; 2:695-703. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 7 Active Immunization Larry K. Pickering, Walter O. Orenstein Vaccines are among the most effective means of preventing disease, disability, and death. The use of vaccines, initiated by Jenner in 1796 with the demonstration that inoculation of material from cowpox lesions could prevent smallpox, predates the germ theory of disease. Use of conventional viral and bacterial culture techniques led to development of vaccines to prevent 7 diseases in 1985. Subsequently, advances in understanding the immunologic basis of immunity and new molecular biologic techniques, including genome sequencing, have facilitated the definition of the precise composition and structure of antigens, the development and extensive use of new vaccines, and an expansion of their potential uses beyond prevention of childhood diseases. The profound impact of vaccines on disease incidence is a result not only of availability of safe and effective vaccines but also of strategies for disease control and programs to deliver vaccines to target groups. Eradication of smallpox in 1977 is among the greatest public health achievements of its age and was based on competent disease surveillance and containment of spread of disease with a highly effective vaccine. [1] Global efforts under way to eradicate poliomyelitis and to certify eradication of polio involve more comprehensive disease control strategies. National and multicountry mass vaccination campaigns, intensive surveillance for wild poliovirus, and house-tohouse vaccination programs have succeeded in terminating transmission of wild poliovirus in the Americas, the Western Pacific, and Europe, and gains are being made in the remaining endemic countries in the Indian subcontinent and Africa. [2] [3] [4] Efforts to reduce or even eliminate measles and neonatal tetanus, two of the major causes of child fatality worldwide, also are progressing. [5] The Global Alliance for Vaccines and Immunization, an alliance between organizations in the public and private sectors, provides support for introduction of vaccines in countries that previously could not support them (www.gavialliance.org ). Benefits of successful vaccines include not only reductions in disease incidence, disability, pain, and suffering, but also savings in healthcare costs in both the economically developed and developing world. Studies in the United
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States have reaffirmed benefits of childhood immunization, [6] [7] [8] indicating that: (1) each of the traditional vaccines diphtheria and tetanus toxoids, and acellular pertussis (DTaP), measles, mumps, and rubella (MMR), and oral polio vaccine (OPV) is cost-saving in terms of direct medical costs alone. A costbenefit analysis covering 10 vaccine-preventable diseases of childhood, including diphtheria, tetanus, pertussis, polio, hepatitis B, Haemophilus influenzae type b (Hib), measles, mumps, rubella, and varicella (MMRV), estimated that for every dollar spent on childhood immunization in 2001, there were $5.3 dollars saved in direct costs and $16.5 saved by society. [8] IMMUNIZATION AND VACCINES Immunization is the process of artificially inducing immunity or providing protection from disease. Active immunization is the process of stimulating the body to produce antibody and other immune responses (e.g., cellmediated immunity) through administration of a vaccine or toxoid. Passive immunization is provision of temporary immunity by administration of preformed antibodies derived from humans or animals (see Chapter 6 , Passive Immunization).
Vaccine Content
Biologic agents used to induce active immunization include vaccines and toxoids. Traditionally, a vaccine is defined as a suspension of live (usually attenuated) or inactivated microorganisms, or fractions thereof, which is administered to induce immunity and prevent infectious disease or its sequelae; efforts to develop vaccines to increase immune response to cancers or to treat diseases like diabetes mellitus necessitate rethinking of this definition. Live-attenuated vaccines traditionally have been developed by means of serial passage (in culture or animals) of an initially pathogenic bacteria or virus strain with selection for strains that are less pathogenic for humans but that induce protective immunity (MMRV). Live-attenuated vaccines can also be developed with the use of reassortants of attenuated animal or human virus strains with virus coat antigens from pathogenic strains (cold-adapted influenza, rotavirus). Inactivated vaccines can consist of: (1) whole organisms inactivated by heat, formalin, or other agents (polio, hepatitis A, rabies); (2) purified protein (acellular pertussis and influenza) or polysaccharide antigens (pneumococcal, meningococcal, and im typhoid) from whole organisms; and (3) purified antigens produced by genetically altered organisms (hepatitis B and human papillomavirus (HPV) vaccines produced by yeast); or (4) chemically modified antigens, such as polysaccharides conjugated to carrier proteins to increase immune response (conjugated Hib, pneumococcal and meningococcal vaccines). Toxoids are modified bacterial toxins produced in bacterial culture. These toxoids have been rendered nontoxic but retain the ability to stimulate formation of antitoxin. Vaccine and toxoid preparations also contain other constituents that are intended to enhance immunogenicity and stability but that can also be responsible for adverse reactions. [9] Such constituents include: (1) suspending fluid, which can be saline or complex fluids containing constituents derived from the biologic system or medium in which the vaccine is produced (e.g., egg or serum proteins); (2) preservatives, stabilizers, and antimicrobial agents, which are used to inhibit bacterial growth in viral cultures or the final product or to stabilize antigens (e.g., mercurials, phenols, albumin, glycine, neomycin); and (3) adjuvants, which enhance response to inactivated antigens (aluminum hydroxide or phosphate). Concern about the possibility of adverse effects from cumulative exposure to mercury in the environment has led to the removal of thimerosal as a preservative from United States vaccines recommended for infants. [10] Only some formulations of influenza vaccine that can be administered to infants contain thimerosal as a preservative. Physicians should be knowledgeable about the constituents of each vaccine, which are described in package inserts. TYPES OF VACCINES
Immunologic Basis of Response to Vaccines
The two major approaches to active immunization are use of: (1) live-attenuated vaccines and (2) inactivated or detoxified agents or their purified components. For some diseases, such as poliomyelitis and influenza, both approaches have been used to develop vaccines. Live-attenuated vaccines have the advantage of producing a complex immunologic response simulating natural infection. Because replication of the organism and processing of antigens mimic those of the natural organism, both humoral and cell-mediated responses can be generated to a variety of antigens. Generally, immunity induced by one dose of a live-attenuated vaccine is long-lasting, possibly lifelong. However, the strength of response, particularly the humoral response, is usually less than the response following natural infection, and detectable antibodies can wane with time, resulting in some loss of protection. Induction of immunity by live vaccines can be inhibited by passive antibody, whether from transplacental acquisition from the mother or receipt of immunoglobulin-containing blood products; thus, optimal response depends on ensuring that this level of passive antibody has declined (e.g., primary measles vaccination at 12 months of age instead of earlier, delay of measles vaccination after administration of blood products). In addition, because response may be only 90% to 95% after a single dose, a two-dose or multiple-dose
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regimen may be necessary to induce higher levels of protection in the community and prevent spread of disease if the population is exposed (herd immunity). Inactivated or purified antigen vaccines induce response only to components present in the vaccine. Generally, multiple doses, usually three or more, are necessary to induce satisfactory antibody levels that persist for long periods of time; booster doses at longer intervals (e.g., 10 or more years for tetanus and diphtheria toxoids (Td)) are sometimes needed to ensure lasting protection. The nature of response depends on antigen type. Protein (and glycoprotein) antigens usually induce both humoral immunity and memory (T-helper lymphocytes) after multiple doses, evidenced as more rapid and intense response to successive doses. Polysaccharide antigens by themselves induce only humoral antibody without T-lymphocyte stimulation and fail to induce anamnestic response with repeated antigenic challenge. This shortcoming can be overcome by conjugation of polysaccharides to protein carriers (e.g., Hib polysaccharide conjugated to whole or modified diphtheria or tetanus toxoids or to outermembrane protein (OMP) complex of Neisseria meningitidis) to induce stronger immune response in younger children as well as immunologic memory.
Immune Response to Active Immunization
Development of an immune response generally requires interaction of T lymphocytes with antigen-processing and antigen-presenting cells (dendritic cells or macrophages). [11] [12] Certain types of antigens (thymus-independent, e.g., polysaccharide) can initiate B-lymphocyte antibody production without help of T lymphocytes but fail to induce immunologic memory. T-lymphocyte immunity is induced after uptake of antigen by mononuclear phagocytes or dendritic cells, which can be enhanced by use of an adjuvant, followed by processing and presentation of the antigen, in association with major histocompatibility complex (MHC) antigens, to helper T lymphocytes. T lymphocytes recognize polypeptide antigens of approximately 8 amino acids in size, presented in association with specific MHC molecules; the type of MHC molecule with which the antigen is presented by antigen-processing cells depends on the source and processing of the polypeptide. Inactivated antigens, absorbed into vacuoles, are processed and presented with MHC2 antigens; antigens from live-attenuated vaccines or vectored vaccines, produced within the cell, are processed in microtubules and presented with MHC1 antigens. These antigenMHC complexes determine the primary type of T-lymphocyte response, either cytotoxic or helper. Presentation to helper T lymphocytes results in secretion of immune mediators (cytokines) that can stimulate the maturation of naive T lymphocytes and communicate between leukocytes (interleukins) to regulate the immune response. Depending on the antigen and its MHC presentation, T lymphocytes differentiate into either type 1 T-helper lymphocytes (Th1, stimulated by MHC1-associated antigen), which mediate cellular immune response, or type 2 T-helper lymphocytes (Th2, stimulated by MHC2-associated antigen), which assist B lymphocytes in developing antibody production. [13] Each of these subsets produces different interleukins and other immune mediators responsible for modulating the immune response. Antibodies produced in response to immunization can function in any of several ways: (1) direct neutralization of toxin; (2) opsonization (neutralization) of organisms; (3) initiation of or combination with the complement pathway to lyse organisms or promote phagocytosis (pneumococcus); (4) reaction with nonsensitized lymphocytes to promote phagocytosis; or (5) sensitization of macrophages to promote phagocytosis. These mechanisms can occur simultaneously with cell-mediated responses. Rarely, vaccination can result in immune responses that alter the course of natural infection detrimentally. For example, killed measles vaccine, a formalin-inactivated vaccine administered to some children in the United States between 1963 and 1967, sensitized some vaccine recipients so that when they were exposed to wild virus they developed an atypical infection with enhanced severity of disease. The prevailing theory has been failure of formalininactivated vaccine to produce response to the measles virus fusion protein, leading to altered immune response and atypical disease upon subsequent challenge. More recent theories suggest killed measles virus failed to induce highavidity antibody, and immune complex deposition is the major cause of atypical measles. [14] After immunization with inactivated antigens, antibody response to initial doses develops in 2 to 6 weeks but may be incomplete after even two doses; after effective priming, booster responses occur within 4 to 14 days. The initial response is usually immunoglobulin M (IgM) antibodies, followed within weeks by IgG antibodies. Response to live vaccines requires one incubation period, followed by several weeks to months for development of a strong immune response. Response to measles vaccination is usually maximal by 6 weeks, but in younger children, antibody levels can continue to rise for several months.
Determinants of Response
Determinants of vaccine immunogenicity and response involve characteristics of the vaccine and of the host. Vaccine dose, presence of an adjuvant, route and site of administration, timing of doses, and vaccine handling can affect
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response. Vaccine doses are adjusted before licensure to ensure a high level of response (generally > 90%); adjuvants permit a better response with a lower dose of inactivated antigen. The routes of administration (e.g., intradermal, subcutaneous, intramuscular, and mucosal) can determine the strength and nature of the immune response. Mucosal administration (intranasal or oral) stimulates higher levels of mucosal immunity (IgA antibodies) that may inhibit disease transmission with greater effectiveness than parenteral administration, which induces limited or no mucosal response. [15] Intradermal vaccination with low doses can induce antibody responses similar to responses induced by intramuscular or subcutaneous administration of recommended doses, but intradermal vaccine is more difficult to deliver precisely and, in practice, achieves less predictable responses.
Sites of Administration
Intramuscular injections should be given in the anterior thigh (infants) or deltoid (toddlers, children, and adults); injection into the buttocks may produce lower antibody response, which has been documented for hepatitis B and rabies vaccines in adults, probably owing to delivery of vaccine into adipose tissue. [16] [17] Vaccines with adjuvants should be given in deep muscle, because subcutaneous or intradermal injection can induce local inflammation, granuloma formation, or necrosis. [18] Timing of doses of killed vaccines is important; a minimal interval of 1 month between primary doses is usual. [7] Delay of a third or reinforcing dose for 6 months or longer after the first dose enhances response and duration of antibody persistence and is recommended unless high disease risk necessitates shorter intervals. The recommended routes and sites of administration and timing of doses are devised to ensure optimal effectiveness in disease prevention and should be used.
Host Factors
Intrinsic factors in the host that affect immune response include genetic factors, [19] [20] age, nutritional or disease status, primary or secondary immunodeficiency, gender, pregnancy, and smoking. Although genetic factors such as MHC polymorphism are known to affect both cellular and humoral immune response at a molecular level for some vaccines, the precise mechanisms for these genetic influences are often unknown. [19] [20] [21] Age is an important factor in response to immunization. With killed vaccines, neonates generally do not develop as strong a response as older infants or children (i.e., hepatitis B), and with certain vaccines, too early immunization may result in poor response or development of tolerance (DTaP, inactivated poliovirus vaccine (IPV), Hib conjugates). For live (and some killed) vaccines, inhibition of response by maternal antibodies determines the optimal timing for vaccination in early childhood (measles, hepatitis A). Generally, response to all vaccines is excellent in young children, adolescents, and young adults but diminishes with increasing age. In adults, male sex and pregnancy have minor dampening effects on antibody response that have limited significance; smoking decreases response to many antigens and may raise the risk of nonresponse to vaccination when other negative factors are present. [16] [18] Extreme debilitation, primary or secondary immunodeficiency disorders, including diseases or treatments that cause immunosuppression, and some chronic diseases (renal disease, diabetes mellitus) can diminish immune response. For people with such conditions, inactivated vaccines may be recommended despite their lower effectiveness, although higher or more frequent doses may be required; live vaccines are often contraindicated because of the risk of disseminated disease and possible death due to the vaccine organism. [18] [22]
Measurement of Response
Ideally, reliable laboratory tests should be available to measure the presence and strength of each of the major effectors of protection against the disease for which the vaccination is administered. In practice, a wide variety of tests for presence of antibody are available, and include radioimmunoassay (RIA), enzyme immunoassay (EIA), complement fixation, polymerase chain reaction, and immunofluorescent techniques, but these tests often do not measure the presence of functional (neutralizing or opsonizing) antibody. Tests for cell-mediated immunity are available in reference laboratories and research facilities; different tests are required to determine cytotoxic and helper T-lymphocyte (memory) functions. For certain diseases, such as hepatitis B, poliovirus, and measles, reliable tests exist and antibody levels that correlate with protection are known; however, inexpensive tests are only widely available for hepatitis B. For other diseases, such as rubella, commercial tests are available, often using EIA methods, but their specificity is often less well defined, and their sensitivity is lower than sensitivity of neutralization assays. For some diseases, such as pertussis, no serologic correlate of protection has been defined. Development of better laboratory methods to measure protection and to permit rapid diagnosis of acute disease continues to be a priority of vaccine-preventable disease control programs.
Vaccine Licensure and Approval
Before Food and Drug Administration (FDA) licensure, a new vaccine generally requires 10 to 15 years of preclinical testing and clinical trials. Prior to testing a vaccine in humans, a manufacturer files an investigational new drug (IND) application with the FDA, followed by three phases of clinical trials that are performed to study vaccine safety,
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immunogenicity, and efficacy. [23] [24] Following completion of the prelicensure clinical trials, the following steps are required: the manufacturer must apply for a Biologics Licensure Application (BLA) with the United States FDA; the FDA must license the vaccine; the Advisory Committee on Immunization Practices (ACIP), the American Academy of Family Physicians (AAFP), and the Committee on Infectious Diseases (COID) of the American Academy of Pediatrics (AAP) must recommend the vaccine for use; and financing for the vaccine must be secured for people in the public and private sectors ( Figure 7-1 ).
Figure 7-1 Development of pediatric vaccine recommendations and policies. FDA, Food and Drug Administration; CDC, Centers for Disease Control and Prevention; COID, Committee on Infectious Diseases; AAP, American Academy of Pediatrics BoD, Board of Directors. (Redrawn from Pickering LK, Orenstein WA. Development of pediatric vaccine recommendations and policies. Semin Pediatr Infect Dis 2002;13:148-154, with permission.)
Following licensure of a new vaccine by the FDA, information about the vaccine is reviewed by the ACIP. The ACIP is comprised of 15 voting members appointed by the Secretary of the Department of Health and Human Services. In addition, many professional medical and public health groups and industry representatives participate in ACIP discussions. To formulate recommendations, the ACIP establishes subject-specific work groups to review and synthesize data months to years before presentation to the ACIP, vote, and a recommendation is released. ACIP recommendations are subject to the approval of the director of the Centers for Disease Control and Prevention (CDC) (www.cdc.gov/nip/ACIP/charter ). The COID of the AAP also develops recommendations for vaccine use which are approved by the Board of Directors of the AAP. These recommendations are usually the same as, or similar to, recommendations of the ACIP. After vaccine licensure, monitoring for rare adverse events continues for some vaccines through formal phase IV trials con-ducted by the FDA and the manufacturer. In addition, postmarketing surveillance for adverse events permits detection of new or unanticipated adverse events; reporting of adverse events observed after vaccines is required by the National Childhood Vaccine Injury Act for vaccines covered under the Vaccine Injury Compensation Program. [25] The importance of postmarketing surveillance was demonstrated following licensure and wide use of tetravalent rhesus rotavirus vaccine (RRV) in United States infants during 1999. Surveillance of adverse events detected cases of intussusception within 1 week after receipt of the first or second doses of RRV. Follow-up studies determined that risk of intussusception was 1 case per 10000 doses of vaccine administered. [26] Subsequently, the
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vaccine was withdrawn from distribution, and recommendation for universal use in infants in the United States was withdrawn. [27] PRINCIPLES OF IMMUNIZATION PROGRAMS
Disease Reduction
Childhood immunization programs have reduced substantially the occurrence of vaccine-preventable diseases in the United States from the representative annual morbidity during the 20th century ( Table 7-1 ). [28] [29] [30] Declines exceed 95% for all diseases for which universal vaccination has been well implemented, with the exception of hepatitis B, which remains a common clinical disease in adults not reached by universal vaccine programs [31] and pertussis. [32] Smallpox has been eradicated, poliomyelitis due to indigenous wild poliovirus has not occurred since 1979, and endemic rubella has been declared eliminated in the United States. [33] [34] Fewer than 10 cases each of diphtheria and tetanus in children are now reported each year, and indigenous transmission of measles has been interrupted. Wide use of Hib conjugate vaccines has reduced Hib disease by more than 98% in the United States and in some European countries. [35] [36] Use of pneumococcal conjugate vaccine has led to marked reductions in invasive pneumococcal disease among vaccinated children as well as unvaccinated very young infants, adolescents, and adults. [37] [38] [39] [40] Building on the success of the program to date, the United States Public Health Service has established 2010 goals to eliminate indigenous transmission of measles, rubella and congenital rubella syndrome, mumps, diphtheria, poliomyelitis, Hib disease in children younger than 5 years of age, and tetanus in persons younger than 35 years of age, and to reduce hepatitis B in people 2 to 18 years of age by 90%. [41] TABLE 7-1 -- Reported Morbidity of Selected Vaccine-Preventable Diseases and Vaccine Coverage Levels United States, 20th Century and 2004 [e] United States, 20thHealthy People United States, Century Annual 2006 Morbidity Vaccine Coverage 2010 Coverage Morbidity [a] Disease Levels, 2005 % [c] Level Goals [b] Diphtheria Tetanus Pertussis Poliomyelitis (paralytic) Measles Mumps Congenital rubella Haemophilus influenzae type b and unknown; < 5 years of age Varicella 175,885 1314 147,271 16,316 503,282 152,209 823 20,000 0 38 5826 0 73 6585 1 242 86% ( 4 doses) 86% ( 4 doses) 86% ( 4 doses) 92% [d] ( 3 doses) 92% ( 1 dose) 92% ( 1 dose) 92% ( 1 dose) 94% ( 3 doses) 90% 90% 90% 90% 90% 90% 90% 90%
Unknown
26,683
88% ( 1 dose)
90%
a MMWR 2004;53:687696, number of reported cases. b MMWR 2007; 54:192, number of reported cases. c MMWR 2006; 55:98893 reference 30. d Vaccine-associated paralytic poliomyelitis. e Inactivated poliovirus vaccine.
Immunization Coverage
Immunization coverage among preschool children has increased steadily after the measles resurgence that began in 1989 and stimulated unprecedented efforts to improve delivery of immunization. In 2005, coverage with three doses of DTaP, Hib conjugate, polio, and hepatitis B vaccines, and one dose of MMR vaccine among children 19 to 35 months of age each reached or exceeded 92%, whereas coverage with one or more doses of varicella vaccine was 88%. [42] Coverage with the recommended series of four DTaP, three OPV, one MMR, three Hib, and three hepatitis B vaccines was 81%. Among school-aged children as well as attendees of childcare centers and Head Start programs, coverage with recommended vaccines has been more than 95% since the early 1980s, as a result of enforcement of comprehensive state immunization laws requiring receipt of specified vaccines for school attendance. School laws are now being expanded to include newly recommended vaccines. [43]
Vaccine Administration
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Vaccine Schedules
The CDC, the AAFP, and AAP annually publish harmonized childhood and adolescent immunization schedules. The ACIP and AAFP also publish an annual adult immunization schedule (www.cdc.gov/vaccines ). The ACIP, with input from many liaison organizations, periodically reviews the schedules to ensure consistency with new vaccine developments and policies. The first harmonized childhood immunization schedule was published in 1995 and recommended six vaccines containing antigens against nine infectious diseases [44] : diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP); Td; MMR; Hib; OPV; and hepatitis B virus (HBV) vaccine. In January 2007 there were 12 vaccines against 16 infectious diseases in the childhood and adolescent immunization schedule ( Figure 7-2 ). The harmonized schedule specifies both timing and the acceptable range of timing recommended for each dose of universally recommended vaccine and for vaccines recommended for children and adolescents in selected highrisk populations.
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Figure 7-2 Recommended ages for administration of currently licensed childhood vaccines, 2007. (Redrawn from Pickering LK, Baker CJ, Long SS, et al. (eds) Red Book 2006: Report of COID, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, pp 73-74.)
Since inception, the major focus of the United States immunization program has been on immunizing infants and young children. In 1996, following growing concern about morbidity associated with vaccine-preventable diseases in the hard-to-reach adolescent population, the ACIP recommended expanding efforts to immunize adolescents (11 to 18 years of age) by establishing a routine vaccination visit at 11 to 12 years of age. [45] In addition to providing Td and previously missed vaccinations, the report emphasized that this visit should be used to provide other important preventive health services. The addition of several new vaccines for adolescents (tetravalent meningococcal conjugate vaccine (MCV4), tetanus toxoid and reduced-content diphtheria toxoid and acellular pertussis vaccine (Tdap) and HPV) to the recommended schedule has stimulated a reappraisal of approaches that will most effectively and efficiently increase the proportion of adolescents who receive newly recommended vaccines and develop ways to integrate these approaches into other adolescent health, education, and development programs. [46]
Vaccine Spacing
Minimal spacing of vaccine doses is generally 1 month for the initial doses of killed vaccines; longer intervals are needed for booster doses to provide optimal boosting. [7] The minimal spacing for MMR vaccines is 28 days. For children with delayed initiation of immunization (after 6 months of age), an accelerated schedule is recommended ( Figure 7-2 ). [7] [47] To optimize adherence to the schedule in this circumstance, visits should be scheduled at 1month intervals, and all recommended vaccines should be given at each visit. There is no need to restart any of the vaccine series among people with long delays between doses.
Simultaneous Administration
All childhood vaccines can be administered simultaneously. This practice is based on extrapolation of data from multiple studies showing that most vaccines can be administered at the same time without compromising safety or immunogenicity. [48] Thus, DTaP, Hib, IPV, hepatitis B, heptavalent pneumococcal conjugate vaccine (PCV7),
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MMR, varicella, and rotavirus vaccines can be administered simultaneously or within any interval of one another when appropriate. [7] [47] Interference between live virus vaccines other than OPV, rotavirus, and cold-adapted influenza vaccine (e.g., MMR and varicella) theoretically can occur if they are given within a short interval; live virus vaccines should be given either simultaneously or at least 1 month apart. Vaccines should not be mixed in the same syringe unless specifically licensed for such use. Interference has been found between certain vaccines (cholera and yellow fever).
Spacing of Antibody-Containing Products and Vaccines
Immunoglobulins or blood products containing immunoglobulins inhibit response to certain live-virus vaccines (MMR and possibly varicella). The duration of inhibition of response is related to the dose of immunoglobulin delivered, and algorithms for calculating appropriate delays of MMR or measles vaccination after receipt of such products are available. [18] [47] [49] In general, MMR vaccines should be delayed 3 months or longer after administration of usual doses of immunoglobulin (e.g., to prevent hepatitis A) or blood products, and for longer periods of time after higher doses (e.g., 10 months or more after 2 g/kg immune globulin intravenous such as for treatment of Kawasaki disease).
Interchangeability of Vaccines
Available data support interchangeability of most vaccines produced by different manufacturers to prevent the same disease (tetanus, diphtheria, hepatitis B, and hepatitis A). Studies indicate that response to a three-dose series using different Hib conjugate vaccines equals or exceeds that when the same vaccine is used for all doses. [50] The ACIP and AAP recommend that, when feasible, the same vaccine should be used for the primary series but that three doses of any vaccine are sufficient. [7] [47] Data are limited regarding safety, immunogenicity, and efficacy of using acellular pertussis (as DTaP) vaccines from different manufacturers for successive doses of the pertussis series. Data suggest that two of the current DTaP preparations may be used interchangeably for the first three doses of the DTaP series without affecting safety or immunogenicity. [51] Whenever feasible, use of the same DTaP product for the entire series is recommended. When the specific product is not known or available, any DTaP vaccine should be used to continue or complete the series.
Vaccine Safety and Compensation for Vaccine Injury
In 1986, the National Childhood Vaccine Injury Act was passed, creating a compensation program for families affected by childhood vaccine-associated adverse events. Several other government programs and committees to ensure safety of the vaccine supply were also created by this act ( Table 7-2 ). TABLE 7-2 -- National Childhood Vaccine Injury Act, 1986 National Vaccine Injury Compensation Program Limits manufacturer liability Provides payments to families of children who sustain documented injuries following routine immunization Develops and coordinates a comprehensive national vaccine plan Advises Secretary of Health and Human Services on injury compensation program Advises Secretary of Health and Human Services on national vaccine policy 1987 amendment to Compensation Act Proceeds used to finance payments to families of children affected by a vaccine-associated adverse event
National Vaccine Program Advisory Commission on Childhood Vaccines National Vaccine Advisory Committee Federal Excise Tax on Childhood Vaccines
Data from Schwartz B, Orenstein WA. Vaccination policies and programs: the federal government's role in making the system work. Prim Care 2001;28:697-711.
Studies of Vaccine Safety
As many vaccine-preventable diseases approach or reach elimination in the United States, continuing to balance the risks and benefits of each vaccine becomes increasingly important. [52] For example, OPV, formerly recommended for routine use in the United States, was associated with vaccine-associated paralytic poliomyelitis (VAPP: 1 case
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among 2.4 million vaccine doses distributed). This rare adverse event was no longer considered acceptable following elimination of polio in the United States in 2000, and ACIP recommended using IPV for all doses of polio vaccine. [53] Public perceptions of vaccine safety are a challenge to the continued success of the vaccination program. New parents and younger physicians grew up without appreciating the morbidity and mortality of several vaccinepreventable diseases. Therefore risk, or perception of risk, for adverse events becomes an important concern. In the early 1990s, the Institute of Medicine (IOM) reviewed available information regarding the possible causality of serious adverse events after each of the then licensed childhood vaccines. [54] [55] [56] For many events, information was considered insufficient to determine causality. For some events, however, the investigating panels classified events more definitively, as follows: (1) evidence establishes definitively that vaccine plays a causal role; (2) evidence supports a causal role for the vaccine; and (3) evidence indicates that the vaccine definitely does not play a causal role. These events are summarized in Table 7-3 . These investigations represented a comprehensive compilation of data on vaccine safety, although controversy persists regarding certain events. Reanalysis of available data on the occurrence of GuillainBarr syndrome (GBS) after OPV suggests that evidence does not support causation. [57] TABLE 7-3 -- Summary of Institute of Medicine (IOM) Findings on the Relationship of Adverse Events to Individual Vaccines Favoring Rejection of Vaccine Establishes Causation Favoring Causation Causation DT/Td/T Anaphylaxis GuillainBarr syndrome [a] Brachial neuritis Pertussis (whole-cell) (DTP) Anaphylaxis; protracted, inconsolable Acute encephalopathy crying Shock and unusual shocklike state (hypotonichyporesponsive episode) Chronic encephalopathy (after acute encephalopathy) Measles Death from measles vaccine strain in primarily immunocompromised individuals Anaphylaxis Thrombocytopenia Mumps (see MMR) OPV Poliomyelitis Death from polio vaccine strain, mainly in immunocompromised people IPV Hepatitis B Anaphylaxis Early-onset Haemophilus influenzae b disease GuillainBarr syndrome [a] Anaphylaxis Encephalopathy Infantile spasms Death from SIDS Infantile spasms
Hypoarrhythmia Reye syndrome SIDS -
MMR
Autistic spectrum disorders
Hib (conjugate) -
Rubella [b] (see Acute arthritis MMR)
Chronic arthritis
Abbreviations: DT, diphtheria and tetanus toxoid; DTP, diphtheria and tetanus toxoid and pertussis (whole-cell) vaccine; Hib, Haemophilus influenzae type b conjugate vaccine; IPV, inactivated poliovirus vaccine; MMR, measles, mumps, and rubella vaccine; OPV, live oral poliovirus vaccine; SIDS, sudden infant death syndrome; T, tetanus toxoid; Td, tetanus and diphtheria toxoids.
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a The Advisory Committee on Immunization Practice of the United States Public Health Service disagreed with these IOM findings (se e reference
Evidence is consistent with a causal relationship, and Evidence does not indicate a causal relationship.
[32] ).
b Data were reviewed by an earlier IOM committee. Initial report categories corresponding to those table headings were Evidence indicates a causal relationship,
Two prominent public vaccine safety concerns are the perceived causal association of MMR with autism and thimerosal-containing vaccines with autism. As a result of continued concerns about vaccine safety, in 2000 the CDC and National Institutes of Health commissioned the National Academy of Science IOM to convene an Immunization Safety Review Committee. [58] Between 2001 and 2004, this independent expert committee published eight reports related to various immunization safety concerns. The committee has made recommendations in the areas of public health response, policy review, research, and communications for each of the eight subjects reviewed ( Box 7-1 ). With respect to autism, the IOM concluded that the body of epidemiologic evidence favors rejection of a causal relationship between the MMR vaccine and autism. The committee also concluded that there is no relationship between thimerosal-containing vaccines and autism. [58] None of the eight IOM reports recommended a policy review of the current vaccine recommendations or change in the immunization schedule. BOX 7-1 Institute of Medicine Immunization Safety Review Committee Reports and Dates of Release, 2001 to 2004 a Measles-Mumps-Rubella Vaccine and Autism (April 2001) Thimerosal-Containing Vaccines and Neurodevelopmental Disorders (October 2001) Multiple Immunizations and Immune Dysfunction (February 2002) Hepatitis B Vaccine and Demyelinating Neurological Disorders (May 2002) SV40 Contamination of Polio Vaccine and Cancer (October 2002) Vaccinations and Sudden Unexpected Death in Infancy (March 2003) Influenza Vaccines and Neurological Complications (October 2003) Vaccines and Autism (May 2004) .
Data from: http://www.iom.edu/?SearchText=immunization%20safety

Monitoring of Vaccine Safety
To help ensure safety of vaccines, a robust infrastructure consisting of several systems has been established to monitor vaccine safety following vaccine licensure. The Vaccine Adverse Event Reporting System (VAERS), operated jointly by the CDC and FDA, is a national passive surveillance system used to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of recognized events. [59] Intussusception associated with receipt of rotavirus vaccine, leading to withdrawal of the vaccine from the market in 1999, was an adverse event detected by VAERS. [26] [27] A second system is the Vaccine Safety Datalink (VSD), which consists of large linked databases from health maintenance organizations. [52] Associations between serious medical events and immunizations can be evaluated through the VSD. A third system is the Clinical Immunization Safety Assessment centers network, which consists of selected clinical academic medical centers in partnership with CDC to study the pathophysiology of vaccine reactions and develop clinical management protocols for affected patients. These systems are crucial to the vitality and strength of the United States immunization program.
Reporting System for Adverse Events after Immunization
In addition to mandating review of causality of adverse events and creating a unified reporting system for adverse events after vaccination, the National Childhood Vaccine Injury Act (NCVIA) of 1986 established a program to provide compensation to people who experience permanent injury after vaccination. [25] A table of injuries eliciting automatic compensation was developed and has been revised on the basis of the findings of the IOM studies; in addition, any person who shows medical evidence of causality may be compensated. This program is funded by a special excise tax on each dose of vaccine ($0.75 per antigen) to which the program applies (at present, DTaP, Tdap, DTP-Hib, DT, Td, TTIPV, OPV, MMR, Hib, hepatitis A, hepatitis B, PCV7, varicella, rotavirus, pneumococcal conjugate, meningococcal conjugate and polysaccharide, human papillomavirus, and trivalent influenza vaccines). People who believe they have been injured by vaccines should call 800-338-2382 or go to www.hrsa.gov/osp/vicp to obtain information or to file a claim. Physicians should be aware of contraindications to and precautions for each vaccine as defined in package inserts and by the ACIP and AAP. To view the National Childhood Vaccine Injury Act Reporting and Compensation table and
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for qualifications and aid to interpretation of the table, go to www.hrsa.gov/vaccinecompensation/table.htm . Parents should be questioned about the presence of such conditions before any vaccine is administered to their children.
Vaccination in Special Situations Premature Infants
Studies show that response to hepatitis B vaccine may be diminished in infants with birthweights less than 2000 grams after administration of hepatitis B vaccine at birth. [60] However, by 1 month of chronologic age, all preterm infants, regardless of initial birthweight or gestational age, are as likely to respond as adequately as do older and larger infants. [18] [47] Preterm infants born to hepatitis B surface antigen (HBsAg)-positive mothers and mothers with unknown HBsAg status should receive immunoprophylaxis with hepatitis B vaccine and hepatitis B immunoglobulin within 12 hours of birth. If these infants weigh < 2000 grams at birth, the initial vaccine dose should not be counted towards completion of the hepatitis B vaccine series, and 3 additional doses of hepatitis B vaccine should be administered, beginning when the infant is 1 month of age. Preterm infants weighing < 2000 grams and born to HBsAg-negative mothers should receive the first dose of the hepatitis B vaccine series at 1 month of postnatal age if medically stable or at hospital discharge.
Pregnant Women
Risk of vaccination during pregnancy is largely theoretical. [16] The benefit of vaccinating a pregnant woman may outweigh the risk when the risk for disease exposure is high; infection may harm the mother or infant, and the vaccine is unlikely to cause harm. Td and influenza vaccination are indicated for susceptible pregnant women. Healthcare providers can choose to administer Tdap instead of Td to add protection against pertussis. When Td or Tdap is administered during pregnancy, the second or third trimester is preferred. [32] [61] Hepatitis B, hepatitis A, meningococcal and pneumococcal vaccines may be given to pregnant women at high risk of these diseases (see adult ). The greatest concerns have been raised about live vaccines. immunization schedule at www.cdc.gov/vaccine MMR vaccine is contraindicated in pregnant women on theoretical grounds; however, because no case of congenital rubella syndrome has been reported after MMR vaccination among susceptible women exposed to rubella virus through MMR vaccine, inadvertent vaccination is not a reason to interrupt pregnancy. Varicella vaccination also is contraindicated in pregnant women because of the theoretical risk that it may cause birth defects. Pregnancy in a household member is not a reason to postpone vaccination of other family members. In fact, vaccination of family members may be the best way to protect a pregnant mother from being exposed to natural infection. Breastfeeding does not adversely affect the responses to live or killed vaccines; breastfed infants should be vaccinated according to the recommended childhood and adolescent immunization schedule. [7]
Immunocompromised People
People with altered immunocompetence require special considerations for vaccination [18] [22] [47] [62] since they may be at increased risk for serious adverse consequences of disease, at risk for increased risk of serious consequences of vaccination, or at risk for poor response to vaccination. The safety and efficacy of vaccines in people with immune deficiencies are determined by the nature and degree of immune suppression. Immunodeficiency conditions can be grouped into primary and secondary (acquired) disorders. Primary disorders of the immune system generally are inherited as single-gene disorders, may involve any part of the immune system, and share the common feature of susceptibility to infection with various organisms, depending on the specific deficiency. Categories of immunocompromised people with acquired immune deficiency disorders include people with human immunodeficiency virus (HIV) infection; hematopoietic or solid-organ malignancies; immunosuppression due to administration of chemotherapy, systemic corticosteroids, radiation, monoclonal antibodies, or other drugs with significant side effects; and with other chronic conditions, including splenectomy and diabetes mellitus. People in these categories can be safely vaccinated with killed vaccines, which usually are recommended in the same doses and on the same schedules as for immunocompetent people. Response to both killed and live vaccines may be suboptimal, and higher doses or additional doses may be needed to ensure protection. Live vaccines are generally not recommended for any of these groups, except people with chronic conditions (e.g., diabetes mellitus), because of known or theoretical risks of disseminated infection due to the vaccine. Exceptions are MMR and varicella vaccines, which are recommended for susceptible people with HIV infection, with CD4 + T-lymphocyte percentage 15% or greater with no or mild symptoms of disease. [18] [47] [62] Table 7-4 shows recommendations for immunization of children and adolescents with primary and secondary immune deficiencies. TABLE 7-4 -- Immunization of Children and Adolescents with Primary and Secondary Immune Deficiencies Examples of Specific Category Immunodeficiency Vaccine Contraindications Effectiveness and Comment
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Primary [a] B-lymphocyte (humoral) Severe antibody deficiencies (e.g., X-linked agammaglobulinemia and common variable immunodeficiency) OPV, [b] smallpox, LAIV, rotavirus, and live-bacteria vaccines [c] ; consider measles vaccine; no data for varicella vaccine Effectiveness of any vaccine dependent only on humoral response is doubtful; IGIV therapy interferes with measles and possibly immune response All vaccines probably effective. Immune response may be attenuated All vaccines ineffective
Less severe antibody OPV [b] ; other live vaccines [d] deficiencies (e.g., selective IgA seem to be safe, but caution is deficiency and IgG subclass urged deficiencies) T-lymphocyte (cell-mediated and humoral) Complete defects (e.g., severe All live vaccines [c] , [d] combined immunodeficiency, complete DiGeorge syndrome) Partial defects (e.g., most patients with DiGeorge syndrome, WiskottAldrich syndrome, ataxia telangiectasia) Complement Deficiency of early components (C1, C4, C2, C3) All live vaccines [c] , [d]
Effectiveness of any vaccine depends on degree of immune suppression. Recommend inactivated vaccines All routine vaccines probably effective. Pneumococcal and meningococcal vaccines are recommended
None
Deficiency of late components (C5C9), properdin, factor B
None
All routine vaccines probably effective. Meningococcal and pneumococcal vaccines are recommended
Phagocytic function
Chronic granulomatous disease Live-bacteria vaccines [c] Leukocyte adhesion defects Myeloperoxidase deficiency
All inactivated vaccines safe and probably effective. Live viral vaccines probably safe and effective
SECONDARY [a] HIV/AIDS OPV, [b] smallpox, BCG, LAIV [d] ; withhold MMR, varicella, and rotavirus in severely immunocompromised children MMR, varicella, rotavirus, and all inactivated vaccines, including influenza, may be effective [e]
Malignant neoplasm, Live-virus and -bacteria, Effectiveness of any vaccine transplantation, autoimmune depending on immune status depends on degree of immune disease, immunosuppressive or [c] , [d] suppression radiation therapy Reprinted with permission from the American Academy of Pediatrics from AAP immunization in special circumstances. Pickering LK, Baker CJ, Long SS, McMillian JA (eds) Red Book: 2006 Report of COID, 27th ed. Elk Grove Village, IL, AAP, 2006, pp 7374. Abbreviations: AIDS, acquired immunodeficiency syndrome; BCG, bacille Calmette-Gurin; HIV, human immunodeficiency virus; Ig, immunoglobulin; IGIV, immune globulin intravenous; LAIV, live-attenuated influenza vaccine; MMR, measles, mumps, rubella; OPV, oral poliovirus.
a All children and adolescents should receive an annual age-appropriate inactivated influenza vaccine. LAIV is only indicated for healthy people 5 to 49 years of age
(an application has been filed to cover children 2 years of age).
b OPV vaccine is no longer recommended for routine use in the United States. c Live-bacteria vaccines: BCG and Ty21a Salmonella typhi vaccine. d Live-virus vaccines: LAIV, MMR, OPV, varicella, vaccinia (smallpox), yellow fever and rotavirus. Smallpox vaccine is not recommended for children.
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e HIV-infected children should receive immune globulin after exposure to measles (see Chapter 227 Rubeola Virus) and may receive varicella vaccine if CD4 +
lymphocyte count 15% of expected for age (see Chapter 205 Varicella-Zoster Virus).
International Travelers
International travelers frequently have increased risk of exposure to vaccine-preventable diseases, even in economically developed countries. Parents and physicians of children and adolescents planning international travel should ensure that all routine childhood and adolescent immunizations are up to date and that adults are up to date on their immunizations. The need for other vaccines should be determined through consultation with specific guidelines for travelers. [63] Additional information for international travelers can be found on the CDC website at www.cdc.gov/travel or the World Health Organization website at www.who.int/ith/en .
Immigrants
The immunization status of all children immigrating from other countries should be reviewed upon their entry into the United States, and necessary vaccinations administered. Since 1996, the Immigration and Naturalization Act has required that people seeking permanent residency show proof of having received the recommended vaccines as established by the ACIP. Most vaccines given in other countries meet high standards of potency, and immunizations that are documented on an immunization record generally can be presumed to have been effective. Doses that are consistent in initial timing and intervals with United States recommendations can be considered acceptable, and only doses needed to comply with United States recommendations for age need be given. [7] If a child has no immunization record, the immunization series should be initiated; the most significant risk of serious reaction may be to the tetanus component of DTP or DTaP, for which immunization in the presence of high levels of antibody due to prior undocumented immunization can cause serious local Arthus-type reactions.
International Adoptees
Studies have shown that immunization records for international adoptees from some areas (e.g., Eastern Europe, former Soviet Union, and China), especially children from orphanages, may not accurately reflect protection because of inaccurate or unreliable records, lack of vaccine potency, poor nutritional status, or other problems. For any international adoptee, if there is a question as to whether vaccines were administered or were immunogenic, the best course is to administer all vaccines recommended by age. If there is desire to avoid unnecessary injections, the judicious use of serologic testing may help the healthcare provider determine which injections can be avoided (see Chapter 4 , Infectious Diseases in Refugee and Internationally Adopted Children).
Other Programmatic Issues
Responsibility for ensuring that children and adolescents are immunized adequately lies with parents and primary care providers. For children and adolescents without primary healthcare providers, public and hospital-based clinics provide immunizations through federal- and state-funded programs. Each child's immunization status should be assessed every time the child is seen for healthcare, whether for preventive or curative treatment. Physicians should ensure that each child has an immunization record and that the record is updated each time an immunization is given. [64] Parents should be encouraged to bring the immunization record for each healthcare visit. Immunization information systems (i.e., immunization registries) are intended to compile and make available to all providers the immunization records of all children in a city or state. These registries will provide a system whereby reminders about impending or missed immunizations can be generated and providers can gain access to a reliable record for mobile children. [65]
Standards for Child and Adolescent Immunization
The National Vaccine Advisory Committee has developed the following Standards for Child and Adolescent Immunization Practices to help providers maintain practices that optimize children's immunization status [64] : 1. Vaccination services are readily available. 2. 3. 4. 5. 6. Vaccinations are coordinated with other healthcare services and provided in a medical home when possible. Barriers to vaccination are identified and minimized. Patient costs are minimized. Healthcare professionals review the vaccination and health status of patients at every encounter to determine which vaccines are indicated. Healthcare professionals assess for and follow only medically accepted contraindications.
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7. 8. 9.
Parents/guardians and patients are educated about the risks and benefits of vaccination in a culturally appropriate manner and in easy-to-understand language. Healthcare professionals follow appropriate procedures for vaccine storage and handling. Up-to-date, written vaccination protocols are accessible at all locations where vaccines are administered.
10. Persons who administer vaccines and staff who manage or support vaccine administration are knowledgeable and receive ongoing education. 11. Healthcare professionals simultaneously administer as many indicated vaccine doses as possible. 12. Vaccination records for patients are accurate, complete, and easily accessible. 13. Healthcare professionals report adverse events following vaccination promptly and accurately to the VAERS and are aware of a distinct program, the National Vaccine Injury Compensation Program (NVICP). 14. All personnel who have contact with patients are appropriately vaccinated. 15. Systems are used to remind parents/guardians, patients, and healthcare professionals when vaccinations are due and to recall those who are overdue. 16. Office- or clinic-based patient record reviews and vaccination coverage assessments are performed annually. 17. Healthcare professionals practice community-based approaches. The preceding standards provide guidelines for appropriate clinic practices, including identification of appropriate contraindications to immunization (www.cdc.gov/vaccines/recs/vac-admin/contraindications-vacc.htm ), use of tracking systems, and avoidance of missed opportunities. The Task Force for Community Preventive Services has extensively reviewed the scientific literature regarding best practices to improve immunization of young children. [66] [67] The most effective and most strongly recommended interventions are divided into: (1) interventions that increase community demand for vaccines (client reminderrecall systems, multicomponent interventions that include education, and vaccination requirements for school, childcare, and college attendance); (2) interventions that enhance access to vaccination services (reducing out-of-pocket costs for vaccination, expanding access in medical or public health settings, including the Women, Infants, and Children program); and (3) interventions that utilize provider-based interventions (reminderrecall and assessment and feedback for vaccine providers). Conducting audits of patient immunization records in both public clinics and private provider offices is recommended to educate providers about the immunization status of patients as well as to identify practices that can be changed to improve immunization coverage. Routine use of audits in public clinics has reduced missed opportunities for immunization and markedly improved immunization coverage. Self-assessment methods are available from the CDC and AAP. Informed consent and education of parents regarding the importance of immunization are critical features of successful immunization programs. The NCVIA mandated that parents should be provided with written materials for vaccines covered by NVICP that describe the diseases that vaccines are intended to prevent, the risks and benefits of the vaccines, and the procedure for reporting adverse events and seeking compensation for vaccine-related injury. [25] Vaccine information statements, including some not covered by NVICP, are available at www.cdc.gov/vaccines/pubs/vis/default.htm .
Vaccine Shortages
In addition to the rising cost of vaccines, an unparalleled number of vaccine shortages in the United States have had a substantial impact on vaccine delivery. From 2000 through 2007, vaccine shortages, vaccine supply issues, and changes in routine recommendations occurred for almost all vaccines in the childhood and adolescent immunization schedule. [68] [69] [70] [71] [72] [73] [74] [75] The shortages affected millions of children and their healthcare providers, even triggering suspension of school entry requirements for vaccines. [75] [76] [77] Two vaccine shortages (PCV7 and Td) lasted nearly 2 years, one (PCV7) occurred twice, and one (inactivated influenza vaccine, 2004/2005 season) halved the nation's influenza vaccine supply virtually overnight. [73] The causes of these widespread vaccine shortages are multifactorial. One important long-term factor is the decrease in the number of vaccine manufacturers of childhood vaccines routinely recommended in the United States. In 1993, six manufacturers produced the six vaccines. Over a decade later, although several vaccines (PCV7, varicella, influenza, Tdap, rotavirus, MMRV, herpes zoster, conjugated meningococcal, and HPV) have been added to the recommended schedules, the number of manufacturers decreased to five. In addition, there are single manufacturers for many of the childhood and adolescent vaccines (MMR, varicella, PCV7, and conjugated meningococcal). In response to concerns over the fragility of the United States vaccine supply, the General Accounting Office and National Vaccine Advisory Committee both conducted indepth reviews of the vaccine shortages and concluded that future disruptions in vaccine supply are likely to continue, and they proposed solutions. [68] [78]
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Handling and Storage of Vaccines
Vaccines are perishable products that require specific care in handling and storage; ensuring that a vaccine maintains potency and safety is a responsibility shared by the manufacturer and all people handling the vaccine. Live-attenuated vaccines are more susceptible to degradation when exposed to temperature extremes, whereas inactivated vaccines and toxoids generally are more stable when exposed to ambient temperatures. However, inactivated vaccines containing adjuvants must be protected from freezing to ensure potency. [18] Vaccines that are exposed to damaging environmental conditions can suffer loss of potency without a change in appearance. A vaccine quality control program should be established in each clinical practice and should focus on education of personnel, maintenance of equipment, and adherence to established daily monitoring of vaccines.
Vaccine Financing
Ensuring that all children and adolescents, regardless of health insurance status or income level, have access to recommended vaccines requires a complex system of financing which includes private and public funding mechanisms ( Table 7-5 ). In 2002, 57% of United States children received vaccines purchased through the public sector, and 43% received vaccines purchased through the private sector. Most of the public-purchase vaccines are financed through the Vaccines for Children program, an entitlement program established in 1994 as part of the Social Security Act. [23] [24] Other government funding mechanisms include Section 317 of the Public Health Service Act of 1962, a federal grant program, and state and local government funding. These programs support states to provide immunizations to children who do not qualify for the Vaccines for Children program but who are not covered by private insurance. Several states use a combination of federal and state funding to purchase and distribute vaccines recommended for children to all immunization providers in private and public sectors. Insurance programs provide vaccines for children in the private sector. TABLE 7-5 -- Major Government Financing Programs for Childhood Immunization Variable Type of program Vaccines for Children Program Entitlement funded through Medicaid trust fund Section 317 Annual discretionary appropriation by Congress State/Local Government Appropriations through state or local legislatures Varies by state or local area
Eligibility
Age < 19 years and membership in 1 of the No federal following categories: Medicaid-eligible; eligibility uninsured; Alaska Native or American Indian; restrictions or underinsured at a federally qualified health center Vote of ACIP and establishment of a federal contract; funds must be approved by the Office of Management and Budget and the Department of Health and Human Services Funding must be sought from Congress
Financing of new vaccines and recommendations
Funding must be sought from state legislatures
Proportion of childhood 41% 11% 5% vaccine market purchased Data from Hinman AR, Orenstein WA, Rodewald L. Financing immunizations in the United States. Clin Infect Dis 2004;38:14401446. Abbreviation: ACIP, Advisory Committee on Immunization Practices.
Surveillance for Vaccine-Preventable Diseases and Adverse Events
Monitoring the effect of vaccination programs and the safety of vaccines is critical for refining immunization strategies and reassuring the public and medical community that vaccines are safe. Surveillance for vaccinepreventable diseases is mandated by each state, and data are compiled in the National Notifiable Disease Surveillance System at the CDC. [79] These data are monitored to assess effectiveness of vaccines and of the vaccination program. For each reported case of disease, confirmation of disease by laboratory testing and documentation of the patient's vaccination status are critical to determining whether continued occurrence of disease is due to failure to deliver vaccine or failure of vaccine. As programs approach elimination of indigenous transmission, determination of chains of disease transmission as well as whether the case is indigenous or imported, and rapid implementation of control measures also become critical. All physicians are urged to report all suspected cases of vaccine-preventable diseases
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promptly to their local and state health departments. Monitoring of adverse events after vaccination is the joint responsibility of the FDA and CDC. [25] [52] Physicians are required to report certain events that occur after vaccination and should report all suspected adverse reactions after vaccination to VAERS. VAERS forms are available through state health departments, physicians, and from VAERS at 800-822-7967; forms also can be obtained and submitted electronically through a secure website at http://vaers.hhs.gov . ROUTINE CHILDHOOD AND ADOLESCENT VACCINES
Diphtheria and Tetanus Toxoids, and Pertussis Vaccines
In 1980 cutaneous diphtheria was no longer a nationally notifiable disease in the United States. Since 1990, 28 cases of respiratory diphtheria have been reported. Since 2000, 208 cases of tetanus have been reported in the United States, with 38 cases reported in 2006, [29] and 27 in 2005, the majority (76%) of which occurred in people over 40 years of age. In 2004 the number of reported cases of pertussis increased for the third year in a row, with 25827 cases reported, the highest since 1959. [29] In 2006 the number of cases was 5826. Although infants have the highest morbidity associated with pertussis, adolescents and adults account for the majority of reported cases. [80] Immunization of children and adolescents to prevent diphtheria, tetanus, and pertussis usually is completed with a vaccine composed of diphtheria and tetanus toxoids combined with an acellular pertussis component. [32] [61] [81] [82] [83] Diphtheria and tetanus toxoids are purified preparations of formalin-inactivated diphtheria and tetanus toxins, respectively. Table 7-6 shows the composition and recommended use of vaccines with tetanus toxoid, diphtheria toxoid, and acellular pertussis components licensed in the United States for children under 7 years of age and people over 7 years of age. Whole-cell DTP was the only pertussis vaccine available from 1948 through 1992; because of its relatively high rate of adverse reactions compared with the newer acellular pertussis vaccines, DTP is no longer recommended for use in the United States. [82] Nevertheless, DTP made with whole-cell pertussis vaccine continues to be the most frequently used pertussis-containing vaccine worldwide. TABLE 7-6 -- Composition of Selected Vaccines with Tetanus Toxoid, Diphtheria Toxoid, and Acellular Pertussis Components Licensed in the United States, 2006 Pertussis antigen (g/dose) Vaccines for children < 7 Trade years of age [a] name PT FHA PRN FIM Recommended Use DTaP DTaPIPVHepB DTaP DTaP Infanrix Pediarix Daptacel Tripedia 25 25 10 25 25 5 8 8 3 5 All 5 doses First 3 doses First 4 doses All 5 doses Fourth dose only Use instead of DTaP if pertussis contraindicated Single dose indicated for people 10 through 18 years of age Single dose indicated for people 11 through 64 years of age Every 10 years
23.4 23.4 23.4 23.4 -
DTaP + HIB (Tripedia + ACT Trihibit + HIB) DT No trade name Boostrix Adacel Several
Vaccines for people 7 years of age Tdap Tdap Td 8 2.5 8 5 2.5 3 5 -
DT, diphtheria and tetanus toxoid; DTaP, diphtheria and tetanus toxoids, and acellular pertussis for use < 7 years of age; FHA, filamentous hemagglutinin antigen; FIM, fimbriae; HepB, hepatitis B; IPV, inactivated poliovirus vaccine; PRN, pertactin; PT, pertussis toxoid, Td, tetanus and reduced-content diphtheria toxoid for use 7 years of age; Tdap, tetanus toxoid and reduced-content diphtheria toxoid and acellular pertussis vaccine for use in adolescents.
a In mid 2007 combination vaccine DTaP-IPV reconstituted with Hib-tetanus toxoid conjugate vaccine (Pentacel) is under review for licensure for doses 14 of
DTaP.
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Recommendations for DTaP Immunization for Children < 7 Years of Age
Immunization with DTaP vaccine is recommended for all children < 7 years of age. Primary vaccination consists of three doses of DTaP vaccine given at 2, 4, and 6 months of age; the minimal age for initiating vaccination is 6 weeks, and the minimal interval between doses is 4 weeks (see Figure 7-2 ). [7] [81] [82] To ensure protection, a reinforcing dose of DTaP is given at 15 to 18 months of age, and a booster dose at school entry (4 to 6 years of age). Diphtheria and tetanus (DT) toxoids are used in children for whom pertussis vaccination is contraindicated. If the schedule is interrupted, there is no need to restart the series. Although DTP vaccines are still licensed in the United States, they are no longer available or recommended for use in the United States childhood and adolescent immunization schedule. The vaccination advisory bodies consider data insufficient to support expression of a preference among the different acellular pertussis vaccines. [81] Whenever feasible, the same brand of DTaP vaccine should be used for all doses of the vaccination series in a patient, although data suggest that two of the available preparations may be used interchangeably for the first 3 doses of the DTaP series. [51] If the vaccine provider does not know or does not have available the type of DTaP vaccine previously administered, any of the DTaP vaccines can be used to complete the vaccination series. DTaP vaccines can be given simultaneously with other recommended childhood vaccines (hepatitis B, Hib, IPV or OPV, PCV7, rotavirus) at 2, 4, and 6 months of age, and can be given with these vaccines as well as with MMR, varicella, and hepatitis A vaccines at 15 to 18 months of age. DTaP is not licensed for use in adults or in children > 7 years of age. Vaccination to prevent diphtheria and tetanus is recommended for previously unvaccinated children (> 7 years of age and in whom pertussis vaccine is contraindicated) and adults. Tetanus toxoid and Tdap are available for people from 10 to 65 years of age. [32] Use of tetanus toxoid-containing preparations, with or without tetanus immunoglobulin, may be indicated after penetrating or other types of injuries in people who are not adequately vaccinated. [83] For any such person who has not previously received the three-dose primary series, initiation or continuation of the primary vaccination appropriate for age (DTaP, Tdap, DT, or Td) is recommended after any wound. Vaccination is not necessary in people who have received three prior doses of tetanus vaccine, unless: (1) the last vaccination occurred more than 10 years previously (5 years for wounds other than clean and minor wounds); or (2) only three doses of fluid (nonadjuvant) tetanus toxoid were received, in which case one dose of Td vaccine should be given (see Chapter 188 , Clostridium tetani).
Precautions and Contraindications
Vaccination with any pertussis-containing vaccine is contraindicated in any child who has had an anaphylactic reaction to any component of the vaccine or has experienced acute encephalopathy within 7 days of administration of a previous dose. [81] The following events are considered precautions to pertussis immunization: (1) temperature 40.5C or higher within 48 hours of a prior dose not attributed to another cause; (2) collapse or shocklike state (hypotonic-hyporesponsive episode) within 48 hours of DTP or DTaP administration; (3) persistent inconsolable crying (3 hours or longer) within 48 hours of administration of DTP or DTaP; and (4) convulsions with or without fever within 3 days of immunization. When these events occur, the physician may elect to continue vaccination if the benefits are judged to outweigh the risks, as when a pertussis outbreak is occurring in the community. In addition, DTaP immunization should be deferred in children with evolving neurologic disorders until the situation is clarified; when stable, the child can receive a DTaP vaccine. Decisions about pertussis vaccination of such children should be made before the first birthday. If pertussis vaccine is not used, pediatric DT should be administered.
Recommendations for Tdap Immunization for Adolescents 11 Through 18 years of age
Adolescents 11 through 18 years of age should receive a single dose of Tdap instead of Td for booster immunization against tetanus, diphtheria, and pertussis if they have completed the recommended childhood DTP/DTaP vaccination series [7] and have not received Tdap. The preferred age for Tdap vaccination is 11 to 12 years of age; routinely administering Tdap to young adolescents will reduce the morbidity associated with pertussis in adolescents. Adolescents 11 to 18 years of age who received Td, but not Tdap, are encouraged to receive a single dose of Tdap to provide protection against pertussis if they have completed the recommended childhood DTP/DTaP vaccination series. [7] [32] [61] An interval of at least 5 years between Td and Tdap is encouraged to reduce the risk for local and systemic reactions after Tdap vaccination. However, an interval less than 5 years between Td and Tdap can be used. [32] [61] The benefit of using Tdap at a shorter interval to protect against pertussis generally outweighs the risk for local and systemic reactions after vaccination in settings with increased risk for pertussis or its complications. [84]
Contraindications, Precautions, and Reasons to Defer Tdap or Td among Adolescents 11 Through 18 years of age
Contraindications to Tdap include a history of serious allergic reaction (i.e., anaphylaxis) to vaccine components or
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encephalopathy (e.g., coma or prolonged seizures) not attributable to an identifiable cause within 7 days of administration of a vaccine with pertussis components. This is a contraindication for the pertussis components; Td can be used. Precautions and reasons to defer Tdap include: GBS less than 6 weeks after a previous dose of a tetanus toxoidcontaining vaccine; progressive neurologic disorder, including progressive encephalopathy, or uncontrolled epilepsy, until the condition has stabilized (these conditions are precautions for the pertussis components; Td can be used); moderate or severe acute illness; and history of an Arthus reaction after a tetanus toxoid-containing and/or diphtheria toxoid-containing vaccine administered < 10 years previously.
Special Situations for Tdap (Single-Dose) and Td Use among Adolescents 11 Through 18 Years of Age
If simultaneous vaccination is not feasible, inactivated vaccines can be administered at any time before or after a different inactivated or live vaccine. ACIP recommends that Tdap (or Td) and MCV4 vaccines (which all contain diphtheria toxoid) can be administered using any sequence. Because sequential Tdap and MCV4 have not been studied, and people who recently received diphtheria-containing vaccine might not respond adequately to additional antigen, the AAP recommends that, if simultaneous administration of Tdap and MCV4 is not feasible, administration should be separated by 1 month. [61] The following situations for administration of Tdap should be considered [32] : Pertussis outbreaks and other settings with increased risk for pertussis or its complications: vaccine providers can administer Tdap to adolescents 11 through 18 years of age at an interval less than 5 years after Td, particularly when the benefit of providing protection against pertussis is likely to be increased (e.g., pertussis outbreaks and close contact with an infant less than 12 months of age). The safety of an interval as short as approximately 2 years between Td and Tdap is supported by a Canadian study among children and adolescents. [84] Postexposure chemoprophylaxis and other pertussis control guidelines are available. [85] Lack of availability of Tdap or MCV4. If Tdap and MCV4 are both indicated for adolescents but only one vaccine is available, the available vaccine should be administered. Use of Td when Tdap is not available. When Tdap is indicated but not available, vaccine providers should administer Td if the last pediatric DTP/DTaP/DT or Td dose was > 10 years earlier to provide protection against tetanus and diphtheria. Tetanus prophylaxis in wound management. Adolescents who require a tetanus toxoid-containing vaccine as part of wound management should receive a single dose of Tdap instead of Td if they previously have not received Tdap; if Tdap is not available or previously was administered, adolescents who need a tetanus toxoid-containing vaccine should receive Td. History of pertussis. Adolescents who have a history of pertussis generally should receive Tdap according to the routine recommendations. No history of pertussis vaccination. Adolescents who have not received vaccines with pertussis components but completed the recommended tetanus and diphtheria vaccination series with pediatric DT or Td should generally receive Tdap according to the routine recommendations if they do not have a contraindication to the pertussis components. No history of pediatric DTP/DTaP or Td/Tdap vaccination. Adolescents who have never received tetanusdiphtheria-pertussis vaccination should receive a series of three vaccinations. The preferred schedule is a single Tdap dose, followed by a dose of Td > 4 weeks after the Tdap dose and a second dose of Td 6 to 12 months after the earlier Td dose. Tdap can be substituted for any one of the three Td doses in the series. Routine postpartum Tdap. Pregnant women who have not previously received a dose of Tdap (including women who are breastfeeding) should receive Tdap after delivery, before discharge from the hospital or birthing center, if > 2 years since the last Td; shorter intervals can be used. If Tdap cannot be administered before discharge, it should be given as soon as feasible. The dose of Tdap replaces the next decennial dose of Td. [86] A major goal of this dose is to decrease exposure of young infants to pertussis. Considerations for use of Td and Tdap in pregnant women. The AAP recommends that pregnant adolescents be given the same considerations for immunization with Tdap as nonpregnant adolescents. [61] If Td or Tdap is given, administration in the second or third trimester is preferred. [61] [86] ACIP recommends Td when tetanus and diphtheria protection is required during pregnancy. In some situations, healthcare providers can choose to administer Tdap instead of Td to add protection against pertussis. Pregnancy is not a contraindication for use of Tdap. Data on safety, immunogenicity, and the outcomes of pregnancy are not available for pregnant women who receive Tdap. When Tdap is administered during pregnancy, transplacental maternal antibodies might protect the infant against pertussis in early life. These antibodies also could interfere with the infant's immune response to infant doses of DTaP, potentially leaving the infant
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less well protected against pertussis. Providers who choose to administer Tdap to pregnant women should discuss the lack of data with the pregnant women. They are encouraged to report Tdap administrations, regardless of the trimester, to the appropriate manufacturer's pregnancy registry: for Boostrix to GlaxoSmithKline Biologicals at 1-888-8255249, or for Adacel to Sanofi Pasteur at 1-800-822-2463 (1-800-vaccine).
Haemophilus influenzae Type b Conjugate Vaccines
Before introduction of conjugated Hib vaccines in 1987, the incidence of invasive Hib diseases among children 5 years of age was estimated to be 100 cases/100000. In 2005, the incidence of invasive Hib disease from all serotypes and all age groups was 0.78 cases per 100000. In 2005 there were 361 cases of invasive disease due to H. influenzae reported in children 5 years of age, of which 2.5% were type b, 37% were nonserotype b, and 60% were of unknown serotype. [29] Hib conjugate vaccines, first licensed for 18-month-old children in 1987 and for infants 2 months of age and older in 1990, have replaced the polysaccharide vaccines available from 1985 to 1989. [87] Hib conjugate vaccines contain Hib polysaccharide covalently linked with a protein carrier, which induces a T-lymphocyte-dependent immune response and immune memory not induced by polysaccharide (polyribosylribotol phosphate (PRP)) vaccine alone. Carrier proteins for vaccines licensed for infants include tetanus toxoid (PRP-T vaccine); a mutant, nontoxic diphtheria toxin, CRM197 protein conjugate (HbOC); and the OMP of Neisseria meningitidis (PRP-OMP). One combination DTaP-Hib vaccine is licensed for use only for the dose given at 12 to 15 months of age (PRP-T reconstituted with DTaP). When given as a two-dose (PRP-OMP) or three-dose (PRP-T, HbOC) primary series to infants, Hib vaccine induces a high level of antibody to Hib polysaccharide, which wanes over the next 6 to 12 months, necessitating a booster dose at 12 to 18 months of age. PRP-OMP induces a substantial response after a single dose and may be preferred for populations at highest risk of infant infection (Native Americans, including Alaska Natives); the other vaccines require three doses for optimal response in infants. [87] Controlled trials showed 93% to 100% efficacy for both PRPOMP and HbOC in infants in the United States; licensing of PRP-T was based on comparable immunogenicity, efficacy data from a British trial, and ecologic data from Finland. Several studies have shown that giving different Hib vaccines during the primary series induces a response similar to that induced by a primary series with the same vaccine and that booster doses with different vaccines induce strong responses. [50] [87]
Recommendations for Immunization
Hib vaccination is recommended for all infants starting at 6 weeks to 2 months of age ( Figure 7-2 ). [7] [47] [87] For HbOC and PRP-T, three primary doses are given at 2-month intervals (1 month is acceptable), with a booster dose at 12 to 15 months of age. For PRP-OMP, two doses are given at 2-month intervals followed by a booster at 12 to 15 months of age. When primary immunization is delayed, the number of doses is reduced; for children vaccinated beginning at 6 to 11 months of age, two primary doses with a 2-month interval are recommended for each of the three vaccines, followed by a booster at > 12 months of age. If vaccination is initiated at 12 to 14 months of age, two doses with a 2-month interval are indicated. For initiation of vaccination in children 15 to 59 months of age, a single dose of any of the licensed vaccines is recommended. Although the primary series ideally should be completed with the same vaccine, three doses of any vaccine are sufficient if the initial vaccine is not available or is unknown. Booster doses can consist of any of the licensed vaccines. The licensed combination DTaP-Hib vaccine can be used only for booster doses in children 12 months of age or older. [7] [47] [87] Hib vaccines (and the DTaP-Hib combination) can be given simultaneously with all other childhood vaccines, including DTaP, IPV or OPV, hepatitis B, PCV7, MMR, varicella, hepatitis A, and rotavirus vaccines. Vaccination of children older than 59 months of age can be considered for certain high-risk groups, including children with sickle-cell disease, splenectomy, leukemia, or HIV infection. [18] [47] [87] For these children, one or two doses of vaccine are indicated but may not be as highly immunogenic as in healthy children. Immunization is indicated in children with prior Hib disease during the first 2 years of life, in whom adequate immunity may not develop after infection, but is not necessary in older children who have had Hib disease.
Contraindications and Precautions
The only known common adverse events following administration of Hib vaccines are fever and local reactions, observed in fewer than 4% of recipients. Unlike polysaccharide vaccines, Hib conjugate vaccines are not associated with increased risk of invasive Hib disease within the week after vaccination. [55] [57] The only contraindication to Hib vaccine is an anaphylactic reaction to a previous dose of the same vaccine.
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Hepatitis B Vaccine
During 1990 to 2004, the number of acute hepatitis B cases reported annually declined 68%. [31] [88] This steady decline has coincided with implementation of a national strategy to achieve elimination of hepatitis B. The primary elements of this strategy are: (1) screening of all pregnant women for HBV infection with the provision of postexposure prophylaxis to infants born to infected women; (2) routine vaccination of all infants and children less than 19 years of age; and (3) vaccination of others at increased risk for hepatitis B (e.g., healthcare providers, men who have sex with men (MSM), injection drug users (IDUs), and household and sexual contacts of people with chronic HBV infection). [31] [88] In 2004, the rate of hepatitis B among children < 13 years of age, the cohort born since routine infant vaccination was implemented, was 0.07 per 100000 population, representing a 94% decline for that age group since 1990. Since 1990, the disparity between the population with the highest (Asian Pacific Islanders) and the lowest (whites) incidence has been reduced by greater than 90%. Since 1990, rates among adolescents 14 to 18 years of age have also declined to approximately 94%, but the 2004 rate (0.4 per 100000 population) remains substantially higher than the rate for children less than 13 years of age. [88] During 1990 to 1999, rates among adults declined 63%, but have since remained essentially unchanged. Among adults, a high proportion of cases occur among people in identified risk groups (i.e., IDUs, MSM, and people with multiple sex partners), indicating a need to strengthen efforts to reach these populations with vaccine. [31]
Hepatitis B vaccine consists of purified HBsAg particles produced through recombinant DNA technology in yeast. Table 7-7 shows vaccine products that contain hepatitis B antigen licensed in the United States. Vaccine usually is given as a three-dose series; the second and third doses are administered 1 and 6 months, respectively, after the first dose. An alternative schedule includes four doses, the second, third, and fourth given at 1, 2, and 12 months, respectively, after the first. Schedules that vary the timing of the second and third doses to permit integration into the recommended childhood and adolescent immunization schedule have been shown to be highly immunogenic. A twodose schedule (second dose given 4 to 6 months after the first) has been approved for adolescents 11 to 15 years of age for one hepatitis B vaccine. Dosages vary by age, vaccine, and whether the child is born to an HBsAg-positive mother; dosages for infants and children are half of those required for adults. Minimal intervals between doses should be 1 month between the first two doses, and 2 months, but preferably 4 to 6 months or more, between the second and third doses; lapsed immunization does not necessitate restarting the vaccine series. [7] Three products that combine hepatitis B vaccine with other vaccine antigens are licensed for use at various ages ( Table 7-7 ). TABLE 7-7 -- Hepatitis B-Containing Vaccines Licensed in the United States Vaccine Antigen content Recommended age group Recombivax HB Hepatitis B Engerix-B Comvax Pediarix Twinrix Hepatitis B Hepatitis B + DTaP + IPV Hepatitis B + hepatitis A All age groups All age groups 6 weeks to 6 years of age 18 years of age
Hepatitis B and Hib conjugate 6 weeks to 71 months of age
DTaP, diphtheria and tetanus toxoids and acellular pertussis; Hib, Haemophilus influenzae; IPV, inactivated poliovirus vaccine.
Response to a three-dose series is excellent in all age groups, producing antihepatitis B antibodies (anti-HBs) in 85% to 99% of recipients; response is highest in children 2 to 19 years of age. [31] [88] People with immunocompromising conditions, such as renal failure, have poorer response, and higher dosages are recommended. Vaccine efficacy measured in placebo-controlled trials in both high-risk children (infants of HBsAg-positive mothers) and adults has shown a short-term efficacy of 80% to 95%. Long-term follow-up of children and adults has demonstrated protection against serious consequences of infection (chronic carriage and chronic liver disease) in almost all people who show response to the initial series (anti-HB level of 10 mIU/mL or greater), but continued studies are needed. Booster doses of hepatitis B vaccine are not recommended for any age group; however, the need for booster continues to be evaluated. Hepatitis B vaccine can be given simultaneously with all other childhood vaccines.
Hepatitis B vaccination is contraindicated for people with a history of hypersensitivity to yeast or to any hepatitis B
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vaccine component. Despite a theoretic risk for allergic reaction to vaccination in people with allergy to Saccharomyces cerevisiae (baker's yeast), no evidence exists that documents adverse reactions after vaccination of people with a history of yeast allergy. People 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, immunization of people with moderate or severe acute illness, with or without fever, should be deferred until the acute phase of the illness resolves. Immunization is not contraindicated in people with a history of multiple sclerosis, GuillainBarr syndrome, autoimmune disease (e.g., systemic lupus erythematosus or rheumatoid arthritis), or other chronic diseases. [57,] [58] Pregnancy is not a contraindication to vaccination. Limited data indicate no apparent risk for adverse events to developing fetuses when hepatitis B vaccine is administered to pregnant women.
Measles, Mumps, and Rubella Vaccine
Vaccination programs have reduced the incidence of disease due to measles, mumps, and rubella in the United States. [29] Implementation of these strategies has resulted in interruption of measles transmission in the United States and an all-time low number of 37 measles cases reported in the year 2004, 27 of which were imported and resulted in 6 secondary cases. The largest outbreak of measles cases in the United States in 2005 involved 34 cases. [89] On October 29, 2004, a nine-person independent panel unanimously agreed that rubella is no longer endemic in the United States. [33] In 2006 there was one case of congenital rubella reported in the United States. The incidence of reported cases of mumps in the United States had been decreasing until 2006 when an outbreak involving several thousand people occurred. [90] Protection against measles, mumps, and rubella is provided by the combined MMR and MMRV vaccines. [91] [92] Measles vaccine is a live-attenuated virus vaccine produced from the Moraten strain of measles virus, which was derived from the Edmonston B strain. Mumps vaccine is a live-attenuated vaccine derived from the Jeryl Lynn strain of mumps virus. Rubella vaccine is a live-attenuated vaccine derived from the RA27/3 strain of rubella virus that was grown on human diploid cells. Other rubella strains, with slightly different safety and efficacy profiles, were used in the United States before 1979. These vaccines also are available in monovalent and bivalent preparations, use of which is limited for outbreak control and for catch-up immunization of people known not to have received these vaccines.
A single dose of measles vaccine given to children 12 months of age or older induces antibody and produces protection in 95% to 98% of recipients; protection is long-lasting, and waning of immunity, although documented in several studies, appears to be uncommon and plays a minimal role in measles outbreaks, [91] [93] which occur in the United States because of importation and spread to unimmunized people. [89] Nevertheless, because infrequent vaccine failure with one dose led to frequent measles outbreaks among schoolchildren, a second dose of MMR vaccine is now recommended for all children. In most studies, the second dose increases measles antibody response to greater than 99%, whether it is given within 3 months of the initial dose or years later upon a child's entry to primary or middle school. Additionally the booster dose can induce antibody increases in people with low levels of antibody, but the increases appear to be short-lived. A single dose of mumps vaccine given at 12 to 15 months of age induces detectable antibodies in 97% of recipients. Immunity is long-lasting, possibly lifelong, but waning immunity (or possibly primary vaccine failure) has been suggested as a contributing cause in some mumps outbreaks in highly vaccinated school populations. A large mumps outbreak that began in Iowa in December 2005 and spread to several other states prompted a change in recommendations for use of mumps-containing vaccines. [90] In addition to routine immunization, the CDC recommends MMR vaccine for people born after 1957 who do not have a history of physician-diagnosed mumps infection, laboratory evidence of immunity, or immunity through vaccine, which the ACIP has redefined as 1 dose of mumps vaccine for preschool children and adults not at high risk and 2 doses for children in grades K to 12 and adults at high risk (healthcare providers, international travelers and posthigh-school students). During an outbreak, a second dose should be considered for all adults and children 1 to 4 years of age who have not received two doses; the second dose is given at least 28 days after the first dose. The CDC suggests that unvaccinated healthcare providers born before 1957 who do not have other evidence of immunity also should receive two doses of the vaccine during an outbreak. Rubella vaccine induces a primary response in 95% to 98% of children vaccinated at 12 months of age or older; protection is long-lasting, with greater than 90% of recipients protected against clinical disease and viremia for more than 15 years.
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Vaccination to prevent measles, mumps, and rubella is recommended for all children and adolescents. [91] Measles vaccination and now mumps vaccine are recommended in a two-dose series, given as MMR or MMRV, for all susceptible people. MMRV vaccine is indicated for simultaneous immunization against measles, mumps, rubella, and varicella among children 12 months through 12 years of age; MMRV is not licensed for people outside this age group. [92] For infants and young children, the first dose should be given at 12 to 15 months of age, and the second at 4 to 6 years of age. [91] The timing of the first dose is based on the likelihood that maternal antibody persists during the second year of life; in the past, persistence of maternal antibody accounted for lower efficacy when vaccine was given at 12 to 14 months of age. Later studies have shown that younger mothers, who have acquired antibody through vaccination, may transfer less measles antibody to their infants (because vaccine induces lower titers than natural measles infection), who then become susceptible at a younger age. [94] During outbreaks that affect children younger than 1 year of age (and for international travel to areas where measles is endemic), the age of measles vaccination should be lowered to 6 months of age (with use of the monovalent measles vaccine); children vaccinated before 12 months of age should be vaccinated with two doses of MMR or MMRV at the recommended ages. [95] Recommendations for timing of the second dose of MMR are based on: (1) the major benefit of the second MMR in reducing the proportion of children who remain susceptible to measles because of failure of the primary vaccine; and (2) the ease of implementation by using the preschool immunization visit. All children should be given the second dose of MMR vaccine at school entry if it was not given previously. The ACIP recommends that states implement requirements that all children entering school have received two doses of MMR after the first birthday. [91] Receipt of two doses of MMR vaccine is also recommended for all people entering or enrolled in college; many states now implement prematriculation requirements, which have been shown to reduce the risk of measles outbreaks in these populations. Rubella vaccination is recommended for all susceptible adults. [91] Adolescents and adults should be considered susceptible to rubella and should be vaccinated unless they have a history of at least one dose of vaccine or have serologic evidence of immunity. Ensuring rubella immunity is especially important in women of childbearing age. A clinical history of rubella is not sufficiently reliable. Delivery of rubella vaccine to adults is more successful in programs that do not use prevaccination screening, because screening requires a second visit for susceptible people to be vaccinated. Programs to ensure immunity to measles, mumps, and rubella are recommended for all healthcare providers and for international travelers, who may be exposed to these diseases in countries with less effective control programs. [91] Among people born after 1956, measles immunity should be based on receipt of two doses of measles vaccine, serologic evidence of immunity, or a prior physician-diagnosed case of measles. Acceptable presumptive evidence of immunity to mumps includes one of the following: (1) documentation of adequate vaccination; (2) laboratory evidence of immunity; (3) birth before 1957; or (4) documentation of physician-diagnosed mumps. Evidence of immunity through documentation of adequate vaccination is now defined as 1 dose of a live mumps virus vaccine for preschool-aged children and adults not at high risk and 2 doses for school-aged children (i.e., grades K to 12) and for adults at high risk (i.e., healthcare providers, international travelers, and students at posthigh-school educational institutions).
Measles, MMR, and MMRV vaccines produce minor reactions, including fever of 39.4C or greater in 5% to 15% and transient rash in 15% of recipients. Fever and rash occur between 4 and 14 days after vaccination and last for several days. More serious reactions include febrile convulsions, in 1/2000 to 3000 recipients 1 to 2 years of age; risk is higher in people with a personal or family history of convulsions. [57] [92] [96] Thrombocytopenia, which usually is transient, may occur in 1/30 000 recipients of MMR vaccine, and anaphylaxis, more rarely. [91] Cases of encephalitis have been reported, with an onset of about 10 days after vaccination, after fewer than 1/1 million vaccine doses, but a causal role of measles vaccination has not been established. Available data do not support a relationship between measles-containing vaccine and subacute sclerosing panencephalitis (SSPE); in fact, widespread use of measles vaccines has virtually eliminated SSPE; no case of SSPE confirmed to be caused by vaccine virus has been reported. [56] [91] [97] The IOM rejected a hypothesized causal relationship between MMR vaccine and autism spectrum disorders. [57] Uncommon adverse events after mumps vaccines include aseptic meningitis, parotitis, orchitis, and low-grade fever. Reactions are expected to be less frequent among recipients of the second dose. Adverse events after rubella vaccination include fever and mild rash in 5% to 10% of recipients, and joint pain, generally without arthritis. The frequency of arthritis increases with age of vaccination, particularly for recipients older than 15 years of age, and can reach 40% in older adult women. [91] The rate of acute arthritis is lower than that observed for natural rubella virus infection in the same age group. [54] [57] In one study, the IOM concluded that rubella vaccination may cause chronic arthritis in adult women at rates as high as 5%. [57] However, other studies have found no evidence for a risk of onset of chronic arthropathy after rubella vaccination, and a randomized trial found only a small risk of persistent joint pains. [98] [99] The RA 27/3 rubella vaccine has not been linked to
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radiculoneuritis or neuropathy. Vaccination with MMR or any component vaccine is contraindicated in pregnant women, people with anaphylaxis to neomycin or gelatin, and in people who are immunocompromised because of: (1) congenital or acquired immune disorders, such as leukemia, lymphoma, and HIV infection with severe immunocompromise; (2) long-term systemic corticosteroid treatment; or (3) chemotherapy. [91] Rarely, disseminated infection and death due to measles encephalitis have been reported in immunocompromised people who were inadvertently given measles vaccine. [55] Measles (and MMR) vaccination is indicated for people with asymptomatic HIV infection, because measles disease can be severe in such people and vaccine may induce immunity; vaccination should be considered for symptomatic HIV-infected people if they do not have evidence of severe immunocompromise and they lack measles immunity. [22] [62] Data show that even people with severe egg allergy can be vaccinated. Most anaphylactic reactions appear to be related to other vaccine components (e.g., gelatin). [100] Rubella vaccine virus is able to cross the placenta and cause fetal infection; however, no case of congenital rubella syndrome due to vaccine virus has been reported in infants of 680 susceptible women who received rubella vaccine within 3 months of conception and who carried their pregnancies to term. [101] The ACIP recommends that rubella vaccination not be considered a reason to interrupt pregnancy, but also that rubella vaccine not be given knowingly to a pregnant woman. A reasonable approach is to ask women whether they are pregnant now or may become pregnant within the next 28 days after immunization and to vaccinate only women who answer negatively.
Pneumococcal Conjugate and Polysaccharide Vaccines
Before use of PCV7, Streptococcus pneumoniae was the most common bacterial cause of acute otitis media and invasive bacterial infections in children, with over 17000 cases of invasive disease in the United States in children younger than 5 years of age. After introduction of routine PCV7 immunization, the incidence of invasive pneumococcal disease declined dramatically, especially in children < 2 years of age. [102] [103] [104] United States population-based active surveillance data show that, within 2 years of PCV7 licensure, the rate of invasive pneumococcal disease in children < 2 years of age declined by 69%. [105] In tandem with the decrease in invasive disease, data suggest that the incidence of pneumococcal noninvasive disease, including otitis media, also decreased. [106] [107] In addition to decreasing the burden of pediatric pneumococcal disease, PCV7 may have an impact on reducing pediatric antibiotic prescriptions and procedures such as blood cultures in young, febrile children and decrease in disease due to S. pneumoniae in adults. [37] [38] [39] [40] Two types of pneumococcal vaccines are available. PCV7, licensed in 2000, contains purified capsular polysaccharides of seven serotypes of S. pneumoniae, each conjugated to CRM197, a nontoxic variant of diphtheria toxin. [102] These seven serotypes (4, 9V, 14, 19F, 23F, 18C, and 6B) and potentially cross-reactive serotypes accounted for 83% to 86% of cases of pneumococcal bacteremia and meningitis and 65% of cases of acute pneumococcal otitis media in United States children prior to vaccine availability. The conjugated vaccine induces a T-lymphocyte-dependent response that includes a primary response in infants and an anamnestic response to booster doses. Three doses of vaccine in infants induce significant increases in serum antibody concentrations to all seven serotypes. Trials have shown 97% efficacy of PCV7 against invasive pneumococcal disease caused by serotypes in the vaccine in fully vaccinated children and 94% protection in partially vaccinated children. [108] Vaccination resulted in reductions of 11% in rates of clinical pneumonia, 33% in pneumonia with infiltrate on radiograph, and 73% in radiographically confirmed pneumonia with consolidation. The vaccine reduced episodes of otitis media by 6% and rates of tympanostomy tube placement by 20%; in two studies, efficacy of the vaccine was 51% against suppurative otitis media with positive cultures for S. pneumoniae and 65% against vaccine serotypes. Pneumococcal polysaccharide vaccine (PPV23) consists of purified capsular polysaccharides of 23 serotypes of S. pneumoniae, which represent 85% of strains isolated from cases of invasive pneumococcal disease in the United States in people of all ages. [109] PPV23 vaccine induces increases in antibodies to pneumococcal polysaccharides in 80% to 95% of healthy recipients after a single dose. Initial studies showed high efficacy in young healthy adults (South African miners and military recruits); subsequent studies have shown about 60% efficacy against invasive disease in adults at risk for disease but lower effectiveness in adults who are immunocompromised, who have cirrhosis or renal failure, or who are older. [110] Efficacy in children has not been measured, and immunogenicity in children younger than 2 years of age is limited. PPV23 does not induce immunologic memory.
Pneumococcal vaccination with PCV7 is recommended for all children younger than 2 years of age. [25] [102] The vaccine is given to infants as a four-dose series at 2, 4, 6, and 12 to 15 months of age. Catch-up immunization is recommended for all children through 23 months of age, using fewer doses depending on age. PCV7 is recommended for all children younger than 60 months of age who are at high risk or presumed high risk of acquiring invasive pneumococcal disease (see Chapter 123 , Streptococcus pneumoniae). Limited efficacy data are available concerning
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use of PCV7 in children > 59 months of age at high risk, but PCV7 is licensed for children up to 9 years of age and is not contraindicated in older, high-risk children, including children with sickle-cell disease, HIV infection, and recurrent respiratory tract infection. [102] PCV7 also may be given to eligible children who have already received PPV23. PCV7 can be given simultaneously with all other childhood vaccines. PPV23 is given as a single-dose vaccine to high-risk children older than 2 years of age and to adults. [109] PPV23 is recommended for children at highest risk of pneumococcal disease irrespective of PCV7 receipt, because PPV23 provides protection against additional serotypes. Revaccination is recommended for people in whom 6 years or more have elapsed since the last dose and who are at highest risk of invasive disease (asplenia, nephrotic syndrome, persistent leakage of cerebrospinal fluid) and should also be considered for children at high risk if 3 to 5 years have elapsed since the last dose and if they are < 10 years of age. Children with high-risk conditions should first receive PCV7 followed by PPV23 2 or more months later (see Chapter 123 , Streptococcus pneumoniae).
Adverse events after PCV7 administration are minor; examples are injection site erythema, swelling, and soreness, which occur in 10% to 23% of recipients, low-grade fever, in about 20%, and higher fever (> 39C) in 1% to 2%. [102] No serious adverse events have been associated with use of PCV7. Use of PCV7 is contraindicated in people who have had prior anaphylactic reactions to a previous dose or to a vaccine component. Safety during pregnancy has not been evaluated. Systemic reactions to PPV23 are uncommon, but mild local reactions occur in about half of recipients and may be worse in people revaccinated within 5 years of initial vaccination. [109] PPV23 vaccine is contraindicated in people who have had prior anaphylactic reactions to the vaccine or to vaccine components.
Poliovirus Vaccines
Through use of OPV, the last case of indigenously transmitted poliomyelitis in the United States occurred in 1979. In 2005 in the United States poliovirus infections occurred in 4 children who were not vaccinated due to religious reasons. [111] All 4 children were asymptomatic and were infected with a poliovirus derived from viruses found in attenuated OPVs used in much of the world. In another report an unimmunized 22-year old female acquired VAPP from a child immunized with OPV in South America. [112] This was the first case of paralytic polio identified in the United States since 1999 and the first imported VAPP case ever documented in the United States. These reports raise concerns about transmission of both vaccine-derived and wild polioviruses and the risk of a polio outbreak occurring in the United States. Worldwide polio remains endemic in only four countries (Afghanistan, India, Nigeria, and Pakistan). [4] Enhanced IPV is the only poliovirus vaccine now available in the United States. [113] IPV is derived from three wild strains of poliovirus, types 1, 2, and 3, which are inactivated by formalin. Until 2000, when recommendations were made for exclusive use of IPV for routine immunization, live-attenuated OPV was available in the United States. OPV is still the most commonly used poliovirus vaccine in the world. OPV is constituted from three Sabin strains of polioviruses, types 1, 2, and 3, in concentrations of 1000000, 100000, and 600000 infective units (TCID50) per dose, respectively. Both IPV and OPV, when given as three-dose primary series, induce protective antibody to each type of poliovirus in 95% to 99% of recipients. Antibody levels decline gradually, and booster doses of each vaccine are recommended at school entry. OPV induces higher levels of mucosal immunity than IPV and, thus, provides greater protection against infection because OPV better prevents replication and shedding of wild-type poliovirus in the intestine. Vaccination against poliovirus is recommended for all children. With the progress in global polio eradication and the continued risk of vaccine-associated poliomyelitis after OPV vaccination (approximately 8 cases per year from 1980 to 1994), the United States vaccination policy was modified, first to a sequential schedule of two doses of IPV followed by two doses of OPV in 1997, and subsequently to a schedule of all IPV in the year 2000. [113] [114]
IPV is recommended to be given at 2, 4, and 6 to 18 months of age, simultaneously with other childhood vaccines. Vaccination can start at 6 weeks of age, and 4-week minimal intervals are acceptable. [113] A booster dose is recommended at school entry. There is no need to restart the series if interrupted. OPV may be used in the same schedule, but OPV is no longer being produced in the United States and, for practical purposes, is no longer available. OPV continues to be the preferred vaccine in countries where poliomyelitis is or recently was endemic, and it is the only vaccine suitable for eradication of the disease. [2] [113]
IPV is only contraindicated in children who have experienced a severe allergic reaction to a previous dose of IPV or
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to streptomycin, polymyxin B, or neomycin. OPV is contraindicated in children who have immunosuppressive conditions due to congenital immunodeficiency (agammaglobulinemia or hypogammaglobulinemia), cancer (leukemia or lymphoma), immunosuppressive chemotherapy, or acquired immunodeficiency syndrome (AIDS). [22] [113] OPV also is contraindicated for family and other close contacts of immunocompromised people because of the risk of spread of OPV to the affected person. Vaccination in pregnancy should be avoided on theoretical grounds, but, if necessary, IPV may be given. No significant adverse reactions have been observed after administration of IPV. The major adverse reaction to OPV is VAPP, which develops at a rate of 1/2.5 million vaccine doses. [115] Before the policy change in the United States, healthy vaccine recipients represented about 40% of cases, contacts of recipients represented about 40% of cases, and immunosuppressed people represented 20%. Highest risk is associated with receipt of the first vaccine dose (1/700000 recipients) and is 10-fold lower for subsequent doses. Risk in people with congenital immunodeficiency is about 2000-fold higher than in healthy recipients. The risk of VAPP appears to be raised by receipt of multiple doses of injectable antibiotics 1 to 30 days after immunization. [116] OPV rarely can cause disseminated infection and death in immunocompromised people. [55]
Varicella Vaccine
Live-attenuated varicella-zoster vaccine was licensed for use in United States children and adults in March 1995, and in 2004, 88% of 19- to 35-month-old children in the United States were immunized. [29] Varicella vaccine, developed in Japan from the Oka strain of varicella virus, has been shown to be greater than 95% effective in protecting against severe disease and 70% to 90% effective against mild to moderate illness for children 1 to 2 years of age for at least 7 to 9 years after vaccination. [117] [118] [119] [120] Children and adults who experience breakthrough infection with wild varicella-zoster virus usually demonstrate mild disease, with an average of fewer than 50 lesions (compared with over 250 lesions observed in typical varicella).
In 2005 and 2006, the ACIP made policy changes for the use of live, attenuated varicella-containing vaccines for prevention of varicella. [120] A routine two-dose schedule of varicella vaccination of children is now recommended along with a second-dose catch-up varicella vaccination for children, adolescents, and adults who previously had received only one dose. The basis for these changes was: (1) the recognition that vaccine failures occur after a first dose; (2) outbreaks of varicella had been reported in populations with high coverage with one dose of vaccine; (3) emergency revaccination during outbreaks, which had previously been recommended, was difficult and costly; and (4) evidence showed that a second dose could decrease rates of failure. The ACIP also expanded recommendations for varicella-containing vaccines to promote wider use of the vaccine for adolescents, adults, and HIV-infected children and approved new criteria for evidence of immunity to varicella. Specific recommendations are as follows. All children < 13 years of age routinely should receive two doses of varicella-containing vaccine, with the first dose administered at 12 to 15 months of age and the second dose at 4 to 6 years of age (i.e., before a child enters kindergarten or first grade). The second dose can be administered at an earlier age provided the interval between the first and second dose is at least 3 months. However, if the second dose is administered at least 28 days following the first dose, the second dose does not need to be repeated. A second catch-up dose of varicella vaccination is recommended for children, adolescents, and adults who previously have received one dose, to improve individual protection against varicella and for more rapid impact on school outbreaks. Catch-up vaccination can be implemented during routine health provision visits and through school and college entry requirements. Catch-up second dose can be administered at any interval longer than 3 months after the first dose. The minimum 3-month interval is the package insert allowance based on studies of the second dose. Future research is likely to evaluate intervals as short as 1 month. The two-dose varicella vaccination schedule is similar to the MMR vaccination schedule. MMRV vaccine is licensed and indicated for simultaneous vaccination against measles, mumps, rubella, and varicella among children 12 months through 12 years of age. For routine immunization, use of licensed combination vaccines, such as MMRV vaccine, is preferred over separate injection of equivalent component vaccines. Students at all grade levels (including college) and children in childcare facilities should be protected against varicella. HIV-infected children > 12 months of age with CD4 + T-lymphocyte counts of > 15% and without evidence of varicella immunity should receive two doses of single antigen varicella vaccine at a minimum interval of 3 months. Varicella vaccine previously was recommended for asymptomatic or mildly symptomatic HIV-infected children (CDC clinical class N and A) with age-specific CD4 + T-lymphocyte counts 25% or greater. Because data are not available on safety, immunogenicity, or efficacy of MMRV vaccine in HIV-infected children, MMRV vaccine should not be administered as a substitute for the component vaccines when vaccinating HIV-infected children.
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Women should be assessed prenatally for evidence of varicella immunity. Upon completion or termination of their pregnancies, women who do not have evidence of varicella immunity should receive the first dose of varicella vaccine before discharge from the healthcare facility. The second dose should be administered 4 to 8 weeks later (at the postpartum or other healthcare visit). To ensure administration of varicella vaccine, standing orders are recommended for healthcare settings where completion or termination of pregnancy occurs. Varicella vaccine previously was recommended for people 13 years of age and older without evidence of immunity who: (1) have close contact with people at high risk for severe disease (healthcare providers and family contacts of immunocompromised people); or (2) are at high risk for exposure or transmission. The ACIP now recommends that all other people 13 years of age and older without evidence of immunity be vaccinated with two doses of varicella vaccine at an interval of 4 to 8 weeks. The vaccine may be offered during routine healthcare visits. During a varicella outbreak, people who have received one dose of varicella vaccine should receive a second dose, provided the appropriate vaccination interval has elapsed since the first dose (3 months for people 12 months to 12 years of age and at least 4 weeks for people 13 years of age or older). Revised criteria for evidence of immunity to varicella include any of the following: (1) documentation of ageappropriate vaccination (preschool-aged children 12 months of age or older: one dose; school-aged children, adolescents, and adults: two doses); (2) laboratory evidence of immunity or laboratory confirmation of disease; (3) birth in the United States before 1980; (4) a healthcare provider diagnosis of varicella or healthcare provider verification of history of varicella disease; and (5) history of herpes zoster based on healthcare provider diagnosis.
[120]
Varicella vaccine can be given simultaneously with all other childhood vaccines. The vaccine also is recommended for postexposure prophylaxis of susceptible people exposed to varicella, and it can be used for control of outbreaks.
Varicella vaccine induces mild varicelliform rash and fever in 5% to 10% of recipients. [117] Vaccine virus rarely can be transmitted from healthy patients who experience rash. More serious adverse events (e.g., encephalitis, ataxia) have been reported rarely, at rates lower than expected after natural varicella and lower than background rates in the community. Varicella vaccine is contraindicated in people who have a blood dyscrasia, except for children with acute lymphocytic leukemia, in people with primary or acquired immunodeficiency (including immunodeficiency due to HIV infection), in pregnant women, and in people who have had an anaphylactic reaction to varicella vaccine or any component, including gelatin. However, vaccine may be given to people with humoral immunodeficiency and may be considered for people with asymptomatic or mildly symptomatic HIV infection with age-specific CD4 + Tlymphocyte percentages greater than 15% after the risks and benefits have been weighed. [118] As with measlescontaining vaccines, vaccination should be delayed for 3 or more months after receipt of immunoglobulin or blood products, because response to vaccine administered within this interval is unknown. Although varicella vaccine virus rarely has been isolated from patients with herpes zoster, the risk of herpes zoster after varicella vaccination appears to be substantially lower than risk after natural varicella infection.
Hepatitis A Vaccine
Since routine childhood vaccination was recommended in 1999 in states where hepatitis A rates were consistently elevated, the overall hepatitis A rate has declined dramatically. In 2005, the rate (1.53 per 100,000 population) was the lowest recorded, with 4488 cases reported. Declines have been greater among age groups and regions where routine vaccination of children is recommended, likely reflecting the result of the current vaccination strategy. To maintain and further reduce the current low rates, the strategy was expanded in October 2005 to include routine vaccination nationwide of children 12 to 23 months of age. [121] [122]
Hepatitis A vaccines are produced in tissue culture and purified and inactivated with formalin; two vaccines have been licensed for use in the United States since 1995. [122] These vaccines are highly immunogenic and are more than 95% effective in preventing hepatitis A infection when given as a two-dose series to children or adults. [122] [123] Hepatitis A vaccine also can provide protection after exposure and can be useful in controlling hepatitis A outbreaks in well-defined populations. Hepatitis A vaccine is licensed for use in children 12 months of age or older. [122] A combination product consisting of hepatitis A and hepatitis B given on a 0-, 1-, and 6-month schedule is licensed for people 18 years of age and older. Hepatitis A vaccine is given as a two-dose series, with doses separated by 6 to 18 months. [122] Recommendations for use of hepatitis A vaccine in children are as follows:
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All children should receive hepatitis A vaccine at 1 year of age (i.e., 12 to 23 months). Vaccination should be completed according to the licensed schedules and integrated into the routine childhood immunization schedule. Children who are not vaccinated by 2 years of age can be vaccinated at subsequent visits. States, counties, and communities with existing hepatitis A vaccination programs for children 2 to 18 years of age are encouraged to maintain these programs. In these areas, new efforts focused on routine vaccination of children 1 year of age should enhance, not replace, ongoing programs directed at a broader population of children. In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children 2 to 18 years of age can be considered. Such programs might be warranted, especially in the context of increasing incidence or ongoing outbreaks among children or adolescents. In addition, high-risk groups recommended to receive hepatitis A vaccine include MSM, users of illicit drugs, persons with cirrhosis or clotting factor disorders, and persons traveling to or working in countries where hepatitis A is highly endemic.
Adverse reactions to hepatitis A vaccine appear to be limited to pain at the injection site. The only contraindication to the vaccine is a severe reaction to a previous dose of the vaccine or to one of its components (alum or phenoxyethanol). Because hepatitis A vaccine is inactivated, no special precautions need to be taken when immunizing immunocompromised people.
Influenza Vaccines
Since the worldwide influenza pandemic of 1918 that caused an estimated 25 to 50 million deaths, the control of influenza circulation has been a major challenge to clinicians and public health experts. The threat of an unpredictable influenza pandemic and the concern that avian influenza strains might mutate to cause severe disease as well as become highly transmissible among people heighten the importance of preventing morbidity and mortality caused by annual epidemics of influenza disease (seasonal influenza) in the United States. Each year on average seasonal influenza causes more than 200000 hospitalizations and more than 36000 deaths. [124] Because of the frequent antigenic changes in influenza viruses, the antigenic content of influenza vaccine is changed annually to optimize protection against the influenza type A and B strains expected to circulate during the following winter and spring. Influenza viruses of type A (H1N1 and H3N2) and B are selected on the basis of immunologic match with circulating strains; viruses are grown in chicken embryos and combined into a single vaccine containing components of all these strains. The efficacy of vaccine is related to the degree of match between the vaccine and circulating influenza viruses. When major antigenic drifts (i.e., a change with the same virus) occur, the vaccine's effectiveness may be reduced substantially. Annual vaccination is necessary to ensure protection against each year's influenza strains. [125] [126]
Two types of influenza vaccines are licensed for use in the United States. One is a vaccine that is inactivated with formalin, followed by splitting apart of the individual unions often with a detergent, and then purified (trivalent inactivated vaccine or TIV). TIV is recommended for children 6 through 59 months of age, and for older children and adolescents in high-risk groups and their close contacts. The second vaccine is a cold-adapted, live, nasally administered vaccine (live-attenuated influenza vaccine or LAIV) licensed for healthy people 5 through 49 years of age, including close contacts of high-risk people. The ACIP and AAP recommended in 2005 to expand influenza vaccine recommendations to include all children 6 through 59 months of age and household contacts of children 0 through 59 months of age as well as to continue immunization of all children in high-risk groups. Recommendations for the annual influenza immunization include [125] [126] : Children 6 to 59 months of age; Women who will be pregnant during the influenza season; People over 50 years of age; Children and adolescents (6 months to 18 years of age) who are receiving long-term aspirin therapy and, therefore, might be at risk for experiencing Reye syndrome after influenza infection; Adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma (hypertension is not considered a high-risk condition); 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 immunodeficiency (including immunodeficiency caused by medications or by
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HIV); Adults and children who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory tract function or handling of respiratory tract secretions, or that can increase the risk for aspiration; Residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions; Persons who live with or care for persons at high risk for influenza-related complications, including healthy household contacts and caregivers of children 0 through 59 months of age; and Healthcare providers [126]
For previously unvaccinated children 6 months through 8 years of age, two doses of vaccine, given at 4-week intervals, are recommended. For other groups, only a single dose is necessary.
Inactivated influenza vaccine should not be administered to people known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician. Chemoprophylactic use of antiviral agents is an option for preventing influenza among such people. However, people 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. People with moderate-to-severe acute febrile illness usually should not be vaccinated until their symptoms have resolved. 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. About 3% to 5% of recipients experience local tenderness or fever after vaccination. The occurrence of GBS within 6 weeks of influenza vaccination was observed in adults after the swine influenza vaccine program campaign (1976) but was not observed subsequently until 1990, when a case-control study suggested a slightly elevated risk in persons 18 to 64 years old but not in people > 65 years of age. [125] Given the substantial benefits of influenza vaccination among the target populations, the risk of GBS, if any, is exceeded by the benefits. A previous anaphylactic reaction to egg proteins is the only contraindication to influenza vaccination. The following populations should not be vaccinated with LAIV: people less than 5 years of age or people > 50 years of age; people with asthma, reactive airways disease, or other chronic disorders of the pulmonary or cardiovascular systems; people with other underlying medical conditions, including metabolic diseases such as diabetes, renal dysfunction, and hemoglobinopathies; people with known or suspected immunodeficiency diseases or who are receiving immunosuppressive therapies; children or adolescents receiving aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection); people with a history of GBS; pregnant women; or people with a history of hypersensitivity, including anaphylaxis, to any of the components of LAIV or to eggs. In July 2005 the FDA received a biologic license application for the use of LAIV in children 12 months of age and older, and for a refrigerator-stable formulation has been licensed.
Meningococcal Vaccines
From 2000 to 2004, approximately 2400 to 3000 cases of invasive meningococcal disease occurred annually in the United States. In 2004 there were 1361 reported cases. [29] The case-fatality ratio for meningococcal disease is approximately 10%, and severe sequelae (e.g., neurologic disability, limb loss) occur in approximately 10% of survivors. [127] [128] Infants younger than 1 year of age have the highest rates of meningococcal disease, with an annual incidence of 6.5 cases per 100 000 population during 2002. [129] During the 1990s, incidence rates of meningococcal disease increased among adolescents and young adults. [127] Evidence also showed that college freshmen living in dormitories have a modestly increased risk of meningococcal disease (4.6 cases per 100000) compared with other people of the same age. [128]
A meningococcal polysaccharide (MPS) vaccine, containing antigens of serogroups A, C, Y, and W135, has been used in the United States since licensure in 1981. This vaccine protects against the serogroups that cause approximately two-thirds of meningococcal disease that occurs in people 18 to 23 years of age in the United States. More than half of the cases in infants are due to serogroup B, for which a licensed vaccine does not exist in the United States. [128] Similar to other polysaccharide vaccines, MPS induces a T-lymphocyte-independent immune
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response resulting in poor long-term immunity and inconsistent immunogenicity in children < 2 years of age. An additional shortcoming is that MPS does not reduce nasopharyngeal carriage or induce herd immunity. [128] Before February 2005, MPS vaccine was recommended for people at high risk for meningococcal disease and for outbreak control. Educating college freshmen about the potential for the MPS vaccine to prevent severe infection also was recommended. Employing the same technology used to develop PCV7, a meningococcal serogroup C conjugate vaccine was licensed in the United Kingdom in 1999. The vaccine was introduced into the routine infant schedule, with catch-up vaccination for older children and adolescents. In the 2 years after introduction of infant meningococcal conjugate vaccine, the incidence of serogroup C meningococcal disease declined by 87% in vaccinated people. [130] Substantial reductions in disease also occurred in unvaccinated populations as a result of herd immunity. In the United States, a quadrivalent meningococcal conjugate vaccine (serogroups A, C, Y, and W-135) (MCV4) was licensed in January 2005, for use in people 11 to 55 years of age. Each of the polysaccharides is linked to diphtheria toxoid. During prelicensure clinical trials antibody levels postvaccination to MCV4 were at least as high among adolescents and adults as responses to MPS, the prior licensed product. Because MCV4 induces T-lymphocytemediated immunity and higher-quality immune responses, the duration of protection is thought to be longer than immunity produced by MPS. In February 2005, the ACIP voted to recommend that MCV4 be administered universally to the following groups: people 11 to 12 years of age, adolescents at high-school entry (or 15 years of age, whichever comes first), college freshmen living in dormitories, and people at higher risk for meningococcal disease (see Chapter 125 , Neisseria meningitidis). [128] Vaccine supply problems delayed full implementation of these recommendations. [74] With the addition of MCV4 to the immunization schedule, a new era of adolescent vaccination was launched. In the United States, meningococcal conjugate vaccines for use in children < 11 years of age are under study. Serogroup B capsular polysaccharide is poorly immunogenic in humans, so the focus in vaccine development has been on common proteins. OMP vaccines to prevent group B meningococcal disease have been shown to be safe and effective in older children and adults but not among infants and young children, in whom rates of serogroup B diseases are highest. In addition the variability in OMP strains causing endemic disease will likely limit their usefulness in the United States since individual vaccines might need to be made for each strain.
Precautions and Contraindications
Vaccination should be deferred for people with moderate or severe acute illness until the person's condition improves. Vaccination with MCV4 or MPS is contraindicated among people known to have a severe allergic reaction to any component of the vaccine, including dipththeria toxoid (for MCV4), or to dry natural rubber latex. Because both MCV4 and MPS are inactivated vaccines, they may be administered to people who are immunosuppressed as a result of disease or medications; however, response to the vaccine might be less than optimal. Studies of vaccination with MPS during pregnancy have not documented adverse effects among either pregnant women or newborns. On the basis of these data, pregnancy should not preclude vaccination with MPS, if indicated. MCV4 is safe and immunogenic among nonpregnant people 11 to 55 years of age, but no data are available on the safety of MCV4 during pregnancy. Women of childbearing age who become aware that they were pregnant at the time of MCV4 vaccination should contact their healthcare provider or the vaccine manufacturer. A possible association between GBS and receipt of MCV4 has been reported. [131] Because the number of excess cases of GBS for every 1 million doses distributed to people 1119 years of age is approximately 1.25, the uncertainty that exists regarding the risk estimate and because the consequences of meningococcal disease are so great, the CDC continues to recommend use of MCV4 for people for when vaccine is indicated. [131] Further monitoring and studies are ongoing.
Rotavirus Vaccine
Rotavirus is the most common cause of severe gastroenteritis in infants and young children worldwide. In developing countries, rotavirus gastroenteritis is a major cause of childhood death and is responsible for more than half a million deaths per year in children < 5 years of age. [132] Rotavirus gastroenteritis results in relatively few childhood deaths in the United States (approximately 20 to 70 per year). However, nearly every child in the United States is infected with rotavirus by 5 years of age and most will develop gastroenteritis, leading to more than 400000 physician visits, more than 200,000 emergency department visits, 55000 to 70000 hospitalizations each year, and direct and indirect costs of approximately $1 billion. [133] A live-attenuated tetravalent rotavirus vaccine prepared from rhesus rotavirus type 3 and human-rhesus reassortant types 1, 2, and 4 was licensed in 1999 for use in infants in the United States. In prelicensure controlled trials, this vaccine, when given to infants at 2, 4, and 6 months of age, was shown to be initially safe and highly effective,
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preventing more than 90% of hospitalizations for rotavirus diarrhea. [134] After licensure, the vaccine was recommended in early March 1999 by the ACIP, AAP, and AAFP to be given to all infants between 6 weeks and 1 year of age, routinely at 2, 4, and 6 months of age. In early June 1999, reports of adverse events suggested that cases of intussusception might follow rotavirus vaccination. Subsequent controlled studies demonstrated that children given this rotavirus vaccine had a relative risk of intussusception of 24.8 during 3 to 7 days after the first dose, with an estimated risk of 1 case per 10000 vaccinated infants. [26] On the basis of these data, the ACIP and the AAP rescinded the recommendation for routine use of rotavirus vaccine in the United States, and the manufacturer withdrew the vaccine from distribution. [27] The next generation of rotavirus vaccines has thus far resulted in two products. One is a monovalent vaccine based on an attenuated human rotavirus strain of P1A[8]G1 specificity, RIX 4414 (Rotarix, GlaxoSmithKline Biologicals). This orally administered vaccine, given in two doses, has shown good clinical efficacy [135] and in a trial of more than 60000 infants, no increase in intussusception was noted among recipients of the vaccine versus placebo. [136] As of Februrary 2006, Rotarix was licensed in over 30 countries in Latin America, Africa, and Asia. A licensure application is under consideration in the United States by the FDA. The second vaccine is a pentavalent reassortant vaccine (PRV) (Rotateq, Merck) that was licensed in the United States by the FDA in February 2006. This vaccine is a live oral vaccine that contains five reassortant rotaviruses (G1, G2, G3, G4, and P1A) developed from human and bovine parent rotavirus strains. [137] The reassortants are propagated in Vero cells using standard tissue culture techniques in the absence of antifungal agents. The five humanbovine reassortants in this vaccine are suspended in a solution of buffer (sodium citrate and phosphate) and stabilizer (sucrose) that can be stored refrigerated at 2C to 8C for up to 24 months. No preservatives or thimerosal are present. Phase III trials of PRV have involved a total of 72 324 infants (36 423 in the PRV group, 35 825 in the placebo group, and 76 subjects who received a mixed regimen) in 11 countries, with the United States and Finland accounting for more than 80% of enrolled subjects. [138] In these trials, 3 doses of PRV were given orally beginning at 6 to 12 weeks of age with a 4- to 10-week interval between doses. Data from these trials showed immunogenicity of 93% to 100%, and efficacy of 74% against rotavirus gastroenteritis of any severity, 98% against severe gastroenteritis. The incidence of serious adverse events, intussusception, fever, and irritability was similar among PRV and placebo recipients. [133] [139]
All infants should be immunized routinely with 3 doses of RPV administered orally at 2, 4, and 6 months of age. The first dose should be administered between 6 and 12 weeks of age. Subsequent doses should be administered at 4- to 10-week intervals, and all 3 doses of vaccine should be administered by 32 weeks of age. RPV can be administered together with other childhood vaccines indicated at the same visits. Premature infants (i.e., infants born at less than 37 weeks' gestation) can be immunized if they are at least 6 weeks of age, are being or have been discharged from the hospital nursery, and are clinically stable. Infants living in households with people who have or are suspected of having an immunodeficiency disorder or impaired immune status can be vaccinated, including infants living in households with pregnant women. Readministration of a dose of PRV to an infant who regurgitates, spits out, or vomits during or after administration of vaccine is not recommended. The infant should receive the remaining recommended doses of PRV at appropriate intervals. If a recently vaccinated child is hospitalized for any reason, no precautions other than routine universal precautions need be taken to prevent the spread of vaccine virus in the hospital setting.
There are two contraindications for use of PRV: (1) history of severe hypersensitivity to any component of the vaccine; or (2) history of serious allergic reaction to a previous dose of vaccine. Precautions for PRV include use in people with altered immunocompetence, including infants with a blood dyscrasia, leukemia, lymphoma of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system, and infants on immunosuppressive therapy (including high-dose systemic corticosteroids). Other precautions include use in infants with primary and acquired immunodeficiency states, including HIV/AIDS or other clinical manifestations of infection with HIV; cellular immune deficiencies, and hypogammaglobulinemic and dysgammaglobulinemic states; infants with indeterminant HIV status who are born to mothers with HIV/AIDS; and infants who have received a blood transfusion or blood products, including immunoglobulins, within 42 days. Other precautions include infants with moderate to severe illness, including acute gastroenteritis, pre-existing chronic gastrointestinal disease, and previous history of intussusception.
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Human Papillomavirus Vaccine
More than 100 types of papillomaviruses have been recognized on the basis of DNA sequence analyses, [140] over 40 of which infect the genital area. HPV is associated with a variety of clinical conditions that range from benign skin and mucous membrane lesions to cancer. Clinical manifestations with the most frequently associated HPV types include skin warts (types 1, 2, 3, and 10), recurrent respiratory papillomatosis (types 6 and 11), condyloma acuminata (types 6 and 11), and cervical cancer (types 16, 18, 31, 33, and 45). HPV is one of the most common causes of sexually transmitted infections in the United States and worldwide, causing almost all of the morbidity and mortality associated with cervical cancer. [140] Based on the association of HPV with cervical cancer and precursor lesions, HPVs can be grouped into low-risk and high-risk HPV types. [140] In the United States and Europe, HPV-16 accounts for approximately 50% of the cases of cervical cancer, with types 18, 31, and 45 accounting for an additional 25% to 30% of cases. [141] Vaccination against high-risk HPV types could substantially reduce the incidence of cervical cancer. Administration of HPV-16 vaccine has been shown to reduce the incidence of HPV-16 infection and HPV-related cervical intraepithelial neoplasia. [142] In addition, a bivalent HPV vaccine was efficacious in preventing persistent cervical infections with HPV-16 and HPV-18 and associated cytologic abnormalities and lesions. [143] One HPV vaccine containing HPV types 6, 11, 16, and 18, was licensed by the FDA in June 2006, and application for licensure of a second HPV vaccine that contains types 16 and 18 has been filed with the United States FDA in 2006. Types 16 and 18 account for approximately 70% of all cervical cancers in the United States.
Recommendations for use of quadrivalent HPV vaccine include routine vaccination of females 11 to 12 years of age with three doses of quadrivalent HPV vaccine. [144] The vaccination series can be started in females as young as 9 years of age. Vaccination also is recommended for females 13 to 26 years of age who previously have not been vaccinated or who have not completed the full three-dose vaccine series. Quadrivalent HPV vaccine is administered intramuscularly in a three-dose schedule. The second and third doses should be administered 2 and 6 months after the first dose. HPV vaccine can be administered at the same visit as other age-appropriate vaccines, such as Tdap, Td, and MCV4. Cervical cancer screening recommendations have not changed for females who receive quadrivalent HPV vaccine because approximately 30% of cervical cancers are caused by types not in the vaccine. [144] Quadrivalent HPV vaccine can be given to females who have an equivocal or abnormal Papanicolaou (Pap) test, a positive Hybrid Capture II high-risk test, or genital warts. Women should be advised that data do not indicate that the vaccine will have a therapeutic effect on existing Pap test abnormalities, HPV infection, or genital warts. Lactating women can receive quadrivalent HPV vaccine and females who are immunocompromised, either from disease or medication, can receive quadrivalent HPV vaccine; however, the immune response to vaccination and vaccine effectiveness might be less than in females who are immunocompetent. Quadrivalent HPV vaccine is not recommended for use in pregnancy. The vaccine has not been associated causally with adverse outcomes of pregnancy or adverse events to the developing fetus. However, data on vaccination in pregnancy are limited. Any exposure to vaccine in pregnancy should be reported to the vaccine pregnancy registry (800-986-8999).
Quadrivalent HPV vaccine is contraindicated for people with a history of immediate hypersensitivity to yeast or any vaccine component. Quadrivalent HPV vaccine can be administered to people with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infections, with or without fever). Vaccination of people with moderate or severe acute illnesses should be deferred until after the illness improves. SELECTED OTHER VACCINES THAT MAY BE USED IN CHILDREN AND ADOLESCENTS
Calmette-Gurin Bacillus Vaccine
A live-attenuated vaccine prepared from the Calmette-Gurin bacillus (formerly bacille Calmette-Gurin, BCG) strain of Mycobacterium bovis, BCG vaccine is intended to prevent serious M. tuberculosis disease. [145] The vaccine is used routinely throughout most of the developing world but only in restricted situations in the United States. Data regarding the efficacy of BCG are highly variable and conflicting. Meta-analyses suggest that a single dose of BCG vaccine given at or soon after birth is about 50% effective in preventing the most severe outcomes of M. tuberculosis infection (disseminated or miliary tuberculosis). [146] [147] Vaccine efficacy data in adults, such as healthcare providers, are inconclusive. BCG vaccine can cause conversion of the tuberculin skin test reaction and, thus, reduce its utility for monitoring for M. tuberculosis infection and aiding in the decision whether preventive antimicrobial therapy is indicated.
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In the United States, BCG vaccine is only recommended for tuberculin-negative infants and children who have prolonged, nonoptional contact with people who have active tuberculosis and are untreated, are treated inadequately, or have antibiotic-resistant infection. [145] BCG vaccine also may be considered for infants and children who live in circumstances with high risk of infection, for example, living among people such as the homeless, for whom surveillance and treatment programs may not be effective or feasible. The vaccine may be considered for healthcare providers in settings where multidrug-resistant tuberculosis is a significant problem. BCG vaccine is given as a single dose intradermally or percutaneously. Known adverse events after administration of BCG include regional lymphadenitis (1% to 10%) and, rarely, disseminated infection, osteitis, or both due to the bacillus. [145] Immunocompromised people, including people with known HIV infection, should not receive BCG vaccine because of increased risk of disseminated infection. In evaluation of people for tuberculosis, history of receipt of BCG vaccine should not alter interpretation of the tuberculin skin test reaction.
Vaccines for Travelers Cholera Vaccine
Cholera vaccine is not available in the United States. The previously available vaccine prepared from killed whole Vibrio cholerae organisms was approximately 50% effective for 6 months after vaccination, but use was not recommended routinely except to satisfy requirements for entry into certain countries. An oral cholera vaccine (DuKoral) is available in some European countries and in Canada but it is not recommended for travelers. Other vaccines are under development. [148]
Japanese Encephalitis Vaccine
Japanese encephalitis vaccine is a purified preparation of whole virus grown in mouse brains and inactivated with formalin. When given as a three-dose series, the vaccine has 91% efficacy in adults. [149] [150] Antibody persists for at least 2 years; the need for booster doses is uncertain. Japanese encephalitis vaccine is recommended for certain travelers or residents in areas where the disease is endemic (South and East Asia) who will potentially be exposed during the transmission season, particularly in rural areas near pig farms and rice paddies, and when duration of travel is 30 days or longer. Primary immunization consists of three doses, with the second dose given at 7 days, and the third dose at 30 days after the first; the third dose may be given at 14 days if the traveler's schedule does not permit the longer interval. The vaccine dose for young children (1 to 3 years of age) is 0.5 mL and that for older children and adults is 1.0 mL. No data are available on safety and immunogenicity of this vaccine in children < 1 year of age. Adverse events include local reactions (20%) and minor systemic symptoms (10%). Generalized allergic reactions (angioedema, urticaria) occur in 1 to 6 per 1000 recipients; more rarely, respiratory distress and hypotension have been reported. Rare neurologic events have been reported, but causation by vaccine has not been established.
Typhoid Fever Vaccine
Two typhoid vaccines are available in the United States for travelers: a purified capsular polysaccharide parenteral vaccine prepared from the typhoid Vi antigen, and an oral live-attenuated vaccine (Salmonella typhi Ty21a strain). [151] The inactivated Vi vaccine is given as a single dose, with booster doses at 2-year intervals if exposure continues. The oral vaccine is given as a four-dose series of enterically coated capsules at 2-day intervals, taken before meals; the need for booster doses after this vaccine is uncertain. Both vaccines have efficacy of 50% to 80%. The minimal recommended ages for use of these vaccines are 2 years for the inactivated Vi vaccine and 5 years for the oral vaccine. Typhoid vaccination is indicated for people who will potentially be exposed to contaminated food and water while traveling to areas in which typhoid is endemic, for laboratory workers exposed to the organism, and for people exposed to typhoid carriers in the household. Inactivated Vi vaccine produces local reactions (swelling, induration) in 7% and fever or headache in fewer than 3% of recipients. Oral typhoid vaccine produces only minor adverse events, including nausea, vomiting, and abdominal discomfort. Oral typhoid vaccine should not be given to immunocompromised people (including people with HIV infection).
Yellow Fever
Yellow fever vaccine is a live-attenuated strain of yellow fever virus that is prepared in eggs. A single dose, given subcutaneously, is highly effective in inducing protection that may last for 10 years or longer; booster doses are recommended at 10-year intervals. [152] Yellow fever vaccine is recommended for people 9 months of age and older who will travel to endemic areas and for whom vaccination may be required for entry into a country where the
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disease is endemic. Some countries in Africa require an international certificate of vaccination or physician waiver letter against yellow fever from all entering travelers. The vaccine is only available in the United States from providers certified by state health departments (www.cdc.gov/vaccines/vpd-vacyf/default.htm ). The vaccine causes local and limited systemic symptoms in 2% to 5% of recipients 5 to 10 days after vaccination. Serious reactions, including encephalitis, are rare; risk is highest in children 4 to 9 months of age, therefore the vaccine is contraindicated in this age group. Between 1996 and 2001, 7 cases of severe systemic illnesses with fever, jaundice, and multisystem organ failure were reported globally, mainly in elderly people. 153 The estimated rate of these serious reactions was 2.5 per 1 million doses in the United States. Physicians should only administer yellow fever vaccine to people truly at risk of exposure to yellow fever. Yellow fever vaccine should not be given to pregnant women; however, if a pregnant woman is traveling to an endemic area and cannot avoid potential exposure, she may be given the vaccine. The vaccine is contraindicated in people who have anaphylactic allergy to eggs and people who are immunocompromised. Response to yellow fever vaccine can be inhibited by cholera vaccine, so these two vaccines should be given at least 3 weeks apart with yellow fever vaccine being given before cholera vaccine. SOURCES OF INFORMATION ON VACCINES Important sources for information about vaccines are as follows:
Official Package Circular
Manufacturers provide product-specific information for each vaccine; some of these are reproduced in their entirety in Physicians' Desk Reference (PDR) and are dated.
Morbidity and Mortality Weekly Report
This report, published weekly by the CDC, contains vaccine recommendations, reports of specific disease activity, policy statements, and regular and special recommendations of the ACIP. Subscription information is available from the following sources: MMWR Morb Mort Wkly Rep, Superintendent of Documents, United States Government Printing Office, Washington, DC 20402-9235 (202-783-3238); and online at www.cdc.gov/mmwr/ .
Health Information for International Travel
CDC publishes this annual booklet as a guide to the requirements and recommendations for specific immunizations and health practices for travel to various countries. The booklet can be obtained from the Superintendent of Documents, United States Government Printing Office, Washington, DC 20402-9235. Travelers' health information , or through the CDC information can also be obtained through the CDC internet site, at www.cdc.gov/travel center (1-800-232-4636).
AAP Red Book: Report of the Committee on Infectious Diseases
The full report containing recommendations on all licensed vaccines, published by the AAP, is updated every 3 years. The most recent Red Book was published in 2006 and can be ordered from American Academy of Pediatrics, 141 Northwest Point Blvd, PO Box 927, Elk Grove Village, IL 60009-0927, or from the AAP website, at www.aap.org/bookstore/ , or 888-227-1770.
Control of Communicable Diseases in Man
The American Public Health Association publishes this manual at approximately 5-year intervals. The 18th edition (2004) is available. The manual contains valuable information concerning infectious diseases; their occurrence worldwide; immunization, diagnostic, and therapeutic information; and up-to-date recommendations on isolation and other control measures for each disease presented. The manual can be ordered from the American Public Health Association, 1015 15th St NW, Washington, DC 20005.
Health Departments
Most state and many local health departments provide routine immunizations, immunization cards, and schedules to patients. They also send out routine reports of disease incidence. Many states have print information online to be downloaded.
World Health Organization
Additional information about the World Health Organization and international vaccine programs may be found
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online at www.who.int/vaccines/
Global Alliance for Vaccines and Immunization
Information on the Global Alliance on Vaccines and Immunization may be found at the website www.vaccinealliance.org/ .
Additional Information
Specific information on immunization and vaccine-preventable diseases is available from the following sources: (1) National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta GA 30333; (2) CDC Immunization Voice/fax Information System: voice, 1-800-232-SHOT; documents (fax), 404-3324565; (3) CDC website at www.cdc.gov/vaccines/ ; (4) the Immunization Action Coalition, online at www.immunize.org/ ; and (5) the National Network for Immunization Information, online at www.idsociety.org/ . References 1. Fenner F, Henderson DA, Arita I, et al: Smallpox and its Eradication, Geneva, Geneva, World Health Organization, 1988. 2. Hull HF, Ward NA, Hull BP, et al: Paralytic poliomyelitis: seasoned strategies, disappearing disease. Lancet 1994; 343:1331. 3. Centers for Disease Control and Prevention. : Certification of poliomyelitis elimination the Americas. MMWR 1994; 43:720. 4. Centers for Disease Control and Prevention. : Progress toward interruption of wild poliomyelitis transmission worldwide, January 2005 March 2006. MMWR 2006; 55:458-462. 5. World Health Organization. : Vaccines and Biologicals Biennial Report 20002001, Geneva, World Health Organization, 2000. 6. Hatziandreu EJ, Brown RE, Halpern MT. A cost benefit analysis of the measles-mumps-rubella (MMR) vaccine. Final report prepared for National Immunization Program, Centers for Disease Control and Prevention. Arlington, VA, Center for Public Health Research and Evaluation, Battelle Memorial Institute, 1994. 7. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): recommended childhood and adolescent immunization schedule. MMWR 2007; 55:Q1-Q4. 8. Zhou F, Santoli J, Messonnier ML, et al: Economic evaluation of the 7 vaccine routine childhood immunization schedule in the United States, 2001. Arch Pediatr Adolesc Med 2005; 159:1136-1144. 9. Finn TM, Egan W: Vaccine additives and manufacturing residuals in United States licensed vaccines. In: Plotkin S, Orenstein WA, ed. Vaccines, 4th ed.. Philadelphia: WB Saunders; 2004:81-90. 10. Centers for Disease Control and Prevention. : Summary of joint statement on thimerosal in vaccines. American Academy of Family Physicians, American Academy of Pediatrics, Advisory Committee on Immunization Practices, Public Health Service. MMWR 2000; 49:622. 11. Delves PJ, Roitt IM: The immune system (part 1). N Engl J Med 2000; 343:37. 12. Delves PJ, Roitt IM: The immune system (part 2). N Engl J Med 2000; 343:108. 13. Spellberg B, Edwards Jr. JE: Type 1/type 2 immunity in infectious diseases. Clin Infect Dis 2001; 32:76-102. 14. Polack FP, Hoffman SJ, Crujeiras G, et al: A role for nonprotective complement-fixing antibodies with low avidity for measles virus in atypical measles. Nat Med 2003; 9:1209-1213. 15. McGee JR, Mestecky J, Dertzbaugh MT, et al: The mucosal immune system: from fundamental concepts to vaccine development. Vaccine 1992; 10:75.
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16. Shaw Jr FE, Guess HA, Roets JM, et al: Effect of anatomic injection site, age and smoking on the immune response to hepatitis B vaccination. Vaccine 1989; 7:425-430. 17. Fishbein DB, Sawyer LA, Reid-Sanden FL, et al: Administration of human diploid-cell rabies vaccine in the gluteal area. N Engl J Med 1988; 318:124-125. 18. Kroger AT, Atkinson WL, Marcuse EK, et al: General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006; 55(RR-15):1-47. 19. Tan P, Jacobson RM, Poland GA, et al: Twin studies of immunogenicitydetermining the genetic contribution to vaccine failure. Vaccine 2001; 19:2434-2439. 20. Kotb M: Genetics of susceptibility to infectious diseases. AMS News 2004; 70:457-463. 21. Jacobson RM, Poland GA: The genetic basis for measles vaccine failure. Acta Paediatr Suppl 2004; 93:43-46. 22. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993; 42(RR-4):1. 23. Pickering LK, Orenstein WA: Development of pediatric vaccine recommendations and policies. Semin Pediatr Infect Dis 2002; 13:148-154. 24. Schwartz B, Orenstein WA: Vaccination policies and programs: the federal government's role in making the system work. Prim Care 2001; 28:697-711. 25. Centers for Disease Control and Prevention. : National Childhood Vaccine Injury Act: requirements for permanent vaccination records and for reporting of selected events after vaccination. MMWR 1988; 37:197. 26. Murphy TV, Gargiullo PM, Mehan MS, et al: Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001; 344:564. 27. Centers for Disease Control and Prevention. : Withdrawal of rotavirus vaccine recommendation. MMWR 1999; 48:1007. 28. Orenstein WA, Rodewald LE, Hinman AR: Immunization in the United States. In: Plotkin S, Orenstein WA, ed. Vaccines, 4th ed.. Philadelphia: WB Saunders; 2004:1357-1386. 29. Centers for Disease Control and Prevention. : Summary of notifiable diseasesUnited States, 2005. MMWR 2007; 54:1-92. 30. Centers for Disease Control and Prevention. : Vaccination coverage among children entering schoolUnited States, 200506 school year. MMWR 2006; 55:1124-1126. 31. Centers for Disease Control and Prevention. : A comprehensive immunization strategy to eliminate transmission of hepatitis b virus infection in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP) part 2: immunization of adults. MMWR 2006; 55(RR-16):1-33. 32. Centers for Disease Control and Prevention. : Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1-34. 33. Centers for Disease Control and Prevention. : Achievements in public health: elimination of rubella and congenital rubella syndromeUnited States, 19692004. MMWR 2005; 54:279-282. 34. Meissner HC, Reef SE, Cochi S: Elimination of rubella from the United States: a milestone on the road to global elimination. Pediatrics 2006; 117:933-935. 35. Bisgard KM, Kao A, Leake J, et al: Haemophilus influenzae invasive disease in the United States, 19941995: Near disappearance of a vaccine-preventable childhood disease. Emerg Infect Dis 1998; 4:229. 36. Peltola H, Kilpi T, Anttila M: Rapid disappearance of Haemophilus influenzae type b meningitis after routine
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childhood immunisation with conjugate vaccines. Lancet 1992; 340:592. 37. Flannery B, Schrag S, Bennett NM, et al: Impact of childhood vaccination on racial disparities in invasive Streptococcus pneumoniae infections. JAMA 2004; 291:2197-2203. 38. Kyaw MH, Lynfield R, Schaffner W, et al: Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006; 354:1455-1463. 39. Lexau CA, Lynfield R, Danila R, et al: Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005; 294:2043-2051. 40. Stephens DS, Zughaier SM, Whitney CG, et al: Incidence of macrolide resistance in Streptococcus pneumoniae after introduction of the pneumococcal conjugate vaccine: population-based assessment. Lancet 2005; 365:855-863. 41. U.S. Department of Health and Human Services. Healthy People 2001, 2nd ed., with Understanding and Improving Health and Objectives for Improving Health. Washington, D.C., U.S. Government Printing Office. 42. Centers for Disease Control and Prevention. : National, state and urban vaccination coverage among children aged 1935 monthsUnited States, 2005. MMWR 2006; 55:988-993. 43. Salmon DA, Teret SP, MacIntyre CR, et al: Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future. Lancet 2006; 367:436-442. 44. Centers for Disease Control and Prevention. : Recommended childhood immunization scheduleUnited States, January 1995. Advisory Committee on Immunization Practices, American Academy of Pediatrics, American Academy of Family Physicians, National Immunization Program, CDC. MMWR 1995; 43:959-960. 45. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): immunization of adolescents. MMWR 1996; 45(RR-13):1-16. 46. Middleman AB, Rosenthal SL, Rickert VI, et al: Adolescent immunizations: a position paper of the Society for Adolescent Medicine. J Adolesc Health 2006; 38:321-327. 47. American Academy of Pediatrics. : Active and passive immunization. In: Pickering LK, Baker CJ, Long SS, et al ed. 2006 Red Book: Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village: IL, American Academy of Pediatrics; 2006:1-66. 48. King GE, Hadler SC: Simultaneous administration of childhood vaccines: an important public health policy that is safe and efficacious. Pediatr Infect Dis J 1994; 13:394. 49. Siber GR, Werner BC, Halsey NA: Interference of immune globulins with measles and rubella immunization. J Pediatr 1993; 122:204. 50. Anderson EL, Decker MD, Englund JA, et al: Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. JAMA 1995; 273:849. 51. Greenberg DP, Pickering LK, Senders SD, et al: Interchangeability of two diphtheria-tetanus-acellular pertussis vaccines in infancy. Pediatrics 2002; 109:666-672. 52. Chen RT, Davis R, Sheedy KM: Safety of immunizations. In: Plotkin SA, Orenstein WA, ed. Vaccines, Philadelphia: WB Saunders,; 2004:1557-1577. 53. Centers for Disease Control and Prevention. : Poliomyelitis prevention in the United States: updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000; 49(RR-5):1-22. 54. In: Howson CP, Howe CJ, Fineberg HV, ed. Institute of Medicine: Adverse Effects of Pertussis and Rubella Vaccines, National Academy Press: Washington, DC; 1991. 55. In: Stratton KR, Howe CJ, Johnston RB, ed. Institute of Medicine: Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causation, Washington, DC: National Academy Press; 1993. 56. In: Stratton KR, Howe CJ, Johnston RB, ed. Institute of Medicine: DPT Vaccine and Chronic Nervous System
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Dysfunction: A New Analysis, Washington DC: National Academy Press; 1994. 57. Centers for Disease Control and Prevention. : Update: vaccine side effects, adverse reactions, contraindications and precautions: recommendations of the Advisory Committee on Immunization Practices. MMWR 1996; 45(RR12):1. 58. Institute of Medicine. : Immunization Safety Review: Committee Reports, Washington, DC, National Academy of Sciences, 2004. 59. Varricchio F, Iskander J, Destefano F, et al: Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J 2004; 23:287-294. 60. Lau YL, Tam AY, Ng KW, et al: Response of preterm infants to hepatitis B vaccine. J Pediatr 1992; 121:962965. 61. American Academy of Pediatrics. : Prevention of pertussis among adolescents: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1-41. 62. Tasker SA, Wallace MR: Vaccination in HIV-infected patients. Curr Infect Dis Rep 2000; 2:247. 63. Centers for Disease Control and Prevention. : Health Information for International Travel 20052006, Atlanta, US Department of Health and Human Services, Public Health Service, 2005. 64. National Vaccine Advisory Committee. : Standards for Pediatric and Adolescent Immunization Practices. Standards for Child and Adolescent Immunization Practices. Pediatrics 2003; 112:958-963. 65. Centers for Disease Control and Prevention. : Immunization Information System ProgressUnited States, 2004. MMWR 2005; 54:1156-1157. 66. Task Force on Community Preventive Services. : Vaccine preventable diseases: improving vaccination coverage in children, adolescents and adults. MMWR 1999; 48:1. 67. Shefer AM, Briss P, Rodewald L, et al: Improving immunization coverage rates: an evidence based review of the literature. Epidemiol Rev 1999; 21:96. 68. National Vaccine Advisory Committee. : Strengthening the supply of routinely recommended vaccines in the United States: recommendations from the National Vaccine Advisory Committee. JAMA 2003; 290:3122-3128. 69. Centers for Disease Control and Prevention. : Shortage of tetanus and diphtheria toxoids. MMWR 2000; 49:1029-1030. 70. Centers for Disease Control and Prevention. : Update on the supply of tetanus and diphtheria toxoids and of diphtheria and tetanus toxoids and acellular pertussis vaccine. MMWR 2001; 50:189-190. 71. Centers for Disease Control and Prevention. : Notice to readers: decreased availability of pneumococcal conjugate vaccine. MMWR 2001; 50:783-784. 72. Centers for Disease Control and Prevention. : Shortage of varicella and measles, mumps and rubella vaccines and interim recommendations from the Advisory Committee on Immunization Practices. MMWR 2002; 51:190-197. 73. Centers for Disease Control and Prevention. : Experiences with obtaining influenza vaccination among persons in priority groups during a vaccine shortage United States, OctoberNovember, 2004. MMWR 2004; 53:1153-1155. 74. Centers for Disease Control and Prevention. : Notice to readers: limited supply of meningococcal conjugate vaccine, recommendation to defer vaccination of persons aged 1112 years. MMWR 2004; 55:567-568. 75. Stokley S, Santoli JM, Willis B, et al: Impact of vaccine shortages on immunization programs and providers. Am J Prev Med 2004; 26:15-21. 76. Freed GL, Davis MM, Clark SJ: Variation in public and private supply of pneumococcal conjugate vaccine during a shortage. JAMA 2003; 289:575-578.
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77. Centers for Disease Control and Prevention. : Limited supply of pneumococcal conjugate vaccine: suspension of recommendation for fourth dose. MMWR 2004; 53:108-109. 78. United States General Accounting Office. Report to congressional requesters: childhood vaccines: ensuring an adequate supply poses continuing challenges. 2002. Available at: www.gao.gov/new.items/d02987.pdf. Accessed June, 2007. 79. Wharton M, Strebel PM: Vaccine-preventable diseases. In: Wilcox LS, Marks JS, ed. From Data to Action: CDC's Public Health Surveillance for Women, Centers for Disease Control and Prevention: Infants and Children (CDC Monograph). Atlanta; 1994:281. 80. Hewlett EL, Edwards KM: Clinical practice. Pertussisnot just for kids. N Engl J Med 2005; 352:1215-1222. 81. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): pertussis vaccination: use of acellular pertussis vaccines among infants and young children. MMWR 1997; 46(RR-7):1. 82. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): supplemental recommendations: use of acellular pertussis vaccine and diphtheria and tetanus toxoids (DTaP) as a five dose series. MMWR 2000; 49(RR-13):1. 83. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): diphtheria, tetanus, and pertussis: guidelines for vaccine prophylaxis and other preventive measures. MMWR 1991; 40(RR-10):1. 84. Halperin SA, Sweet L, Baxendale D, et al: How soon after a prior tetanus-diphtheria vaccination can one give adult formulation tetanus-diphtheria-acellular pertussis vaccine?. Pediatr Infect Dis J 2006; 25:195-200. 85. Centers for Disease Control and Prevention. : Recommended antimicrobial agents for treatment and postexposure for prophylaxis of pertussis: 2005 guidelines. MMWR 2005; 55(RR-14):1-16. 86. Centers for Disease Control and Prevention. Preventing tetanus, diphtheria, and pertussis among pregnant women and their infants: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap). Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007 (in press). 87. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. MMWR 1991; 40(RR-1):1. 88. Centers for Disease Control and Prevention. : A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2005; 54:1-31. 89. Parker AA, Staggs W, Dayan GH, et al: Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States. N Engl J Med 2006; 355:447-455. 90. Centers for Disease Control and Prevention. : Updated recommendations of the Advisory Committee on Immunization Practices (ACIP) for the control and elimination of mumps. MMWR Recomm Rep 2006; 55:629-630. 91. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): measles, mumps and rubella-vaccine use and strategies for elimination of measles, rubella and congenital rubella syndrome and control of mumps. MMWR 1998; 47(RR-8):1. 92. Centers for Disease Control and Prevention. : Licensure of a combined live attenuated measles, mumps, rubella, and varicella vaccine. MMWR 2005; 54:1212-1214. 93. Atkinson WL, Orenstein WA: The resurgence of measles in the United States, 19891990. Annu Rev Med 1992; 43:451. 94. Pabst HF, Spady DW, Marusyk RG, et al: Reduced measles immunity in infants in a well-vaccinated population. Pediatr Infect Dis J 1992; 11:525.
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95. Gans H, Yasukawa L, Rinki M: Immune responses to measles and mumps vaccination of infants at 6, 9 and 12 months. J Infect Dis 2001; 184:817. 96. Barlow WE, Davis RL, Glasser JW, et al: The risk of seizures following receipt of whole cell pertussis or measles-mumps-rubella vaccine. N Engl J Med 2001; 345:656. 97. Bellini WJ, Rota JS, Lowe LE, et al: Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized. J Infect Dis 2005; 192:1686-1693. 98. Tingle AJ, Mitchell LA, Grace M, et al: Randomized double blind placebo-controlled study on adverse effects of rubella immunization of seronegative women. Lancet 1997; 349:1277. 99. Ray P, Black S, Shinefield H, et al: Risk of chronic arthropathy among women after rubella vaccination. JAMA 1997; 278:551. 100. James JM, Burks W, Robertson PK, et al: Safe administration of the measles vaccine to children allergic to eggs. N Engl Med 1995; 332:1262. 101. Centers for Disease Control and Prevention. : Revised ACIP recommendation for avoiding pregnancy after receiving a rubella-containing vaccine. MMWR 2001; 50:1117. 102. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): preventing pneumococcal disease among infants and young children. MMWR 2000; 49(RR-9):1. 103. Black S, Shinefield H, Baxter R, et al: Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente. Pediatr Infect Dis J 2004; 23:485-489. 104. Kaplan SL, Mason Jr EO, Wald ER, et al: Decrease of invasive pneumococcal infections in children among 8 children's hospitals in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine. Pediatrics 2004; 113:443-449. 105. Whitney CG, Farley MM, Hadler J, et al: Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003; 348:1737-1746. 106. Poehling KA, Lafleur BJ, Szilagyi PG, et al: Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics 2004; 114:755-761. 107. Fireman B, Black SB, Shinefield HR, et al: Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J 2003; 22:10-16. 108. Black S, Shinefield H, Fireman B, et al: Efficacy, safety and immunogenicity of heptavalent conjugate pneumococcal vaccine in children. Pediatr Infect Dis J 2000; 19:187. 109. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): pneumococcal polysaccharide vaccine. MMWR 1989; 38:64. 110. Shapiro ED, Berg AT, Austrian R, et al: The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991; 325:1453. 111. Centers for Disease Control and Prevention. : Poliovirus infections in four unvaccinated childrenMinnesota, AugustOctober 1005. MMWR 2005; 4:1053-1057. 112. Centers for Disease Control and Prevention. : Imported vaccine-associated paralytic poliomyelitisUnited States, 2005. MMWR 2006; 55:97-99. 113. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): poliomyelitis prevention in the United States. MMWR 2000; 49(RR-5):1. 114. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): poliomyelitis prevention in the United States: introduction of a sequential vaccination schedule of inactivated poliovirus vaccine followed by oral poliovirus vaccine. MMWR 1997; 46(RR-3):1.
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115. Strebel PM, Sutter RW, Cochi SL, et al: Epidemiology of poliomyelitis in the United States one decade after the last reported case of indigenous wild virus-associated disease. Clin Infect Dis 1992; 14:568. 116. Strebel PM, Ion-Nedelcu I, Baughman AL, et al: Intramuscular injections within 30 days of immunization with oral poliovirus vaccinea risk factor for vaccine-associated paralytic poliomyelitis. N Engl J Med 1994; 332:500. 117. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): prevention of varicella. MMWR 1996; 45(RR-11):1. 118. Centers for Disease Control and Prevention. : Recommendations of the Advisory Committee on Immunization Practices (ACIP): update varicella prevention. MMWR 1999; 48(RR-6):1. 119. Seward JF, Watson BM, Peterson CL, et al: Varicella disease after introduction of varicella vaccine in the United States, 19952000. JAMA 2002; 287:605-611. 120. Centers for Disease Control and Prevention. : Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56(RR-04):1-40. 121. Centers for Disease Control and Prevention. : FDA approval of Havrix (hepatitis A vaccine, inactivated) for persons aged 118 years. MMWR 2005; 54:1235-1236. 122. Centers for Disease Control and Prevention. : Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:123. 123. Innis BL, Snitbhan R, Kunasol P, et al: Protection against hepatitis A by an inactivated vaccine. JAMA 1994; 271:1328. 124. Thompson WW, Shay DK, Weintraub E, et al: Influenza-associated hospitalizations in the United States. JAMA 2004; 292:1333-1340. 125. Centers for Disease Control and Prevention. : Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1-41. 126. Centers for Disease Control and Prevention. : Influenza vaccination of health-care personnel: recommendations of the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006; 55:1-16. 127. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): prevention and control of meningococcal disease and meningococcal disease and college students. MMWR 2000; 49(RR-07):1-20. 128. Centers for Disease Control and Prevention. : Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005; 54:1-21. 129. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections Program Network. Available at:http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm#pubs. Accessed June, 2007. 130. Raghunathan PL, Bernhard SA, Rosenstein NE: Opportunities for control of meningococcal disease in the US. Annu Rev Med 2004; 55:333-353. 131. Centers for Disease Control and Prevention. : Update: GuillainBarr syndrome among recipients of Menactra meningococcal conjugate vaccineUnited States, June 2005September 2006. MMWR 2006; 55:1120-1124. 132. Glass RI, Parashar UD, Bresee JS, et al: Rotavirus vaccines: current prospects and future challenges. Lancet 2006; 368:323-332. 133. Centers for Disease Control and Prevention. : Prevention of rotavirus gastroenteritis among infants and children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006; 55(RR-12):1-13. 134. Rennels MB, Glass RI, Dennehy PH, et al: Safety and efficacy of high-dose rhesus-human reassortant rotavirus
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vaccinesreport of the National Multicenter Trial. United States Rotavirus Vaccine Efficacy Group. Pediatrics 1996; 97:7-13. 135. Salinas B, Perez SI, Linhares AC, et al: Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J 2005; 24:807-816. 136. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al: Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354:11-22. 137. Heaton PM, Goveia MG, Miller JM, et al: Development of a pentavalent rotavirus vaccine against prevalent serotypes of rotavirus gastroenteritis. J Infect Dis 2005; 192(Suppl. 1):S17-S21. 138. Vesikari T, Matson DO, Dennehy P, et al: Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006; 354:23-33. 139. Committee on Infectious Diseases, AAP. : Prevention of rotavirus gastroenteritis in infants and children. Pediatrics 2007; 119:171-182. 140. Burd EM: Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003; 16:1-17. 141. Harro CD, Pang YY, Roden RB, et al: Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 2001; 93:284-292. 142. Koutsky LA, Ault KA, Wheeler CM, et al: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 2002; 347:1645-1651. 143. Harper DM, Franco EL, Wheeler C, et al: Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364:1757-1765. 144. Centers for Disease Control and Prevention. : Quadrivalent human papillomavirus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007; 56(RR-2):1-23. 145. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): the role of BCG vaccines in the prevention and control of tuberculosis in the United States: a joint statement by the Advisory Committee for Elimination of Tuberculosis and the ACIP. MMWR 1996; 45(RR-4):1. 146. Rodriques LC, Diwan K, Wheeler JG: Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Int J Epidemiol 1993; 22:1154. 147. Colditz GA, Brewer TF, Berkey CS, et al: Efficacy of BCG vaccine in the prevention of tuberculosis: metaanalysis of the published literature. JAMA 1994; 271:698. 148. Ryan ET, Calderwood SB: Cholera vaccines. Clin Infect Dis 2000; 31:561. 149. Centers for Disease Control and Prevention. : Recommendation of the Advisory Committee on Immunization Practices (ACIP): inactivated Japanese encephalitis virus vaccine. MMWR 1993; 42(RR-1):1. 150. Hoke CH, Nisalak A, Sangawhipa N, et al: Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med 1988; 319:609. 151. Basnyat B, Maskey AP, Zimmerman MD, et al: Enteric (typhoid) fever in travelers. Clin Infect Dis 2005; 41:1467-1472. 152. Monath TP, Cetron MS: Prevention of yellow fever in persons traveling to the tropics. Clin Infect Dis 2002; 34:1369-1378. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
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Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 8 Chemoprophylaxis Gary D. Overturf Chemoprophylaxis is prevention of disease by administration of a drug. An antimicrobial agent is given to an individual who is at risk of developing an infection because of exposure or an impairment of host defense. The term prophylaxis does not apply to those situations in which infection is already established. Immunoprophylaxis (see Chapter 6 , Passive Immunization; Chapter 7 , Active Immunization), barrier prophylaxis (e.g., use of condoms; see Chapter 55 , Urethritis, Vulvovaginitis, and Cervicitis; Chapter 56 , Pelvic Inflammatory Disease), and chemical repellents for arthropod vectors are discussed elsewhere. Specific discussions of the prevention of travelers' diarrhea (see Chapter 9 , Protection of Travelers), neonatal conjunctivitis (see Chapter 84 , Conjunctivitis in the Neonatal Period (Ophthalmia Neonatorum)), malarial chemoprophylaxis (see Chapter 271 , Plasmodium Species (Malaria)), and antiviral prophylaxis of human immunodeficiency virus (HIV) infection (see Chapter 109 , Epidemiology and Prevention of HIV Infection in Children and Adolescents) can also be found elsewhere. Similarly, immune or chemoprophylaxis for immunocompromised hosts, such as solid organ or bone marrow transplant subjects, or those subjects being treated for cancer, are not specifically discussed in this chapter. Ideally, recommendations for antimicrobial prophylaxis should be based on data documenting efficacy in prospective, randomized, controlled studies. This standard is met uncommonly because of the infrequency and highly variable rate of infection after a given exposure. Such studies necessitate very large sample sizes to document prophylactic efficacy. Most prophylactic regimens are presumed efficacious on the basis of small clinical trials, supporting pharmacology or clinical analogy, rather than proven efficacy in prevention of infection. Also, prophylaxis may be justified solely by the severe consequences of possible infection (e.g., endocarditis after dental procedures, infection of a surgical prosthesis). Chemoprophylaxis of infection in children can be classified as general or specific. Chemoprophylaxis is general when all children, regardless of underlying disease or other factors, are at significant risk of infection and administration of an antimicrobial agent may prevent disease (e.g., Neisseria meningitidis in households). Specific chemoprophylaxis is administered to individual children who are deemed at special risk, either by exposure to specific infection (e.g., plague) or by the presence of an immunodefective state. GENERAL PRINCIPLES For prophylaxis to be effective, four criteria should be met: 1. The antimicrobial drug or drugs used for prophylaxis must have activity against the likely infectious agent or must disrupt pathogenesis (e.g., prevent toxin production). 2. The host should have a defined and finite risk of disease. An assessment to determine the risk is multifactorial, taking into account both the incidence and severity of infection if it occurs and the communicability of the agent. The safety of a chemoprophylactic agent must be such that complications of its administration do not outweigh the risks of infection (i.e., an acceptable risk-to-benefit ratio). The chemoprophylactic agent must have been taken or given, and adequate tissue concentration must be present at the time of exposure to the infectious agent.
3. 4.
Often, these criteria are not met or are not documented by prospective study. Recommendations for prophylaxis are often based solely on an acceptable risk-to-benefit ratio, knowledge of the in vitro activity and pharmacology of the agent, and the concern for severity of infection should it occur. Recommendations change periodically on the basis of evolving knowledge, changing pathogens, and the susceptibility to antimicrobial agents. Updated guidelines are published periodically by the Centers for Disease Control and Prevention (CDC), by the Committee on Infectious Diseases of the American Academy of Pediatrics (in the Red Book), [1] in the Medical Letter on Drugs and Therapeutics, [2] by the American Heart Association, [3] and in peer-reviewed journals. CHEMOPROPHYLAXIS IN HEALTHY CHILDREN
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Chemoprophylaxis is recommended for surgical infections ( Table 8-1 ) or exposure to agents causing septicemia, meningitis, and other infections with significant morbidity ( Table 8-2 ). TABLE 8-1 -- Classification of Operative Wounds and Risk of Infection Classification Clean Cleancontaminated Contaminated Criteria Risk (%)
Elective, not emergency, nontraumatic; primarily closed; no acute inflammation; no break < 2 in technique; respiratory, GI, biliary, and GU tracts not entered Urgent or emergent, otherwise clean; elective opening of respiratory, GI, biliary, or GU tract with minimal spill and not infected urine or bile; minor technique break Nonpurulent inflammation; gross spill from GI tract; entry into biliary or GU tract in the presence of infection; major break in technique; penetrating trauma < 4 hours' duration; chronic open wounds to be grafted or covered Purulent inflammation (e.g., abscess); preoperative perforation of respiratory GI or GU tract; penetrating trauma > 4 hours' duration < 10 20
Dirty
40
GI, gastrointestinal; GU, genitourinary.
TABLE 8-2 -- Chemoprophylaxis for Healthy Children Exposed to Specific Pathogens a Maximum Divided Dose/Day Doses Pathogen Prophylactic Agent Dose/Day Bordetella pertussis [b] Erythromycin Azithromycin or Clarithromycin Haemophilus influenzae type Rifampin b Corynebacterium diphtheriae Erythromycin or Benzathine penicillin 600,000 units (IM) if < 30 kg 1.2 million units (IM) if 30 kg Neisseria meningitidis Rifampin 20 mg/kg 1.2 g or 600 mg or Ceftriaxone 125 mg (IM) if < 12 years 250 mg (IM) if 12 years or Ciprofloxacin Yersinia pestis (pneumonic) Sulfonamide or TMP-SMX 8 mg/kg TMP 2 500 mg if 18 years 40 mg/kg if < 9 years 2 1 2 15 mg/kg 20 mg/kg 4050 mg/kg 1.0 g 600 mg 2.0 g 2 1 4 4050 mg/kg 10 mg/kg 2.0 g 500 mg 4 1
Duration 14 days 5 days 7 days 4 days 7 days
Once
2 days 4 days Once
Once 7 days
7 days
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Tetracycline Vibrio cholerae c < 9 years > 9< 18 years 18 years Streptococcus agalactiae Mycobacterium leprae (borderline or lepromatous) Herpes simplex virus [d] TMP-SMX Tetracycline Ciprofloxacin Ampicillin (maternal intrapartum) Dapsone Acyclovir (neonate; see text) Acyclovir (suppression of genital infection or recurrent erythema multiforme) Influenza A [e] Amantadine, rimantadine Oseltamivir
15 mg/kg if 9 years 8 mg/kg TMP 50 mg/kg 15 mg/kg
1.0 g
7 days
2 2.0 g 1.0 g 2.0 g; then 1.0 g (IV) q4 h 4 2
3 days 3 days 3 days Until delivery
1 mg/kg 15 mg/kg (IV) 1020 mg/kg
100 mg
1 3
3 years 7 days Up to 12 months See text See text
800
24
5 mg/kg 30 mg if 12 years; 45 mg if 35 years 60 mg if 612 years
150 mg if 19 12 years 200 mg if 10 years 75 mg if 13 years 1
Scabies Neisseria gonorrhoeae ophthalmia neonatorum Sexual exposure < 45 kg
5% permethrin 1% silver nitrate, 1% tetracycline, or 0.5% erythromycin Ceftriaxone alt Spectinomycin [f] plus Erythromycin
Topically Topically
Once Once
125 mg (IM) 40 mg/kg (IM) 2.0 g (IM) 40 mg/kg 125 mg (IM) 1.0 g 500 mg 400 mg 2.0 g (IM) 200 mg 50 mg/kg 4 mg/kg 2.0 g 200 mg 2 4 2 2.0 g 4
Once Once 7 days Once Once Once Once Once 7 days 7 days 7 days
45 kg and 9 years
Ceftriaxone or Azithromycin or Ciprofloxacin [g] or Cefixime or Spectinomycin plus Doxycycline
Chlamydia trachomatis < 9 years 9 years Erythromycin Doxycycline or
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Azithromycin Treponema pallidum Benzathine penicillin G alt Doxycycline if 9 years alt Erythromycin Calymmatobacterium granulomatis Doxycycline if 9 years or TMP-SMX
1.0 g 50 000 units/kg (IM) 4 mg/kg 40 mg/kg 4 mg/kg 2.4 million units (IM) 200 mg 2.0 g 200 mg 2 4 2
Once Once [a]
14 days 14 days 3 weeks
8 mg/kg TMP 320 mg TMP 2
3 weeks
alt, alternative; IM, intramuscularly; IV, intravenously; SMX, sulfamethoxazole; TMP, trimethoprim.
a Alternative drugs used only if other(s) cannot be used; listings are not exhaustive. Some regimens are not of proven benefit. Administration is oral except as noted. b See Chapter 162 , Bordetella pertussis (Pertussis) and Other Species, for doses by age. c Resistance of isolate requires revision of chemoprophylactic regimen. d Agents listed only as guidelines to possible dosing; data evolving. e Agents not approved for use in children younger than 1 year. f Not recommended for pharyngeal infection; a 5-day course of TMP-SMX could be substituted for persons who cannot take cephalosporin, quinolone, or
spectinomycin.
g Quinolones are not approved for persons < 18 years, pregnant women, or nursing mothers.
Specific Pathogens Neisseria meningitidis
For meningococcal disease, the reported secondary attack rates among household contacts of index cases range from 0.25% in adults to 10% for infants younger than 1 year. Prophylaxis is reviewed in Chapter 125 , Neisseria meningitidis, and doses of primary and alternative agents are listed in Table 8-2 . Studies of large outbreaks have shown penicillin to be an ineffective prophylactic agent. [4] Previously sulfonamides were effective in preventing infection in close contacts, but because of the emergence of sulfonamide resistance, they are no longer recommended. [5] Rifampin is effective in eliminating nasopharyngeal carriage of N. meningitidis when given in a standard 2-day regimen. Although rifampin is likely to be effective in preventing meningococcal disease, a study establishing such efficacy has never been published. Prophylaxis should be instituted as soon as possible, preferably within 24 hours for contacts in households and childcare centers, and sometimes for school contacts, as well as persons who have had contact with infected oral secretions. [1] Rifampin is excreted into body fluids, causing red discoloration of urine and tears in 80% of individuals. Rifampin alters the metabolism of some drugs, including oral contraceptives, phenytoin, phenobarbital, carbamazepine, warfarin compounds, and other agents utilizing the hepatic cytochrome P-450 enzyme system. Safety of rifampin in pregnancy has not been established. Alternative agents include ceftriaxone [6] and fluoroquinolones; [7] however, ceftriaxone requires injections and is relatively expensive, and it has only been studied for eradication of carriage of N. meningitidis serogroup A. Fluoroquinolones have also been evaluated for eradication of carriage of N. meningitidis serogroup C, but they are relatively contraindicated in pregnant women and prepubertal children.
Haemophilus influenzae type b
Prophylaxis of Haemophilus infections is discussed in Chapter 172 , Haemophilus influenzae, and Chapter 173 , Other Haemophilus Species. Doses of primary and alternative agents for prophylaxis are listed in Table 8-2 . Rifampin is approximately 95% effective in the eradication of nasopharyngeal carriage of Haemophilus influenzae type b (Hib) in children, but studies have fallen short of clearly documenting its efficacy in prevention of disease. [8] [9] Prophylaxis is indicated if an incompletely immunized child younger than 4 years has close exposure to a case of invasive Haemophilus disease. The efficacy of prophylaxis for invasive strains of H. influenzae other than type b (e.g. types a, f, and others) has not been evaluated. In childcare or school settings, recommendations for institution of prophylaxis vary; local public health authorities should be consulted.
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In general, prophylaxis is recommended in childcare settings when: (1) 2 or more cases of Hib disease have occurred within a 60-day period; or (2) incompletely immunized children younger than 4 years have been exposed. Similar prophylactic regimens should be considered when exposure to other invasive H. influenzae infection occurs, including exposure to encapsulated serotypes such as types a and f, although there are no data supporting the efficacy of rifampin prophylaxis against serotypes other than Hib.
Group B Streptococcus
Early-onset disease due to group B streptococcus (Streptococcus agalactiae) can be prevented by intrapartum administration of ampicillin or penicillin to women [10] [11] (see Chapter 119 , Streptococcus agalactiae (Group B Streptococcus)). Intrapartum administration of antibiotics does not prevent disease in infants who were infected before commencement of therapy.
Human Immunodeficiency Virus
Perinatal or intrauterine transmission of HIV is diminished by the administration of zidovudine to the mother during pregnancy, with continued treatment of the infant for 6 weeks after delivery. Initial studies showed that regimens of zidovudine reduced the rate of HIV transmission to the infant from 25.5% to 8.3%. [12] Current HIV maternal prophylactic regimens with zidovudine and other agents or cesarean delivery have reduced the rate of transmission in worldwide studies to < 2% (see Chapter 109 , Epidemiology and Prevention of HIV Infection in Children and Adolescents). Evaluation of zidovudine in combination with other classes of HIV drugs after occupational exposure is continuing, but this agent has been shown to reduce the risk of HIV infection if provided within 12 to 24 hours after exposure (see Chapter 109 , Epidemiology and Prevention of HIV Infection in Children and Adolescents).
Herpes Simplex
Herpes simplex virus (HSV) infection usually results from transmission at the time of delivery. Prophylaxis is controversial. [13] With vaginal delivery during maternal primary genital infection, transmission of HSV to the infant may exceed 50%, whereas in delivery during maternal reactivation disease, the risk drops to less than 5%. It may be difficult to determine whether HSV infection is active, primary, or recurrent, because genital infection is often asymptomatic. Most experts recommend cultures at 48 hours of age in asymptomatic infants exposed to mothers with suspected HSV reactivation (e.g., cultures of the umbilicus, conjunctiva, mouth, and nasopharynx) and observation for signs of illness. Positive results from culture specimens taken 48 hours or more after delivery are considered indicative of colonization and a probable higher risk for infection. In this case, some authorities recommend the administration of intravenous acyclovir (pre-emptive treatment) to prevent symptomatic disease. [13] Acyclovir prophylaxis has also been shown to be effective in reducing the frequency of recurrent genital and oral cutaneous HSV infections. In addition, acyclovir has been used prophylactically in children younger than 3 years who were exposed to HSV infections in childcare center outbreaks (30 to 60 mg/kg per day in 3 to 5 doses) [14] and reduces recurrences of herpes labialis in adults by 53% to 71%. [15] Preliminary data suggest that similar regimens reduce recurrent HSV-associated erythema multiforme minor (see Chapter 295 , Antiviral Agents).
Respiratory Tract Pathogens
Isoniazid is effective in preventing new Mycobacterium tuberculosis infection in uninfected individuals and in preventing tuberculosis in latently infected asymptomatic individuals. [16] [17] Treatment of latent tuberculosis infection is therapy rather than prophylaxis, because isoniazid administration prevents the progression to symptomatic disease (see Chapter 134 , Mycobacterium tuberculosis). Macrolide agents are effective in preventing the transmission of Bordetella pertussis and in halting the progression of pertussis in household contacts if it is given before symptoms occur. [18] [19] Hypertrophic pyloric stenosis associated with administration of erythromycin to neonates exposed to pertussis has been reported. The risk of pyloric stenosis with other macrolides such as clarithromycin and azithromycin is unknown, but is probably signigicantly less. Both 5 days of azithromycin and 7 days of clarithromycin administration in older children and adults who are colonized with B. pertussis have been as effective as 14 days of erythromycin administration. Prophylaxis against influenza in high-risk patients, such as those with underlying cardiac or pulmonary disease, is best achieved by annual immunization. However, when this is not possible or is delayed, both amantadine and rimantadine are effective as prophylaxis against influenza A (in susceptible agents) in high-risk children 12 months and older during the epidemic season or until immunization can be completed. [1] Neuraminidase inhibitors (zanamivir and oseltamivir) are effective for treatment against both influenza A and influenza B but may be used for prophylaxis of influenza infections 2, in children older than 1 years of age. [20] Healthcare providers should follow annual recommendations by public health authorities for optimal prophylactic strategy.
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Scabies
Scabies is highly transmissible among close contacts within households. Prophylactic therapy is recommended for household members, because clinical symptoms can appear as late as 2 months after exposure, during which time individuals can transmit the infection.
Unusual Agents
Prophylaxis is recommended for a number of infrequent infections (see Table 8-2 ), including diphtheria, plague, cholera, and leprosy. Consultation with reference sources or public health or infectious disease experts is recommended for dealing with these unusual infections in the United States.
Sexually Transmitted Agents
Prophylaxis is recommended after exposure to certain sexually transmitted agents. Despite the lack of evidence, prophylaxis is justified because: (1) transmission rates of disease after exposure are high; and (2) the diagnosis of infection is indeterminate until active disease develops. Additionally, identification and treatment of index cases and contacts are critical to decreasing transmission in the community. Therefore, for certain infections that may be asymptomatic and for which transmission rates exceed 50%, such as gonorrhea, Chlamydia trachomatis infection, and syphilis, it is reasonable to provide therapy on an empiric basis (see Table 8-2 ). The evaluation and treatment of sexually abused children are discussed in Chapter 58 , Infectious Diseases of Child Abuse. After sexual assault, individuals 9 years or older are generally given ceftriaxone, doxycycline, and metronidazole (2 g once orally). CHEMOPROPHYLAXIS FOR SURGICAL PROCEDURES AND TRAUMA Surgical procedures (see Chapter 101 , Clinical Syndromes of Hospital-Associated Infections) and traumatic injuries (see Chapter 90 , Infection Following Trauma) are associated with a variable risk for infection. Studies documenting the efficacy of systemic prophylaxis of surgical wound infections have been performed primarily in adults, and because the pathogenesis of such infections is similar in children, the principles of antimicrobial prophylaxis have been applied to children. Systemic prophylaxis is indicated when the benefits of preventing wound infection outweigh the risks of potential adverse effects of the prophylactic regimen. Risk of infection can be estimated by categorizing procedures as clean, clean-contaminated, contaminated, or dirty (see Table 8-1 ). [21] Antibiotic prophylaxis is warranted in all procedures that are clean-contaminated, contaminated, or dirty (see Chapter 69 , Peritonitis, Chapter 70 , Appendicitis and Mesenteric Lymphadenitis; Chapter 90 , Infection Following Trauma; Chapter 101 , Clinical Syndromes of Hospital-Associated Infections).
Principles
During surgical procedures, the time of maximum risk of infection is relatively finite, and, therefore, chemoprophylactic regimens are appropriately limited in duration. A single dose of antimicrobial agent given 30 minutes or less before the initial incision provides adequate tissue concentrations throughout operations of less than 4 hours' duration. [21] In one prospective study, a lower infection rate was documented in patients undergoing elective surgical procedures if antibiotic prophylaxis was administered in the 2 hours before the time of surgical incision. [22] When surgery is prolonged, major blood loss occurs, or an agent with a short half-life is used, a second dose may be advisable during the procedure. [23] Unfortunately, inappropriate timing and duration of antibiotic prophylaxis in surgery are common. [24] [25] [26] Surgical prophylaxis should be reserved for use in situations in which: (1) the risks of infection outweigh the risks of antibiotic therapy, such as when foreign material (e.g., a ventriculoperitoneal shunt) is implanted; and (2) infection would have major consequence. The choice of antibiotic is based on spectrum of activity against the most likely complicating pathogens and penetration to site of interest, although both the spectrum of activity and the cost should be limited. Periodic consensus recommendations for prophylaxis during surgical procedures are published in the Medical Letter on Drugs and Therapeutics. [2] Quality standards for prophylaxis in surgical procedures have been proposed, [23] and guidelines for evaluation of newer drugs for surgical prophylaxis have been suggested. [27] Despite rising rates of community-associated colonization by methicillin-resistant Staphylococcus aureus (MRSA) and attendant postsurgical infections, there is not consensus on the use of a prophylactic agent with activity against MRSA.
Surgical Procedures Head and Neck Surgery
Placement of a ventriculoperitoneal shunt is classified as a clean procedure. However, the morbidity associated with
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infection of ventriculoperitoneal shunts is high and may necessitate antimicrobial therapy with or without replacement of the shunt. Two meta-analyses have suggested a favorable role for prophylactic antibiotic therapy, with reductions in infection rate by approximately 50%; [28] [29] the benefit would disappear if baseline infection rates, that is, in procedures performed without prophylactic antibiotics, were less than 5%. For clean-contaminated surgery involving the head and neck, some prospective studies of adults with cancer suggest that more prolonged therapy (5 days versus 1 day) and combination therapy (gentamicin plus clindamycin versus cefazolin alone) are associated with lower infection rates. [30]
Noncardiac Thoracic Surgery
Few studies document the efficacy of prophylactic antibiotics in thoracic surgery, but antibiotics are nearly always given. Studies in adults undergoing chest procedures generally have shown reduced rates of wound infection with brief antibiotic administration and variable effects on the incidence of pneumonia and empyema for periods of up to 48 hours of antibiotic therapy. [31] No studies have been performed in children.
Cardiac Surgery
In cardiovascular surgery, antibiotic prophylaxis is almost always given. Even with a small risk, the high morbidity of infection and the belief that prophylactic antibiotic therapy reduces infection rates have justified its use. [32] In one large study of adults undergoing open-heart procedures, patients were randomly assigned to receive prophylaxis with cefazolin, cefamandole, or cefuroxime for a 48-hour period. [33] Patients in the cefazolin group experienced slightly more postoperative infections than patients in the other two groups; cefuroxime was deemed to be the most costeffective agent. In another study comparing vancomycin, cefazolin, and cefamandole prophylaxis given for 48 hours, patients receiving vancomycin experienced fewer wound infections than patients receiving the other two agents (approximately 4% versus 11% to 12%), but infections of grafts and implants were uncommon in all three groups (0 to 2%). [34] A meta-analysis of seven placebo-controlled randomized studies of antimicrobial prophylaxis during implantation of pacemakers showed a significant reduction in the incidence of infection with the use of such prophylaxis. [35]
Abdominal Surgery
A large number of studies performed in adults document efficacy of antimicrobial prophylaxis in abdominal surgical procedures, particularly for colorectal procedures and appendectomy when perforation has occurred. [23] Prophylactic agents should have activity against common flora of the gastrointestinal tract, especially gram-negative enteric and anaerobic bacteria. Preoperative oral antibiotics may lower the incidence of infection for elective operations. An oral regimen of neomycin and erythromycin may be as effective as parenteral drugs.
Orthopedic Surgery
Prophylactic antibiotics (particularly antistaphylococcal agents) reduce the incidence of infection after several orthopedic procedures when a foreign body (such as an artificial joint or internal fixation device) is implanted. The morbidity associated with infection justifies prophylactic regimens even with low infection rates. Efficacy of prophylaxis has been demonstrated most strikingly in joint replacement procedures in adults; [36] current regimens most commonly employ single-dose or short-course (48 hours or less) cefazolin or a similar agent with good antistaphylococcal activity. Use of antimicrobial drugs for compound fracture is considered treatment rather than prophylaxis and should be continued postoperatively for several days.
Trauma
Traumatic injury has higher risk for infection than surgical procedures, but the risk varies by type and location of injury (see Chapter 90 , Infection Following Trauma; Chapter 92 , Infection Following Bites). Trials of prophylactic antibiotics after significant trauma have inconsistently demonstrated a benefit in preventing infection. In one retrospective study of burned patients treated on an outpatient basis, no differences between wound infection rates were observed in those receiving empiric antibiotic therapy (3.8%) and those not receiving it (3.1%). [37] Another retrospective study of extremity gunshot wounds in 75 children and adolescents likewise demonstrated no benefit for antibiotic prophylaxis; no infections occurred in the 38 patients receiving antibiotics or the 14 patients not receiving them, with adequate follow-up. [38] Conversely, a prospective, randomized, double-blind trial of intravenous cefonicid for patients requiring tube thoracostomy after chest trauma found significant benefit for antibiotic therapy (1.6% in treated patients versus 10.7% in untreated patients), and the hospital stay was longer in individuals who experienced infectious complications. [39]
Animal Bite Wounds
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Prophylaxis or early treatment of animal bite wound injuries is controversial (see Chapter 92 , Infections Following Bites). Most studies fail to show a benefit of prophylactic antibiotics, and infection rates after dog bites are low (e.g., < 5%). [40] [41] A meta-analysis of 8 studies of antibiotic prophylaxis of dog bite wounds suggested a benefit for antibiotics, [42] with a relative risk of infection in treated groups of 0.56 compared with control groups. The benefit was accentuated when only bites to the hand were analyzed. Amoxicillin-clavulanate (20 to 40 mg/kg per day of the amoxicillin component in 3 divided doses for 5 to 7 days) provides the best spectrum of activity for animal bites and human bites, considering the most frequently responsible pathogens causing severe infections (Pasteurella multocida, anaerobic bacteria, streptococci, and Staphylococcus aureus). CHEMOPROPHYLAXIS IN CHILDREN WITH CONDITIONS PREDISPOSING TO INFECTION Children predisposed to development of infection by virtue of a defined immunodeficient state or underlying anatomic defect may benefit from chemoprophylaxis (see Table 8-2 ). Prophylaxis is required over a prolonged period of risk, and strict compliance with regimens is critical to preventing breakthrough infections.
Prior Rheumatic Fever
Patients who have a well-documented history of acute rheumatic fever (including disease manifested by carditis, arthritis, or chorea) should receive continuous antibiotic prophylaxis to prevent recurrent attacks associated with either symptomatic or asymptomatic infection. Prophylaxis should be initiated as soon as the diagnosis of acute rheumatic fever is made. The preferred prophylaxis, ensuring compliance, is monthly administration of benzathine penicillin (1.2 million units intramuscularly for children weighing more than 27 kg (60 lb); 600,000 units for those weighing less than 27 kg). Adequate serum antibiotic levels may not persist beyond 3 weeks in some patients, and, in high-exposure situations, recurrences are less likely if therapy is provided every 3 weeks rather than every 4 weeks. [43] [44] The appropriate duration of chemoprophylaxis for rheumatic fever is not known; some studies suggest that treatment can be discontinued in young adults who are at low risk for recurrent episodes of group A streptococcal infection. [45] Current minimum recommendations for duration is for 5 years (or until age 21 years) for those without carditis, and 10 years (or well into adulthood) for those with carditis without residual heart disease, and lifelong (or > 40 years) for those with carditis and residual heart disease. Recommendations for cardiac prophylaxis of the American Academy of Pediatrics and American Heart Association are shown in Table 8-3 . [1] [46] TABLE 8-3 -- Chemoprophylaxis in Special Situations Prophylactic Agents Disorder Dosing [c] Prior rheumatic fever
[46]
Duration
Benzathine penicillin G or or Penicillin V
1.2 million units every RF without carditis: 5 years after episode, or 21 4 weeks (every 3 years of age, whichever is longer weeks if high-risk) 250 mg twice daily RF with carditis, without regurgitation (clinical or echocardiograph): 10 years after episode, or well into adulthood, whichever is longer
or Sulfisoxazole 500 mg if 27 kg (60 lb); 1 g if > 27 kg; once daily 250 mg twice daily RF with carditis, with regurgitation: 10 years after episode, or at least 40 years of age, sometimes lifelong
or Erythromycin
Asplenic states [a] 47,49 Penicillin V
125 mg twice daily if < At least until 5 years of age or 5 years after 5 years surgical removal, whichever is longer; see text 250 mg twice daily if 5 years
Pneumocystis jirovecii infection
TMP-SMX
5 mg/kg TMP (maximum 320 mg TMP) once daily or 3
Duration chemotherapy, significant immunosuppression [e]
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consecutive days/week In children with cancer, organ transplantation, HIV infection [51] Recurrent otitis media [53] [56] Sulfisoxazole alt Amoxicillin alt Amoxicillin 40 mg/kg per day divided q8 hours at onset of upper respiratory tract infection 2 mg/kg TMP once daily 12 mg/kg once daily 50 mg/kg (maximum 2 Once 30 to 60 minutes before the procedure g) procedure; then 25 mg/kg 6 hours after initial dose 35 days 20 mg/kg at bedtime 36 months 50 mg/kg at bedtime 36 months
Recurrent urinary tract infection [57] [62]
TMP-SMX or Nitrofurantoin
Variable
Endocarditis [3] Dental, oral, or upper respiratory tract procedures
Standard Amoxicillin (PO)
Standard (penicillinallergic) or Clindamycin (PO) or Oral medication impossible Ampicillin (IM or IV) or Azithromycin or Clarithomycin Cefazolin or Ceftriaxone Gentamicin (IM or IV) 2 mg/kg (maximum 80 mg) before procedure; can be repeated 8 hours after initial dose 50 mg/kg (maximum 3 g) 1 hour before procedure; then 25 mg/kg 6 hours after initial dose 50 mg/kg (maximum 1 Once 30 to 60 minutes before the procedure g) 15 mg/kg (maximum 500 mg) Once 30 to 60 minutes before the procedure 50 mg/kg (maximum 2 g) 20 mg/kg (maximum 600 mg)
Alternate for low-risk patient Amoxicillin
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(PO) alt, alternative; C, carditis; HIV, human immunodeficiency virus; IM, intramuscularly; IV, intravenously; PO, by mouth; R, residual valvular disease; RF, rheumatic fever; SMX, sulfamethoxazole; TMP, trimethoprim.
a Asplenic states include congenital and surgical asplenia, and splenic dysfunction associated with hemoglobinopathies; also considered for individuals with
complement disorders. Vaccinations are also very important.
c Efficacy of prophylaxis is not proven in all circumstances. Dosing is listed only as guideline. e See Chapter 525, Pneumocystis jirovecii.
Recommendations for other infections associated with Streptococcus pyogenes are less certain. Most experts recommend prophylaxis for children with poststreptococcal chorea similar to that for rheumatic fever. Information for the costbenefit, safety, and efficacy of treatment of suspected poststreptococcal sequelae (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, PANDAS) has not been established; currently, routine prophylaxis is not recommended. Some experts recommend prophylaxis for several years in children who have had an episode of poststreptococcal reactive arthritis. In general in those exposed to cases of severe invasive group A streptococcal disease, including toxic shock syndrome and necrotizing fasciitis, although they are at modestly increased risk of disease, the risk is not sufficient to recommend prophylaxis, nor have studies been conducted to establish the efficacy of such treatment.
Asplenia
Children with functional or anatomic asplenic states, particularly sickle-cell anemia, have been shown to benefit from continuous penicillin prophylaxis to prevent pneumococcal and other bacterial infections (see Chapter 108 , Infectious Complications in Special Hosts). A single prospective controlled study showed an 84% reduction in rate of infection in children younger than 3 years who received daily oral penicillin V (125 mg twice daily for children < 5 years; 250 mg twice daily for children 5 years) compared with those receiving placebo. [47] A follow-up placebocontrolled trial of penicillin prophylaxis beyond 5 years of age in children receiving com prehensive care for sicklecell disease showed a low incidence of infection and no significant benefit for prophylaxis in preventing pneumococcal bacteremia or meningitis (2% in penicillin group versus 1% in placebo group). [48] It is recommended that prophylaxis be discontinued in children older than 5 years, provided that they have not previously had invasive pneumococcal infection and are appropriately immunized for age. Asplenia from other causes (congenital, surgical, functional) is also associated with increased risk of fulminant septicemia. In comparison with the incidence in healthy children, the incidence of mortality from septicemia is 50fold higher after splenectomy for trauma (compared with > 350-fold higher in children with sickle-cell disease). Although the risk is higher in younger children and in the first 5 years after splenectomy, fulminant septicemia has been reported in adults more than 25 years after splenectomy. [1] The general consensus is that asplenic children with malignancy, thalassemia, congenital anomalies, or other diseases with high risk of fulminant infection should receive daily chemoprophylaxis. There is less certainty about the need for prophylaxis in children who undergo splenectomy for trauma. In general, prophylaxis (in addition to appropriate immunization) should be strongly considered for asplenic children younger than 5 years and should be considered for older children. Asplenic children should receive conjugate pneumococcal, meningococcal, and Haemophilus vaccines in the recommended series; pneumococcal polysaccharide multivalent vaccines should be added after 2 years of age; revaccination with pneumococcal polysaccharide vaccine should be strongly considered after 3 to 5 years for children older than 5 years who are at high risk of severe pneumococcal infection. [1]
Other Underlying Conditions
Individuals lacking terminal components of complement, properidin deficiency, or other abnormalities of complement pathways are at risk of recurrent meningococcal and other disseminated neisseria infections and may benefit from penicillin prophylaxis, but immunization with protein-polysaccharide or conjugate vaccines in children older than 2 years of age with these conditions is likely to be more protective (see Chapter 105 , Infectious Complications of Complement Deficiencies). [49] Trimethoprim-sulfamethoxazole (TMP-SMX) can prevent bacterial infections in children with chronic granulomatous disease, HIV infection, or acute lymphoblastic leukemia, although emergence of resistant bacteria is a potential problem. [50] TMP-SMX is also beneficial in the prevention of Pneumocystis carinii pneumonia in many immunosuppressive conditions, including bone marrow and organ transplantation and acquired immunodeficiency syndrome (AIDS). [51] Strategies to prevent serious clinical disease due to cytomegalovirus and herpes simplex virus after bone marrow and solid organ transplantation have been published. [52]
Recurrent Otitis Media
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Both sulfisoxazole and amoxicillin are effective for prophylaxis in otitis-prone children, and TMP-SMX has also been used with apparent efficacy. [53] [54] Children are considered candidates for prophylaxis if they have experienced 3 episodes of acute otitis media within the previous 6 months or 4 episodes within the previous 12 months. Continuous prophylaxis may be more effective than intermittent prophylaxis. [54] Increase in -lactam resistance of Streptococcus pneumoniae and in -lactamase-producing organisms during prophylaxis with amoxicillin compared with sulfisoxazole favors choice of the latter agent. [55] Most authorities recommend a trial of prophylactic antimicrobial therapy before consideration of placement of tympanostomy tubes. [56]
Urinary Tract Infection
Antibiotic prophylaxis is effective in preventing recurrent urinary tract infection and is indicated in children with underlying anatomic or neurologic lesions leading to a higher risk of infection, especially those with obstructive lesions or vesicoureteral reflex. Children without identifiable risk factors who suffer recurrent infections may also benefit from prophylaxis. In the latter group, documentation of 3 or more urinary tract infections within a 1-year period is a recommended indication for consideration of prophylaxis. [57] Nitrofurantoin (1 to 2 mg/kg per day), TMP-sulfadiazine, and TMP-SMX (1 to 2 mg/kg per day of TMP component) are the best-studied regimens in children. [58] [59] [60] [61] [62] The benefit of prophylaxis against asymptomatic bacteriuria in an unobstructed urinary tract without ureteral reflux is unproven.
Cardiac Abnormalities
The American Heart Association (AHA) periodically publishes guidelines for endocarditis prophylaxis. In 2007, major changes were made based on the Committee's conclusions that 1) extremely small numbers of cases of infective endocarditis might be prevented by antibiotic prophylaxis for dental procedures even if prophylaxis were 100% protective; 2) prophylaxis should not be recommended solely on the basis of an increased lifetime risk of acquisition of endocarditis; 3) infective endocarditis prophylaxis for dental procedures should be recommended only for people with underlying conditions associated with the highest risk of adverse outcome from infective endocarditis; 4) for patients with these underlying conditions, prophylaxis should be given for all dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa. [3] Recommendations also focus emphasis on good oral hygiene, access to routine dental care and eradication of dental disease to decrease the frequency of bacteremia from routine daily activities. Cardiac conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis with dental procedures is recommended are shown in Box 8-1 . Antibiotic prophylaxis is no longer recommended for any other form of congenital heart disease, including mitral valve prolapse with regurgitation, or acquired valvulopathy, hypertrophic cardiomyopathy or presence of cardiac pacemakers or implanted defibrillators unless there is a history of previous endocarditis or placement of a prosthetic valve. Antibiotic prophylaxis is not recommended for shedding of deciduous teeth or bleeding from trauma to the lips or oral mucosa. BOX 8-1 Prophylaxis for Infective Endocarditis According to Cardiac Conditions and Dental Procedures [3] Cardiac Conditions Associated with Highest Risk of Adverse Outcome from Endocarditis for Which Prophylaxis with Dental Procedures is Recommended Prosthetic cardiac valve Previous infective endocarditis Congenital heart disease (CHD) [a] Unrepaired cyanotic CHD including palliative shunts and conduits Completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedureb Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) Cardiac transplantation in which cardiac valvulopathy has developed
Dental Procedures for which Endocarditis Prophylaxis is Recommended for Patients Above All dental procedures that involve manipulation of gingival tissue or the periapical region of teeth or perforation of the oral mucosa Professional cleaning with gingival probing, biopsies, suture removal, placement of orthodontic bands
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Dental Procedures for which Endocarditis Prophylaxis is not Recommended even for Patients Above Routine anesthetic injections through noninfected tissue Taking of dental radiographs Drilling of carious teeth Orthodontic/prosthodontic procedures placement or removal of appliances placement of orthodontic brackets adjustment of orthodontic appliances
a Except for conditions listed, antibiotic prophylaxis is no longer recommended for any other form of CHD. b Prophylaxis is recommended because endothelialization of prosthetic material occurs within 6 months after the procedure.
Antibiotics recommended when prophylaxis is appropriate according to Box 8-1 are shown in Table 8-3 . A single dose of antibiotic should be administered before the procedure. If the dose was inadvertently omitted, it could be administered up to 2 hours after the procedure. Antibiotic prophylaxis is no longer recommended for routine respiratory tract procedures (e.g., intubation, extubation, bronchoscopy). [3] Antibiotic prophylaxis may be considered for patients listed in Box 8-1 who undergo an invasive procedure that involves incision or biopsy of the respiratory tract mucosa (e.g., tonsillectomy, adenoidectomy, bronchoscopy with incision of the respiratory mucosa) or when performed to treat an established infection (e.g., to drain an abscess or empyema). Antibiotic regimens should always include an agent active against viridans group streptococcus. Suspected or proven etiology of an abscess may dictate broader spectrum or an additional antibiotic. Antibiotic prophylaxis is no longer recommended solely to prevent endocarditis in patients who undergo genitourinary (GU) or gastrointestinal (GI) tract procedures, including diagnostic esophagogastroduodenoscopy or colonoscopy. [3] For patients listed in Box 8-1 who have an established GU or GI tract infection or for those who receive antibiotic therapy to prevent wound infection or septicemia associated with a GU or GI procedure, it may be reasonable that the antibiotic regimen includes an agent active against Enterococcus species. [3] For patients listed in Box 8-1 scheduled for elective cystoscopy or other urinary tract manipulation who have enterococcal urinary tract infection or colonization, antibiotic therapy to eradicate/suppress enterococci in the urine before the procedure may be reasonable. If the procedure is not elective, it may be reasonable that the empiric or specific antimicrobial regimen administered include an agent active against enterococci. [3] Antibiotic prophylaxis is recommended for procedures on infected skin, skin structures, or musculoskeletal tissue only for patients listed in Box 8-1 . In 2007, the AHA reaffirmed previous recommendations of settings for which endocarditis prophylaxis is not indicated (including cardiac catheterization and Cesarean delivery) [63] and added the following procedures: ear and body piercing, tattooing, vaginal delivery and hysterectomy. [3] References 1. American Academy of Pediatrics. : Antimicrobial Prophylaxis. In: Pickering LK, ed. 2006 Red Book: Report of the Committee on Infectious Diseases, 52. 27th ed.. Elk Grove Village, IL: American Academy of Pediatrics; 2006:83-90. 2. Antimicrobial prophylaxis in surgery. Treat Guidelines Med Lett 2004; 2:27-32. 3. Wilson W, Taubert KA, Gewite M, et al: Prevention of infective endocarditis. Guidelines from the American Heart Association. Circulation 2007; 115:May 8. 4. Artenstein MS, Lamson TH, Evans JR: Attempted prophylaxis against meningococcal infection using intramuscular penicillin. Mil Med 1967; 132:1009. 5. Band JD, Chamberland ME, Platt T, et al: Trends in meningococcal disease in the United States, 19751980. J Infect Dis 1983; 148:754. 6. Schwartz B, Al-Tobaiqi A, Al-Ruwais A, et al: Comparative efficacy of ceftriaxone and rifampin in eradicating pharyngeal carriage of group A Neisseria meningitidis. Lancet 1988; 1:1239. 7. Gaunt PN, Lambert BE: Single dose ciprofloxacin for the eradication of pharyngeal carriage of Neisseria
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meningitidis. J Antimicrob Chemother 1988; 21:489. 8. Band JD, Fraser JW, Ajello MA: Prevention of Haemophilus influenzae type b disease. JAMA 1984; 251:2381. 9. Shapiro ED, Wald ER: Efficacy of rifampin in eliminating pharyngeal carriage of Haemophilus influenzae type b. Pediatrics 1980; 66:5. 10. Boyer KM, Gotoff SP: Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl Med 1986; 314:1665. 11. Committee on Infectious Diseases and Committee on Fetus and Newborn. : Guidelines for prevention of group B streptococcal (GBS) infection by chemoprophylaxis. Pediatrics 1992; 90:775. 12. Connor EM, Sperling RS, Gelber R, et al: Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173. 13. Prober CG, Corey L, Brown ZA, et al: The management of pregnancies complicated by genital infections with herpes simplex virus. Clin Infect Dis 1992; 15:1031. 14. Kuzushima K, Kudo T, Kimura H, et al: Prophylactic acyclovir in outbreaks of primary herpes simplex virus type 1 infection in a closed community. Pediatrics 1992; 89:379. 15. Rooney JF, Straus SE, Mannix ML, et al: Oral acyclovir to suppress frequently recurrent herpes labialis. Ann Internal Med 1993; 118:268. 16. Hsu KHK: Isoniazid in the prevention and treatment of tuberculosis: a 20-year study of the effectiveness in children. JAMA 1974; 229:528. 17. Hsu KH: Thirty years after isoniazid: its impact on tuberculosis in children and adolescents. JAMA 1984; 251:1283. 18. Bass JW: Erythromycin for treatment and prevention of pertussis. Pediatr Infect Dis 1986; 5:154. 19. Sprauer MA, Cochi SL, Zell ER, et al: Prevention of secondary transmission of pertussis in households with early use of erythromycin. Am J Dis Child 1992; 146:177. 20. Centers for Disease Control and Prevention. : Neuraminidase inhibitors for treatment of influenza A and B infections. MMWR 1999; 48(RR-14): 21. Woods RK, Dellinger EP: Guidelines for antibiotic prophylaxis of surgical wounds. Am Fam Physician 1998; June:1-13. 22. Classen DC, Evans RS, Pestotnik SL, et al: The timing of prophylactic administration of antibiotics and the risk of surgical wound infection. N Engl J Med 1992; 326:289. 23. Dellinger EP, Gross PA, Barrett TL, et al: Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis 1994; 18:422. 24. Kesler RW, Guhlow LJ, Saulsbury FT: Prophylactic antibiotics in pediatric surgery. Pediatrics 1982; 69:1. 25. Nahata MC, Winters CB, Powell DA: Variation in prophylactic antibiotic use in pediatric orthopedic surgery. Drug Intell Clin Pharm 1985; 19:834. 26. Ehrenkranz NJ: Antimicrobial prophylaxis in surgery: mechanisms, misconceptions, and mischief. Infect Control Hosp Epidemiol 1993; 14:99. 27. Gorbach SL, Condon RE, Conte Jr JE, et al: Evaluation of new anti-infective drugs for surgical prophylaxis. Clin Infect Dis 1992; 15(Suppl 1):S313. 28. Langley JM, LeBlanc JC, Drake J, et al: Efficacy of antimicrobial prophylaxis in placement of cerebrospinal fluid shunts: meta-analysis. Clin Infect Dis 1993; 17:98.
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29. Haines SJ, Walters BC: Antibiotic prophylaxis for cerebrospinal fluid shunts: a meta-analysis. Neurosurgery 1994; 34:87. 30. Johnson JT, Myers EN, Thearle PB, et al: Antimicrobial prophylaxis for contaminated head and neck surgery. Laryngoscope 1984; 94:46. 31. Bernard A, Pillet M, Goudet P, et al: Antibiotic prophylaxis in pulmonary surgery: a prospective randomized double-blind trial of flash cefuroxime versus forty-eight-hour cefuroxime. J Thorac Cardiovasc Surg 1994; 107:896. 32. Guglielmo BJ, Hohn DC, Koo PJ, et al: Antibiotic prophylaxis in surgical procedures: a critical analysis of the literature. Arch Surg 1983; 118:943. 33. Slama TG, Sklar SJ, Misinski J, et al: Randomized comparison of cefamandole, cefazolin, and cefuroxime prophylaxis in open-heart surgery. Antimicrob Agents Chemother 1986; 29:744. 34. Maki DG, Bohn MJ, Stolz SM, et al: Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations: a double-blind randomized trial. J Thorac Cardiovasc Surg 1992; 104:1423. 35. Mounsey JP, Griffith MJ, Tynan M, et al: Antibiotic prophylaxis in permanent pacemaker implantation: a prospective randomised trial. Br Heart J 1994; 72:339. 36. Hill C, Mazas F, Flamant R, et al: Prophylactic cefazolin versus placebo in total hip replacement. Lancet 1981; 1:795. 37. Boss WK, Brand DA, Acampora D, et al: Effectiveness of prophylactic antibiotics in the outpatient treatment of burns. J Trauma 1985; 25:224. 38. Victoroff BN, Robertson Jr WW, Eichelberger MR, et al: Extremity gunshot injuries treated in an urban children's hospital. Pediatr Emerg Care 1994; 10:1. 39. Nichols RL, Smith JW, Muzik AC, et al: Preventive antibiotic usage in traumatic thoracic injuries requiring closed tube thoracostomy. Chest 1994; 106:1493. 40. Boenning DA, Fleisher GR, Campos JM: Dog bites in children: epidemiology, microbiology, and penicillin prophylactic therapy. Am J Emerg Med 1983; 1:17. 41. Dire DJ, Hogan DE, Walker JS: Prophylactic oral antibiotics for low-risk dog bite wounds. Pediatr Emerg Care 1992; 8:194. 42. Cummings P: Antibiotics to prevent infection in patients with dog bite wounds: a meta-analysis of randomized trials. Ann Emerg Med 1994; 23:535. 43. Kaplan EL, Berrios X, Speth J, et al: Pharmacokinetics of benzathine penicillin G: serum levels during the 28 days after intramuscular injection of 1 200 000 units. J Pediatr 1989; 115:146. 44. Lue HC, Wu M, Hsieh K, et al: Long-term outcome of patients with rheumatic fever receiving benzathine penicillin G prophylaxis every three weeks versus every four weeks. J Pediatr 1994; 125:812. 45. Berrios X, del Campo E, Guzman B, et al: Discontinuing rheumatic fever prophylaxis in selected adolescents and young adults. Ann Intern Med 1993; 118:401. 46. Dajani A, Taubert K, Ferrieri P, et al: Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever. Pediatrics 1995; 96:758. 47. Gaston MH, Verter JI, Woods G, et al: Prophylaxis with oral penicillin in children with sickle cell anemia: A randomized trial. N Engl J Med 1986; 314:1593. 48. Falletta JM, Woods GM, Verter JI, et al: Discontinuing penicillin prophylaxis in children with sickle cell anemia. J Pediatr 1995; 127:685.
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49. Potter PC, Frasch CE, Van der Sande WJM, et al: Prophylaxis against Neisseria meningitidis infections and antibody responses in patients with deficiency of the sixth component of complement. J Infect Dis 1990; 161:932. 50. Goorin AM, Hershey BJ, Levin MJ, et al: Use of trimethoprim-sulfamethoxazole to prevent bacterial infections in children with acute lymphoblastic leukemia. Pediatr Infect Dis 1985; 4:265. 51. Centers for Disease Control. : Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR 1991; 41:1. 52. Centers for Disease Control and Prevention. : Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR 2000; 49(RR-10):1-128. 53. Liston TE, Foshee WS, Peirson WD: Sulfisoxazole chemoprophylaxis for frequent otitis media. Pediatrics 1983; 71:524. 54. Berman S, Nuss R, Roark R, et al: Effectiveness of continuous vs. intermittent amoxicillin to prevent episodes of otitis media. Pediatr Infect Dis J 1992; 11:63. 55. Brook I, Gober AE: Prophylaxis with amoxicillin or sulfisoxazole for otitis media: effect on the recovery of penicillin-resistant bacteria from children. Clin Infect Dis 1996; 22:143. 56. Casselbrant ML, Kaleida PH, Rockette HE, et al: Efficacy of antimicrobial prophylaxis and of tympanostomy tube insertion for prevention of recurrent otitis media: results of a randomized clinical trial. Pediatr Infect Dis J 1992; 11:278. 57. Stamay TA, Condy M, Mibara G: Prophylactic efficacy of nitrofurantoin macrocrystals and trimethoprimsulfamethoxazole in urinary infections: biologic effect on the vaginal and rectal flora. N Engl J Med 1977; 296:780. 58. Brendstrup L, Hjelt K, Petersen KE, et al: Nitrofurantoin versus trimethoprim prophylaxis in recurrent urinary tract infection in children: a randomized, double blind study. Acta Paediatr Scand 1990; 79:1225. 59. Hanson E, Hansson S, Jodal U: Trimethoprim-sulfadiazine prophylaxis in children with vesicoureteral reflux. Scand J Infect Dis 1989; 21:201. 60. Jodal U, Koskimies O, Hanson E, et al: Infection pattern in children with vesicoureteral reflux randomly allocated to operation or long term antimicrobial prophylaxis: the international reflux study in children. J Urol 1992; 148:1650. 61. Lohr JA, Nunley DH, Howards SS, et al: Prevention of recurrent urinary tract infections in girls. Pediatrics 1977; 59:562. 62. Johnson HW, Anderson JD, Chambers GK, et al: A short-term study of nitrofurantoin prophylaxis in children managed with clean intermittent catheterization. Pediatrics 1994; 93:752. 63. Dajani AS, Taubert KA, Wilson W, et al: Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1997; 2777:1794. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 9 Protection of Travelers Maryanne E. Crockett,
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Jay S. Keystone Increasing numbers of people travel internationally each year: more than 750 million travelers crossed international borders in 2004. [1] An estimated 4% of these people are children; consequently, more than 30 million children travel internationally each year. [2] Annually up to 8% of travelers to the developing regions of the world are ill enough to seek medical healthcare while abroad or upon returning home. [3] [4] Although travel may expose children to certain risks, the benefits are many. Therefore, a careful pretravel evaluation to provide appropriate guidance and preparation is critical to protect pediatric travelers and their families and allow them to enjoy their time abroad. PREPARATION FOR TRAVEL
General Advice
A pretravel evaluation should be performed at least 6 to 10 weeks prior to travel. The entire itinerary for the trip should be reviewed, including destinations, time and duration of travel, types of accommodation, activities, and potential exposure to insects and animals. The evaluation should also review the medical and particularly the immunization history of the child in order to ensure that appropriate advice is given regarding preventive measures, including necessary vaccines. This evaluation can be accomplished by providing a form for the parents to complete and bring to the initial pretravel assessment visit. Particular attention should be given to children of immigrants who are returning to their home countries to visit friends and relatives because these children have been shown to be at increased risk of many infectious diseases and may be less likely to seek pretravel advice. [5] [6] There are many excellent resources available that provide pretravel advice for pediatricians. The majority of these resources are accessible online ( Box 9-1 ). BOX 9-1 Resources and Additional Information for Travelers International Travel and Health, print version updated biannually, online version updated regularly by the World Health Organization (WHO). Available online at www.who.int/ith/ WHO vaccine summaries: www.who.int/vaccines/globalsummary/immunization/countryprofileselect.cfm Centers for Disease Control and Prevention (CDC) Health Information for International Travel, updated approximately every 2 years by the CDC, Atlanta, USA: US Department of Health and Human Services (The Yellow Book). Available online at www.cdc.gov/travel/yb/index.htm CDC travel information section: www.cdc.gov/travel/ CDC Morbidity and Mortality Weekly Report (MMWR): http://www.cdc.gov/mmwr/ CDC Emerging Infectious Diseases Journal: http://www.cdc.gov/ncidod/EID/index.htm CDC Malaria Hotline: 770-488-7788 CDC Travelers' Health Automated Information Line (toll-free): 1-877-FYI-TRIP GIDEON (Global Infectious Diseases and EpidemiOlogy Network), available online at www.gideononline.com/ Pickering LK, Baker CJ, Long SS, et al. (eds) Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics. (1-888-227-1770 Publications) a new edition is published every 3 years The Pan American Health Organization, the regional office of the WHO: www.paho.org/ Immunization Action Coalition: www.immunize.org/izpractices/p5120.pdf United States State Department Hotline for American Travelers (202-647-5225) United States State Department: http://travel.state.gov/ International Association for Medical Assistance to Travellers: www.iamat.org Program for Monitoring Emerging Diseases (Pro-MED-mail): www.promedmail.org Committee to Advise on Tropical Medicine and Travel (CATMAT): www.travelhealth.gc.ca Travax: www.travax.scot.nhs.uk/
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United States: American Society for Tropical Medicine and Hygiene travel health: www.astmh.org The International Society for Travel Medicine: www.istm.org United Kingdom: www.travelhealth.co.uk/diseases/travelclinics.htm Canada: www.travelhealth.gc.ca
Guidance regarding travel health should be provided regarding safety issues and infectious diseases. [7] [8] [9] Motor vehicle crashes are the most common cause of death among travelers; therefore, particular attention must be given to use of seat belts and car seats as recommended according to the age and size of the child. Car seats may not be readily available at the destination and therefore should accompany the family. Other injury concerns for children include drowning, falls from unprotected balconies or windows, and electrical injuries from unprotected outlets. A parent traveling alone with children should have notarized documentation authorizing him or her to travel with the children. Advice regarding food and water precautions and insect avoidance should be thoroughly reviewed. Skin protection is an important topic and includes both risk of serious sunburn and avoidance of infectious diseases. For sunblock, 30 is the minimum sun protection factor (SPF) recommended for children. Sunblock should be applied 30 minutes before exposure and always before insect repellent is applied where both are needed. Adolescent travelers should be counseled regarding safer sex practices and risks of body piercing and tattooing in less developed countries. Fresh water exposure of any kind should be avoided in areas that are endemic for schistosomiasis or where Leptospira organisms may contaminate the water. Exposure to infected stool of animals or humans can result in several types of parasitic infection either directly (e.g., hookworm) or through fecaloral exposure (e.g., Toxocara spp.). Shoes provide more protection than sandals for children exposed to contaminated environments. Animal bites may result in injury, bacterial infection at the site, or rabies; therefore, children should be cautioned to avoid unknown animals, particularly dogs, while traveling. Since disposable diapers may not be available in some countries, parents should be aware that cloth diapers must be ironed after washing to kill eggs and larvae deposited on clothing by the tumbu fly, the vector of myiasis, in parts of Africa. A travel medical kit should be assembled prior to travel and carried with the family at all times ( Box 9-2 ). As at home, medications should be stored in childproof containers out of reach of children. A discussion of travel health insurance and what to do in the event of illness should be included in the evaluation. Written material summarizing the pretravel advice also may be helpful for families. BOX 9-2 Pediatric Travel Medical Kit NONPRESCRIPTION ITEMS Personal information card: name, birth date, chronic medical conditions, regular medications, allergies, blood type, vaccination record, emergency contact information First-aid supplies: bandages, adhesive tape, gauze, antiseptic cleaning solution, commercial suture/syringe kit (with letter from physician) Thermometer Analgesics/antipyretics: acetaminophen, ibuprofen Skin care products: barrier ointment/cream, topical corticosteroid cream, disinfectant solution (e.g., chlorhexidine) Antihistamine (e.g., diphenhydramine) Insect repellent (diethyltoluamide: DEET), insecticide (permethrin) Water purification system Oral rehydration packets Antimotility agent (e.g., loperamide) if older child Extra pair of prescription glasses
PRESCRIPTION ITEMS
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Currently prescribed medications Antimalarial prophylaxis Antibiotic for travelers' diarrhea (see text) Topical antibacterial ointment/cream Topical antifungal ointment/cream Topical ophthalmic/otic antibiotic solution
Immunizations
Although immunization rates have been increasing over the last few years in the United States, there remain a significant number of children who are underimmunized. [10] Many countries with low immunization rates have ongoing transmission of vaccine-preventable illnesses that rarely are seen in North America. Consequently, children who travel must have up-to-date immunization coverage to minimize their risk of contracting vaccine-preventable diseases if they travel to countries where these diseases are prevalent. Country-specific vaccine-preventable disease statistics and immunization schedules can be found on the World Health Organization (WHO) website and a listing of international vaccine names also is available online. [11] [12] Travel vaccines are divided into the categories of routine, required, and recommended. Required travel vaccines are needed by travelers to cross international borders, according to health regulations at destination. Proof of yellow fever vaccination may be required for entry into or travel from endemic countries. Vaccination against meningococcus and polio are required for travelers to the Hajj in Saudi Arabia. [13] Recommended travel vaccines include vaccines that should be considered according to the risk of infection during travel. During the pretravel evaluation, some children may need to receive vaccines in the recommended childhood and adolescent immunization schedule administered in an accelerated manner to complete their primary series, catch-up with routine vaccinations, or complete the recommended pretravel vaccine series prior to departure [13] [14] [15] [16] ( Table 9-1 ). The routine or catch-up schedule for immunizations should be continued when the child returns from traveling. TABLE 9-1 -- Acceleration of Routine Vaccine Schedule for Travel Vaccine Earliest Age for First Dose Minimum Interval Between Doses Combined hepatitis A and B [a] Hepatitis A DTaP IPV OPV Hib (conjugate) Hepatitis B PCV7 Measles MMR Varicella 1 year 1 year 6 weeks 6 weeks Birth 6 weeks Birth 6 weeks 6 months followed by MMR at 12 months and at 4 to 6 years of age 12 months 12 months 1 week, 2 weeks between 2nd and 3rd doses (booster after 1 year) 6 months [b] 4 weeks, 6 months between 3rd and 4th doses 4 weeks 4 weeks 4 weeks (booster after 12 months of age) 4 weeks, 8 weeks between 2nd and 3rd doses (3rd dose should be given 16 weeks after 1st dose) 4 weeks, 8 weeks between 3rd and 4th doses (after 12 months of age) 4 weeks 4 weeks 4 weeks if 13 years of age 3 months if < 13 years of age DTaP, diphtheria, tetanus, acellular pertussis; Hib, Haemophilus influenzae b; IPV, inactivated polio virus; MMR, measles, mumps, rubella; OPV, oral polio virus; PCV7, pneumococcal conjugate. Regular immunization schedule should be reinstituted upon return from the endemic area.
a Combined hepatitis A and B accelerated schedule is an off-label use for children. b Hepatitis A booster does not need to be given as an accelerated schedule as seroconversion rate following the first dose is high. The second dose can be given any
time after 6 months to induce long-lasting immunity.
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Two or more inactivated vaccines may be administered simultaneously or with any interval between doses, as can inactivated and live vaccines. Two parenterally administered live vaccines, if not given at the same time, should be administered at least 28 days apart. [17] Caution must be used when scheduling live vaccine administration following immune globulin (IG) administration because decreased immunogenicity of the vaccines may result. [15] This is particularly true of measles and varicella-containing vaccines. IG should not be given less than 14 days prior to administration of a live vaccine, and measles and varicella-containing vaccines should be deferred from 3 to 11 months after IG administration depending on the indication and dose of IG required (see Chapter 6 , Passive Immunization). Although the effect of IG administration on the immunogenicity of varicella vaccine is unknown, the current recommendation is to use the same guidelines for varicella vaccine and IG as are used for measles-containing vaccines. [18] IG administration does not interfere with the immune response to yellow fever, oral polio virus (OPV), rotavirus vaccines or any inactivated vaccines.
Routine Childhood Immunizations
Many vaccine-preventable diseases are endemic in most of the world; therefore, a child's routine vaccine schedule should be brought up-to-date prior to travel. [16] In particular, the primary series of vaccines, including at least 3 doses of the diphtheria and tetanus toxoids and the acellular pertussis (DTaP) vaccine, should be administered and may be given according to accelerated dosing schedules as required (see Table 9-1 ). The Tdap adolescent preparation with acellular pertussis vaccine should be used as the adolescent booster beginning at 11 years of age. [19] Children under 6 years of age should also receive the conjugate Haemophilus influenzae type b (Hib) vaccine prior to travel. Although global polio eradication previously had been targeted for 2005, 21 previosuly polio-free countries documented polio infection between 2002 and 2005, and polio remains endemic in a few countries in Asia and Africa. (An up-to-date listing of polio cases can be found at www.polioeradication.org ). [20] OPV, although widely used in the WHO Expanded Programme on Immunization Plus (EPI-PLUS), is not available in the United States. An accelerated schedule for inactivated poliovirus vaccine (IPV) may be initiated if required, with the first dose being given at 6 weeks of age and subsequent doses being given at least 4 weeks apart. [16] If a child is traveling in the first few weeks of life and OPV is available, vaccination with OPV may be initiated at birth, with subsequent doses at 4-week intervals. [13] A booster dose of IPV should be given at 4 to 6 years of age. More than half a million children die of measles annually, with children less than 1 year of age having the highest risk of severe disease. The risk of subacute sclerosing panencephalitis also is related to acquisition of measles virus at a young age. Maternal antibodies generally protect infants for less than 6 months. Children between 6 and 12 months of age who are traveling to countries where measles is endemic (including all countries where measles vaccination is not universal) should receive one dose of monovalent measles vaccine prior to travel. The measles, mumps, rubella (MMR) vaccine may be used if monovalent measles vaccine is unavailable; however, only doses given at or after 12 months of age count as part of the routine immunization schedule. Children older than 12 months of age should receive two doses of MMR given at least 28 days apart prior to travel. Hepatitis B is part of the routine immunization schedule in the United States. [21] Children who have not completed their hepatitis B series should receive hepatitis B vaccine prior to travel to highly endemic areas. The hepatitis B series may be accelerated with an interval of 4 weeks after the first dose and 8 weeks between the second and third doses (with at least 16 weeks between the first and third doses). There is also an accelerated schedule with doses given at 0, 1, and 2 months, followed by a fourth dose at 12 months. A hyperaccelerated schedule of 0, 7, and 21 days with a fourth dose at 12 months can be used if necessary, but this schedule is not licensed by the Food and Drug Administration. A 2-dose schedule of adult Recombivax at 0 and 4 to 6 months is licensed in the United States for adolescents 11 to 15 years of age. [21] Hepatitis A vaccine is universally recommended for children in the United States and should be given as a 2-dose schedule beginning at 12 to 24 months of age with the second dose 6 to 18 months later. [22] Children who have not received their hepatitis A vaccine series should be vaccinated prior to travel to developing countries. The majority of hepatitis A cases imported into the United States by travelers are related to travel to Mexico and Central America. [22] Although hepatitis A generally causes asymptomatic or mild infection in young children, such children may shed the virus for prolonged periods; consequently, vaccination of young travelers is recommended to protect both the recipient and any contacts. Children from birth to younger than 1 year of age who are at high risk of exposure to hepatitis A may be given 0.02 mL/kg of IG intramuscularly as passive hepatitis A prophylaxis. [22] For travel lasting longer than 3 months, a larger dose of 0.06 mL/kg should be used. If a child is traveling within 2 weeks of receiving the first dose of vaccine, the concomitant administration of IG may be considered; however, most travel medicine advisors do not recommend IG in this situation, even for travelers leaving the day after vaccination. Twinrix (GlaxoSmithKline) is a combined hepatitis A and B vaccine that is licensed for individuals 18 years of age
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and older. [13] [21] Twinrix-Junior is not licensed in the United States but is widely available in Europe and Canada for children between 1 and 15 years of age. These vaccines are given in a 3-dose schedule at 0, 1, and 6 months. For last-minute travel they can be accelerated in a schedule of 0, 7, and 21 days with a booster given at 1 year. [23] Recently, in Canada and parts of Europe, two adult doses of the vaccine 6 months apart have been approved for children 1 to 15 years of age. [24] Varicella vaccine is recommended for all susceptible children and is given in the United States 2 as doses to children from 12 months through 12 years of age. For children less than 13 years of age, the second dose should be given 3 months after the first. For adolescents 13 years of age and older, 2 doses are required with an interval of at least 4 weeks between doses. [16] For children with unknown varicella status, a cost analysis suggests that serotesting before immunization is cost-effective for children 5 years of age and older if follow-up for immunization is assured, whereas immunization without assessing antibody status is cost-effective up to 4 years of age. [25] The conjugate pneumococcal vaccine is part of the routine childhood immunization schedule and should be given as a 4-dose series at 2, 4, 6, and 12 to 15 months of age, although it also can be accelerated as needed (see Chapter 123 , Streptococcus pneumoniae). A quadrivalent conjugate meningococcal vaccine for serogroups A/C/Y/W-135 was licensed in 2005 in the United States for children 11 years and older. It is recommended for use in all children 11 to 12 years of age and unvaccinated adolescents at high-school entry (15 years) (see Chapter 125 , Neisseria meningitidis). [26] [27] This vaccine has been shown to be safe and to produce an excellent immune response in children between 2 and 10 years of age, although it is not yet approved for use in this age group. [28] GuillainBarr syndrome (GBS) was reported in adolescents vaccinated with the quadrivalent conjugate meningococcal vaccine; [29] rate of GBS among vaccine recipients is slightly higher than that seen in unvaccinated people. Surveillance for additional cases is ongoing. Influenza vaccine is recommended for children 6 months of age and older who are at risk of developing complications, such as children with chronic diseases. Influenza vaccine also is recommended for healthy infants and children from 6 to 59 months of age and close contacts of infants and children from 0 to 59 months of age. [30] It is noteworthy for children who are traveling that the influenza season occurs from April to September in the southern hemisphere and year-round in the tropics. [31] Influenza outbreaks have occurred on cruise ships and on organized group tours in any latitude and season. [30]
Required and Recommended Vaccines for Travel
Table 9-2 provides details regarding travel vaccines recommended for children. TABLE 9-2 -- Schedule and Dosing for Travel Vaccines Minimum Vaccine Schedule age Dose (mL) BCG (live attenuated) 1 dose Birth < 30 days: 0.3 mL (dilute to half concentration) > 30 days: 0.3 mL 0.5 mL
Route Intradermal preferred but subcutaneous acceptable Intramuscular
Booster Dose None
Hepatitis A/B, combined (inactivated/recombinant) Japanese encephalitis (inactivated) Meningococcal A/C/Y/W135 (polysaccharide)
3 doses: 0, 1, and 6 months
1 year
None
3 doses: 0, 1 year 7, and 14 or 30 days 1 dose 3 months (see text)
13 year: 0.5 mL > 3 Subcutaneous years: 1.0 mL 0.5 mL Subcutaneous
3 years
< 4 years: 2 3 years 4 years: 3 5 years Unknown
Meningococcal A/C/Y/W135 (conjugated polysaccharide) Rabies (inactivated cell culture) Typhoid, Ty21a (live
1 dose
11 years
0.5 mL
Intramuscular
3 doses: 0, Birth 7, 21, or 28 days 4 doses: 6 years
1.0 mL
Intramuscular
Consider at 2 years if high-risk 5 years
1 capsule
Oral
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attenuated) Typhoid, Vi (capsular polysaccharide) BCG, bacille Calmette-Gurin.
alternate days 1 dose 2 years 9 months 0.5 mL 0.5 mL Intramuscular Subcutaneous 2 years 10 years
Yellow fever (live attenuated) 1 dose
Cholera Vaccine
The risk of cholera is low for travelers. Cholera vaccines are not available in the United States. Cholera vaccines are licensed in some countries: WC/rBS (inactivated), variant WC/rBS (inactivated), and CVD 103-HgR (live attenuated). [32] Cholera vaccine is not required for entry into any country. The WHO recommends use of cholera vaccine only for travelers who plan to work in refugee camps or as healthcare providers in endemic areas. [33]
Typhoid Vaccine
Typhoid vaccine is recommended for pediatric travelers to the Indian subcontinent and other developing countries in Central and South America, the Caribbean, Africa, and Asia. [34] Children are particularly at risk of developing the disease and of becoming chronic carriers. Two vaccines are available for prevention of typhoid: a live attenuated oral vaccine (Ty21a), which can be used in children 6 years of age and older, and a purified Vi capsular polysaccharide vaccine that is delivered intramuscularly to children 2 years of age and older. The efficacy of both vaccines is approximately 70%; therefore, receipt of the vaccine does not eliminate the need for food and water precautions. [35] If exposure continues, revaccination is recommended every 2 years for the polysaccharide vaccine and every 5 years for the oral Ty21a vaccine. The Ty21a vaccine is only available in capsules in the United States, which limits usefulness in younger children. The Ty21a vaccine must be refrigerated and taken with cool liquids approximately 1 hour before eating. The Ty21a vaccine should not be taken concurrently with the antimalarial proguanil, and antibiotics should not be used from the day before the first capsule until 7 days after completing the vaccine course. Clinical trials of a Vi conjugate vaccine demonstrating safety, efficacy, and immunogenicity in children 2 years of age and older are ongoing. [36] [37]
Yellow Fever Vaccine
Yellow fever vaccine is a live attenuated vaccine that may be required or recommended for travel to central South America and sub-Saharan Africa. Some countries in Africa require an international certificate of vaccination (or physician waiver letter) against yellow fever of all entering travelers; other countries may require evidence of vaccination from travelers coming from or traveling through endemic or infected areas. The vaccine is recommended for all children 9 children of age and older traveling to endemic areas. Yellow fever vaccine is effective 10 days after administration of the first dose and a booster is required every 10 years for travelers at ongoing risk. Risks and benefits of yellow fever vaccination and likelihood of infection must be considered carefully in pregnant women and people who are immunocompromised. [38] Yellow fever vaccine contains egg protein; therefore, people with previous anaphylaxis to eggs should not receive the vaccine. The vaccine is only available in the United States from providers certified by state health departments. [39] A vaccine-associated encephalitis syndrome has been reported in young infants at a rate of 0.5 to 4 per 1000 infants vaccinated. [13] Neurologic symptoms occur 7 to 21 days after immunization; disease is related to reversion of vaccine virus to wild-type neurotropic virus. Consequently, the vaccine is contraindicated in infants less than 6 months of age. For infants 6 to 9 months of age who cannot avoid travel to a yellow fever-endemic area, consultation with an expert in the field is recommended. Yellow fever vaccine-associated viscerotropic disease, a severe systemic illness that can result in fatal organ failure, rarely has been reported.
Rabies Vaccine
Rabies is highly endemic in Africa, Asia (particularly India), and parts of Latin America, but the risk to travelers is low. Pre-exposure rabies immunization is recommended for travelers with an occupational risk of exposure, for people planning extended stays in endemic areas where medical care is limited, and for outdoor travelers. [40] Given that children are more likely to interact with animals and not report an animal bite, rabies pre-exposure vaccination should be considered for children traveling to endemic countries for at least 1 month. The pre-exposure vaccine series involves 3 doses of 1.0 mL given intramuscularly at 0, 7, and 21 or 28 days. [40] The series can be administered using either of the two licensed vaccines in the United States: human diploid cell vaccine (HDCV), and purified chick embryo cell (PCEC) vaccine. If a child is bitten or sustains a skin-penetrating scratch by a potentially rabid animal, 2
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additional doses must be completed as soon as possible, but rabies IG is not required. Without pre-exposure immunization, treatment requires rabies IG and 5 doses over 28 days of an approved vaccine. (Note: rabies IG is often not available in many developing countries.)
Japanese Encephalitis Virus Vaccine
Japanese encephalitis, an arboviral infection transmitted by Culex mosquitoes, is endemic in rural areas of Asia although occasional epidemics occur in periurban areas. In temperate regions, transmission occurs from April to November, but disease occurs year-round in tropical and subtropical areas. The disease is uncommon in travelers. [41] Although the majority of cases are subclinical, half of patients with clinical disease have persistent neurologic abnormalities and the case fatality rate is close to 25%. [42] Vaccine is recommended for all travelers older than 12 months of age who are traveling in rural endemic areas for at least 1 month. Three doses of the inactivated vaccine that is available in the United States are given over 2 to 4 weeks. The vaccine has been associated with both immediate and delayed hypersensitivity reactions; therefore, travelers should receive their last dose of vaccine at least 10 days prior to travel and be observed for 30 minutes after vaccine administration. The duration of immunity is unknown. A booster can be administered after 36 months.
Meningococcal Vaccine
Five serogroups of Neisseria meningitidis (A, B, C, Y, and W135) are responsible for the vast majority of meningococcal disease. The epidemiology of serogroups responsible for disease is changing worldwide; B, C, and Y are most prevalent in the United States, whereas A, C, and more recently W135 cause the majority of epidemic disease in sub-Saharan Africa where the incidence of meningococcal disease can be as high as 30 cases per 100,000 annually. [26] [27] Meningococcal vaccine is required for travelers to the Hajj and is also recommended for people traveling to the meningitis belt in equatorial Africa during the dry season from December to June. The quadrivalent conjugate vaccine for serogroups A/C/Y/W-135 should be given to children 11 years of age and older. For children 2 years of age and older who are traveling to areas where epidemics are occurring, the polysaccharide quadrivalent A/C/Y/W135 vaccine is recommended. Although there is little response to polysaccharide vaccines in children less than 2 years of age, some short-term protection to serogroup A may be provided by two doses of the vaccine given 3 months apart; consequently, this is advised for infants from 3 to 24 months of age who are traveling to high-risk areas. Children who received the polysaccharide meningococcal vaccine before 4 years of age should be revaccinated within 2 to 3 years if they remain at risk. [27] Conjugate vaccines for serogroups A, C, and A/C are available in a number of countries other than the United States for use in infants and older children. Seventeen cases of GBS have been reported in adolescents who received conjugated A/C/Y/W-135 meningococcal vaccine in the United States during 2005 and 2006; an association between the two events has been shown, with an excess risk of 1.25/million doses. [29] A vaccine for group B meningococcus has proven elusive, although development is ongoing and an epidemic strain-specific vaccine (MeNZB) has been licensed in New Zealand and is undergoing postlicensure evaluation. [43] [44]
Tickborne Encephalitis Virus Vaccine
Tickborne encephalitis is transmitted by Ixodes rincinus ticks in the forests of central and eastern Europe during the summer months. [42] Although 2 vaccines are licensed in some countries, including Canada, for use in children, neither is available in the United States.
BCG
Bacille Calmette-Gurin (BCG) vaccine is part of the routine vaccination schedule in many developing countries where tuberculosis (TB) is highly endemic. BCG does not prevent TB infection but has been shown to decrease the incidence of severe TB disease such as miliary TB and TB meningitis. Vaccination with BCG can be considered for a young human immunodeficiency virus (HIV)-negative traveler (under 5 years of age) who will be spending a substantial period of time in a country that is highly endemic for TB when contact with people with active TB is likely. [13] [45] In addition, children who do not receive BCG and who have traveled to a country with a high TB burden should have a tuberculin skin test prior to and 3 months following their travel. [31]
Malaria Prophylaxis
Malaria is caused by infection with Plasmodium species, most commonly through the bite of an infected female Anopheles mosquito. Malaria is one of the leading causes of death among children under 5 years of age worldwide, causing more than half a billion infections and 1 million deaths each year. Young children, pregnant women, and
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people who previously or recently have not been exposed to malaria have the highest risk of severe disease. Although malaria is endemic throughout the tropics, the highest risk for malaria infection in travelers occurs in sub-Saharan Africa, Papua New Guinea, the Solomon Islands, and Vanuatu. [46] There is no vaccine available for prevention of malaria infection; therefore, families traveling with children must be given advice regarding personal protective measures and malaria chemoprophylaxis if they are traveling to endemic areas.
Chemoprophylaxis
The type of chemoprophylaxis recommended depends on the likelihood of drug resistance, potential adverse reactions, cost, and convenience. In addition, characteristics of the individual traveler, including age, ability to swallow tablets, and any specific contra-indications, are relevant. [47] Breastfeeding infants require prophylaxis since antimalarial drugs do not reach high enough levels in human milk. Several medications are recommended for prevention of malaria in children: chloroquine, mefloquine, doxycycline, and atovaquone/proguanil (AP, Malarone). Primaquine, a second-line drug for prophylaxis, may be useful when other antimalarial drugs cannot be used (see Chapter 271 , Plasmodium Species (Malaria)). Chloroquine and mefloquine should be initiated 1 to 2 weeks prior to travel although doxycycline, AP, and primaquine may be started 1 day before exposure. All chemoprophylaxic agents must be continued for 4 weeks after departure from malaria-endemic areas, except for AP and primaquine which need be continued for only 1 week after exposure.
Protective Measures
Because no malaria chemoprophylaxis is 100% effective, personal protective measures, such as barrier and chemical protection and exposure avoidance, should be used to minimize risk of contact with mosquitoes. These protective measures also can decrease risk of other insectborne diseases, such as dengue and other arboviruses. Since Anopheles mosquitoes that transmit malaria bite from dusk to dawn children must have adequate protection during these hours. The Aedes mosquito that transmits yellow fever, chikungunya, and dengue virus bites primarily in the early morning and late afternoon. The vector of Japanese encephalitis, the Culex mosquito, bites between dusk and dawn. When there is a risk of insect exposure, children should be dressed in light-colored clothing that covers their arms and legs. Other measures to avoid insect bites include staying in air-conditioned or well-screened accommodation or using insecticide-treated bed nets. Chemical protection provides additional defense against insectborne diseases. The safest and best studied is N,Ndiethyl-meta-toluamide (DEET). [47] Although adverse reactions, such as encephalopathy and rashes, have been described with use of high concentrations of DEET in children, this compound is considered safe when used appropriately according to product label instructions [46] [48] ( Box 9-3 ). The concentration of DEET correlates with duration of protection; therefore, products with lower concentrations need to be reapplied. DEET is approved by the Environmental Protection Agency and the American Academy of Pediatrics in a concentration of 30% down to 2 months of age; in standard preparations, this concentration will provide 4 to 6 hours of protection. Picaridin (7%), recently approved as Bayrepel and Cutter Advanced in the United States, appears to be a safe and well-tolerated repellent that provides protection for only 2 to 3 hours. Citronella oil is impractical since its duration of action is less than 1 hour. [49] BOX 9-3 Precautions for Use of Diethyltoluamide (DEET) Use repellents containing > 30% DEET only Apply sparingly to exposed skin Apply only to intact skin Apply to face by wiping; avoid eyes and mouth; do not spray directly on face Wash off with soap and water when coming indoors Do not inhale or ingest repellent Do not apply on hands or other areas that are likely to come in contact with the eyes or mouth Do not allow children under 10 years to apply DEET themselves. Apply to your own hands then apply to the child Do not use on children less than 2 months of age
Permethrin (a safe chrysanthemum derivative) is a contact insecticide that may be used for treatment of bed nets and
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clothing. [50] Permethrin-treated fabric has a duration of efficacy between 2 weeks and 6 months depending on the method of treatment. The best chemical protection against mosquito bites is the use of a combination of permethrintreated clothing and DEET on exposed skin. TRAVELERS' DIARRHEA
Risk
Travelers' diarrhea is one of the most common illnesses among travelers, affecting 9% to 40% of children who travel. [50] Both the incidence and severity of travelers' diarrhea are age-dependent, with the highest rates, longest duration, and greatest severity occurring in infants and children under 3 years of age. [51] Children's stools may normally be quite variable; consequently, travelers' diarrhea is defined as a twofold or greater increase in the frequency of unformed stools lasting at least 2 to 3 days. The infectious causes of travelers' diarrhea in children and adults are predominantly bacterial and include enterotoxigenic Escherichia coli (ETEC), which is the most common cause, enteroaggregative Escherichia coli (EAEC), Salmonella, Campylobacter, Shigella, enteropathogenic Escherichia coli (EPEC), and, rarely, enterohemorrhagic Escherichia coli (EHEC). Viral and parasitic infections are less common causes of pediatric travelers' diarrhea, although rotavirus, Cryptosporidium parvum, Giardia lamblia, and Entamoeba histolytica also account for a small proportion of diarrhea in young travelers. The risk of developing travelers' diarrhea depends on the travel destination, with rates as high as 73% among children traveling to North Africa and 61% among children visiting India. [51] Travel to Southeast Asia, Latin America, and other African countries has been associated with rates of approximately 40%. Although travelers' diarrhea is generally a self-limited infection, it can cause significant morbidity, particularly if it results in moderate to severe dehydration. Parents must be counseled regarding the symptoms and signs of dehydration as well as the approach to oral rehydration and when to seek medical attention.
Preventive Measures
Because there are no vaccines licensed in the United States for prevention of travelers' diarrhea in children, counseling regarding food and water precautions is the most important preventive measure. Vaccines are in development in preclinical and clinical phases against ETEC, Shigella spp., and Campylobacter jejuni; a combined cholera and ETEC oral vaccine is licensed in Canada for children 2 years of age and older. [52] General rules regarding food and water precautions when traveling apply to both children and adults; however, young children are more likely to explore the environment with their hands and mouths, thus creating opportunities for infection. Frequent handwashing with soap and water is critical, particularly before eating, although alcohol-based handwashes may be used no water is not available. Children must be reminded to use safe water sources for all drinking, toothbrushing, and food preparation. Safe water sources include bottled water from a trusted source or water that has been boiled, chemically treated, or filtered. Combination chemical and filter pumps may provide the best protection in filtered water as filters vary in the size of microbes which are removed. [2] Water should be boiled for at least 1 minute at altitudes less than 2000 meters and 3 minutes at greater than 2000 meters. [31] Carbonated drinks also are considered safe for drinking, but water used to make ice may be contaminated. For infants, breastfeeding is the safest form of nutrition. In addition to its many health benefits, breastfeeding does not require a source of clean water, unlike the use of formula, both in its preparation and the cleaning of bottles. The selection and preparation of foods are important during travel to minimize the risk of travelers' diarrhea. Although the advice to boil it, cook it, peel it, or forget it frequently is given, it is often not practical to follow. If possible, only steaming-hot freshly made food should be consumed. Families traveling with children should have a ready supply of snacks and avoid buying food from street vendors ( Box 9-4 ). BOX 9-4 Prevention of Travelers' Diarrhea in Children DO Eat only thoroughly cooked food served hot Peel fruit Drink only bottled, carbonated, boiled, chemically treated, or filtered water
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Don't
Prepare all beverages and icecubes with boiled or bottled water Wash hands before eating or preparing foods Continue breastfeeding throughout travel period
Eat raw vegetables or unpeeled fruit Eat raw seafood or shellfish or undercooked meat Eat food from street vendors Drink tap water Consume milk or dairy products unless labeled as pasteurized or irradiated
Additional food and water precautions can decrease risk of other infectious diseases while traveling. These include avoidance of unpasteurized dairy products to eliminate risk of brucellosis and other bacterial infections. Raw or undercooked meat and fish should not be consumed due to risk of parasitic infections. Avoiding undercooked seafood can decrease risk of hepatitis A. In developing countries raw vegetables and fruit that cannot be self-peeled should be avoided. Chemoprophylaxis for travelers' diarrhea generally is not advised in children. [51] However, short-term prophylaxis (< 3 weeks) could be considered for children with increased susceptibility to travelers' diarrhea, such as children with achlorhydria, or children in whom travelers' diarrhea might have significant medical consequences (e.g., children with chronic renal failure, congestive heart failure, diabetes mellitus, or inflammatory bowel disease). [53]
Treatment
Treatment of travelers' diarrhea in children must include close attention to hydration status, and parents should be counseled regarding early signs of dehydration. Oral rehydration therapy (ORT) using a homemade or commercially prepared oral rehydration solution (ORS) can be used to prevent dehydration associated with diarrheal disease. Commercial ORS should be used to treat mild to moderate dehydration; severe dehydration may require intravenous fluid resuscitation. [54] [55] ORS packets should be part of a family's travel medical kit. Locally made preparations can be used early in therapy, although they differ in composition from the reduced-osmolarity ORS recommended by WHO ( Table 9-3 ). [54] [55] Breastfeeding should be continued in infants, and solid food intake should be maintained along with rehydration with ORT throughout the diarrheal episode, although foods high in simple sugars should be avoided because the increased osmotic load may worsen fluid losses. TABLE 9-3 -- Formulation of Oral Rehydration Solution (ORS) World Health Organization Home Formula Sodium chloride 2.6 g/L (75 mmol/L sodium) Potassium chloride 1.5 g/L (20 mmol/L potassium) Trisodium citrate, dihydrate 2.9 g/L (10 mmol/L citrate) Glucose, anhydrous 13.5 g/L (75 mmol/L glucose) 3.5 g NaCl (-teaspoon table salt) 1.5 g KCl (1 cup orange juice) 2.5 g NaHCO3 (1 teaspoon baking soda) 20 g glucose (4 tablespoons sugar) Water to final volume of 1 L (33 oz) Loperamide generally is used in combination with antibiotics for treatment of travelers' diarrhea in adults; however, the role of loper-amide in pediatric travelers' diarrhea remains controversial, despite being licensed for use in children 2 years of age and older. Although loperamide has been shown to decrease duration and severity of acute diarrhea in children, this drug has been associated with significant side effects in children and is not recommended for younger children. [54] [56] Racecadotril is an enkephalinase inhibitor that has been associated with decreased stool output in clinical trials; however, further studies are required. Zinc supplementation has been associated with improved outcomes in diarrheal disease in children in developing countries, but zinc supplementation is not recommended in treatment of travelers' diarrhea. [54] There is little evidence for use of antimicrobial agents in pediatric travelers' diarrhea. [51] Fluoroquinolones for 1 to 3
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days are the drug of choice for adults with travelers' diarrhea that is moderate to severe, persistent (> 3 days), or associated with fever or bloody stools. Although there are concerns regarding the potential for development of arthropathy and antimicrobial resistance with fluoroquinolone use in children, the Food and Drug Administration has approved ciprofloxacin for anthrax and as a second-line agent for the treatment of urinary tract infections in children from 1 to 17 years of age. [57] [58] Therefore, fluoroquinolones could be considered safe in children for the short course required for travelers' diarrhea. A 3-day course of ciprofloxacin at a dose of 20 to 30 mg/kg per day divided twice daily with a maximum dose of 500 mg bid is recommended for children with moderate to severe or bloody diarrhea. [51] Azithromycin is often used as the first choice for treatment of pediatric travelers' diarrhea, especially in areas with a high prevalence of fluoroquinolone-resistant Campylobacter species such as India and Thailand because it is given once a day and has a known safety profile in children. A dose of 10 mg/kg once daily for 3 days (maximum dose of 500 mg) is appropriate. [51] In adults a single dose of antibiotic has been shown to be as effective as 3 days' treatment; therefore, in children a full 3-day course may not be necessary. [59] [60] Rifaximin (Xifaxan), a nonabsorbed rifamycin derivative, has been approved in the United States for treatment and prevention of travelers' diarrhea for people 12 years of age and older. [61] A liquid preparation is available in some countries for pediatric use. If travelers' diarrhea does not respond to a course of antimicrobial therapy, medical attention should be sought to investigate other possible causes of the diarrhea. EMERGING INFECTIOUS DISEASES Over the past few years, several infectious agents, such as severe acute respiratory syndrome (SARS) coronavirus, and the H5N1 strain of avian influenza, have emerged as potentially widespread health threats. Although the SARS coronavirus does not appear currently to be of concern, pediatricians who are advising families regarding travel health must keep informed of the current status of emerging infectious diseases that may pose a threat to the traveler. Several websites provide up-to-date information regarding such infections, including that of the WHO and the Centers for Disease Control and Prevention (see Box 9-1 ). A highly pathogenic strain of avian influenza (H5N1) has caused outbreaks in poultry in several countries in Asia, Africa, the middle East, and eastern Europe. Human cases of H5N1 also have been documented in Cambodia, China, Indonesia, Iran, Thailand, Turkey, and Vietnam. Although there have been rare confirmed human-to-human transmissions of H5N1, which have high case-fatality rates have also been documented in a number of these countries. (An up-to-date listing of confirmed human cases can be found. Although there have been rare confirmed human-to-human transmission of H5N1 in these outbreaks, there is concern that further mutations in the virus may result in a pandemic strain of influenza. A number of recommendations for travelers have been made to decrease their risk of acquiring H5N1 infection [62] ( Box 9-5 ). Although oseltamivir has been used in treatment of and prophylaxis against H5N1, it is not recommended that a prescription for oseltamivir be given to travelers. BOX 9-5 Precautions to Decrease Risk of H5N1 Infection Avoid all direct contact with poultry and ducks, including poultry farms and bird markets Wash hands frequently with soap and water (alcohol-based handwashes can be used if hands are not visibly soiled) Cook all poultry-based foods, including eggs, thoroughly
THE IMMUNOCOMPROMISED TRAVELER Children with immunodeficiencies require special consideration at their pretravel evaluation because of increased risk of travel-related illness. [63] Most patients with altered immune systems, particularly those with decreased Tlymphocyte immunity, should not receive live vaccines because of risk of developing clinical illness from the vaccine strain. [64] IPV should be given instead of OPV to all members in the family of an immunocompromised person, and vi typhoid vaccine should be administered instead of the Ty21a vaccine to an immunocompromised child, although there is no risk to the patient if family members receive the live oral vaccine. [15] [21] However, MMR, varicella, and yellow fever vaccines should be considered for HIV-seropositive children who are not severely immunocompromised (see Chapter 227 , Rubeola Virus (Measles and Subacute Sclerosing Panencephalitis); Chapter 205 , Varicella-Zoster Virus). Killed or subunit vaccines may be administered to children with altered immunity, although responses to the vaccines may be diminished. [64] Asplenic patients may respond poorly to polysaccharide vaccines in particular. Patients with certain B-lymphocyte deficiencies, such as X-linked and common variable agammaglobulinemia,
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should avoid OPV, vaccinia, and live bacterial vaccines, although other patients with humoral deficiencies, including selective immunoglobulin A (IgA) and IgG subclass deficiency, need only avoid OPV; other live vaccines can be considered. Some travel-associated illnesses may be more severe in immuno-compromised travelers. Asplenic travelers are at greater risk of severe babesiosis and malaria, and organ and stem cell transplant recipients are more likely to develop bacteremia associated with gastroenteritis due to Salmonella or Campylobacter spp. [65] HIV-seropositive travelers with low CD4 lymphocyte counts must be particularly conscious of risk factors associated with opportunistic infections such as Toxoplasma gondii, Isospora belli, Salmonella spp. and Cryptosporidium parvum, [65] and, therefore, must be particularly cautious regarding food, water, and animal exposures. RETURN FROM TRAVEL Routine posttravel screening generally is not required for asymptomatic, short-term travelers, although screening may be considered for long-term travelers, expatriates, adventure travelers, and people who have experienced significant illness while traveling. [4] [66] If post-travel screening is indicated, the tests required should be determined by the potential exposures associated with the travel itinerary and any symptoms, if present. Children who develop symptoms after travel should seek immediate medical attention, and parents must inform the physicians caring for them of their travel itinerary. This is particularly critical if the itinerary has included a malariaendemic area, since chemoprophylaxis cannot prevent all cases of malaria. Because malaria can present with nonspecific symptoms in children, any symptoms of fever, rigors, headache, malaise, abdominal pain, vomiting, diarrhea, poor feeding, or cough following travel to an endemic country should be evaluated promptly by a physician. [67] Travel-relatetd illness has been shown to be highly dependent on itinerary. In a report of disease and relationship to place of exposure among ill returned travelers, significant regional differences in proportionate morbidity were reported. [4] Typhoid fever was seen most frequently in travellers returning from South Asia. Malaria was one of the three most frequent causes of systemic febrile illness among travelers from every region, especially sub-Saharan Africa, although travelers from every region except sub-Saharan Africa and Central America had confirmed or probable dengue more frequently than malaria. Rickettsial infection, primarily tickborne spotted fever, occurred more frequently than malaria or dengue among travelers returning from southern Africa. [4] References 1. World tourism maintains momentum. 2005. Available online at: www.worldtourism.org 10, 2005). (accessed September
2. Stauffer WM, Konop RJ, Kamat D: Traveling with infants and young children. Part I: Anticipatory guidance: travel preparation and preventive health advice. J Travel Med 2001; 8:254-259. 3. Steffen R, de Bernardis C, Banos A: Travel epidemiologya global perspective. Int J Antimicrob Agents 2003; 21:89-95. 4. Freedman DO, Weld LH, Kozarsky PE, et al: Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006; 354:119-130. 5. Bacaner N, Stauffer B, Boulware DR, et al: Travel medicine considerations for North American immigrants visiting friends and relatives. JAMA 2004; 291:2856-2864. 6. Behrens RH: Visiting friends and relatives. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:281-285. 7. Balkhy HH: Travelling with children. Int J Antimicrob Agents 2003; 21:193-199. 8. Christenson JC: Preparing children for travel to tropical and developing regions. Pediatr Ann 2004; 33:676-684. 9. Advice for travelers. Treat Guidelines Med Lett 2006; 4:25-34. 10. Centers for Disease Control and Prevention (CDC). : National, state, and urban area vaccination coverage among children aged 1935 monthsUnited States, 2005. MMWR Morb Mortal Wkly Rep 2006; 55:988-993.
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11. WHO Vaccine Summaries. Available online at:http://www.who.int/vaccines/globalsummary/immunization/countryprofileselect.cfm 2005). 12. Vaccines and biologics used in U.S. and foreign markets. Available online at: www.immunize.org/izpractices/p5120.pdf (accessed September 14, 2005).
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13. Mackell SM: Pediatric vaccinations. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:123-130. 14. Stauffer WM, Kamat D: Traveling with infants and children. Part 2: immunizations. J Travel Med 2002; 9:8290. 15. American Academy of Pediatrics. : Immunization in special clinical circumstances: international travel. In: Pickering LK, Baker CJ, Long SS, et al ed. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village: IL, American Academy of Pediatrics; 2006:67-103. 16. Centers for Disease Control and Prevention. : (CDC). Recommended immunization schedules for persons aged 018 yearsUnited States, 2007. MMWR Morb Mortal Wkly Rep 2007; 55:Q1-Q4. 17. American Academy of Pediatrics. : Active immunization. In: Pickering LK, Baker CJ, Long SS, et al ed. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed.. Elk Grove Village: IL, American Academy of Pediatrics; 2006:23-35. 18. Centers for Disease Control and Prevention (CDC). : General recommendations on immunization: recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 2006; 55 (RR15):1-48. 19. Committee on Infectious Diseases. : Prevention of pertussis among adolescents: recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Pediatrics 2006; 117:965-978. 20. Digest V2005 #408. 2005. Available online at: www.promedmail.or (accessed September 14, 2005).
21. Centers for Disease Control and Prevention. : A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part 1: immunization of infants, children and adolescents. MMWR 2005; 54(RR-16):1-33. 22. Centers for Disease Control and Prevention. : Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006; 55(RR-7):1-23. 23. Murdoch DL, Goa K, Figgitt DP: Combined hepatitis A and B vaccines: a review of their immunogenicity and tolerability. Drugs 2003; 63:2625-2649. 24. Jarvis B, Figgitt D: Combined two-dose hepatitis A and B vaccine (AmBirix). Drugs 2003; 63:207-213. 25. Figueira M, Christiansen D, Barnett E: Cost-effectiveness of serotesting compared with universal immunization for varicella in refugee children from six geographic regions. J Travel Med 2003; 10:203-207. 26. American Academy of Pediatrics Committee on Infectious Diseases. : Prevention and control of meningococcal disease: recommendations for use of meningococcal vaccines in pediatric practice. Pediatrics 2005; 116:496-505. 27. Centers for Disease Control and Prevention (CDC). : Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2005; 54(RR-7):1-21. 28. Pichichero M, Casey J, Blatter M, et al: Comparative trial of the safety and immunogenicity of quadrivalent (A, C, Y, W-135) meningococcal polysaccharide-diphtheria conjugate vaccine versus quadrivalent polysaccharide vaccine in two- to ten-year-old children. Pediatr Infect Dis J 2005; 24:57-62. 29. Centers for Disease Control and Prevention (CDC) : Update: GuillainBarr syndrome among recipients of Menactra meningococcal conjugate vaccineUnited States, June 2005September 2006, MMRW 2007; 55:11201124.
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30. Centers for Disease Control and Prevention. : Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2006; 55:1-41. 31. Maloney SA, Weinberg M: Prevention of infectious diseases among international pediatric travelers: considerations for clinicians. Semin Pediatr Infect Dis 2004; 15:137-149. 32. Currently available oral cholera vaccines. 2005. Available online at:http://www.who.int/topics/cholera/vaccines/current/en/index.html (accessed January 17, 2006).
33. In: Nuttall I, ed. Vaccines for selective use. International Travel and Health, Geneva: World Health Organization; 2005:106. 34. Luxemburger C, Dutta AK: Overlapping epidemiologies of hepatitis A and typhoid fever: the needs of the traveler. J Travel Med 2005; 12(Suppl 1):S12-S21. 35. Katz BZ: Traveling with children. Pediatr Infect Dis J 2003; 22:274-276. 36. Lin FYC, Ho VA, Khiem HB, et al: The efficacy of a Salmonella typhi Vi conjugate vaccine in two- to-five-year old children N Engl J Med. 2001; 344:1263-1269. 37. Lanh MN, Bay PV, Ho VA, et al: Persistent efficacy of Vi conjugate vaccine against typhoid fever in young children. N Engl J Med 2003; 349:1390-1391. 38. Suzano C, Amaral E, Sato H, et al: The effects of yellow fever immunization (17DD) inadvertently used in early pregnancy during a mass campaign in Brazil. Vaccine 2006; 24:1421-1426. 39. Directory. Available online at: www2.ncid.cdc.gov/travel/yellowfever. 40. Rupprecht CE, Gibbons RV: Clinical practice. Prophylaxis against rabies. N Engl J Med 2004; 351:2626-2635. 41. Centers for Disease Control and Prevention. : Japanese encephalitis in a US traveler returning from Thailand, 2004. MMWR 2005; 54:123. 42. Mackell SM: Vaccinations for the pediatric traveler. Clin Infect Dis 2003; 37:1508-1516. 43. Healy CM, Baker CJ: The future of meningococcal vaccines. Pediatr Infect Dis J 2005; 24:175-176. 44. Ameratunga S, Macmillan A, Stewart J, et al: Evaluating the post-licensure effectiveness of a group B meningococcal vaccine in New Zealand: a multi-faceted strategy. Vaccine 2005; 23:2231-2234. 45. Centers for Disease Control and Prevention (CDC). : The role of BCG vaccine in the prevention and control of tuberculosis in the United States. MMWR Morb Mortal Wkly Rep 1996; 45(RR-4):1-18. 46. Chen LH, Keystone JS: New strategies for the prevention of Malaria in travelers. Infect Dis Clin North Am 2005; 19:185. 47. Stauffer WM, Kamat D, Magill AJ: Traveling with infants and children. Part IV: insect avoidance and malaria prevention. J Travel Med 2003; 10:225-240. 48. Fight the bite for protection from malaria: guidelines for DEET insect repellent use. 2005. Available online at:http://www.cdc.gov/Malaria/toolkit/DEET.pdf (accessed January 13, 2006). 49. Fradin M, Day J: Comparative efficacy of insect repellents against mosquito bites. N Engl J Med 2002; 347:1318. 50. Fischer PR: Pediatric, neonatal and adolescent travelers. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:217-226. 51. Stauffer WM, Konop RJ, Kamat D: Traveling with infants and young children. Part III: travelers' diarrhea. J Travel Med 2002; 9:141-150. 52. Walker RI: Considerations for development of whole cell bacterial vaccines to prevent diarrheal diseases in
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children in developing countries. Vaccine 2005; 23:3369-3385. 53. Plourde PJ: Travellers' diarrhea in children. Paediatr Child Health 2003; 8:99-103. 54. Centers for Disease Control and Prevention (CDC). : Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Morb Mortal Wkly Rep 2003; 52(RR-16):1-16. 55. World Health Organization. Oral Rehydration Salts: Production of the New ORS. Report no.: WHO/FCH/CAH/06.1. Geneva, World Health Organization, 2006. 56. Kaplan M: A multicenter randomized controlled trial of a liquid loperamide product versus placebo in the treatment of acute diarrhea in children. Clin Pediatr 1999; 38:579-591. 57. Schaad UB: Fluorquinolone antibiotics in infants and children. Infect Dis Clin North Am 2005; 19:617-628. 58. Pediatric Exclusivity Labeling Changes as of November 23, 2005. Available online at:http://www.fda.gov./cder/pediatric/labelchange.htm. (accessed January 18, 2006). 59. Shanks GD, Smoak BL, Aleman GM, et al: Single dose of azithromycin or three-day course of ciprofloxacin as therapy for epidemic dysentery in Kenya. Acute Dysentery Study Group. Clin Infect Dis 1999; 29:942-943. 60. Salam I, Katelaris P, Leigh-Smith S, et al: Randomised single dose ciprofloxacin for travelers'diarrhea. Lancet 1994; 344:1537-1539. 61. Adachi J, DuPont H: Rifaxamin: a novel nonabsorbed rifamycin for gastrointestinal disorders. Clin Infect Dis. 2006; 42:541-547. 62. Outbreak notice: Update: Human Infection with Avian Influenza A (H5N1) Virus in Asia. 2006. Available online at:http://www.cdc.gov/flu/avian (accessed May 30, 2006). 63. Mileno MD, Bia FJ: The compromised traveler. Infect Dis Clin North Am 1998; 12:369-412. 64. Mileno MD: Preparation of immunocompromised travelers. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:249-255. 65. Castelli F, Pizzocolo C: The traveler with HIV. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:257-265. 66. Clerinx JC, Van Gompel A: Post-travel screening. In: Keystone JS, Kozarsky PE, Freedman DO, et al ed. Travel Medicine, St. Louis,: Elsevier Science; 2003:473-480. 67. Nield LS, Stauffer W, Kamat D: Evaluation and management of illness in a child after international travel. Pediatr Emerg Care 2005; 21:184-195.quiz 9698 Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier Section C Host Defenses Against Infectious Diseases
CHAPTER 10 Immunologic Development and Susceptibility to Infection
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Maite de la Morena The human immune system has evolved to protect the individual from infectious microbes. It does this by utilizing a complex interactive network of cells, proteins, and organs. This response is both innate and adaptive, each with unique characteristics. The innate response to a pathogen occurs immediately (within hours), lacks clonal specificity for a particular pathogen, and does not confer long-lasting protection, i.e., immunologic memory. The adaptive immune response, although triggered by components of the innate immune response, takes days to evolve, requires processing and presentation of antigens derived from the pathogen, is specific to the particular pathogen and most importantly confers immunologic memory, i.e., the organism remembers the signature of a pathogen upon subsequent encounter. Experiments of nature in humans, such as those recognized as the inherited disorders of immune function, [1] have taught us that despite the apparent redundancy of the system, quantitative and qualitative defects in individual components and/or pathways result in abnormal function and susceptibility to particular infections. This chapter provides a general overview of the development of innate and adaptive immune responses, addresses some of the immunologic developmental characteristics unique to the fetus and newborn, and addresses pathogen susceptibility in general terms, which can serve as an introduction to Sections M, N, and R of this textbook. THE INNATE IMMUNE RESPONSE The innate immune system offers a first line of defense against invading pathogens. Both cellular and humoral factors constitute its major components. These include: (1) antimicrobial products and phy sical barriers such as skin and mucosal surfaces; (2) receptors for pathogen molecules, including the family of Toll-like receptors (TLRs); (3) phagocytic cells: neutrophils and macrophages; (4) dendritic cells (DC); (5) the complement system; and (6) natural killer (NK) cells.
Antimicrobial Products, the Skin, and Mucosal Barriers
In mammals, epithelial cells are capable of secreting two classes of antimicrobial peptides: defensins and cathelicidins. Defensins can be further categorized into - or -defensins and contribute to host defense by disrupting the cytoplasmic membranes of microbes. -Defensins are produced by neutrophils, monocytes, and Paneth cells of the gut whereas -defensins are produced by epithelial cells. A human cathelicidin, hCap18/LL-37, has been found in epithelial cells, mast cells, monocytes, and lymphocytes and has neutralizing capability against lipopolysaccharide (LPS), stimulates angiogenesis, and acts as a chemoatractant for neutrophils, monocytes, and T lymphocytes. [2] [3]
[4] [5]
The skin is the most important barrier to pathogen entry. Tight junctions between epithelial cells, skin thickness, and a dry environment offer a shield against microbes. Loss of skin integrity, as seen in wounds, burns, and inflammation, allows the entry of pathogens through this barrier. Both psoriasis and atopic dermatitis (AD) are known inflammatory skin conditions associated with skin disruption. However, although infection is rarely associated with psoriasis, patients with AD are commonly infected with Staphylococcus aureus. Human -defensin 2 (HBD2) and the cathelicidin LL-37 appear to be strongly expressed in psoriasis and not in eczematous skin. Interleukin (IL)-13, produced under atopic conditions, suppresses the induction of these antimicrobial peptides. [6] Interestingly, LL-37 has also been identified in the ductal epithelium of salivary and sweat glands, suggesting a role in the protection of the gland itself from microbial invasion and providing protection to the epithelial surface via secreted products. [7] During the third trimester of pregnancy, the fetus becomes covered by the vernix caseosa, which contains antimicrobial peptides, including -defensins, LL-37, and psoriasin, a calcium-binding protein that is upregulated in psoriasis. Vernix extracts exhibited both antibacterial activity against gram-negative bacteria and antifungal properties against Candida albicans, whereas amniotic fluid derived proteins and peptides showed only the former activity. [8] The more common entry pathway for pathogens is through the mucosal barrier. Mucosal epithelial cells secrete mucus that contains many antimicrobial peptides, including defensins and cathelicidins. Mucus acts dually. First, it coats the pathogen, allowing the antimicrobial peptides to exert their action; and second, it acts as a vehicle for particles and pathogens to be cleared by the action of cilia. Within the respiratory tract, cilia move the mucus towards the upper airways where it is either expelled through cough mechanism or swallowed. Ineffective clearance, as seen in patients with immotile cilia syndrome or after lung transplantation, may further contribute to colonization with pathogens such as Pseudomonas aeruginosa (see Chapter 155 , Pseudomonas aeruginosa). The balance between the fluid composition of the mucus and antimicrobial properties is disrupted in patients with cystic fibrosis (CF) due to mutations in the CF transmembrane conductance regulator (CFTR) gene, leading to bacterial overgrowth and chronic inflammation. Recently, LL-37 gene transfer experiments preformed in C57B mice conferred protection against
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intratracheal injection of Pseudomonas aeruginosa, suggesting a potential therapeutic approach for these antimicrobial peptides. [9] Furthermore, HDB2 and LL37 appear to be consistently elevated in states of infection and may contribute to pathogen clearance, as knockout mice lacking -defensin cannot clear Haemophilus influenzae. [10] Surfactant-associated proteins, specifically surfactant protein A (SP-A) and surfactant protein D (Sp-D), contribute to the innate immune responses in the lung. Produced by type II pneumocytes and nonciliated respiratory epithelial cells, they belong to the family of proteins called collectins. SP-A and SP-D can interact with microorganisms, modulate local inflammatory responses, modulate neutrophil responses in vitro, and participate in clearance of pollens and other complex organic antigens. [11] Recently SP-D has been shown to limit the intracellular growth of bacilli in macrophages by increasing phagosomelysosome fusion, but not by generating a respiratory burst. [12] Lysozyme, lactoferrin, and phospholipase A2 in tears and saliva, and histatins in saliva, are potent antibacterial enzymes as well. [13] [14] The gastrointestinal tract is protected by digestive enzymes, bile salts, fatty acids, and lysolipids. Paneth cells in the human gut secrete -defensins and influence the virulence of orally ingested bacteria. Thus, children and adults with infections due to Shigella or virulent Salmonella strains have demonstrated decreased synthesis by colonic enterocyte of HBD1 and cathelicidin LL-37. HBD2 expression is also reduced in enterocytes of patients with Crohn disease and gastric mucosa-derived -defensins are seen in Helicobacter pylori infections. Interestingly, in vitro, this microbe is susceptible to HBD2. Commensal bacteria are resistant to endogenous antimicrobial peptides but induce epithelial defensins. Porphyromonas gingivalis does not induce HBD2 and behaves as a silent invader (for an excellent review, see reference 14).
Pathogen Receptors and Toll-like Receptors
Although the innate immune response is not specific in terms of immunologic memory, features that may be common to different pathogens can be recognized by the cells of the innate immune system. These unique features of microbe are known as pathogen-associated molecular patterns (PAMP) and include carbohydrates and lipoproteins or nucleic acids expressed as part of their life cycle within the host. For example, bacterial DNA as unmethylated repeats of dinucleotide CpG and double-stranded (ds) or single-stranded (ss) RNA are known PAMPs. Pathogen recognition receptors such as mannose-binding lectin (MBL), which is a circulating soluble protein, can bind mannose or fucose residues of a certain spatial orientation, and allows the bacteria to become susceptible to phagocytosis and complement activation. Macrophages can carry a C-type lectin called macrophage mannose receptor (MMR) which not only binds carbohydrate moieties found on the surface of bacteria but can also recognize viruses such as the human immunodeficiency virus (HIV). [16] Toll receptors are an important group of signaling molecules capable of recognizing PAMPs. Their importance lies in their ability to link innate and adaptive effector functions (for a review see Chapter 11 , Fever and the Inflammatory Response). Toll receptors were first identified in Drosophila melanogaster and discovered in humans due to similarities to the mammalian IL-1 receptor (IL-1R), thus the name Toll-like receptor. [17] [18] They are present on many cells, including airway and gut epithelial cells, antigen-presenting cells (APC: B lymphocytes, macrophages, DC, monocytes), mast cells, regulatory T lymphocytes, NK lymphocytes, and endothelial cells. [19] A total of 10 different TLRs have been identified in humans: TLR-1, -2, -4, -5, TLR-6 and TLR-10 are found on cell surfaces, whereas TLR-3, -7, -8, and -9 are localized within the endosomes. TLR-2 is involved in responses to gram-positive bacteria (peptidoglycans and lipoproteins) and yeast. [20] TLR-4 mediates the interaction of gram-negative bacteria by transducing signals derived from LPS. A model for TLR-4 mutations renders mice resistant to endotoxin but highly susceptible to gram-negative organisms. [21] All TLRs are capable of interacting with different ligands (see Table 11-1 ). RSV F protein, LPS, and Pseudomonas exoenzyme S have been shown to interact with TLR-4 whereas flagellin is recognized by TLR-5. [22] TLR-2 recognizes envelope proteins of herpes simplex virus (HSV) whereas TLR-9 identifies CpG motifs within the viral genome. [23] Binding of the microbial components to the TLR triggers the activation of two downstream signaling pathways where myeloid differentiation factor 88 (MyD88) and/or Toll-IL-1 receptor domain containing adaptor-inducing interferon (IFN)- (TRIF) lead to activation of NF-kappaB and subsequent transcription of proinflammatory cytokines: tumor necrosis factor- (TNF-, IL-1, and IL-6. MyD88 recruits the IL-1R-associated kinase (IRAK) family of proteins: IRAK-1 and IRAK-4. Humans and mice with IRAK-4 deficiency have severe impairment of IL-1 and TLR downstream signaling and are susceptible to recurrent bacterial infections. [24] [25] TRIF signaling results in the activation of IFN-regulatory factor (IRF) 3 and induction of type 1 IFN genes such as IFN- and IFN-, [26] helpful for viral clearance. TLR polymorphism may be linked to diseases such as asthma [27] and atherosclerosis, [19] TLR-2 has been linked to different responses to ischemia and reperfusion injury after solid-organ transplantation [27] ; and a deletion of the
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signaling domain of TLR-5 has been found to increase susceptibility to legionnaire disease. [29] Finally, Toll signaling pathways have been implicated in the pathogenesis of sepsis and shock [30] [31] [32] (see Chapter 12 , The Systemic Inflammatory Response Syndrome (SIRS), Sepsis and Septic Shock, for review).
Phagocytes
Major phagocytic cells are neutrophils and macrophages. In humans, myeloid precursors are found in the yolk sac by day 19 of development, 2 days before the onset of blood circulation. Hematopoiesis then shifts to the fetal liver and finally to the bone marrow. In the bone marrow phagocyte development is under the control of multiple growth factors, including IL-3, granulocytemacrophage colony-stimulating factor (GM-CSF), granulocyte colonystimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF). The marrow pool of neutrophils in adults is 20 times the number of neutrophils in circulation. The mechanisms responsible for the release of neutrophils from the marrow are not well understood. Once in the circulation neutrophils circulate for a few hours and then move into tissues where they are active for 2 to 6 days. At term, the neonatal peripheral neutrophil count is higher than that of adults, but there appears to be little reserved capacity to respond with an outpouring of phagocytic cells which are often immature, during infection. Newborn infants with septicemia often have severe neutropenia and depletion of phagocytic storage pools, a finding associated with a high mortality rate. [34] [35] The cause of depletion remains unknown; it often occurs in the presence of increased numbers of neutrophil precursors and elevated levels of cerebrospinal fluid in blood. [35] Perhaps a decreased number of neutrophils at the site of infection contribute to the susceptibility of neonates to pneumonia and skin infection and to the development of multiple sites of infection after bacterial or fungal bloodstream infection. [36] This lack of adequate numbers of cells at the site of infection may cause or result in functional deficiencies. Monocytes also move from the circulation to tissue spaces, where they develop into macrophages and live for 2 to 3 months, assuming specialized characteristics most determined by their location (e.g., lung, liver, or spleen). Circulating monocytes also have chemotactic and phagocytic activities and have receptors for immunoglobulin G (IgG) Fc receptor domains (FcR) and the complement complex iC3b. [37] The function of phagocytes (which are particularly important in defense against bacteria and fungi) requires not only sufficient numbers of cells but adequate ability to sense and migrate toward the site of infection (chemotaxis) and to ingest and kill (phagocytosis) microorganisms. These processes are mediated by the expression of adhesion molecules, opsonins (complement and antibodies), and release of toxic substances ( Figure 10-1 ).
Figure 10-1 Aspects of immunologic function. *Indicates aspects that are immature or defective in the neonatal period. C, complement; CD, cluster of differentiation; CR, complement receptor; G-CSF, granulocyte colony-stimulating factor; Ig, immunoglobulin; IL, interleukin; M-CSF, macrophage colonystimulating factor.
Chemotaxis
As a result of a local inflammatory response, endothelial cells within the local vessels express adhesion molecules called selectins (CD62E, CD62P). These molecules reversibly bind to ligands on neutrophils (sialyl-Lewis X and PSGL1) and consequently make the neutrophil slow down and roll along the endothelium. Subsequently, another group of adhesion molecules, called integrins, are upregulated on the surface of neutrophils. Integrins are composed of one of three different alpha chains: CD11a, CD11b (CR3), or CD11c (CR4); they are noncovalently linked to a beta chain, CD18, thus forming CD11a/CD18 or LFX1, CD11b/CD18 or MAC-1, and CD11c/CD18 or p150,95 integrin complex. Integrin molecules stop the neutrophil, which then undergoes skeletal changes and migrates through the vascular lumen into the extravascular space by adhering to intracellular adhesion molecules (ICAMs).
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Interestingly, the sialic acid constituent of the group B streptococcus (GBS) capsular polysaccharide mimics the human Lewis X antigen, making this a poor immunogen and perhaps rendering the neonate more susceptible to this organism. [38] Defects in the expression of adhesion molecules have been described in humans. Leukocyte adhesion defects (LADs) include lack of integrin expression (LAD I), lack of sialyl-Lewis X expression (LAD II) and defects of integrin activation (LAD III). Affected children have persistent leukocytosis, delayed separation of the umbilical cord, skin ulcers, periodontitis, and delayed wound healing. [39] L-selectin (CD62L) levels on fetal and immature infant neutrophils are comparable with those of adults. However, their expression is downregulated in the term neonate and is further diminished during acute bacterial infection in vivo. [40] Other defects in chemotaxis have been described. [39] [41] [42] [43] [44] In the newborn infant defects in chemotaxis have been linked to decreased expression of Rac2, a signaling molecule, on cord blood neutrophils. [36]
Phagocytosis
Phagocytosis is an active process by which a previously bound pathogen is engulfed by a phagocyte in a membranebound vesicle called a phagosome. Both macrophages and neutrophils contain lysosomes, which are membranebound acidic organelles containing proteolytic enzymes, and are capable of producing toxic products: nitric oxide (NO), superoxide anion (O2) and hydrogen peroxide (H2O2). Fusion of the lysosome and phagosome membranes is necessary for killing of the organism. Within azurophilic granules, a bactericidal/permeability-increasing protein (BPI) binds to bacterial LPS and kills gram-negative bacteria. Once bacteria are killed, neutrophils die whereas macrophages are capable of generating new lysosomes. Abnormal BPI function has been implicated in both neonatal sepsis [45] and chronic Pseudomonas infection in CF patients. [46] Superoxide and H2O2production is dependent on the NADPH oxidase enzyme complex (see Chapter 106 , Infectious Complications of Dysfunction or Deficiency of Polymorphonuclear and Mononuclear Phagocytes). Defects in the different components of this enzyme result in the immunodeficiency, chronic granulomatous disease. Affected patients are susceptible to infections with catalase-positive organisms, Aspergillus and Nocardia species. Because phagocytes are unable to kill the microbes, the host tries to contain the infection by calling in more macrophages and lymphocytes, resulting in granuloma formation. There are no well-described phagocytic defects in the developing human embryo. The capability of the newborn for nonopsonic adherence to organisms and phagocytosis is nearly equal to that of adult cells. However, deficiencies in chemotaxis and superoxide production have been described. [38] [47] [48] [49] Bacterial killing by cord blood phagocytes is effective against Escherichia coli and Streptococcus pyogenes and is similar to adults, but killing appears abrogated for GBS. [50] Abnormalities in chemoattractants (IL-8, complement fragment C5a, fibronectin) [51] [52] and defective expression of complement receptors, such as C5a receptor, caused by C5amediated exocytosis of myeloperoxidase, [53] are also described. Defects in membrane fluidity and cytoskeletal changes may also contribute to defects in neutrophil motility. [54] Intrapartum administration of magnesium sulfate has been reported to decrease neutrophil motility and phagocytosis of cord blood neutrophils, as measured by chemotaxis, random motility, and chemiluminescence. [55]
Dendritic Cells
In humans, CD34 + hematopoietic stem cells (HSC) capable of generating DC are detected in the fetal liver at 20 weeks' gestation, after which they are mainly found in the bone marrow. After birth, 1% to 3% of cord blood cells express CD34. During differentiation these CD34 + cells lose CD34 expression and express CD4, CD45RA, IL-3R, and major histocompatibility complex (MHC) class II antigens. [56] [57] A class of DC called Langerhans cells (LC) were first described by Paul Langerhans in 1868. It is difficult to identify lineage ontogeny of DC in humans. Bone marrow differentiation studies of DC suggest a dual origin of DC in myeloid and lymphoid cells, but debate remains. [58] [59] LC can derive from blood DC. [60] Although lineage-specific markers are still being defined, three transcription factors have been shown to regulate their development: PU.1, RelB, and Ikaros. PU.1 is important for myeloid-derived DC, [61] RelB is associated with DC activation, [62] and ikaros proteins are transcriptional activators and influence chromatin remodeling and histone deacetylation. [63] DC are prototypic APCs and are capable of regulating both innate and adaptive immune responses. When activated, they have unique morphologic characteristics. Several pathogen receptors have been identified: TLRs, which appear to be involved in DC maturation, and scavenger receptors, which mediate bacterial internalization. MAC-1 (CD11b/CD18) or the CR3 complement receptor have demonstrable phagocytosis of complement-coated bacteria.
[64]
In the skin LC are localized to the basal and suprabasal layers of the epidermis; in the murine gut, DC are found in the Peyer patches; and in the human lungs, they can be found within the airway epithelium, alveolar septa, visceral pleura, and vascular wall. [65] [66] [67]
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While surveying the tissue environment, DC can be recognized by an immature phenotype (CD11b bright , CD11c mod , CD86 low , class II low , CD4 - ). Upon uptake of antigen/microbial products by different mechanisms of phagocytosis, they migrate via the afferent lymphatics to the regional lymph node where they arrive as mature nonphagocytic DC (CD40 high ). These DC cells can produce inflammatory cytokines and chemokines. Bacterial uptake of Mycobacterium tuberculosis, bacille Calmette-Guerin (BCG), Saccharomyces cerevisiae, Corynebacterium parvum, Staphylococcus aureus, Leishmania spp. and Borrelia burgdorferi has been demonstrated in vitro [68] [69] [70] [71] (reviewed in reference 63). Once in the lymph nodes, DC move around from the marginal zones to the T zones until they encounter a naive T lymphocyte. [72] When the naive T lymphocyte and the DC meet, they remain stuck together for a while, forming the important immunologic functional unit called the immunologic synapse. [73]
Complement
The complement system comprises a series of serum proteins that function in host defense as an enzymatic cascade (see Chapter 105 , Infectious Complications of the Complement System). When microorganisms invade the host, activation of complement occurs locally by one of three pathways that converge at the stage of the formation of an enzyme called C3 convertase. This enzyme cleaves complement component C3 into C3b and C3a. C3b, the major effector molecule of the complement system, binds to the bacterial cell membrane. This important molecule functions as an opsonin (to facilitate phagocytosis) and also helps cleave C5 into C5a and C5b. C5a is a potent chemoattractant, and C5b is an integral part of the membrane attack complex along with other terminal components: C6, C7, and C9. One pathway (classical) is activated by antibodyantigen complexes and thus depends on and enhances specific humoral immunity. A second pathway (alternative) can be activated by direct binding to the surface of some microorganisms and thus functions to provide innate (nonspecific) immunity. A third pathway (MBL pathway) is initiated by the binding of MBL on mannose and fucose-containing surfaces of bacteria and viruses favoring their phagocytosis. Until 18 months of age, the concentration of most complement proteins is lower than that of adults, with the exception of C7. Between 28 and 33 weeks of gestation, there appears to be little development of the complement system. Levels of C8 and C9 are the most markedly reduced at all gestational ages. Levels correlate with gestational age, but not with birthweight, type of delivery, or sex. [74] Deficiencies of complement activation in both classical and alternative pathways have been described (see Chapter 105 , Infectious Complications of the Complement System). [75] [76] Low levels of total hemolytic complement activity are a significant predictor of mortality in neonates with septicemia. [76] The molecular basis for defects in complement function in neonates and the details of the consequences are only partially under stood. For example, a possible defect has been described in formation of a reactive thioester bond on C3 that is essential for opsonic and covalent binding of C3b to bacteria. [77] Inefficient killing of E. coli by neonatal sera appears to correlate with low concentrations of C9. [78] and can be overcome by adding C9 to ampicillin-treated serum from neonates in vitro. [79] Finally, deficient formation of C5a may also increase the newborn infant's risk of infection. Although levels of C5 are similar in adult and neonatal sera, neonatal sera form significantly less C5a on exposure to type III GBS. [80] This deficiency was apparent in newborn sera with antibody levels similar to those of adults and could be corrected by in vitro addition of C3. Hemolyticuremic syndrome (HUS) occurs in childhood and is frequently preceded by a diarrheal illness caused by E. coli O157:H7. Plasma protein factor H and plasma serine protease I, regulatory proteins of the alternative complement pathway, have been associated with the atypical form of HUS (aHUS). [81] [82] A study of 120 patients with aHUS found that 10% of patients had mutations in the membrane cofactor protein (MCP; CD46). The onset was typically in early childhood; most did not develop endstage renal failure. [83]
Natural Killer Cells
NK cells are a subgroup of lymphocytes that exhibit cytolytic activity against tumor cells or cells infected with viruses ( Table 10-1 ). In humans, NK cells are similar to T lymphocytes in their effector function, but lack the Tlymphocyte receptor/CD3 complex and express the low-affinity Fc receptor for IgG (CD16, Fc RIII). They comprise up to 10% of peripheral blood lymphocytes (PBL) in adults. TABLE 10-1 -- Comparison of Natural Killer Cells and Cytolytic T Lymphocytes Characteristic Natural Killer Cell Cytolytic T Lymphocyte Identification of target for kill Nonspecific killing of virusinfected cells or Binding to antibody-coated cells via CD16 (ADCC) TCR specifically identifies viral peptide complexed with MHC class I molecule on surface of infected cell
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Surface markers Signal(s) for activation Onset of function
CD16 and/or CD56 IFN-, IFN-, IL-12 16 days after infection
CD3/CD8 IL-2 and antigen (on surface of antigen-presenting cell) 510 days after infection Granule exocytosis and secretion of toxin
Mechanism of killing Granule exocytosis and secretion of toxin
ADCC, antibody-dependent cell-mediated cytotoxicity; IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor.
NK cells appear in substantial numbers by 6 to 9 weeks of gestation in the embryonic liver and later in the fetal liver, thymus, and spleen. After birth, NK cells primarily develop from HSC in the marrow and are driven to maturity by cytokines, in particular IL-15. IL-15 has the same intracellular signaling molecule, the common gamma chain (C), as other cytokines (IL-2, IL-4, IL-7, IL9, and IL-21). Mutations in C are responsible for a form of severe combined immunodeficiency (SCID) that lacks both T and NK cells (see Chapter 11 , Fever and the Inflammatory Response). Unlike cytotoxic T lymphocytes (CTL), NK cells do not require MHC class I antigens to recognize their targets, do not recognize particular viral antigens, [84] and can be activated by cytokines without previous exposure to the antigen making this cell an important contributor to innate responses. However, NK cells can function with some degree of antigenic specificity because they can lyse cells that are coated with specific antibody molecules. This process is called antibody-dependent cell-mediated cytotoxicity (ADCC). Both NK and CTLs mediate cytolysis in a similar manner as these two cell populations contain granules composed of cytolytic proteins called perforin and enzymes called granzymes. Perforin creates pores in target cell membranes; granzyme introduced through these pores induces target cell apoptosis. [85] Defects in the vesicle membrane fusion, perforin, and granzyme have been described in patients with hemophagocytosis (see Chapter 14 , Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome). A subset of T lymphocytes that coexpress markers associated with NK cells are termed NKT cells. They are defined by surface markers and functionality, express CD1d, use a limited T-cell receptor (TCR) repertoire, and upon stimulation secrete large amounts of IFN- and IL-4. When deficient, development of both autoimmunity and tumors is enhanced (reviewed in reference 86). NK cell activity in cord blood from infants born between 32 and 36 weeks of gestation is low compared with activity in infants born after 36 weeks. Antenatal glucocorticoid therapy for preterm labor can accelerate maturation of NK cells. [87] Compared with adult NK cells, neonatal NK cells have decreased cytotoxic activity [88] and diminished ADCC [87] until at least 6 months of age. On the other hand, when IFNs, IL-2, IL-12, and IL-15 are added to cultured NK cells, they are capable of responding similarly to adult cells. [84] Neonatal HSV infection and severe recurrent herpesvirus infections in adults provide evidence of the importance of NK cells in host defense. [89] [90] Human umbilical cord blood cells demonstrate defective NK cell cytotoxicity and ADCC against HSV-infected targets. [91] [92] [93] Evidence for the relevance of ADCC in protecting the infant from HSV is provided by the association of high levels of maternal- or neonatal-specific ADCC with HSV, or high levels of neonatal HSV-neutralizing antibodies with absence of disseminated HSV infection in infants. [94] Term infants infected perinatally with HIV are deficient in ADCC, whereas preterm infants are deficient in both NK cell cytotoxicity and ADCC against HIV-infected targets. These observations may relate to an increased risk of HIV transmission in preterm neonates. Low NK cell cytotoxicity and ADCC of newborn lymphocytes to HIV-infected cells may further explain the newborn's inability to reduce plasma levels of HIV after acute infection. [95] Recently, NK defects have been recognized as either part of a broad immunodeficiency syndrome or as isolated defects within NK cell populations. [96] THE ADAPTIVE IMMUNE RESPONSE The adaptive immune response is essential for host defense, as shown by the primary immunodeficiency syndromes outlined in Chapter 103 , Evaluation of the Child with Suspected Immunodeficiency. Specificity and immunologic memory are the two most important consequences of adaptive immunity. Specificity is determined by the vast range of molecular diversity of the antigen receptor. Immunologic memory is the ability to respond rapidly and effectively to pathogens previously encountered. This mechanism implies the pre-existence of clonally expanded populations of antigen-specific lymphocytes. The effector cells of the adaptive immune response are T and B lymphocytes. These cells derive from a common
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HSC ( Figure 10-2 ). It is generally accepted that HSC differentiate into a common lymphoid progenitor (CLP) that will give rise to T, B, and NK cells. Lymphopoiesis is a tightly regulated sequence of events that leads to the expression of a functional antigen receptor on the surface of the lymphocyte. For the B lymphocyte it is the immunoglobulin molecule and for the T lymphocyte, the TCR complex. Cellular microenvironment, growth factors, cytokines, and chemokines, along with silencing or activation of certain genes at different stages of lineage commitment, are some of the multiple factors contributing to a successful and mature lymphocyte. Although mouse lymphoid development has been well elucidated, human lymphoid development has been fragmented, as our knowledge is patched together from in vitro analysis of bone marrow-derived cells, analysis of patients, and comparisons with mouse models (reviewed in reference 96).
Figure 10-2 Developmental stages of T, B, and natural killer (NK) lymphocytes. B, B lymphocyte; CD, cluster of differentiation; CLP, common lymphoid precursor; CSR, class switch recombination; HSC, hematopoietic stem cell; IG, immunoglobulin; MHC, major histocompatibility complex; T, T lymphocyte.
B Lymphocytes
B lymphocytes play a critical role in pathogen-specific immunity by producing antibodies. B lymphocytes recognize soluble antigens via immunoglobulins anchored on their surface and differentiate into antibody-producing cells, called plasma cells, capable of secreting immunoglobulins. These proteins function alone (neutralization) or with complement or phagocytes to inactivate microorganisms (see Chapter 104 , Infectious Complications of Antibody Deficiency). The B-lymphocyte system is fully developed at birth. The origin of the human B lymphocyte is not well defined but fetal B lymphocyte can be recognized in the yolk sac, omentum, and fetal liver. [97] [98] After birth B-lymphocyte development takes place in the bone marrow. The ordered steps of B-lymphocyte development are marked by a rearrangement of the heavy chain first and then the light chain variable region genes of the Ig molecule. From a lymphoid progenitor, B lymphocytes mature following a sequence from pro-B pre-B immature B lymphocyte mature B lymphocyte plasma cell (see Figure 10-2 ). Transcriptional factor PU.1, E2A, and early B lymphocyte factor (EBF) are essential for the early stages. Intracellular proteins such as recombinase-activating gene (RAG) 1 and 2 are identified during the pro and pre-B lymphocyte stage. Surface IgM appears at the immature B
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stage and the mature B lymphocyte carries both IgD and IgM. Surface markers can further identify these cells using flow cytometry analysis and are commonly used in clinical practice. A mature B lymphocyte can be identified by CD19, CD20, CD21 (the EpsteinBarr virus receptor) and CD40 (ligand for CD154, defective in hyper-IgM syndrome), amongst others. All B-lymphocyte surface markers are lost when the cell reaches the plasma cell state. Thus the monoclonal antibody anti-CD20 used for management of B-cell CD20 + lymphomas will not interfere with the plasma cell pool.
Passively Acquired Antibodies
Neonates have a limited serum antibody repertoire (at least 10 11 ) of actively formed (self-produced) antibodies as they have not had the opportunity to encounter pathogens. This is alleviated by transplacental transfer of maternal antibody, which occurs by a selective, active process. Only IgG antibodies appear in umbilical cord blood, and some IgG subclasses are transferred better than others. [99] [100] This mechanism may be related to differential binding of FcRII isoforms in the placenta. [101] [102] At birth, full-term infants have serum IgG levels that are equal to the maternal level or exceed it by 5% to 10%. [103] Most antibody transfer occurs during the third trimester of pregnancy and, therefore, preterm infants may have substantially low levels. For example, most infants born at 32 weeks of gestation or earlier have serum IgG levels below 400 mg/dL. [104] Transplacentally acquired antibody disappears rapidly after birth, reaching a nadir at 3 months ( Table 10-2 ). Average concentrations at this time are 60 mg/dL for infants born at 25 to 28 weeks of gestation, 104 mg/dL for infants born at 29 to 32 weeks, and 430 mg/dL for infants born at term. [105] [106] However, these low levels of maternal IgG antibody appear to be associated with less risk of infection than might be expected. A longitudinal study of the ability of preterm infants to form specific antibodies provides a partial explanation for this low risk. [107] By about 6 months of age, infants have formed specific IgG antibodies in response to immunization with diphtheria, tetanus toxoids, and pertussis vaccine. Also by about this age, their antibodies have functional opsonic activity against E. coli and coagulase-negative staphylococci. TABLE 10-2 -- Concentration of Serum Immunoglobulin G (IgG) in Term and Premature Infants Gestational Age: Mean Serum IgG (mg/dL) Postnatal Age 2528 weeks [a] 2932 weeks [a] Term [b] 1 week 3 months 6 months
a
251 60 159
368 104 179
1031 430 427
Data for premature infants based on samples at 1 week, 3 months, and 6 months of age. [105]
b Data for term infants based on cord blood and samples at 13 months and 46 months of age. [106]
The maternal repertoire of specific antibodies is critical for protection of the newborn infant from commonly encountered pathogens. [108] Baker & Kasper [109] demonstrated that a concentration of 2 g/mL or less of serum antibody to type III GBS in cord blood correlated with susceptibility to invasive disease. Evidence of the protective effect of maternal antibodies against HSV [94] [104] and varicella-zoster virus infection is well established. [111] Many gram-negative organisms require IgM antibodies and complement for efficient opsonization. [112] [113] Since IgM does not cross the placenta, neonatal sera opsonize these organisms poorly. [107] The apparent protective role of transplacental IgG antibodies against GBS infection has led to extensive attempts to prevent or treat such infection with passively administered antibody or by immunization of women with GBS vaccines [114] (see Chapter 119 , Streptococcus agalactiae (Group B Streptococcus)).
Active Production of Antibodies
The ability of newborn infants to produce an active antibody response to antigenic stimulation develops in an orderly fashion. An adult pattern of antibody responses is not acquired until 4 to 5 years of age. Analysis of the factors responsible for this developmental pattern is complex because production of antibody depends not only on Blymphocyte maturity but also on interactions with other cells that mature at different rates ( Table 10-3 ). TABLE 10-3 -- Developmental Milestones of Humoral Immunity Event Surface-positive B lymphocytes of all isotypes present in liver Stimulated B lymphocytes secrete primarily IgM Production of antibody in response to protein antigens
Age 16 weeks of gestation Fetusnewborn Fetusnewborn
Surface-positive B lymphocytes of all isotypes present in bone marrow 22 weeks of gestation
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Serum IgG reaches 60% of adult levels Production of antibody in response to polysaccharide antigens Stimulated B lymphocytes secrete all isotypes Serum IgA reaches 60% of adult levels Ig, immunoglobulin.
1 year 23 years 25 years 68 years
After birth, active production of IgG slowly increases, with differences among IgG subclasses; IgG1 and IgG3 production matures before IgG2 and IgG4. [99] The last isotype to achieve adult concentrations is IgA. [115] [116]
[117]
Postmortem studies of fetuses suggest that secretory IgA (sIgA)-containing epithelial cells appear at 20 to 21 weeks of gestation and their number increases from 2.5 cells per 10000 m at 23 to 26 weeks, and to 8 cells per 10 000 m at 36 to 40 weeks. In fetuses with pneumonia or sepsis, the number of sIgA-containing epithelial cells in the trachea, bronchi, and intrahepatic duct decreases and, at times, completely disappears. This suggests that sIgA is an important component of mucosal immunity at as early as 20 weeks of gestation. [117] [118] Fetuses can produce serum antibodies, IgM, predominantly in response to intrauterine infection. [119] Preterm infants respond nearly as well as term infants to immunization beginning at 2 months with diphtheria and tetanus toxoids and the acellular pertussis (DTaP), poliovirus, and hepatitis B vaccines. [120] [121] [122] Term infants immunized or infected during the first few days of life usually produce protective antibody responses, although at somewhat lower levels than adults. [123] [124] [125] The presence of fetal bone marrow B-lymphocyte pools similar in size to those of adults and with comparable isotype diversity suggests that their functional deficits may reflect a developing memory repertoire with increased specificity to antigen or the need to generate T lymphocytes capable of producing strong Blymphocyte signals, rather than inherent B-lymphocyte immaturity as a sole factor. Studies of B-lymphocyte activation have revealed much about the complexities of B-lymphocyte signaling [126] and suggest possible mechanisms for deficits of B-lymphocyte function that can be examined in healthy neonates. [127] In contrast to the early development of antibody responses to most protein antigens, responses to thymus (T)independent antigens, such as polysaccharides, develop much later. The basis for this remains unclear. [128] [129] Cord blood B lymphocytes are capable of activation in vitro with T-independent activators. This suggests that signal transduction pathways within the B lymphocyte are normal. [130] However, the mechanism of B-lymphocyte activation by polysaccharides differs from protein antigens in that it involves co-stimulation through a B-lymphocyte surface molecule called CD21 and may be influenced by the expression of yet another B-lymphocyte surface molecule, CD22. [128] Both CD21 and CD22 were noted to be reduced on neonatal B lymphocytes upon stimulation, suggesting a unique role for these molecules in antibody production to polysaccharide antigens. [128] [131] Although the extent to which neonatal deficiencies of neutrophil function, complement, or antibody contribute to the increased risk of infection is unknown, these factors are important in vitro to the opsonophagocytic killing of E. coli, GBS, and Candida species. Thus the combined effect of these deficiencies no doubt contributes to the increased risk of serious infection with these pathogens in this group of children. [108]
T Lymphocytes
T lymphocytes play a central role in the regulation of antigen-specific immune responses, modulating the function of APCs, B lymphocytes, and other T lymphocytes both through contact with receptor binding and secretion of cytokines. [126] T lymphocytes are effector cells of cell-mediated immune response and function as cytotoxic cells (CTLs), able to kill target cells that express foreign antigens. Most mature T lymphocytes (95%) recognize antigen through a TCR. In contrast to B lymphocytes, T lymphocytes can only recognize antigens that are displayed on cell surfaces. These antigens can be derived from pathogens that replicate within the cell, such as viruses or intracellular bacteria, or products internalized from the extracellular space. The reason T lymphocytes can recognize intracellular pathogens is that these infected cells display on its surface fragments/peptides derived from the pathogens' proteins. The molecules responsible for holding these peptides within their groove are the MHC molecules. Two classes of MHC molecules are recognized: class I, which include human leukocyte antigen (HLA)-A, -B, and C, and MHC class II molecules, HLA-DR, -DQ, and -DP. MHC class I are present on all nucleated cells, whereas MCH class II are present on APCs and other specialized cells. Peptide MCH class I complexes (MHC I) present antigen to CTL (CD8 + ). Peptide MHC class II complexes (MHC II) present to helper T lymphocytes (Th1/CD4 + ). Cytosolic peptides derived from vaccinia virus, influenza virus, rabies virus and Listeria are copled to MHC I
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molecules on the surface of the infected cell. These peptide-MCH I complexes can be recognized by cytotoxic CD8 + cells, which then kill the targeted infected cell. Mycobacterium tuberculosis, M. leprae, Leishmania donovani, and Pneumocystis carinii are localized within macrophage vesicles. PeptideMHC II complex as on the infected macrophage result in IL-12 production and subsequent activation of CD4 + cells (Th1). These then produce IFN- which recruits more macrophages, a granuloma is formed, and the activated macrophage kills their intracellular pathogen by releasing the antimicrobial products within its vesicles. Clostridium tetani, Staphylococcus aureus, Streptococcus pneumoniae, polio viruses, Pneumocystis carinii, and Trichinella spiralis require both a humoral and a cellular immune response for effective killing. [16] It is therefore understandable that defects in antigen processing, presentation, and both T- and B-effector functions make the individual susceptible to pathogens that require a particular pathway for clearance (see Section R). Sir Peter Medawar first recognized that antigen presentation in fetal life leads to a form of immunologic tolerance that was different than in adult life. [132] This mechanism was postulated to be due to a state of immunologic naivet of the fetus. However, an alternative hypothesis suggests that perhaps certain adaptive immune responses may be actively suppressed in the developing fetus, mediated by an important population of T lymphocytes called regulatory T lymphocytes. [133] This theory is favored by the fact that that fetuses are capable of generating specific adaptive responses after transplacental spread of infectious agents. [134] [135] [136] HSC progenitors migrate to the thymus where, similar to B lymphocytes, T lymphocytes rearrange their TCR genes by somatic recombination. In contrast to B cell receptors, TCR do not diversify their variable (V) region genes through somatic hypermutation. Also, unlike the B lymphocytes, T lymphocytes must develop into two populations T lymphocytes (the most abundant, 95% of the circulating pool) or T lymphocytes (approximately 5% of the circulating pool). Maturing T lymphocytes move within the thymus in a directed manner from the cortex to the medulla. During this maturational process, T lymphocytes express CD4 and CD8 molecules on their surface (see Figure 10-2 ). The expression of these molecules can further serve to identify their state of maturity. Thus T lymphocytes start as the double-negative (CD4 - /CD8 - ) stage double-positive (CD4 + /CD8 + ) single-positive CD4 + or CD8 + just before being released to the periphery. During maturation in the thymus, T lymphocytes are selected to proceed to the next developmental stage thanks to the interactions of a successfully assembled TCR with self-MHCself-peptide complexes. As in B lymphocytes, RAG1/2 genes and their products are identified during early stages of development and the expression of transcription factors and signaling events drives clonal commitment. [137] [138] [139] [140] The ontogeny of T-lymphocyte immunity in the neonate has been reviewed ( Table 10-4 ). [141] [142] Cord blood has an increased absolute number of T lymphocytes compared with the peripheral blood of older children and adults. The mean T-lymphocyte counts in newborn infants, children, and adults are 3100/mm 3 , 2500/mm 3 , and 1400/mm 3 , respectively. The ratio of CD4 + to CD8 + cells in cord blood is the same as that in adults (1.2), but it is increased to 1.9 from birth through 11 months of life. [143] [144] Although the absolute number of T lymphocytes decreases beyond the neonatal period, the percentage of T lymphocytes among the total lymphocyte population increases. TABLE 10-4 -- Comparison of Newborn and Adult T Lymphocytes Characteristics Newborn Repertoire of TCR-binding specificity Mean T-lymphocyte count CD4 + /CD8 + (ratio) Proliferation (mitogen-stimulated) Proliferation (antigen-stimulated) Unknown 3100/mm 3 1.2 Good Poor
Adult Broad 1400/mm 3 1.2 Good Good Good 48%
Ability to provide help to B lymphocytes Poor CD45RA + (naive CD4 + T lymphocytes) 90% Production of cytokines
Decreased IFN-, IL-4, G-CSF, GM-CSF, IL-3 Multiple
G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocytemacrophage colony-stimulating factor; IFN, interferon-; IL-4, interleukin-4; TCR, T-cell receptor.
Proliferative Responses
Neonatal T lymphocytes proliferate normally in response to phytohemagglutinin and allogenic cell stimulation but have a limited ability to develop immunologic memory. [145] [146] [147] Cord blood cell populations have been shown to contain large numbers of naive T lymphocytes (CD45RA + ) versus memory T lymphocytes (CD45RO + ). [147] [148] This proportion declines slowly to 61% by 7 years of age, as naive lymphocytes are replaced by memory
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lymphocytes, which probably represents an intrinsic maturation of T lymphocytes as a consequence of antigenic stimulation. [140] [149]
Cytokine Production
The predominant naive phenotype of newborn T lymphocytes may further account for differences in cytokine production. Neonatal T lymphocytes produce less INF-, IL-2, IL-4, IL-10, and TNF- than adult T lymphocytes in response to various stimuli. A modest reduction of GM-CSF and decreased G-CSF and IL-3 production and gene expression have also been described. [150] [151] [152] [153] [154] Dysregulation of various immunoregulatory and cytokine genes in cord blood mononuclear cells could explain the apparent immaturity of neonatal cell-mediated immunity. [155] A group of soluble polypeptide mediators, called chemokines, are also important in immune surveillance. Chemokines regulate leukocyte chemotaxis, inflammation, antitumor activity, and HIV infection in humans. Placental cord blood mononuclear cells, in comparison to adult peripheral blood mononuclear cells, produce smaller amounts of the chemokine called RANTES (regulated upon activation, T lymphocyte expressed). Since RANTES is a known ligand for CCR5, it suggests a role of this chemokine in HIV pathogenesis. [156] [157] T lymphocytes influence the functional activity of many other cell types responsible for both natural and specific immunity. Decreased T-lymphocyte function in neonates is likely to increase their susceptibility to infection by many pathogens. For example, decreased T-lymphocyte help in antibody production and isotype switching via CD40L CD40 interaction, [158] along with decreased phagocytic function, probably contribute to increased susceptibility to bacterial infection. Susceptibility to viral infection and other intracellular pathogens, such as Toxoplasma gondii and Listeria, probably results from decreased cytolytic activity of T lymphocytes and decreased IFN-. [150] The specific role of T-lymphocyte immaturity in severe clinical HSV infection in neonates is suggested by the observation that neonates infected with HSV showed decreased antigen-specific cellular responses (decreased proliferation and IFN- production) compared with adults who had primary HSV infection. [159] Finally, NK cell cytotoxicity and ADCC, along with defective chemokine production, may be contributors to perinatally acquired HIV infection. INTERRELATIONSHIPS AND FUTURE Humans resist infection in several ways. The innate defense mechanisms act first and may be capable of eliminating the pathogen completely. If not, adaptive responses are initiated and put in place, releasing clonally expanded effector T and B cells to the sites of infection. The mechanisms that regulate the final clearance are dependent on the pathogen itself. For certain pathogens, an effective adaptive immune response leads to a state of protective immunity. However, many pathogens evolve mechanisms that permit their evasion from an effective immune response. Since Edward Jenner's studies of cowpox 200 years ago, vaccination has become a successful application of our interpretation of nature's experiments. Furthermore, the study of patients with primary immunodeficiency provides not only a better understanding of biologic systems as they relate to humans but potentially leads to therapies not only for these groups of patients but for others as well. References 1. Bonilla FA, Geha RS: Update on primary immunodeficiency diseases. J Allergy Clin Immunol 2006; 117 (suppl.):S435-SS41. 2. Yang D, Chertov SN, Bykovskaia , et al: Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999; 286:525-528. 3. Harder J, Bartels J, Christophers E, et al: A peptide antibiotic from human skin. Nature 1997; 387:861. 4. Frohm M, Agerberth B, Ahangari G, et al: The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J Biol Chem 1997; 272:15258-15263. 5. Gropp R, Frye M, Wagner TO, et al: Epithelial defensins impair adenoviral infection: implication for adenovirusmediated gene therapy. Hum Gene Ther 1999; 10:957-964. 6. Ong PY, Ohtake T, Brandt C, et al: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med 2002; 347:1151-1160. 7. Murakami M, Ohtake T, Dorschner RA, et al: Cathelicidin anti-microbial peptide expression in sweat, an innate defense system for the skin. J Invest Dermatol 2002; 119:1090-1095.
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susceptibility to infection. Rev Infect Dis 1990; 12(Suppl. 4):S410-S420. 154. English BK, Hammond WP, Lewis DB, et al: Decreased granulocyte-macrophage colony-stimulating factor production by human neonatal blood mononuclear cells and T cells. Pediatr Res 1992; 31:211-216. 155. Satwani P, Morris E, van de Ven C, et al: Dysregulation of expression of immunoregulatory and cytokine genes and its association with the immaturity in neonatal phagocytic and cellular immunity. Biol Neonate 2005; 88:214227. 156. Hariharan D, Ho W, Cutilli , et al: C-C chemokine profile of cord blood mononuclear cells: selective defect in RANTES production. Blood 2000; 95:715-718. 157. Dekel B, Rubinstein M, Mazkeret R, et al: Common perinatal insults diminish cord blood RANTES. Biol Neonate 2002; 82:70-72. 158. Han P, McDonald T, Hodge G: Potential immaturity of the T-cell and antigenpresenting cell interaction in cord blood with particular emphasis on the CD40- CD40 ligand costimulatory pathway. Immunology 2004; 113:26-34. 159. Burchett SK, Corey L, Mohan KM, et al: Diminished interferon-gamma and lymphocyte proliferation in neonatal and postpartum primary herpes simplex virus infection. J Infect Dis 1992; 165:813-818. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com

Copyright 2008 Churchill Livingstone, An Imprint of Elsevier CHAPTER 11 Fever and the Inflammatory Response Alexei A. Grom FEVER
Genesis
Fever has been recognized as an important manifestation of childhood infections since ancient times. Fever is often the first symptom noted by parents signaling that their child is ill. Fever is defined as a centrally mediated rise of body temperature above the normal daily variation in response to many different pathologic insults. [1] A variety of microbial products, including endotoxins and exotoxins, are exogenous pyrogens. Although these molecules can act directly to induce fever, evidence indicates that they stimulate host cells to secrete mediators known as endogenous pyrogens. The pivotal endogenous pyrogens are cytokines produced during the inflammatory response, most notably tumor necrosis factor- (TNF-), interleukin-1 (IL-1), IL-6, and, to a lesser degree, the interferons (IFNs). [2] [3] [4] Fever is more likely to be caused by infection, but any inflammatory, neoplastic, immunologic, or traumatic event can also generate fever. Once these pyrogenic cytokines are produced, they enter the systemic circulation and stimulate the rich vascular network surrounding the preoptic area of the hypothalamus (thermoregulatory center). Here they activate phospholipase A2, liberating plasma membrane arachidonic acid as a substrate for the cyclooxygenase pathway. [5] [6] Some cytokines can increase cyclooxygenase expression directly, causing liberation of the arachidonate metabolite prostaglandin (PG) E2. Because this small lipid molecule easily diffuses across the bloodbrain barrier, it is believed by some to be the local mediator that activates thermoregulatory neurons which in turn raise the thermostat set point ( Figure 11-1 ). Although the bloodbrain barrier prevents migration of large proteins such as circulating cytokines, at certain sites the presence of the pyrogenic substances has been demonstrated; these are known as circumventricular organs, and lack a bloodbrain barrier. [6]
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Figure 11-1 Central and peripheral mechanisms of induction of fever. IFN, interferon; IL-1, interleukin-1; PAMPs, pathogen-associated molecular patterns; PG E2, prostaglandin E2; TLRs, Toll-like receptors; TNF-, tumor necrosis factor-.
Subsequently, peripheral mechanisms are activated that stimulate the sympathetic chain and terminal adrenergic efferent nerves leading to vasoconstriction (heat conservation) and muscle contraction (heat production), which generate fever. Additionally, autonomic (decreased sweating) and endocrine (decreased vasopressin secretion to reduce amount of body fluid to be heated) pathways contribute to thermoregulation. [6] Conservation and production of heat continue until the temperature of the blood bathing the hypothalamic neurons matches the new setting. When cytokine stimulation ceases, the hypothalamic set point is revised downward and the processes of heat loss through vasodilatation and sweating are initiated. In addition to these thermoregulatory mechanisms, certain areas in the cerebral cortex are stimulated to promote behavioral changes designed to help control temperature, such as pulling on extra blankets during a shaking chill to save heat or removing clothing to dissipate heat. Fever must be distinguished from hyperthermia, which is an uncontrolled increase in the body temperature. Hyperthermia typically develops when exogenous heat exposure or endogenous heat production exceeds the body's ability to lose heat. This occurs despite a normal hypothalamic set point.
Clinical Aspects
Body temperature varies with age, physical activity, and at various times of the day; it usually fluctuates from values less than 37C in the early morning to values near 38C in the late afternoon. Normal diurnal fluctuation of temperature is also exhibited in febrile patients. In general, values higher than 37.8C are considered to be fever, although single elevations do not always infer a pathologic process. Young infants tend to have blunted fever rises more often than older children do in response to the same antigenic stimulus. In clinical practice, core temperature is measured best by use of a rectal thermometer; oral temperatures can be influenced by prior ingestion of hot or cold foods and are reduced in the presence of open-mouth-breathing in patients with tachypnea. Axillary readings are less reliable and are typically 0.5C lower than oral values and 1C lower than rectal readings. In theory, the tympanic membrane is an ideal site for measuring core body temperature because it is perfused by a tributary artery supplying
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the body's thermoregulatory center. Unfortunately, numerous studies of many different tympanic membrane thermometers have shown that, although convenient, such instruments tend to give highly variable readings that correlate poorly with simultaneously obtained oral or rectal readings. [7] [8]
Antipyretic Therapy
Controversy continues about whether febrile episodes should be treated. [9] Substantial evidence suggests that fever is more beneficial than harmful to the host. High temperatures interfere with the replication and virulence of certain pathogens and may speed the recovery of infected patients. In addition, some immunologic responses (e.g., leukocyte migration and phagocytosis, as well as IFN production) are enhanced by temperature elevation. Moreover, fever is likely to represent a regulatory mechanism to reduce cytokine activation of the acute inflammatory response through a negative biofeedback process. Finally, nonspecific suppression of fever may eliminate an important clue for the need for further diagnostic investigations or for changes in therapy. Short courses of approved doses of standard antipyretic drugs carry a low risk of toxicity, and most of these drugs have analgesic as well as antipyretic properties. Their delivery reduces the intensity of the symptoms of an illness, but it must be remembered that the illness may be prolonged by their administration. An individual approach is suggested to determine which patients should be given antipyretic medications.
Antipyretic Agents
Because fever is generated after local hypothalamic stimulation by PGs, inhibitors of the cyclooxygenase enzyme system are potent antipyretics. Although acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue, this agent is oxidized in the brain, and the resulting compound inhibits cyclooxygenase activity. Aspirin inhibits PG synthetase in a wide variety of tissues, and its antipyretic effect is equivalent to that of acetaminophen. Because these drugs are broad cyclooxygenase inhibitors, they can cause many side effects. The potential association between aspirin therapy in children with influenza or varicella and the development of Reye syndrome precludes its general use in children. Several nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen) have antipyretic effects similar to those of aspirin and acetaminophen. Because these agents are associated with more adverse effects than is acetaminophen, their use for treatment of simple fever is ill advised and should be restricted to those conditions requiring an antiinflammatory agent. Anti-inflammatory effect could have an adverse effect on clinical course of infection. Corticosteroids are among the most potent antipyretic drugs because not only do they inhibit the activity of phospholipase A2, thereby interfering with arachidonic acid metabolism and PG synthesis, but they also block the production of pyrogenic cytokines (i.e., TNF-, IL-1, and IL-6) at a proximal step in the genesis of a febrile response. Although corticosteroids are excellent anti-inflammatory agents, they should not be used for the management of simple febrile episodes and should be used with caution for noninfectious indications in the presence of infection. The use of a cooling blanket or wateralcohol bathing to accelerate peripheral heat losses is advised by some physicians. Both treatments are uncomfortable, and the latter can lead to alcohol toxicity. Peripheral cooling, in the absence of pharmacologic downregulation of the hypothalamic set point, can be counterproductive because cold receptors in the skin send signals to the spinal cord and brain for reactive vasoconstriction and shivering, thus increasing heat conservation, and eliciting oxygen consumption and heat production. THE INFLAMMATORY RESPONSE The body has a system of sentinels that maintain immunologic surveillance to avoid pathogen-induced derangements of homeostasis. Once this background activity is circumvented, a host inflammatory response ensues. The inflammatory response is a complex reaction that involves the migration of elements of the immune system into sites of tissue injury or microbial invasion. [10] In most clinical situations, the inflammatory response, with or without the aid of antimicrobial therapy, is effective in resolving the infection and contributes to tissue remodeling. If the infection is not brought under control, however, the infectious stimulus gains access to the circulation and stimulates the release of a cascade of systemic and local effector molecules. This host reaction, now called the systemic inflammatory response syndrome (SIRS), can be caused by a variety of immunologic, traumatic, surgical, or druginduced insults; most often, however, an infectious agent is the trigger (see Chapter 12 , The Systemic Inflammatory Response Syndrome (SIRS), Sepsis, and Septic Shock).
Innate and Adaptive Immunity
The immune response to infection and cellular injury can be broadly divided into two categories: the innate and adaptive immunity. [11] The immediate response, associated with the production of the pyrogenic cytokines IL-1, IL6, and TNF-, is mounted by the innate immune system that involves neutrophils, monocytes/macrophages, dendritic
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cells, and natural killer (NK) lymphocytes. The main receptors of the innate immune system recognize broad patterns of conserved and often integral structural components of microbes that are not present in or on human cells. These highly conserved microbial structural components are often called pathogen-associated molecular patterns, or PAMPs, while the host receptors are called pattern recognition receptors, or PRRs. The binding of PAMPs to PRRs results in rapid changes in expression of genes, including those encoding pyrogenic cytokines such as IL-1, Il-6, and TNF-. In addition to inflammatory cytokines, many other pathways are activated, including synthesis of degradative enzymes and enzymes responsible for the production of small-molecule mediators of inflammation such as arachidonic acid derivatives ( Figure 11-2 ).
Figure 11-2 Induction of the innate and adaptive immune responses. The recognition of pathogen-associated molecular patterns (PAMPs) by Toll-like receptors (TLR) results in the activation of intracellular signaling pathways leading to the activation of the transcription factor NFkB. The translocation of NFkB into the nucleus leads to upregulation of expression of genes encoding proinflammatory cytokines interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and colony-stimulating factors (CSF). It also leads to increased expression of costimulatory molecules involved in antigen presentation and induction of the adaptive immune responses. The cytokines IL-1, IL-6, TNF, and granulocyte CSF (G-CSF) initiate the inflammatory cascade through their effects on hypothalamus, bone marrow, liver, and vascular endothelial cells. IFN, interferon; MHC, major histocompatibility complex; T-cell receptor (TCR) hemostatic tissue factor, (TF),
The contribution of the adaptive immune system becomes important at later stages of the immune response. The adaptive immune response is mediated by T and B lymphocytes and is characterized by high specificity and longlasting memory. The adaptive immunity is influenced by the generation of helper T-cell subsets (Th) and the subsequent production of effector cytokines by these cells. Thus, naive T lymphocytes that recognize the antigen presented by antigen-presenting cells (APC) undergo activation and expansion. At this stage, they can differentiate into two subsets: Th1 or Th2. [12] Th1 cells secrete IFN- and primarily promote cellular immunity, whereas Th2 cells produce IL-4, IL-5, IL-10, and IL-13 and primarily promote humoral immunity. The predominant pathway of Tlymphocyte differentiation is determined by the cytokine milieu at this step. The IFNs and IL-12 drive Th1 differentiation, whereas IL-4 induces Th2 differentiation. Infection of intracellular pathogens induces primarily a Th1-dominated response that protects against the majority of microorganisms, whereas some parasitic infections induce a Th2 response that is associated with resistance to helminths. In addition to instructive cytokines, APCs use several costimulatory molecules, including CD80 and CD86, to signal T lymphocytes and to induce clonal expansion of antigen-specific T lymphocytes. Antigen presentation in the
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absence of costimulatory molecules leads to cell anergy. Since the engagement of the innate receptors on APC leads to upregulation of expression of the costimulatory molecules and enhances antigen presentation, the interaction between the innate and adaptive immunity at this step becomes very important. [11]
Receptors of the Innate System
The initial recognition of infectious agents by the innate immune system is mediated by the PRRs. The PRRs recognize PAMPs which are shared by large groups of microorganisms but are not present in mammalian cells. [11] Probably the best-known examples of PAMPs are lipopolysaccharides (LPS). LPS are the mixture of fragments of the outer membrane of gram-negative bacteria. LPS administration induces local and systemic inflammation and tissue damage that is very similar to that observed in infection caused by gram-negative bacteria. For this reason, the LPS-induced response has been used as a model of inflammation for several decades. It was only in 1998, however, when the principal component of the human receptor system recognizing LPS was identified as Toll-like receptor 4 (TLR 4). The term is based on structural similarities with the Drosophila protein Toll which is required for the normal development of the flies and protection against Aspergillus species. [13] [14] At least 9 other human TLRs have been identified. Each appears to recognize a distinct set of PAMPs ( Table 11-1 ). It is becoming clear that, collectively, TLRs can detect most, if not all, microbes, [11] [15] [16] including protozoa, bacteria, viruses, and fungi. Some TLRs may also recognize endogenous ligands such as degradation products of various extracellular matrix components released as a result of tissue damage. Such recognition may contribute to the development and perpetuation of inflammation as well. TABLE 11-1 -- Toll-like Receptors (TLR) and their Microbial Ligands TLR Ligand Microbial Source TLR 2 Lipoproteins Peptidoglycan Lipopolysaccharide Zymosan TLR 3 TLR 4 TLR 5 TLR 9 Lipopolysaccharide Flagellin CpG DNA Bacteria Gram-positive bacteria Leptospira Yeast Gram-negative bacteria Bacteria Bacteria, protozoa
Double-stranded RNA Viruses
TLR 7/8 Single-stranded RNA Viruses
TLRs are expressed in different cell types that are important components of the innate immune system, including monocytes/macrophages, dendritic cells, neutrophils, vascular endothelial cells, and epithelial cells lining mucosal surfaces. The binding of microbial molecules to TLRs leads to the activation of intracellular signaling pathways. The predominant pathway used by TLRs leads to the activation of NFkB, a nuclear transcription factor that initiates rapid changes in expression of several groups of genes (see Figure 11-2 ). Most important are those encoding: cytokines and chemokines (including the pyrogenic cytokines TNF-, IL-1, IL-6, as well as IL-8, colonystimulating factors (CSFs), platelet-activating factor (PAF), among others) [17] enzymes involved in the degradation of extracellular matrix proteins enzymes responsible for the production of small-molecule mediators of inflammation such as arachidonic acid derivatives proteins involved in microbial killing mechanisms
The engagement and activation of TLRs expressed on vascular endothelial cells also lead to increased expression of chemokines and adhesion molecules (selectins and integrin ligands). [18] Combined with the simultaneous upregulation of selectin ligands and integrins on leukocytes (also stimulated by TLR engagement), this results in increased adhesion of leukocytes to the vascular endothelium. Once these cells are firmly attached, they begin transmigration across endothelial surfaces (i.e., extravasation) to the sites of microbial invasion and tissue damage. [18] During extravasation, degranulation of polymorphonuclear cells can occur. Such degranulation is associated with the release of several proteolytic enzymes and toxic oxygen radicals that contribute to increased vascular permeability. Further-more, activation of the complement system (classic and alternate pathways) and coagulation cascades (intrinsic and extrinsic pathways) occurs concurrently with cytokine stimulation. Release of the anaphylatoxins C3a and C5a promotes vascular abnormalities and neutrophil activation. The cytokines and chemokines whose production is stimulated by TLR engagement in turn produce multiple effects
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that further amplify the inflammatory response: [17] The cytokines IL-1, TNF-, and IL-6 further stimulate metabolism of arachidonic acid to form leukotrienes, thromboxane A2, and prostaglandins (especially PGE2 and PGI2) IL-1, TNF-, and IL-6 elevate PGE2 synthesis in the vascular and perivascular cells of the hypothalamus, leading to generation of fever [2] [3] [4] Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophils from the bone marrow to replace those consumed by inflammation, often leading to an increase in absolute neutrophil counts IL-1 and TNF- further stimulate endothelial cells to synthesize a number of secondary factors that contribute to the inflammatory process. These include endothelial-cell adhesion molecules, chemokines (IL8, MIP-1a), the hemostatic tissue factor, as well as IL-1, PGI2, and granulocytemacrophage colonystimulating factor (GM-CSF).
The release of the hemostatic tissue factor by endothelial cells and macrophages appears to be pivotal in the activation of the coagulation cascade. In turn, the activation of the coagulation cascade can trigger activation of the complement system. Combined, these pathways can lead to the development of disseminated intravascular coagulation, often seen in SIRS. [19] Platelets are also primed to interact with endothelium and to aggregate in dense masses that interfere with blood supply to tissues. This generalized endothelial cell activation is critical in the pathogenesis of vascular injury and capillary permeability associated with acute inflammation that may progress to shock and multiorgan dysfunction in some patients. [19]
Acute-Phase Response
In response primarily to IL-1 and IL-6, a structurally and functionally heterogeneous group of proteins change their concentration in peripheral blood. These proteins are known as acute-phase response proteins. [1] [20] Some of these are known as positive acute-phase proteins because they increase in concentration after antigenic stimuli. These proteins are mainly synthesized by the liver; the most important examples are C-reactive protein (CRP), serum amyloid A, [1] -acid glycoprotein, [1] -antitrypsin, haptoglobin, ceruloplasmin, and fibrinogen. Some other acutephase proteins are referred to as negative acute-phase proteins (e.g., albumin, prealbumin, retinol-binding protein, transferrin) because their plasma concentrations are reduced. [1] The exact functions of the acute-phase proteins are not completely understood. CRP appears to be a pattern recognition molecule. [21] CRP typically binds to molecular configurations that are either exposed during cell death or found on the surface of certain pathogens such as Streptococcus pneumoniae. Ligand-bound or aggregated CRP efficiently activates the classic complement pathway through a direct interaction with C1q, and stimulates phagocytosis. This raises the possibility that CRP is involved in clearing the cellular debris from necrotic and apoptotic cells, but it may also provide additional protection against certain microbes. The magnitude of acute-phase responses provides a guide to the intensity of the inflammation or the extent of tissue involvement. For instance, the rise in fibrinogen causes erythrocytes to form stacks (rouleaux) that sediment more rapidly than do individual erythrocytes. This is the basis for measuring erythrocyte sedimentation rate as a simple test for the magnitude of systemic inflammatory response regardless of the initiating stimuli. Mineral changes are uniformly present during the acute-phase host response. The best-documented alterations are decreased serum concentrations of iron and zinc caused by the uptake in hepatocytes and phagocytes. Conversely, serum copper levels are elevated as a consequence of increased synthesis of ceruloplasmin, the copper carrier protein. Because of hypoferremia, reduction of red blood cell synthesis, and decreased red blood cell lifespan, mild but reversible anemia usually accompanies a significant acute inflammatory response. Finally, profound alterations in utilization of carbohydrates, proteins, and lipids occur during acute inflammatory responses. [1] [22] [23] The hypermetabolic state typically seen in patients with sepsis requires massive use of carbohydrate and lipid stores to meet energy needs. In addition, amino acids from muscle tissue are used by the liver to produce glucose (gluconeogenesis). These changes are presumably provoked by cytokine-induced production of cortisol, insulin, glucagon, and growth hormone. Clinically, these abnormalities manifest as reactive hyperglycemia, substantial fluctuation in plasma concentrations of free fatty acids, hypertriglyceridemia, and negative nitrogen balance resulting from catabolism of amino acids. Many of these effects are mediated by TNF-.
The Regulatory Anti-Inflammatory Pathways
The overproduction of proinflammatory substances can lead to extensive tissue damage and vascular injury, disseminated intra-vascular coagulation, and shock. To attenuate potential damage to the host, the inflammatory
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cascade involves participation of regulatory anti-inflammatory pathways. Among these modulating pathways are those that involve anti-inflammatory cytokines such as transforming growth factor- (TGF-), IL-4, and IL-10. TGF also has the ability to stimulate production of extracellular matrix proteins and thus contributes to tissue remodeling after the resolution of inflammation. Other examples of anti-inflammatory mechanisms are natural inhibitors of inflammatory cytokines. [24] For instance, many inflammatory cells, including neutrophils and macrophages, have the ability to shed their TNF receptors. These soluble TNF receptors bind free TNF and neutralize its proinflammatory activity. Also, the IL-1 system has unique pathways of negative regulation that involves natural IL1 receptor antagonists and the type II decoy receptor. Interestingly, some anti-inflammatory cytokines (e.g., IL-4, IL10) can simultaneously inhibit the production of IL-1 and stimulate production of receptor antagonists and the decoy receptor. Thus, an intricate network of positive and negative biofeedback loops operates during the course of a systemic inflammatory response and the net balance determines clinical expression and severity of disease.
Integration and Homeostasis
In summary, the immediate inflammatory response to microbial invasion or tissue injury is mainly controlled by the innate immune system. This innate response is triggered by the binding of certain microbial molecules known as PAMPs to the pattern recognition receptors (i.e., TLRs) expressed in host cells. The subsequent intracellular signaling in host cells leads to increased expression of several groups of genes, including those encoding pyrogenic and proinflammatory cytokines TNF-, IL-1, and IL-6. TLR activation also leads to upregulation of expression of the costimulatory molecules involved in antigen presentation (i.e., CD80/CD86). This leads to the enhancement of the adaptive immunity which becomes more important in the later stages of the inflammatory response. Antiinflammatory pathways are activated simultaneously, and the net balance between pro- and anti-inflammatory stimuli determines the magnitude and the outcome of the inflammatory response. Basic mechanisms of the inflammatory response are similar to those described regardless of whether the response is systemic or local. [25] For instance, in bacterial meningitis, local production of cytokines within the subarachnoidal space in response to presence of bacteria, or their cell wall components, induces the disruption of the bloodbrain barrier, increased vascular permeability, and chemotactic attraction of polymorphonuclear cells to the meningeal site of microbial invasion. The effective cooperation between the adaptive and innate immunity eventually leads to the elimination of the invading microbes. The absence of microbial stimulation leads to the cessation of the proinflammatory stimuli and resolution of inflammation. At this stage, several cytokines and growth factors (including TGF-) contribute to the repair of the damaged tissues. This allows the host to return to a relative state of homeostasis until the next microbial challenge. References 1. Saez-Llorens X, Lagrutta FS: The acute phase host reaction during bacterial infection and its clinical impact in children. Pediatr Infect Dis J 1993; 12:83-87. 2. Dinarello CA: The role of cytokines in the pathogenesis of fever. In: Mackowiak P, ed. Fever: Basic Mechanisms and Management, New York: Raven Press; 1991:23. 3. Dinarello CA: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res 2004; 10:201-222. 4. Dinarello CA, Cannon JG, Wolff SM, et al: Tumor necrosis factor is an endogenous pyrogen and induces production of interleukin-1. J Exp Med 1986; 163:1433-1450. 5. Coceani F, Lees J, Bishai I: Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever. Am J Physiol 1988; 254:R463. 6. Saper CB, Breder CD: The neurologic basis of fever. N Engl J Med 1994; 330:1880-1886. 7. Freed GL, Fraley JK: Lack of agreement of tympanic membrane temperature assessments with conventional methods in a private setting. Pediatrics 1992; 89:384. 8. Peterson-Smith A, Barber N, Coody DK, et al: Comparison of aural infrared with traditional rectal temperatures in children from birth to age three years. J Pediatr 1994; 125:83. 9. Greisman LA, Mackowiak PA: Fever: beneficial and detrimental effects of antipyretics. Curr Opin Infect Dis 2002; 15:241-245. 10. Darville T, Giroir B, Jacobs RF: The systemic inflammatory response syndrome (SIRS): immunology and
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potential immunotherapy. Infection 1993; 21:279. 11. Akira S, Takeda K, Kaisho T: Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol 2001; 2:675-680. 12. Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature 1996; 383:787-793. 13. Poltorak A, He X, Smirnova I, et al: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282:2085-2088. 14. Medzhitov R, Preston-Hurlburt P, Janeway CA: A human homologue of the Drosophila Toll protein signals activation of the adaptive immunity. Nature 1997; 388:394-397. 15. Aderem A, Ulevitch RJ: Toll-like receptors in the induction of the innate immune response. Nature 2000; 406:782-787. 16. Beutler B: Inferences, questions and possibilities in Toll-like receptors signaling. Nature 2004; 430:257-263. 17. Movat HZ, Burrowes CE, Cybulsky MI, et al: Acute inflammation and a Shwartzman-like reaction induced by interleukin-1 and tumor necrosis factor. Synergistic action of the cytokines in the induction of inflammation and microvascular injury. Am J Pathol 1987; 129:463-476. 18. Springer TA: Adhesion receptors of the immune system. Nature 1990; 346:425-433. 19. Hezi-Yamit A, Wong PW, Bien-Ly N, et al: Synergistic induction of tissue factor by coagulation factor Xa and TNF. Proc Natl Acad Sci USA 2005; 102:12077-12082. 20. Dinarello CA: Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med 1984; 311:14131418. 21. Black S, Kushner I, Samols D: C-reactive protein. J Biol Chem 2004; 279:48487-48490. 22. Fleck A: Clinical and nutritional aspects of changes in acute-phase proteins during inflammation. Proc Nutr Soc 1989; 48:347-354. 23. Starnes HF, Warren RS, Jeevanandam M, et al: Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest 1988; 82:1321-1325. 24. Mantovani A, Locati M, Vecchi A, et al: Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines. Trends Immunol 2001; 22:328-336. 25. Saez-Llorens X, Ramilo O, Mustafa M, et al: Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications. J Pediatr 1990; 116:671-684. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com
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6.part I.understanding, Controlling and Preventing Infection Diseases

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6.part I.understanding, Controlling and Preventing Infection Diseases

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PART I - Understanding, Controlling, and Preventing Infectious Diseases from Lon...

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

PART I Understanding, Controlling, and Preventing Infectious Diseases

Section A Epidemiology and Control of Infectious Diseases

8% 50% 69% 90%

> 99% 99% 97% 90%

Select study group

DISEASE CONTROL AND PUBLIC HEALTH POLICY

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Major teaching All others Cardiothoracic

4.0 (3.4, 1.77.6) 3.2 (3.1, 0.86.1) 2.7 (1.8, 04.9)

The Infection Control and Prevention Team

Patient resuscitation Patient placement

Respiratory hygiene/cough etiquette [b]

Droplet Per Standard Precautions

Airborne Per Standard Precautions

Per Standard Precautions

Yes. Don before room entry Per Standard Precautions

Per Standard Precautions

Yes. Don before room entry N95 particulate respirator or

Mask patient Cover infectious skin lesions

SARS, severe acute respiratory syndrome; VHF, viral hemorrhagic fever.

Mycobacterium tuberculosis Airborne Precautions if pulmonary infiltrate

Feces (most common), blood (rare)

Routine screening not recommended

Blood, bodily fluids, vaginal secretions, semen

Blood, vaginal secretions, semen

Herpes simplex virus (HSV)

Vesicular fluid, oropharyngeal and vaginal secretions

Primary genital (33 50%) Recurrent genital (12%)

Rubeola (measles) Respiratory secretions, coughing

Prematurity, spontaneous abortion; no congenital syndrome

Respiratory secretion, blood, immunocompromised patients

Fetal hydrops, stillbirth; no congenital syndrome

Treponemia pallidum (syphilis)

Blood, lesion, fluid, amniotic fluid

Varicella-zoster virus [d]

Varicella IgG serology; history 90% correct

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Scabies Pediculosis Ringworm Conjunctiva

3-dose series beginning at birth

Rotavirus Varicella Human papillomavirus

3-dose series beginning at 2 months of age and completed by 32 weeks of age

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Treponemal test (TPPA, MHA-TP, or FTA-ABS) Stool Examination

All All All Not recommended

Nonpathogens Endolimax nana

Poliovirus serotypes 13 neutralizing antibody Poliovirus serotypes 13 neutralizing antibody

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.

Viral hemorrhagic fever, hantavirus

Staphyloccal enterotoxin, ingestion Staphyloccal enterotoxin, inhalation

Agent Alphaviruses (Venezuelan encephalomyelitis, eastern and western equine encephalitis)

Isolation Precautions Comments

Standard; contact for draining skin lesions

TMP-SMX; TMP-SMX may substitute for rifampin with doxycycline

Doxycycline Droplet [c] ; tetracycline [c]

TMP-SMX is alternative to chloramphenicol for meningitis

Doxycycline Standard [c] or tetracycline [c] Standard

Chloramphenicol is an alternative for treatment/prophylaxis

Viral hemorrhagic fevers

NOTIFICATION OF PUBLIC HEALTH AUTHORITIES

Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed.