Varicella-zoster virus (VZV) causes varicella as a primary infection and, after becoming latent within sensory ganglia, can reactivate and cause herpes zoster (HZ).1,2 The US varicella vaccination program implemented in 1996 had a substantial impact on varicella epidemiology. In Antelope Valley, CA, one of the sites of active varicella surveillance, high one-dose vaccine uptake (81% in 2000 and 95% in 2010) led to declines in varicella incidence of 75% and 98% from 1995 to 2000 and 2010, respectively3,4; the second dose policy implemented in 2007 also contributed to the decline through 2010.3 The median age at varicella increased from 5 years in 2000 to 9 years in 2010 among vaccinated case-patients and from 6 years in 2000 to 16 years in 2010 among unvaccinated case patients.3,5
HZ is more common in older adults but can occur in healthy children and young adults, in whom the disease is usually mild.6,7 A routine varicella vaccination program has the potential to also change the epidemiology of HZ. Like wild-type VZV, vaccine strain VZV also can result in latent infection and reactivation in vaccine recipients.8–10 Data to date for children and adolescents indicate that the rate of vaccine-strain VZV reactivation is substantially lower than that after wild-type VZV infection.10,11 Concerns were raised when varicella vaccination was implemented in the United States regarding the potential for an increase in HZ incidence among persons with a history of varicella after introduction of varicella vaccination. These concerns were based on data suggesting that exposure to varicella boosts VZV immunity and reduces the risk of HZ in persons with latent VZV infection.12,13 The role of external exposures to VZV in modulating the risk for HZ among persons with a history of varicella is still not well understood.14
Using data from a community-based HZ surveillance project among children and adolescents <20 years if age, we reported previously that during 2000 to 2006 the incidence of HZ decreased 55% in children <10 years of age.11 However, among 10- to 19-year olds a 63% increase in incidence was documented. The possible reasons for the increased incidence could not be confidently explained. To assess the risk for HZ over a longer period of time, we extend our earlier analysis to describe HZ incidence among persons <20 years of age using 4 additional years of data since the last publication.
Community-based Surveillance Project
Antelope Valley, part of Los Angeles County, CA, 2010 population ~373,000 with ~118,000 <20 years of age, was one of two active surveillance project sites in the United States that conducted community-based active surveillance for varicella in residents of all ages from 1995 to 20113 and for HZ in residents <20 years of age from 2000 to 2010.11 Detailed methods for this project have been described.4,11 Briefly, every 2 weeks, preschools, schools, hospitals and public and private healthcare providers reported on varicella and HZ, including when no cases were identified. HZ cases were also identified through querying reported varicella case-patients about exposures to HZ. Using a standard questionnaire, research staff interviewed parents/guardians of HZ case patients or patients 18–19 years of age to collect demographic, epidemiologic and clinical data, including information on varicella vaccination. Data from medical charts were collected for confirmation of case status and for case patients who were not available for interview. Varicella vaccination status was confirmed by review of healthcare provider, vaccine registry or school immunization records. History of varicella and age at varicella were collected by interview and validated through chart review when the information was available.
The project was determined by the Institutional Review Boards from the Centers for Disease Control and Prevention and Los Angeles County Department of Public Health to be a nonresearch public health activity.
We defined a case of HZ as a unilateral maculopapular or vesicular rash involving at least one dermatome, diagnosed by a physician in an Antelope Valley resident.
To calculate age-specific incidence of HZ, we used 2006 to 2010 population estimates from the US Census Bureau. Age was categorized by 10-year-age groups (0–9 and 10–19 years) and we report annual age-specific incidence and average rate for 2007 to 2010. To evaluate trends from the beginning of the HZ surveillance period, between 2000 and 2005, we used the incidences reported previously.11 Although the previous study reported incidence through 2006, upon further verification of cases that occurred after publication, one additional case of HZ was confirmed for 2006 for each age group; therefore, we recalculated the incidence for 2006 and the average rate for 2000 to 2006. Poisson regression was used to assess the trend in incidence over time by age group. Incidence rate ratios were used to compare the incidence by race/ethnicity, with White non-Hispanics as the reference group.
We examined the interval between exposure to VZV (either through varicella or through vaccination) and subsequent HZ during 2000 to 2010. We present the results of this analysis for 10- to 19-year olds with a history of varicella; the number of HZ case-patients in other categories, that is, 0- to 9-year olds with a history of varicella, vaccinated 0- to 9-year olds and vaccinated 10- to 19-year olds reported during 2007 to 2010 was small (between 5 and 13 for the 4-year period). We compared the median interval between varicella and subsequent HZ by different study periods using the nonparametric Wilcoxon rank sum test.
Statistical significance was set at 0.05. SAS version 9.3 software (SAS Institute, Cary, NC) was used to analyze the data.
From 2007 to 2010, 383 cases of HZ among persons <20 years of age were reported. Of these, 154 were excluded from the study: 107 (70%) lived outside the surveillance area, 8 (5%) were reporting errors, 8 (5%) did not meet the case definition because they were not physician diagnosed and 31 (20%) had alternative diagnoses (22 herpes simplex virus infection, 5 allergic dermatitis or other skin rashes, 1 localized bacterial infection, 2 ringworm and 1 had scabies). The remaining 229 cases of HZ had case investigations completed.
Of the 229 HZ cases, 29 (13%) were among persons <10 years of age and 200 (87%) were among those aged 10–19 years. During 2007 to 2010, the median age at HZ diagnosis was 15 years (range 1–19 years); 113 (49%) case patients were male. Thirteen (6%) cases were laboratory confirmed. Race/ethnicity was known for 196 (86%) case patients: 73 (37%) reported being White non-Hispanics, 92 (47%) Hispanics, 24 (12%) African Americans, 6 (3%) Asians and 1 (<1%) Other. Of the 209 (91%) case patients with complete clinical information, 205 (98%) reported no immunocompromising conditions.
During 2007 to 2010, of the 29 case patients <10 years of age, 7 (24%) had a history of varicella vaccination only, 5 (17%) reported a history of varicella disease only and 2 (7%) had a history of both disease and vaccine; the remaining had an unknown history of disease and/or vaccine (15, 52%). Of the 200 case-patients aged 10–19 years of age, 13 (7%) had a history of varicella vaccination only, 110 (55%) reported a history of varicella disease only and 18 (9%) had a history of both disease and vaccine; the remaining had either an unknown history of disease and/or vaccine (58, 29%) or denied a history of both (1, <1%).
Time Between Varicella and HZ
During 2007 to 2010, among 110 case patients aged 10–19 years who reported a history of varicella, 95 indicated the age at varicella; the median interval between varicella and subsequent HZ was 13 years (range 5–18 years). During 2000 to 2006, 245 case patients aged 10–19 years reported a history of varicella11 and 232 indicated the age at varicella; the median interval between varicella and subsequent HZ was 10 years (range 2–19 years). The difference in the median interval between the 2 periods was statistically significant (P < 0.001). The increase in the median interval from varicella to subsequent HZ also was statistically significant when analyzed by individual study year (P < 0.001).
During 2007 to 2010, among children <10 years of age annual incidence of HZ continued the decreasing trend observed during 2000 to 2006 (Table 1 and Fig. 1). During 2007 to 2010 the average incidence was 12.8 cases/100,000 children compared with 41.6 cases/100,000 children during 2000 to 2006, a 69% decline (P < 0.0001). If individual calendar years are considered, by 2010 the incidence declined 84% compared with 2000 (11.7 cases/100,000 children vs. 74.8 cases/100,000 children; P < 0.001). For the 10- to 19-year olds, during 2007 to 2010 HZ incidence did not continue the increasing trend reported from 2000 to 2006 (63%); lower rates than in 2006 were observed in 3 of the 4 additional years evaluated. However, during 2007 to 2010 the average incidence was 78.2 cases/100,000 children compared with 68.0 cases/100,000 children during 2000 to 2006, a 13% increase (P = 0.123), with substantial fluctuation in annual rates throughout the 11 years of surveillance. This 13% increase in incidence is similar to the increase obtained if individual calendar years were considered (12%).
Incidence by Race/Ethnicity
During 2000 to 2010, HZ incidence was highest among White non-Hispanics, 58.3 cases/100,000 population (293 cases), followed by Hispanics, 45.4 cases/100,000 population (250 cases) [incidence rate ratio = 0.78, 95% confidence interval: 0.66–0.92, P = 0.004] and African Americans, 35.8 cases/100,000 population (75 cases) (incidence rate ratio = 0.61, 95% CI: 0.48–0.79, P < 0.001).
In this community-based project that assessed trends in HZ incidence among children and adolescents during a period of high one-dose varicella vaccination coverage and low disease circulation,3 we documented through an additional 4 years of data since the last publication11 that the decline identified previously among children <10 years of age was maintained and enhanced. From 2000 to 2010, the incidence of HZ among children <10 years of age declined by 69% to 84%. Among the 10 -to 19-year olds, an increase of 12% to 13% in incidence was found between 2000 and 2010 in this age group. The increases in HZ incidence reported through 2006 among 10- to 19-year olds did not continue further with lower rates being observed in 3 of the 4 additional years analyzed.
The decrease in HZ incidence that we documented among children <10 years of age is significant and robust. Our data are consistent with those of studies that reported a lower risk of HZ among varicella-vaccinated children8,10,11,15,16 and extend over a longer period of time previous reports of a decline in HZ incidence among cohorts targeted for varicella vaccination.11,17 By the end of 2010, children <10 years of age had been born during a period with high varicella vaccination rates and low disease circulation.3 Therefore, their exposure to VZV was increasingly to the vaccine strain and decreasingly to the wild-type with the incidence trend likely reflecting this change. An indirect benefit of low disease circulation is the change in the risk for HZ among children because of increased age at wild-type VZV infection. There is a high risk for childhood HZ among infants and children infected before 18 months of age.18,19 With declining transmission of varicella in the community, the average age at varicella infection has increased and infants and toddlers are less likely to get wild-type VZV infection and therefore to be at risk for childhood HZ from wild-type VZV. In the vaccine era, because of high varicella vaccine coverage more children aged 12–18 months are infected with vaccine strain VZV, which can also result in latent infection and may reactivate, but data reported to date support that HZ risk from vaccine strain is much lower.
Regarding older children and adolescents aged 10–19 years, the increasing HZ incidence that we documented for the years 2000 to 2006 appeared to subsequently plateau. Multiple factors may have increased HZ incidence among these children during the first decade following introduction of varicella vaccination. First, the increase in the interval between varicella and subsequent HZ we report in this article could be one explanation, shifting cases that would have occurred among <10-year olds to older children. Second, several US-based studies have reported secular increases in HZ incidence among young and older adults that started before varicella vaccination was introduced.20–22 Reasons for these increases remain unclear, but they could also have affected older children who, like adults, were infected with wild-type VZV. With either of these two explanations, as the prevalence of wild-type VZV infection declines in these older children and an increasingly larger proportion in this cohort are children and adolescents who had received varicella vaccine and are at a lower risk for HZ, the earlier increases in HZ incidence would plausibly now be reversing.
During our earlier article, we considered two other explanations for the increasing rates of HZ that we observed in older children.11 One was that the quality of HZ surveillance was improving during the earlier years of our surveillance project, ultimately reaching complete ascertainment. While we cannot definitively rule out that explanation, it is not supported by the declines that we noticed among younger children throughout the project. Finally, the possibility persists that children infected by wild-type VZV experienced increasing rates of HZ because they were having fewer opportunities to be exposed to exogenous VZV, leading to reduced immune control of HZ. The case for this hypothesis has weakened as studies have found no acceleration in rates of HZ among adults in the United States since the varicella vaccination was introduced, despite the fact that opportunities for varicella exposure have plummeted20,21; it would seem that the biologic hypothesis itself would be less plausible among older children and adolescents who had only acquired their primary VZV infection relatively recently, and who should have been less prone to waning of VZV-specific immunity than the older adults described in these reports. Moreover, the external boosting hypothesis is not supported by either the plateauing in HZ incidence that we now report among older children and adolescents or the increase in interval between varicella and subsequent HZ.
Our data indicate that the lower risk for HZ among African Americans and Hispanics compared with White non-Hispanics reported among adults20 is also found among children and adolescents. One study examined the racial differences in the risk for HZ among children <12 years of age who received varicella vaccine and also found that the risk for HZ among Black children was lower (40%) than that among White children.23 These findings support the hypothesis of a possible genetic variability in the risk for VZV reactivation.
Our study has several limitations. Because HZ is a rare disease in children and adolescents, small fluctuations in the annual number of cases, completeness of reporting or ascertainment over the 11 years of surveillance could potentially result in important incidence changes. This is particularly important to consider when interpreting the results for the 10–19 age group where fluctuations occurred throughout the study period. We tried to address this limitation by presenting average rates over several years. Nearly all HZ cases were diagnosed clinically without laboratory confirmation; some HZ cases could have been misclassified leading to an increase or decrease in reports, especially because the predictive value of clinical diagnoses is likely to be lower among children in general, and even lower among vaccinated children.10 Age at varicella was mostly self-reported, therefore subject to recall bias.
In summary, we documented that over an 11-year period that included years with high one-dose coverage and low disease circulation enhanced by the adoption of a two-dose varicella vaccination program in 2007, the incidence of HZ among children <10 years of age declined significantly. For children and adolescents aged 10–19 years we found that the increase previously reported through 2006 did not continue further and lower rates were observed during the following years with an even lower rate documented for the last year of the study; a 13% increase in HZ rates was observed between 2000–2006 and 2007–2010. An interesting finding that warrants further confirmation and evaluation of its implications is the increase in the interval between varicella and HZ. The widespread use of varicella vaccine could reduce HZ incidence among the US vaccinated population. Ongoing monitoring of HZ incidence is needed to detect and understand changes in HZ epidemiology as cohorts of children vaccinated against varicella in childhood begin to enter adulthood.
We are indebted to staff at the Antelope Valley surveillance sites for their continued reporting and involvement in the Varicella Active Surveillance Project and staff at Centers for Disease Control and Prevention who oversaw the project over 16 years.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
herpes zoster; varicella vaccine; varicella-zoster virus; impact of varicella vaccination; herpes zoster incidence; active surveillance; race; ethnicity