Aisha O. Jumaan

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.

Incidence of Herpes Zoster, Before and After Varicella-Vaccination-Associated Decreases in the Incidence of Varicella, 1992–2002

BACKGROUND Varicella zoster virus (VZV) causes varicella and, later in the life of the host, may reactivate to cause herpes zoster (HZ). Because it is hypothesized that exposure to varicella may boost immunity to latent VZV, the vaccination-associated decrease in varicella disease has led some to suggest that the incidence of HZ might increase. We assessed the impact that varicella vaccination has on the incidence of varicella and of HZ. METHODS Codes for cases of varicella and of HZ in an HMO were determined in automated databases of inpatients and outpatients, on the basis of the Ninth Revision of the International Classification of Diseases. We calculated the incidence, during 1992-2002, of varicella and of HZ. RESULTS The incidence of HZ remained stable as the incidence of varicella decreased. Age-adjusted and -specific annual incidence rates of varicella decreased steadily, starting with 1999. The age-adjusted rates decreased from 2.63 cases/1000 person-years during 1995 to 0.92 cases/1000 person-years during 2002; among children 1-4 years old, there was a 75% decrease between 1992-1996 and 2002. Age-adjusted and -specific annual incidence rates of HZ fluctuated slightly over time; the age-adjusted rate was highest, at 4.05 cases/1000 person-years, in 1992, and was 3.71 cases/1000 person-years in 2002. CONCLUSIONS Our findings revealed that the vaccination-associated decrease in varicella disease did not result in an increase in the incidence of HZ. These early findings will have to be confirmed as the incidence of varicella disease continues to decrease.

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.

The incidence of varicella and herpes zoster in Massachusetts as measured by the Behavioral Risk Factor Surveillance System (BRFSS) during a period of increasing varicella vaccine coverage, 1998–2003

BackgroundThe authors sought to monitor the impact of widespread varicella vaccination on the epidemiology of varicella and herpes zoster. While varicella incidence would be expected to decrease, mathematical models predict an initial increase in herpes zoster incidence if re-exposure to varicella protects against reactivation of the varicella zoster virus.MethodsIn 1998–2003, as varicella vaccine uptake increased, incidence of varicella and herpes zoster in Massachusetts was monitored using the random-digit-dial Behavioral Risk Factor Surveillance System.ResultsBetween 1998 and 2003, varicella incidence declined from 16.5/1,000 to 3.5/1,000 (79%) overall with ≥66% decreases for all age groups except adults (27% decrease). Age-standardized estimates of overall herpes zoster occurrence increased from 2.77/1,000 to 5.25/1,000 (90%) in the period 1999–2003, and the trend in both crude and adjusted rates was highly significant (p < 0.001). Annual age-specific rates were somewhat unstable, but all increased, and the trend was significant for the 25–44 year and 65+ year age groups.ConclusionAs varicella vaccine coverage in children increased, the incidence of varicella decreased and the occurrence of herpes zoster increased. If the observed increase in herpes zoster incidence is real, widespread vaccination of children is only one of several possible explanations. Further studies are needed to understand secular trends in herpes zoster before and after use of varicella vaccine in the United States and other countries.

Changing Varicella Epidemiology in Active Surveillance Sites—United States, 1995–2005

Significant reductions in varicella incidence were reported from 1995 to 2000 in the varicella active surveillance sites of Antelope Valley (AV), California, and West Philadelphia (WP), Pennsylvania. We examined incidence rates, median age, and vaccination status of case patients for 1995-2005. Coverage data were from the National Immunization Survey. By 2005, coverage among children 19-35 months of age reached 92% (AV) and 94% (WP); 57% and 64% of case patients in AV and WP, respectively, were vaccinated; and varicella incidence declined by 89.8% in AV and 90.4% in WP. Incidence declined in all age groups, especially among children <10 years of age in both sites and among adolescents 10-14 years of age in WP. In AV, since 2000, the incidence among adolescents 10-14 and 15-19 years of age increased. Implementation of school requirements through 10th grade in WP may explain the differences in the decline in incidence among adolescents. Continued surveillance will be important to monitor the impact that the 2-dose vaccine policy in children has on varicella epidemiology.

One Dose of Varicella Vaccine Does Not Prevent School Outbreaks: Is it Time for a Second Dose?

OBJECTIVES. The implementation of a routine childhood varicella vaccination program in the United States in 1995 has resulted in a dramatic decline in varicella morbidity and mortality. Although disease incidence has decreased, outbreaks of varicella continue to be reported, increasingly in highly vaccinated populations. In 2000, a varicella vaccination requirement was introduced for kindergarten entry in Arkansas. In October 2003, large numbers of varicella cases were reported in a school with high vaccination coverage. We investigated this outbreak to examine transmission patterns of varicella in this highly vaccinated population, to estimate the effectiveness of 1 dose of varicella vaccine, to identify risk factors for vaccine failure, and to implement outbreak control measures. METHODS. A retrospective cohort study involving students attending an elementary school was conducted. A questionnaire was distributed to parents of all of the students in the school to collect varicella disease and vaccination history; parents of varicella case patients were interviewed by telephone. A case of varicella was defined as an acute, generalized, maculopapulovesicular rash without other apparent cause in a student or staff member in the school from September 1 to November 20, 2003. Varicella among vaccinated persons was defined as varicella-like rash that developed >42 days after vaccination. In vaccinated persons, the rash may be atypical, maculopapular with few or no vesicles. Cases were laboratory confirmed by polymerase chain reaction, and genotyping was performed to identify the strain associated with the outbreak. RESULTS. Of the 545 students who attended the school, 88% returned the questionnaire. Overall varicella vaccination coverage was 96%. Forty-nine varicella cases were identified; 43 were vaccinated. Three of 6 specimens tested were positive by polymerase chain reaction. The median age at vaccination of vaccinated students in the school was 18 months, and the median time since vaccination was 59 months. Forty-four cases occurred in the East Wing, where 275 students in grades kindergarten through 2 were located, and vaccination coverage was 99%. In this wing, varicella attack rates among unvaccinated and vaccinated students were 100% and 18%, respectively. Vaccine effectiveness against varicella of any severity was 82% and 97% for moderate/severe varicella. Vaccinated cases were significantly milder compared with unvaccinated cases. Among the case patients in the East Wing, the median age at vaccination was 18.5 and 14 months among non–case patients. Four cases in the West Wing did not result in further transmission in that wing. The Arkansas strains were the same as the common varicella-zoster virus strain circulating in the United States (European varicella-zoster virus strain). CONCLUSIONS. Although disease was mostly mild, the outbreak lasted for ∼2 months, suggesting that varicella in vaccinated persons was contagious and that 99% varicella vaccination coverage was not sufficient to prevent the outbreak. This investigation highlights several challenges related to the prevention and control of varicella outbreaks with the 1-dose varicella vaccination program and the need for further prevention of varicella through improved vaccine-induced immunity with a routine 2-dose vaccination program. The challenges include: 1-dose varicella vaccination not providing sufficient herd immunity levels to prevent outbreaks in school settings where exposure can be intense, the effective transmission of varicella among vaccinated children, and the difficulty in the diagnosis of mild cases in vaccinated persons and early recognition of outbreaks for implementing control measures. The efficacy of 2 doses of varicella vaccine compared with 1 dose was assessed in a trial conducted among healthy children who were followed for 10 years. The efficacy for 2 doses was significantly higher than for 1 dose of varicella vaccine. This higher efficacy translated into a 3.3-fold lower risk of developing varicella >42 days after vaccination in 2- vs 1-dose recipients. Of the children receiving 2 doses, 99% achieved a glycoprotein-based enzyme-linked immunosorbent assay level of ≥5 units (considered a correlate of protection) 6 weeks after vaccination compared with 86% of children who received 1 dose. The 6-week glycoprotein-based enzyme-linked immunosorbent assay level of ≥5 units has been shown to be a good surrogate for protection from natural disease. Ten years after the implementation of the varicella vaccination program, disease incidence has declined dramatically, and vaccination coverage has increased greatly. However, varicella outbreaks continue to occur among vaccinated persons. Although varicella disease among vaccinated persons is mild, they are contagious and able to sustain transmission. As a step toward better control of varicella outbreaks and to reduce the impact on schools and public health officials, in June 2005, the Advisory Committee on Immunization Practices recommended the use of a second dose of varicella vaccine in outbreak settings. Early recognition of outbreaks is important to effectively implement a 2-dose vaccination response and to prevent more cases. Although the current recommendation of providing a second dose of varicella vaccine during an outbreak offers a tool for controlling outbreaks, a routine 2-dose recommendation would be more effective at preventing cases. Based on published data on immunogenicity and efficacy of 2 doses of varicella vaccine, routine 2-dose vaccination will provide improved protection against disease and further reduce morbidity and mortality from varicella.

The incidence and clinical characteristics of herpes zoster among children and adolescents after implementation of varicella vaccination.

Background: The varicella-zoster virus (VZV) vaccine strain may reactivate to cause herpes zoster. Limited data suggest that the risk of herpes zoster in vaccinated children could be lower than in children with naturally acquired varicella. We examine incidence trends, risk and epidemiologic and clinical features of herpes zoster disease among children and adolescents by vaccination status. Methods: Population-based active surveillance was conducted among <20 years old residents in Antelope Valley, California, from 2000 through 2006. Structured telephone interviews collected demographic, varicella vaccination and disease histories, and clinical information. Results: From 2000 to 2006, the incidence of herpes zoster among children <10 years of age declined by 55%, from 42 cases reported in 2000 (74.8/100,000 persons; 95% confidence interval [95% CI]: 55.3–101.2) to 18 reported in 2006 (33.3/100,000; 95% CI: 20.9–52.8; P < 0.001). During the same period, the incidence of herpes zoster among 10- to 19-year-olds increased by 63%, from 35 cases reported in 2000 (59.5/100,000 persons; 95% CI: 42.7–82.9) to 64 reported in 2006 (96.7/100,000; 95% CI: 75.7–123.6; P < 0.02). Among children aged <10 years, those with a history of varicella vaccination had a 4 to 12 times lower risk for developing herpes zoster compared with children with history of varicella disease. Conclusions: Varicella vaccine substantially decreases the risk of herpes zoster among vaccinated children and its widespread use will likely reduce overall herpes zoster burden in the United States. The increase in herpes zoster incidence among 10- to 19-year-olds could not be confidently explained and needs to be confirmed from other data sources.

Impact of Varicella Vaccine on Varicella-Zoster Virus Dynamics

SUMMARY The licensure and recommendation of varicella vaccine in the mid-1990s in the United States have led to dramatic declines in varicella incidence and varicella-related deaths and hospitalizations. Varicella outbreaks remain common and occur increasingly in highly vaccinated populations. Breakthrough varicella in vaccinated individuals is characteristically mild, typically with fewer lesions that frequently do not progress to a vesicular stage. As such, the laboratory diagnosis of varicella has grown increasingly important, particularly in outbreak settings. In this review the impact of varicella vaccine on varicella-zoster virus (VZV) disease, arising complications in the effective diagnosis and monitoring of VZV transmission, and the relative strengths and limitations of currently available laboratory diagnostic techniques are all addressed. Since disease symptoms often resolve in outbreak settings before suitable test specimens can be obtained, the need to develop new diagnostic approaches that rely on alternative patient samples is also discussed.

Vaccine effectiveness during a varicella outbreak among schoolchildren : Utah, 2002-2003

Objectives. In the context of a chickenpox outbreak involving 2 Utah elementary schools, we conducted an investigation to assess vaccine effectiveness, describe illness severity, and examine risk factors for breakthrough varicella (ie, varicella in those who have been vaccinated). Methods. All parents were asked to complete a questionnaire about their child’s medical history. Parents of children with recent varicella were interviewed, and vaccination records were verified. Lesions were submitted for polymerase chain reaction testing. Results. Questionnaires were returned for 558 (93%) of 597 students in school A and 924 (97%) of 952 students in school B. A total of 83 schoolchildren (57 unvaccinated and 26 vaccinated) had varicella during the October 2002 through February 2003 outbreak period. An additional 17 cases occurred among household contacts, including infants and adults. Polymerase chain reaction analysis recovered wild-type varicella. Vaccine effectiveness was 87%. With 1 notable exception, vaccinated children tended to have milder illness. Risk factors for breakthrough varicella included eczema, vaccination ≥5 years before the outbreak, and vaccination at ≤18 months of age. Restricting analysis to children vaccinated ≥5 years before the outbreak, those vaccinated at ≤18 months of age were more likely to develop breakthrough varicella (relative risk: 9.3; 95% confidence interval: 1.3–68.9). Conclusions. The vaccine, administered by >100 health care providers to 571 children during a 7-year time period, was effective. Risk factors for breakthrough varicella suggest some degree of biological interaction between age at vaccination and time since vaccination.

Epidemiology of Varicella Hospitalizations in the United States, 1995–2005

To describe the impact of the varicella vaccination program on varicella-related hospitalizations (VRHs) in the United States, data from the Varicella Active Surveillance Project (VASP) were used to compare rates of hospitalization and rates of complications among patients hospitalized for varicella-related conditions from 1995 to 2005. Of the 26,290 varicella cases reported between 1995 and 2005, 170 cases resulted in VRHs, including 1 case that resulted in death. Both VRH rates per 100,000 population and complications during VRH per 100,000 population decreased significantly between the early vaccination period (1995-1998) and the middle/late vaccination period (1999-2005). Infants and adults were at highest risk for VRH, and having been vaccinated against varicella was a protective factor. Varicella vaccination may have prevented a significant number of VRHs. The fact that 4 vaccinated children required hospitalization for varicella-related complications demonstrates that 1 dose of varicella vaccine does not prevent serious disease in all cases, even among previously healthy children.