Melinda Wharton

Intussusception among Infants Given an Oral Rotavirus Vaccine

BACKGROUND Intussusception is a form of intestinal obstruction in which a segment of the bowel prolapses into a more distal segment. Our investigation began on May 27, 1999, after nine cases of infants who had intussusception after receiving the tetravalent rhesus-human reassortant rotavirus vaccine (RRV-TV) were reported to the Vaccine Adverse Event Reporting System. METHODS In 19 states, we assessed the potential association between RRV-TV and intussusception among infants at least 1 but less than 12 months old. Infants hospitalized between November 1, 1998, and June 30, 1999, were identified by systematic reviews of medical and radiologic records. Each infant with intussusception was matched according to age with four healthy control infants who had been born at the same hospital as the infant with intussusception. Information on vaccinations was verified by the provider. RESULTS Data were analyzed for 429 infants with intussusception and 1763 matched controls in a case-control analysis as well as for 432 infants with intussusception in a case-series analysis. Seventy-four of the 429 infants with intussusception (17.2 percent) and 226 of the 1763 controls (12.8 percent) had received RRV-TV (P=0.02). An increased risk of intussusception 3 to 14 days after the first dose of RRV-TV was found in the case-control analysis (adjusted odds ratio, 21.7; 95 percent confidence interval, 9.6 to 48.9). In the case-series analysis, the incidence-rate ratio was 29.4 (95 percent confidence interval, 16.1 to 53.6) for days 3 through 14 after a first dose. There was also an increase in the risk of intussusception after the second dose of the vaccine, but it was smaller than the increase in risk after the first dose. Assuming full implementation of a national program of vaccination with RRV-TV, we estimated that 1 case of intussusception attributable to the vaccine would occur for every 4670 to 9474 infants vaccinated. CONCLUSIONS The strong association between vaccination with RRV-TV and intussusception among otherwise healthy infants supports the existence of a causal relation. Rotavirus vaccines with an improved safety profile are urgently needed.

Changing Epidemiology of Pertussis in the United States: Increasing Reported Incidence Among Adolescents and Adults, 1990-1996

Since 1990, the reported incidence of pertussis has increased in the United States with peaks occurring every 3-4 years. On the basis of analysis of pertussis cases reported to the Centers for Disease Control and Prevention, the incidence remained stable among children aged younger than 5 years, most of whom were protected by vaccination. In contrast to 1990-1993, during 1994-1996, the average incidence among persons aged 5-9 years, 10-19 years, and 20 years or older increased 40%, 106%, and 93%, respectively. Since 1990, 14 states reported pertussis incidences of > or =2 cases per 100,000 population during at least 4 years between 1990 and 1996; seven of these states also reported that a high proportion of cases occurred in persons aged 10 years or older. Analysis of national data on pertussis did not provide sufficient information to fully elucidate the relative importance of multiple possible explanations for the increase in the incidence of pertussis in adolescents and adults. Improvement in diagnosis and reporting of pertussis in this age group, particularly in some states, is an important factor contributing to the overall increase.

Varicella Mortality: Trends before Vaccine Licensure in the United States, 1970–1994

We examined varicella deaths in the United States during the 25 years before vaccine licensure and identified 2262 people who died with varicella as the underlying cause of death. From 1970 to 1994, varicella mortality declined, followed by an increase. Mortality rates were highest among children; however, adult varicella deaths more than doubled in number, proportion, and rate per million population. Despite declining fatality rates, in 1990-1994, adults had a risk 25 times greater and infants had a risk 4 times greater of dying from varicella than did children 1-4 years old, and most people who died of varicella were previously healthy. Varicella deaths are now preventable by vaccine. Investigation and reporting of all varicella deaths in the United States is needed to accurately document deaths due to varicella, to improve prevention efforts, and to evaluate the vaccines impact on mortality.

Serologic Immunity to Diphtheria and Tetanus in the United States

Context Although immunization against diphtheria and tetanus is nearly universal during childhood, immunity wanes as people age. The prevalence of immunity in adults is unknown. Contribution According to the Third National Health and Nutrition Examination Survey (NHANES III), only 60% of the total adult population had serologic protection against diphtheria; 72% were protected against tetanus. By age 70, only 30% of adults had serologic immunity to either disease. Implications Booster immunization every 10 years is important to protect adults against diphtheria and tetanus. The Editors Routine immunization against tetanus and diphtheria has been standard practice in the United States since the late 1940s. To ensure protection against these two diseases, as well as pertussis, the Advisory Committee on Immunization Practices (ACIP) recommends administration of a primary series of diphtheria and tetanus toxoids and acellular pertussis vaccine in the first year of life, followed by doses of these vaccines at 15 to 18 months of age and 4 to 6 years of age. The ACIP then recommends administration of adult-formulation diphtheria and tetanus toxoids beginning at 11 to 12 years of age and every 10 years thereafter (1). Although diphtheria and tetanus occur only rarely in the United States, the recent outbreak of diphtheria in the former Soviet Union is a reminder that even a well-controlled infection can reemerge when population immunity is not maintained (2). In the United States, approximately 95% of children receive three or more doses of diphtheria and tetanus toxoids by 19 to 35 months of age (3), but adherence to the current recommendation for the decennial booster among adults is much lower (4). To document population immunity in the United States, we determined the prevalence of protective antibodies to diphtheria and tetanus by testing serum obtained from participants in the Third National Health and Nutrition Examination Survey (NHANES III). Methods Survey Design and Data Collection The NHANES III was conducted from 1988 to 1994 by the National Center for Health Statistics, U.S. Centers for Disease Control and Prevention. It provided national statistics on the health and nutritional status of the noninstitutionalized civilian U.S. population by conducting household interviews and a standardized physical examination (5). The survey research protocol was reviewed and approved by an institutional review board at the Centers for Disease Control and Prevention. The sampling was based on a complex, stratified, multistage, probability cluster sample design (5) that is representative of the U.S. population. Persons younger than 5 years of age, persons older than 59 years of age, black Americans, and Mexican-Americans were sampled at higher frequencies than were other persons. Race or ethnicity wasdefined by self-report as non-Hispanic white, non-Hispanic black, or Mexican-American. Persons who did not choose one of these categories were classified as other and were analyzed with the total population. The poverty-index ratio was calculated by dividing total family income by the poverty threshold index, adjusted for family size at year of interview. Residence in a county with a population equal to or greater than 1 million was defined as metropolitan residence. Residence in all other counties (including rural areas) was defined as nonmetropolitan. Data on years of education, marital status, occupation, and military service were analyzed for study participants 20 years of age or older. Participants were considered to have access to care if they indicated that they usually visited a particular clinic, health center, or physicians office when they were sick or for routine care. If a participant said that he or she usually saw one particular health professional or physician, he or she was categorized as having access to both a clinic and a physician. Laboratory Methods Serum samples were obtained once when each participant was examined. Diphtheria Antitoxin Antibody levels to diphtheria toxin were determined by a neutralization assay in Vero monkey kidney cells by using a modification of the procedure described by Miyamura and colleagues (6, 7). The serum samples from NHANES were run singly with 20% duplication. Diphtheria antitoxin titers were converted to IU/L after standardization with reference serum specimens provided by the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, by using a standard technique (8). The lowest level of detection for the diphtheria assay was 0.0038 IU/mL, and the upper limit of detection was 5.6 and 8.0 IU/mL on different runs of the assay. An antibody concentration of 0.10 IU/mL or greater was considered a fully protective level (9, 10). Tetanus Antitoxin Tetanus antitoxin was measured by using a solid- phase enzyme immunoassay (Immulon I, Dynatech, Chantilly, Virginia) with a lower limit of detection of 0.001 IU/mL. This method is described in detail elsewhere (11, 12). For all our analyses, protective levels of tetanus antitoxin were defined as greater than 0.15 IU/mL; the rationale for considering this cutoff protective is discussed elsewhere (11, 13). Response Rates All analyses were restricted to persons 6 years of age or older who had sufficient serum specimen for both assays. A total of 30 930 persons 6 years of age or older were selected for the study, and 23 527 (76%) were examined. Of those examined, 18 045 (77%) had a sufficient serum specimen for both tetanus and diphtheria testing. Persons 70 years of age or older had the lowest rates of available serum (69%). No differences by sex were observed, but response rates were lower for non-Hispanic blacks (74%) than for non-Hispanic whites and Mexican-Americans (78%). Careful evaluation using data from the home interview (91.6% completed the interview) detected no systematic selection bias due to nonresponse in the examination data. The results are therefore representative of the U.S. population. Statistical Analysis Prevalence estimates were weighted to represent the total U.S. population and to account for oversampling and nonresponse to the household interview and physical examination (14, 15). Standard errors were calculated by using SUDAAN (Research Triangle Institute, Research Triangle Park, North Carolina) (16), a family of statistical procedures for analysis of data from complex sample surveys. For comparisons between subgroups of NHANES III, data were age-adjusted to the 1980 U.S. population by using the direct method (17). To screen for possible predictors of seropositivity, differences in seroprevalence were evaluated without correction for multiple comparisons by examining the 95% CIs for the seroprevalence values generated by SUDAAN. P values were calculated by using a univariate t-statistic obtained from a general linear contrast procedure in SUDAAN. Results Immunity to Diphtheria Only 60.5% of the sample had protective levels of diphtheria antibody (Table). Mexican-Americans were 5% to 9% less likely than other racial or ethnic groups to have protective levels of antibody. The percentage of men with protective antibody to diphtheria decreased with increasing age, and only 30% of male participants 60 to 69 years of age were protected (Figure 1). Fewer women than men had protective levels of antibody, and the percentage of protected women also decreased with age (Figure 1). Table. Prevalence of Immunity to Diphtheria and Tetanus by Demographic Characteristics, Third National Health and Nutrition Examination Survey, 19881994 Figure 1. Age-specific prevalence of immunity to tetanus and diphtheria by sex, Third National Health and Nutrition Examination Survey, 19881994. When antibody levels were examined by race/ethnicity and age, a similar decrease in the proportion of protected persons was observed among non-Hispanic white persons and black persons until 49 years of age (Figure 2). Among black persons older than 50 years of age, the proportion of those with protective levels of antibody remained stable at approximately 40%. Mexican-Americans had a lower prevalence of protective antibody compared with non-Hispanic white persons and black persons for each 10-year age group from 20 to 49 years of age (P < 0.001). After 59 years of age, white persons had a lower prevalence of protective antibody levels than did non-Hispanic black persons and Mexican-Americans (P < 0.001). Figure 2. Age- and race/ethnicity-specific prevalence of immunity to diphtheria, Third National Health and Nutrition Examination Survey, 19881994. Immunity to Tetanus Seventy-two percent of the sample had protective levels of antibody to tetanus (Table). Mexican-Americans were 8% less likely than white or black persons to have protective levels of antibody (P < 0.001). The disparity between men and women with protective levels of antibody was greater for tetanus than for diphtheria: Seventeen percent more men than women had protective levels of antibody to tetanus (P < 0.001). The proportion of men with protective levels of antibody to tetanus did not decrease by age at the same rate as for diphtheria (Figure 1). At 70 years of age, 45% of men had protective antibody to tetanus. In contrast, the percentage of women with protective levels of tetanus antibody decreased rapidly after 40 years of age. By 70 years of age, only 21% of women had protective levels. As was seen with diphtheria antibody, protective levels of antibody to tetanus differed little by race/ethnicity until after 19 years of age (Figure 3). A smaller percentage (P 0.05) of Mexican-Americans in each 10-year group from 20 to 49 years of age had protective antibody. White persons 50 to 69 years of age were significantly more likely than black persons or Mexican-Americans to have protective levels of tetanus antibody. Figure 3. Age- and race/ethnicity-specific prevalence of immunity to tetanus, Third National Health and Nutrition Examination Survey, 19881994. Demog

Successful control of epidemic diphtheria in the states of the former Union of Soviet Socialist Republics: lessons learned.

Epidemic diphtheria reemerged in the Russian Federation in 1990 and spread to all Newly Independent States (NIS) and Baltic States by the end of 1994. Factors contributing to the epidemic included increased susceptibility of both children and adults, socioeconomic instability, population movement, deteriorating health infrastructure, initial shortages of vaccine, and delays in implementing control measures. In 1995, aggressive control strategies were implemented, and since then, all affected countries have reported decreases of diphtheria; however, continued efforts by national health authorities and international assistance are still needed. The legacy of this epidemic includes a reexamination of the global diphtheria control strategy, new laboratory techniques for diphtheria diagnosis and analysis, and a model for future public health emergencies in the successful collaboration of multiple international partners. The reemergence of diphtheria warns of an immediate threat of other epidemics in the NIS and Baltic States and a longer-term potential for the reemergence of vaccine-preventable diseases elsewhere. Continued investment in improved vaccines, control strategies, training, and laboratory techniques is needed.

Measles Elimination in the United States

In 1962, immediately preceding the licensure of the first measles vaccines in the United States, when measles was a nearly universal disease, Alexander Langmuir described the medical importance of measles to the country and put forth the challenge of measles eradication [1]. Although most patients recovered without permanent sequelae, the high number of cases each year made measles a significant cause of serious morbidity and mortality. Langmuir showed that 190% of Americans were infected with the measles virus by age 15 years [1]. This equated to roughly 1 birth cohort (4 million people) infected with measles each year. Not all cases were reported to the public health system; from 1956 to 1960, an average of 542,000 cases were reported annually. By the late 1950s, even before the introduction of measles vaccine, measles-related deaths and case fatality rates in the United States had decreased markedly, presumably as a result of improvement in health care and nutrition. From 1956 to 1960, an average of 450 measles-related deaths were reported each year (∼1 death/ 1000 reported cases), compared with an average of 5300 measles-related deaths during 1912‐1916 (26 deaths/ 1000 reported cases) [2]. Nevertheless, in the late 1950s, serious complications due to measles remained frequent and costly. As a result of measles virus infections, an average of 150,000 patients had respiratory complications and 4000 patients had encephalitis each year; the latter was associated with a high risk of neurological sequelae and death. These complications and others resulted in an estimated 48,000 persons with measles being hospitalized every year [3].

Preparing for elimination of congenital Rubella syndrome (CRS): summary of a workshop on CRS elimination in the United States.

The goal of eliminating indigenous rubella and congenital rubella syndrome (CRS) in the United States in the near future is now within reach, because rubella incidence has been sustained at record-low levels since the mid-1990s. Effective prevention strategies to eliminate CRS and rubella require improvement in the surveillance of CRS and congenital rubella infection (CRI). The purpose of the workshop was to review rubella and CRS epidemiology, as well as current clinical, diagnostic, and laboratory practices, to determine whether new strategies are needed to achieve and document CRS elimination. Workshop participants agreed that surveillance for CRS must be strengthened, particularly through augmented laboratory capabilities, and the case definition for CRS must be revised to reflect the current scientific information available. Further studies of methods are needed to identify high-risk populations and geographic areas for rubella and CRS and to enhance identification of infants with CRS.

Evidence for Transmission of Pertussis in Schools, Massachusetts, 1996: Epidemiologic Data Supported by Pulsed-Field Gel Electrophoresis Studies

In 1996, 18 of 20 pertussis outbreaks reported in Massachusetts occurred in schools. Pertussis surveillance data were reviewed and a retrospective cohort study was conducted in a high school that experienced an outbreak. Bordetella pertussis isolates from 9 school cases and from 58 cases statewide were examined by use of pulsed-field gel electrophoresis (PFGE). Statewide incidence rates were highest among children aged <1 year, 10-14 years, and 15-19 years (106, 117, and 104 cases per 100,000, respectively). Among 34 confirmed and 20 probable cases at the school, 61% had cough onset within 8 weeks of school opening. Five different PFGE types were identified among the 58 B. pertussis isolates from throughout the state. All 9 isolates from the affected high school were the same PFGE type. School-aged children may play an important role in pertussis epidemics. Consideration should be given to use of acellular pertussis vaccines among school-aged children.

Pertussis outbreak in an elementary school with high vaccination coverage.

BACKGROUND An outbreak of pertussis in a US elementary school with high vaccination coverage was investigated to evaluate vaccine effectiveness and to identify potential contributing factors. METHODS Survey and cohort study of all 215 students of an elementary school (including 36 case patients) and 16 secondary cases among contacts. RESULTS Fifty-two pertussis cases were identified (attack rate among students, 17%). Receipt of <3 doses of pertussis-containing-vaccine compared with receipt of complete vaccination series was a significant risk factor for pertussis [relative risk, 5.1; 95% confidence interval (CI), 3 to 8.6]. The effectiveness of the complete vaccination series was 80% (95% CI 66 to 88). No evidence of waning immunity among students was found. The following contributing factors for the outbreak were identified: multiple introductions of pertussis from the community; delays in identification and treatment of early cases; and high contact rates among students. Antimicrobial treatment initiated >14 days after cough onset was associated with increased risk of further transmission of pertussis (relative risk, 10.1; 95% CI 1.5 to 70.3) compared with treatment within 14 days of onset. CONCLUSIONS This investigation demonstrated the potential for pertussis outbreaks to occur in well-vaccinated elementary school populations. Aggressive efforts to identify cases and contacts and timely antimicrobial treatment can limit spread of pertussis in similar settings. High vaccination coverage should be maintained, because vaccination significantly reduces the risk of the disease throughout the elementary school years, and to ensure timely diagnosis and treatment health care providers should maintain a high index of suspicion for pertussis among elementary school age children.

Myocarditis, Pericarditis, and Dilated Cardiomyopathy after Smallpox Vaccination among Civilians in the United States, January-October 2003

Myocarditis was reported after smallpox vaccination in Europe and Australia, but no association had been reported with the US vaccine. We conducted surveillance to describe and determine the frequency of myocarditis and/or pericarditis (myo/pericarditis) among civilians vaccinated during the US smallpox vaccination program between January and October 2003. We developed surveillance case definitions for myocarditis, pericarditis, and dilated cardiomyopathy after smallpox vaccination. We identified 21 myo/pericarditis cases among 37,901 vaccinees (5.5 per 10,000); 18 (86%) were revacinees, 14 (67%) were women, and the median age was 48 years (range, 25-70 years). The median time from vaccination to onset of symptoms was 11 days (range, 2-42 days). Myo/pericarditis severity was mild, with no fatalities, although 9 patients (43%) were hospitalized. Three additional vaccinees were found to have dilated cardiomyopathy, recognized within 3 months after vaccination. We describe an association between smallpox vaccination, using the US vaccinia strain, and myo/pericarditis among civilians.