Stephanie R. Bialek

Examination of Links Between Herpes Zoster Incidence and Childhood Varicella Vaccination

BACKGROUND Introduction of a universal varicella vaccine program for U.S. children in 1996 sparked concern that less-frequent exposure to varicella would decrease external boosting of immunity to varicella zoster virus and thereby increase incidence of herpes zoster (HZ). OBJECTIVE To determine whether the varicella vaccination program has influenced trends in HZ incidence in the U.S. population older than 65 years. DESIGN Retrospective study of Medicare claims. SETTING Medicare, 1992 through 2010. PARTICIPANTS 2 848 765 beneficiaries older than 65 years. MEASUREMENTS Annual HZ incidence from 1992 through 2010; rate ratios (RRs) for HZ incidence by age, sex, and race or ethnicity; and state-level varicella vaccination coverage. RESULTS 281 317 incident cases of HZ occurred. Age- and sex-standardized HZ incidence increased 39% from 10.0 per 1000 person-years in 1992 to 13.9 per 1000 person-years in 2010 with no evidence of a statistically significant change in the rate of increase after introduction of the varicella vaccination program. Before introduction of this program, HZ incidence was higher in women (RR, 1.21 [95% CI, 1.19 to 1.24]) than men and was lower in black persons (RR, 0.51 [CI, 0.48 to 0.53]) and Hispanic persons (RR, 0.76 [CI, 0.72 to 0.81]) than white persons. In a model adjusted for sex, age, and calendar year from 1997 to 2010, HZ incidence did not vary by state varicella vaccination coverage (RR, 0.9998 [CI, 0.9993 to 1.0003]). LIMITATION Uncertain level and consistency of health-seeking behavior and access and uncertain accuracy of disease coding. CONCLUSION Age-specific HZ incidence increased in the U.S. population older than 65 years even before implementation of the childhood varicella vaccination program. Introduction and widespread use of the vaccine did not seem to affect this increase. This information is reassuring for countries considering universal varicella vaccination. PRIMARY FUNDING SOURCE None.

Impact of a Routine Two-Dose Varicella Vaccination Program on Varicella Epidemiology

OBJECTIVE: One-dose varicella vaccination for children was introduced in the United States in 1995. In 2006, a second dose was recommended to further decrease varicella disease and outbreaks. We describe the impact of the 2-dose vaccination program on varicella incidence, severity, and outbreaks in 2 varicella active surveillance areas. METHODS: We examined varicella incidence rates and disease characteristics in Antelope Valley (AV), CA, and West Philadelphia, PA, and varicella outbreak characteristics in AV during 1995–2010. RESULTS: In 2010, varicella incidence was 0.3 cases per 1000 population in AV and 0.1 cases per 1000 population in West Philadelphia: 76% and 67% declines, respectively, since 2006 and 98% declines in both sites since 1995; incidence declined in all age groups during 2006–2010. From 2006–2010, 61.7% of case patients in both surveillance areas had been vaccinated with 1 dose of varicella vaccine and 7.5% with 2 doses. Most vaccinated case patients had <50 lesions with no statistically significant differences among 1- and 2-dose cases (62.8% and 70.3%, respectively). Varicella-related hospitalizations during 2006–2010 declined >40% compared with 2002–2005 and >85% compared with 1995–1998. Twelve varicella outbreaks occurred in AV during 2007–2010, compared with 47 during 2003–2006 and 236 during 1995–1998 (P < .01). CONCLUSIONS: Varicella incidence, hospitalizations, and outbreaks in 2 active surveillance areas declined substantially during the first 5 years of the 2-dose varicella vaccination program. Declines in incidence across all ages, including infants who are not eligible for varicella vaccination, and adults, in whom vaccination levels are low, provide evidence of the benefit of high levels of immunity in the population.

Fatal varicella due to the vaccine-strain varicella-zoster virus

We describe a death in a 15-mo-old girl who developed a varicella-like rash 20 d after varicella vaccination that lasted for 2 mo despite acyclovir treatment. The rash was confirmed to be due to vaccine-strain varicella-zoster virus (VZV). This is the first case of fatal varicella due to vaccine-strain VZV reported from the United States. The patient developed severe respiratory complications that worsened with each new crop of varicella lesions; vaccine-strain VZV was detected in the bronchial lavage specimen. Sepsis and multi-organ failure led to death. The patient did not have a previously diagnosed primary immune deficiency, but her failure to thrive and repeated hospitalizations early in life (starting at 5 mo) for presumed infections and respiratory compromise treated with corticosteroids were suggestive of a primary or acquired immune deficiency. Providers should monitor for adverse reactions after varicella vaccination. If severe adverse events develop, acyclovir should be administered as soon as possible. The possibility of acyclovir resistance and use of foscarnet should be considered if lesions do not improve after 10 d of treatment (or if they become atypical [e.g., verrucous]). Experience with use of varicella vaccine indicates that the vaccine has an excellent safety profile and that serious adverse events are very rare and mostly described in immunocompromised patients. The benefit of vaccination in preventing severe disease and mortality outweigh the low risk of severe events occurring after vaccination.

Transmission of Varicella Zoster Virus From Individuals With Herpes Zoster or Varicella in School and Day Care Settings

BACKGROUND Because the varicella incidence has declined following varicella vaccine licensure, herpes zoster (HZ) cases may play a larger role in varicella zoster virus (VZV) transmission. We investigated how HZ and varicella cases contribute to the varicella incidence in schools and day care centers. METHODS Surveillance data collected in Philadelphia during September 2003-June 2010 were analyzed. A varicella case was considered to be sporadic if it was reported from a school or day care facility >6 weeks after or ≥10 days before other reports of VZV transmission. A varicella case was considered to be secondary if it occurred 10-21 days after report of a case of HZ or sporadic varicella. Analysis compared VZV transmission from individuals with HZ or sporadic varicella, stratified by varicella vaccination status and disease severity. RESULTS Of 290 HZ cases reported, 27 (9%) resulted in 84 secondary varicella cases. Of 1358 sporadic varicella cases reported, 205 (15%) resulted in 564 secondary varicella cases. Approximately half of the HZ and sporadic varicella cases resulted in single secondary cases. The proportion of individuals who had secondary cases with mild disease was similar for those exposed to HZ and those exposed to varicella (70% and 72%, respectively). VZV transmission was highest from unvaccinated individuals with sporadic varicella (P < .01). CONCLUSIONS VZV transmission from individuals with HZ contributes to varicella morbidity. More research is needed to understand risk factors and guide recommendations for preventing VZV transmission from individuals with HZ.

Challenges in confirming a varicella outbreak in the two-dose vaccine era

BACKGROUND A second dose of varicella vaccine was recommended for U.S. children in 2006. We investigated a suspected varicella outbreak in School District X, Texas to determine 2-dose varicella vaccine effectiveness (VE). METHODS A varicella case was defined as an illness with maculopapulovesicular rash without other explanation with onset during April 1-June 10, 2011, in a School District X student. We conducted a retrospective cohort in the two schools with the majority of cases. Lesion, saliva, and environmental specimens were collected for varicella-zoster virus (VZV) PCR testing. VE was calculated using historic attack rates among unvaccinated. RESULTS In School District X, 82 varicella cases were reported, including 60 from Schools A and B. All cases were mild, with a median of 14 lesions. All 10 clinical specimens and 58 environmental samples tested negative for VZV. Two-dose varicella vaccination coverage was 66.4% in Schools A and B. Varicella VE in affected classrooms was 80.9% (95% CI: 67.2-88.9) among 1-dose vaccinees and 94.7% (95% CI: 89.2-97.4) among 2-dose vaccinees in School A, with a second dose incremental VE of 72.1% (95% CI: 39.0-87.3). Varicella VE among School B students did not differ significantly by dose (80.1% vs. 84.2% among 1-dose and 2-dose vaccinees, respectively). CONCLUSION Laboratory testing could not confirm varicella as the etiology of this outbreak; clinical and epidemiologic data suggests varicella as the likely cause. Better diagnostics are needed for diagnosis of varicella in vaccinated individuals so that appropriate outbreak control measures can be implemented.

Herpes zoster vaccine effectiveness and manifestations of herpes zoster and associated pain by vaccination status

Options for managing herpes zoster (HZ)-related pain and complications have limited effectiveness, making HZ prevention through vaccination an important strategy. Limited data are available on HZ vaccine effectiveness against confirmed HZ and manifestations of HZ among vaccinated persons. We conducted a matched case-control study to assess HZ vaccine effectiveness for prevention of HZ and other HZ-related outcomes and a cohort study of persons with HZ to compare HZ-related outcomes by vaccination status. Cases were identified through active surveillance among persons age ≥60 years with HZ onset and health-care encounters during 2010-2011 in Southeastern Minnesota. Controls were age- and sex-matched to cases. Data were collected by medical record review and from participants via interviews and daily pain diaries. 266 HZ case-patients and 362 matched controls were enrolled in the vaccine effectiveness studies and 303 case-patients in the cohort study of HZ characteristics by vaccination status. Vaccination was associated with 54% (95% CI:32%-69%) reduction in HZ incidence, 58% (95% CI:31%-75%) reduction in HZ prodromal symptoms, and 70% (95% CI:33%-87%) reduction in medically-attended prodrome. HZ vaccine was statistically significant effective at preventing postherpetic neuralgia (PHN) measured at 30 d after rash onset, 61% (95% CI: 22%-80%). Among persons who developed HZ, no differences were found by vaccination status in severity or duration of HZ pain after rash onset. In this population-based study, HZ vaccination was associated with >50% reduction in HZ, HZ prodrome, and medically-attended prodrome.

Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection

The prevalence, characteristics, and risk of sensorineural hearing loss are assessed in children with asymptomatic congenital cytomegalovirus infection identified through hospital-based newborn screening managed through 18 years of age. OBJECTIVES: To assess the prevalence, characteristics, and risk of sensorineural hearing loss (SNHL) in children with congenital cytomegalovirus infection identified through hospital-based newborn screening who were asymptomatic at birth compared with uninfected children. METHODS: We included 92 case-patients and 51 controls assessed by using auditory brainstem response and behavioral audiometry. We used Kaplan–Meier survival analysis to estimate the prevalence of SNHL, defined as ≥25 dB hearing level at any frequency and Cox proportional hazards regression analyses to compare SNHL risk between groups. RESULTS: At age 18 years, SNHL prevalence was 25% (95% confidence interval [CI]: 17%–36%) among case-patients and 8% (95% CI: 3%–22%) in controls (hazard ratio [HR]: 4.0; 95% CI: 1.2–14.5; P = .02). Among children without SNHL by age 5 years, the risk of delayed-onset SNHL was not significantly greater for case-patients than for controls (HR: 1.6; 95% CI: 0.4–6.1; P = .5). Among case-patients, the risk of delayed-onset SNHL was significantly greater among those with unilateral congenital/early-onset hearing loss than those without (HR: 6.9; 95% CI: 2.5–19.1; P < .01). The prevalence of severe to profound bilateral SNHL among case-patients was 2% (95% CI: 1%–9%). CONCLUSIONS: Delayed-onset and progression of SNHL among children with asymptomatic congenital cytomegalovirus infection continued to occur throughout adolescence. However, the risk of developing SNHL after age 5 years among case-patients was not different than in uninfected children. Overall, 2% of case-patients developed SNHL that was severe enough for them to be candidates for cochlear implantation.

Modeling the potential impact of vaccination on the epidemiology of congenital cytomegalovirus infection.

BACKGROUND Understanding the potential for vaccination to change cytomegalovirus (CMV) epidemiology is important for developing CMV vaccines and designing clinical trials. METHODS We constructed a deterministic, age-specific and time-dependent mathematical model of pathogen transmission, parameterized using CMV seroprevalence from the United States and Brazil, to predict the impact of vaccination on congenital CMV infection. FINDINGS Concurrent vaccination of young children and adolescents would result in the greatest reductions in congenital CMV infections in populations with moderate and high baseline maternal seroprevalence. Such a vaccination strategy, assuming 70% vaccine efficacy, 90% coverage and 5-year duration of protection, could ultimately prevent 30-50% of congenital CMV infections. At equilibrium, this strategy could result in a 30% reduction in congenital CMV infections due to primary maternal infection in the United States but a 3% increase in Brazil. The potential for an increase in congenital CMV infections due to primary maternal infections in Brazil was not predicted with use of a vaccine that confers protection for greater than 5 years. INTERPRETATION Modeling suggests that vaccination strategies that include young children will result in greater declines in congenital CMV infection than those restricted to adolescents or women of reproductive age. Our study highlights the critical need for better understanding of the relative contribution of type of maternal infection to congenital CMV infection and disease, the main focus of vaccine prevention.

Herpes Zoster-Related Deaths in the United States: Validity of Death Certificates and Mortality Rates 1979–2007

BACKGROUND Herpes zoster (HZ) vaccine was recommended in the United States to reduce HZ-associated morbidity. Vaccination may reduce HZ-associated mortality, but no strategy exists to monitor mortality trends. METHODS We validated HZ coding on death certificates from California, using hospital records as the gold standard, and applied the results to national-level data to estimate HZ mortality. RESULTS In the validation phase of the study, among 40 available hospital records listing HZ as the underlying cause of death, HZ was the underlying cause for 21 (52.5%) and a contributing cause for 5 (12.5%). Among the 21 hospital records listing HZ as the underlying cause of death, the median age of decedents was 84 years (range, 50-99); 60% had no contraindications for HZ vaccination. Of the 37 available records listing HZ as a contributing cause of death, HZ was a contributing cause for 2 (5.4%) and the underlying cause for 6 (16.2%). Nationally, in the 7 years preceding the HZ vaccination program, the average annual number of deaths in which HZ was reported as the underlying cause of death was 149; however, based on our validation study, we estimate the true number was 78 (range, 31-118). CONCLUSIONS National death certificate data greatly overestimate deaths in which HZ is the underlying or contributing cause of death. The HZ vaccination program could prevent some HZ-related deaths, but the impact will be difficult to assess using national mortality data.

Risk Factors for Herpes Zoster Among Adults.

Background. The causes of varicella-zoster virus reactivation and herpes zoster (HZ) are largely unknown. We assessed potential risk factors for HZ, the data for which cannot be obtained from the medical sector. Methods. We conducted a matched case-control study. We established active surveillance in Olmsted County, Minnesota to identify HZ occurring among persons age ≥50 years during 2010–2011. Cases were confirmed by medical record review. Herpes zoster-free controls were age- and sex-matched to cases. Risk factor data were obtained by telephone interview. Results. We enrolled 389 HZ case patients and 511 matched controls; the median age was 65 and 66 years, respectively. Herpes zoster was associated with family history of HZ (adjusted odds ratio [aOR] = 1.65); association was highest with first-degree or multiple relatives (aOR = 1.87 and 3.08, respectively). Herpes zoster was also associated with prior HZ episodes (aOR = 1.82), sleep disturbance (aOR = 2.52), depression (aOR = 3.81), and recent weight loss (aOR = 1.95). Stress was a risk factor for HZ (aOR = 2.80), whereas a dose-response relationship was not noted. All associations indicated were statistically significant (P < .05). Herpes zoster was not associated with trauma, smoking, tonsillectomy, diet, or reported exposure to pesticides or herbicides (P > .1). Conclusions. We identified several important risk factors for HZ; however, the key attributable causes of HZ remain unknown.