Incidence of herpes zoster among children and adolescents in a community with moderate varicella vaccination coverage

Transcription

1 Vaccine 21 (2003) Incidence of herpes zoster among children and adolescents in a community with moderate varicella vaccination coverage G.S. Goldman P.O. Box 847, Pearblossom, CA 93553, USA Received 20 February 2003; accepted 4 June 2003 Abstract Active surveillance for herpes zoster (HZ) was conducted for 2 years ( ) in the Antelope Valley community of 312,000 residents among 290 public and private schools, daycares, and healthcare providers. The true ascertainment-adjusted HZ incidence rate is 307 per 100,000 person-years and 138 per 100,000 person-years among children <10 and individuals aged 10 19, respectively. The unadjusted rate among vaccinated children is 9.5 per 100,000 person-years and an estimated 22 per 100,000 vaccine doses. Unvaccinated children with a previous history of varicella may have greater sensitivity to exogenous exposures (boosting) and a poorer cell-mediated response following primary infection relative to older age groups Elsevier Ltd. All rights reserved. Keywords: Herpes zoster; Varicella vaccine; Disease 1. Introduction The varicella vaccine was approved by the Food and Drug Administration (FDA) and licensed for use in the United States in March Although success has been maintained with respect to the prevention of varicella [1 3], questions remain as to how herd immunity and increasing impact of vaccination influence the closely related epidemiology of herpes zoster (HZ) [4]. As early as 1965, Dr. Hope-Simpson, in his qualitative model of the pathogenesis of herpes zoster, included exogenous exposures as a means by which an individual s immunity is boosted to suppress reactivation of herpes zoster [5]. In Japan, vaccine coverage remains sparse and incidence of wild-type (natural) varicella among children remains high after 20 years [6]. Likewise, vaccine trials in the United States were conducted under conditions where the immune response was boosted due to individuals periodic re-exposures to wild-type varicella. Since 1995, aggressive vaccination programs in the United States, including mandates adopted in some states requiring varicella vaccination of children entering school, have resulted in a decline of varicella disease, providing opportunity to investigate whether exogenous exposures contribute heavily to boosting cell-mediated immunity (CMI) to suppress reactivation of HZ. Tel.: ; fax: address: pearblossominc@aol.com (G.S. Goldman). In September 1994, the Los Angeles County Department of Health Services entered into a cooperative agreement with the Centers for Disease Control and Prevention (CDC) to establish an active surveillance site for varicella among the 300,000 residents of the Antelope Valley Health Services District with a racial/ethnic composition as follows: 52% white/non-hispanics, 12% African-Americans, 29% Hispanics, and 7% Asians, American Indians, and others. In January 2000, HZ was added to the active surveillance. This 2-year study of true HZ incidence represents approximately 147,884 person-years of observation time among individuals <20 years of age with a previous history of varicella. It is the first to employ active surveillance of HZ among schools and healthcare providers. Goals of active surveillance are to establish a baseline epidemiological profile of disease incidence in different age groups, monitor varicella vaccine coverage levels, obtain a clinical description of HZ disease among children and adolescents, and detect the impact of increasing levels of vaccination on HZ epidemiology. 2. Methods 2.1. Surveillance methods The Varicella Active Surveillance Project (VASP) collected case reports of HZ from approximately 300 reporting sites in the Antelope Valley population from 1 January X/$ see front matter 2003 Elsevier Ltd. All rights reserved. doi: /s x(03)

2 4244 G.S. Goldman / Vaccine 21 (2003) through 31 December Reporting sites were comprised of nearly 100% of known public and private schools and day care centers with enrollments of 12 or more children; and approximately 90% of public health clinics, hospitals, private practice physicians, and health maintenance organization (HMO) offices. The largest HMO (Kaiser serving an estimated 30% of the study population), as well as dermatologists, convalescent and nursing care homes, and other elderly care facilities in the study area were not included among the HZ surveillance, thus biasing the number of reported cases low. HZ cases were accepted on the basis of a healthcare provider diagnosis. All sites submitted the cases encountered, including name, date of birth, address, telephone number, and race, on a Varicella and Zoster Surveillance Log to the VASP on a biweekly basis. With verbal permission from the parent/guardian, a structured telephone interview was conducted with the caregiver, usually within 4 weeks of the reported case, to collect detailed demographic, clinical, and health impact data on HZ cases aged <20 years. Data from each interview were entered into a computer database designed by project staff which automatically assigned a sequential case identification number. Completeness of reporting was estimated using two-source capture recapture methods. This was achieved by tracking all reporting sites that refer to the same case. A Monthly Varivax Immunization Report was submitted on a monthly basis by all 57 providers currently administering the vaccine. Each report contained the number of doses of vaccine administered by age. With telephone and/or fax message prompting following each reporting period, site compliance in submitting reports to VASP was virtually 100% Statistical methods Ascertainment-corrected HZ incidence rates are computed by applying two-source (schools and healthcare providers) capture recapture methods to the number of reported HZ cases [7 10]. The estimator N of the total HZ cases is given by N = [(b + 1)(c + 1)/(a + 1)] 1, where a is the number of HZ cases reported by both ascertainment sources, and b and c denote the number of HZ cases reported by the school and healthcare provider ascertainment sources, respectively. When a 7, there is 95% confidence that the theoretical bias is negligible; however, this does not account for any bias that might result from source dependencies or heterogeneity of the population within an ascertainment source [11,12]. The distribution of the capture recapture estimate is skewed in practice, so we have employed goodness-of-fit confidence intervals (CI) [7]. The Antelope Valley population estimates are based on the 2000 Census from the US Census Bureau. Currently, in the Antelope Valley, the crude (population) incidence rate is confounded since it is influenced by the proportion of (a) children still susceptible to varicella and hence not candidates for reactivation, (b) vaccinees in which HZ incidence is considerably low (reportedly, 18 per 100,000 person-years [13]) and (c) children with a previous history of wild-type varicella. Therefore, in a community with moderate vaccination coverage, in which 50 60% of children <10 have been vaccinated, it is useful to stratify true HZ incidence rates (i.e. by excluding pre-varicella person-time) among (1) those unimmunized with prior wild-type (natural) varicella experience, and (2) those individuals immunized with varicella (Oka strain) vaccine. Reporting a single crude rate of HZ incidence would not be meaningful for a bimodal distribution and could potentially mask important trends and wide differences in rates among vaccinated and unvaccinated cohorts. Likewise, due to underreporting of HZ cases ascertained via active surveillance, failure to adjust for reporting completeness would yield uninterpretable HZ incidence rates. 3. Results 3.1. Active surveillance The 290 surveillance units that participate in the active surveillance of HZ may be divided into two main ascertainment groups: schools comprised of 76 (26%) preschools/ daycares, and 101 (35%) public and private elementary, middle, and high schools; and healthcare providers comprised of 81 (28%) private practice physicians, 18 (6%) HMO offices, 3 (1%) hospitals, and 11 (4%) public health clinics. Of the 723 cases of HZ reported to VASP during 2000 and 2001, 61 (8.4%) were excluded since they referred to individuals residing outside the surveillance boundaries, 14 (1.9%) were ineligible since they were reported by miscellaneous sites (other than schools or healthcare providers), 9 (1.2%) involved children <10 years old that received varicella vaccination, and 639 (88.4%) were among individuals of all ages with a history of natural varicella. The 639 cases reported in unvaccinated individuals during 2 years have a bimodal distribution (not age-standardized) with approximately 21%, or 134 cases, occurring in children and adolescents <20, and 24%, or 152 cases, occurring in adults >70 (Table 1). The mean age is 48.5 years and the age range of the individuals is <1 96 years. Of the 639 cases of all ages, 501 (78%) indicated race/ethnicity as follows: 366 (73.1%) White, 89 (17.8%) Hispanic, 36 (7.2%) Black, and 10 (2.0%) Asian/American Indian. If we assume annual HZ incidence ranges from 250 to 300 per 100,000 population (typical rates for the US), overall case ascertainment is approximately 32 to 39%. Based on monthly reports collected during 2000 and 2001, summer months of July and August exhibited a combined peak of 127 (20.0%) cases. Other studies have suggested a similar trend [14,15]. Active surveillance ascertained a mean of 27 cases (range 16 36) each month (Table 1). The assumption is rarely correct that active surveillance achieves 100% case ascertainment. Consider that schools

3 G.S. Goldman / Vaccine 21 (2003) Table 1 Unvaccinated cases of HZ reported by schools and healthcare providers by month and age category in the Antelope Valley, 2000 and 2001 Year Month Age category (years) Total cases, n (%) >70 Mean age (years) 2000 January 5 (14) 4 (11) 10 (28) 5 (14) 3 (8) 9 (25) 36 (100) 47.1 February 2 (10) 2 (10) 6 (30) 3 (15) 3 (15) 4 (20) 20 (100) 50.7 March 4 (17) 3 (13) 3 (13) 8 (33) 2 (8) 4 (17) 24 (100) 45.0 April 3 (18) 2 (12) 3 (17) 2 (12) 2 (12) 5 (29) 17 (100) 45.0 May 4 (14) 4 (14) 6 (21) 3 (10) 3 (10) 9 (31) 29 (100) 47.3 June 1 (4) 3 (13) 5 (22) 4 (17) 1 (4) 9 (39) 23 (100) 51.9 July 4 (12) 2 (6) 7 (21) 4 (12) 7 (21) 9 (27) 33 (100) 52.0 August 4 (13) 5 (16) 7 (23) 3 (10) 6 (19) 6 (19) 31 (100) 46.5 September 5 (19) 3 (12) 5 (19) 2 (8) 2 (8) 9 (35) 26 (100) 48.9 October 3 (12) 1 (4) 11 (42) 4 (15) 1 (4) 6 (23) 26 (100) 47.8 November 1 (6) 1 (6) 8 (50) 2 (13) 1 (6) 3 (19) 16 (100) 46.6 December 2 (9) 4 (18) 6 (27) 2 (9) 3 (14) 5 (23) 22 (100) January 0 (0) 1 (5) 8 (42) 2 (11) 2 (11) 6 (32) 19 (100) 55.2 February 2 (7) 3 (10) 10 (33) 5 (17) 3 (10) 7 (23) 30 (100) 47.0 March 3 (12) 0 (0) 8 (32) 2 (8) 3 (12) 9 (36) 25 (100) 55.0 April 6 (21) 2 (7) 5 (18) 4 (14) 5 (18) 6 (21) 28 (100) 44.3 May 1 (3) 3 (10) 4 (13) 6 (19) 5 (16) 12 (39) 31 (100) 58.2 June 2 (6) 4 (11) 11 (32) 7 (20) 6 (17) 5 (14) 35 (100) 46.8 July 2 (6) 8 (25) 10 (31) 6 (19) 2 (6) 4 (13) 32 (100) 40.6 August 3 (10) 2 (7) 5 (17) 10 (35) 2 (7) 7 (24) 29 (100) 51.7 September 1 (4) 3 (11) 10 (37) 7 (26) 1 (4) 5 (19) 27 (100) 48.0 October 2 (7) 4 (14) 6 (21) 6 (21) 4 (14) 6 (21) 28 (100) 48.9 November 2 (9) 2 (9) 10 (44) 3 (13) 3 (13) 3 (13) 23 (100) 44.1 December 3 (10) 3 (10) 8 (28) 4 (14) 7 (24) 4 (14) 29 (100) Total 65 (10) 69 (11) 172 (27) 104 (16) 77 (12) 152 (24) 639 (100) 48.5 reported 54 cases and healthcare providers reported 91 cases of HZ among unvaccinated children and adolescents aged 5 19 years. Of these 145 case reports, 19 were duplicates. While all 54 cases that were reported by schools sought attention from healthcare providers participating in the active surveillance project, only 19 (35%) were reported by healthcare providers. We refine this analysis further by applying capture recapture methods to derive a reporting completeness of 50% (95% CI, 34 65%) among individuals aged 5 19 years. Since parents are encouraged by schools to submit a physician s written notice to excuse or validate the students absence, this positive dependence among school and healthcare provider ascertainment sources yields a capture recapture estimate that serves as a likely lower bound [16]. Consistent with past studies of HZ, we first compute crude and unadjusted incidence rates of HZ in children using a numerator consisting of the actual cases reported during 2 years via active surveillance and a denominator consisting of figures from the 2000 population census. The crude HZ incidence rate is 63 per 100,000 person-years among children <10 (or 74 cases, i.e. 65 HZ cases in unvaccinated plus 9 HZ cases in vaccinated/116,548 person-years) and 57 per 100,000 person-years among those aged years (or 69 cases/120,842 person-years). Since reporting completeness of HZ cases among children 5 19 is 50%, the ascertainment-corrected crude rates are approximately double the unadjusted rates HZ incidence among children and adolescents with a history of natural varicella The age-specific 2000 population census for the Antelope Valley, indicates 58,274 children <10 in the Antelope Valley. To derive true incidence among children with a previous history of varicella, we must deduct those children in this cohort that have been vaccinated as well as those still susceptible to varicella. Deducting 33,918 (58.2%) vaccinated children and considering only the cohort <1, or 4518 (7.8%), remains susceptible, we have remaining an estimated 19,838 (34.0%) with a previous history of varicella. The cumulative (2000 and 2001) ascertainment-adjusted HZ incidence rate is 307 per 100,000 person-years (122/39,676). This incidence rate represents a likely lower bound estimate given (a) the positive dependency of the school and healthcare ascertainment sources, (b) the assumption that only the cohort aged <1 remains susceptible, and (c) the active surveillance sites represent 100% of the available sources for ascertainment of HZ cases serving the entire Antelope Valley population (Table 2). Only by investigating the realistic range of susceptibles in this cohort could we properly eliminate pre-varicella observation time from the denominator of the incidence rate calculation and finally derive an upper bound estimate of true HZ incidence among children <10. Similarly, for individuals 10 19, the population census indicates 60,421 individuals. Deducting an estimated 3296 (5.5%) reported as vaccinated and 3021 (5.0%)

4 4246 G.S. Goldman / Vaccine 21 (2003) estimated as susceptible, we have 54,104 (89.5%) with a previous history of varicella. The cumulative (2000 and 2001) ascertainment-adjusted HZ incidence rate is 138 per 100,000 person-years (149/108,208) among individuals (Table 2) HZ incidence among vaccinated children <5 The crude (or unadjusted) HZ incidence rate among vaccinated healthy children aged <5 years is 11.2/100,000 person-years (4/35,673) and 7.9/100,000 person-years (3/38,208) in 2000 and 2001, respectively, for a cumulative (2000 and 2001) crude incidence rate of approximately 9.5/100,000 person-years (Table 3). Again, active surveil- Table 2 Likely lower bound cumulative ( ) incidence rate estimates of herpes zoster among individuals with a previous history of natural varicella in the Antelope Valley Description Age category (years) < Number of HZ cases reported 65 a 69 a Population census (based on 2000) (100%) (100%) Individuals vaccinated based on b (58.2%) 3296 c (5.5%) doses shipped by manufacturer Estimated individuals 4518 d (7.8%) 3021 e (5.0%) susceptible to VZV Population with a history of (34.0%) (89.5%) natural varicella Observation time (person-years) Unadjusted incidence rate (cases /100,000 person-years) Ascertainment-corrected incidence rate (cases/100,000 person-years) 307 f 138 g a Includes 1 recurrent HZ case. b Total doses reported by providers was 27,134 based on the mean of 23,754 and 30,514 in vaccinated children <10 in the year 2000 and 2001, respectively. This figure is approximately 80% of the total doses reported as shipped by the vaccine manufacturer. A later report by the vaccine manufacturer indicated total doses reported represented 72% of doses shipped. We used the more conservative 80% figure. c This figure is based on the mean of 2530 and 4061 vaccinated individuals in the year 2000 and 2001, respectively. d Based on census population for those individuals <1-year-old (which should not be vaccinated); therefore, the estimated number of susceptibles is biased low since it does not consider susceptible children 1 9 years old. e An adolescent survey conducted among all 13 public middle schools in the Antelope Valley indicated 10% susceptible among 10- and 11-year-olds declining to 7% among 14-year-olds. Based on this trend we estimated 5% as the percentage susceptible among year-olds. f Based on an ascertainment-corrected number of 122 (95% CI, ) HZ cases (a = 11, b = 31, c = 45, completeness 53%) and observation time associated with population with a history of natural varicella. The ascertainment corrected incidence rates were 266 and 339 per 100,000 person-years in 2000 and 2001, respectively. g Based on an ascertainment-corrected number of 149 (95% CI, ) HZ cases (a = 8, b = 24, c = 53, completeness 46%) and observation time associated with population with a history of natural varicella. The ascertainment-corrected incidence rates were 146 and 120 per 100,000 person-years in 2000 and 2001, respectively. lance ascertained approximately 50% of the HZ cases in vaccinees if the true incidence rate is 18.8/100,000 person-years as reported in vaccinated children aged 12 months to 12 years [13]. The crude number of HZ cases per 100,000 vaccine doses administered was 26 in 2000 and 18 in 2001, yielding a cumulative (2000 and 2001) rate of 22 per 100,000 vaccine doses administered (Table 3) Clinical description of HZ in unvaccinated individuals <20 Distribution of the 134 HZ unvaccinated cases by age is given in Fig. 1. All cases were physician diagnosed and 121 (90%) were available for interview. The mean age of interviewed cases was 11 years. Caregivers for 80 (74.1%) of 108 cases that recalled age of varicella, indicated onset of varicella before age 5 years. The average time between varicella and HZ was 8.0 years (mean age of zoster 10.9 years minus mean age of varicella 2.9 years). Of the 134 cases <20 years of age, 124 (93%) indicated race/ethnicity as follows: 86 (64%) White, 29 (22%) Hispanic, 5 (4%) Black, and 4 (3%) Asian/American Indian. There was no significant difference between the distribution by race/ethnicity among reported cases of HZ in individuals <20 and that of the Antelope Valley population for that same age group (χ 2 = 12.6, P<0.10). Pain or paresthesia (burning, itching) was the initial symptom prior to the appearance of the HZ rash in 48 (40%) cases. The majority, 89 (74%) cases, involved thoracic dermatomes, followed by cervical then lumbar [17]. Prescription pain medications were administered to 19 (16%) of the cases and 62 (51%) cases took an antiviral (acyclovir or Zovirax). Residual scarring was reported in 44 (36%) cases. Interviewees cited stress as a possible contributing factor (e.g. death of a household member, parental divorce, school, etc.) prior to HZ occurrence in 43 (36%) cases. Nine cases of HZ were reported in vaccinated children aged less than 10 years with an average interval of 27 months (range 6 53 months) between vaccination and occurrence of HZ. No laboratory test was performed to confirm the diagnosis or to determine the virus strain associated with these cases. Vaccination dates were all confirmed by the healthcare providers administering the vaccine. 4. Discussion In the Antelope Valley, the true cumulative ( ) incidence rate of HZ among children <10 with a history of varicella is approaching that of older adults. This result differs from historical studies. An adolescent survey (unpublished VASP data) conducted in 2000 among 4216 students aged (37% of the public middle school population) in essentially the same Antelope Valley study population indicated that true cumulative ( ) incidence was 145 per 100,000

5 G.S. Goldman / Vaccine 21 (2003) Table 3 Prevalence of vaccinated children <5 in 2000 and 2001 in the Antelope Valley Year Prevalence of vaccinated children in 2000 Prevalence of vaccinated children in 2001 Age of vaccinated children (years) Doses administered Multiplier (no. of years) Observation time (person-years a ) Age of vaccinated children (years) Doses administered Multiplier (no. of years) Totals a Assumes all annual doses were administered at the beginning of the year. Observation time (person-years a ) Number of Cases < Age (years ) at Onset of Herpes Zoster Fig. 1. Age distribution of unvaccinated cases of HZ reported among individuals <20 (n = 134), Antelope Valley, person-years (95% CI, per 100,000 person-years) (18 cases/12,457 person-years) among children <10 with a history of varicella in the prelicensure era. This compares with the true incidence rate of 133 per 100,000 person-years (95% CI, per 100,000 person-years) among children <14 reported by a population-based study conducted in Boston, Massachusetts [18]. Interestingly, these rates are similar to the rate of 138 per 100,000 person-years reported both in the medical practice of Hope-Simpson and the present Antelope Valley study based on active surveillance among individuals aged The similarities between these true incidence rates suggest that despite differences in study methodology, the limitations inherent to these studies may have had no significant effect on true HZ incidence. Given the corroborative studies above serve as surrogates for baseline incidence data in the prelicensure era, the cumulative ( ) true incidence rate of HZ has undergone a conservative two-fold increase (307/100,000 person-years and 147/100,000 person-years) among children <10 in the postlicensure period. In 2001, approximately 60% of the children <10 in the Antelope Valley had received varicella vaccine. This was associated with a 71% decrease in varicella incidence from 1995 to 2000 [1]. It is interesting to speculate that increasing vaccination levels reduced exogenous exposures to wild-type VZV, which in turn could have caused VZV immunity to wane among these children to a level at which VZV was more likely to reactivate, causing HZ. Children appear to have a poorer cell-mediated response following primary infection which predisposes them to early reactivation (as is the case with herpes simplex virus) [19]. Children may also have greater sensitivity to boosting effects from exogenous exposures relative to older age groups. The hypothesis that periodic exposures to wild-type varicella suppresses reactivation of HZ was first introduced in 1965, based on observations of varicella and HZ rates in a medical practice in Cirencester, England [5]. Using the Royal College of General Practitioners (RCGP) data set in England, a notable decrease in zoster incidence was reported in children following a varicella epidemic in the winter of 1980 [20]. Japanese pediatricians in their 50s and 60s who were re-exposed to VZV demonstrated HZ incidence rates 1/2 to 1/8 that of the general population [21]. In 1983, Arvin et al. noted a boost in CMI in 71% of adults who were exposed to varicella patients in the family [22]. In a more recent study of HZ in physicians, pediatricians (who have a greater incidence of exposure to VZV) were reported to have lower rates of HZ than psychiatrists (who had the lowest VZV exposure rates) [23]. Finally, in 2002, epidemiological evidence in England and Wales demonstrated higher incidence of HZ among adults living with children compared to those living without children [24] and similarly, in a case-control study in South London, UK, it was suggested that re-exposure to VZV via contact with children seems to protect latently infected individuals against zoster [25]. Interestingly, the cumulative (2000 and 2001) ascertainment-adjusted HZ incidence rate of 138 per 100,000 personyears among individuals aged years determined

6 4248 G.S. Goldman / Vaccine 21 (2003) via active surveillance is the same as that reported by Hope-Simpson in the same age group in the pre-licensure era [5]. This may indicate that CMI to VZV has not as yet declined substantially to cause increased HZ reactivation in this cohort. However, only recently during the past 2 3 years (beginning in 1999) did this cohort experience a dramatic decline in frequency of re-exposures to wild-type varicella [1]. Thus, this cohort is more likely to have already had boosts to immunity because of prior re-exposure. Relative to the HZ incidence rate in the prelicensure era, the higher rate in the post-licensure period among children <10 with a history of natural varicella will become less of an issue as vaccinated children enter this age group; however, there is concern that HZ incidence will increase among adults who are subject to increased morbidity and mortality of disease due to waning of immune containment [26,27]. Increases in reactivation among adults due to reduction in exogenous exposures is implied by vaccine trials in which recipients demonstrate boosting of CMI to VZV [26]. Since the VASP relies on epidemiologic methods, it may not successfully control for confounding and bias in the analysis of true incidence of HZ by age. Factors such as increasing HMO enrollments, easier access to healthcare in general, increasing enrollments of children in daycares and preschools (causing exposures to varicella at younger ages), and greater diagnostic awareness of HZ (due to active surveillance) may all contribute to HZ incidence rates that are higher in the Antelope Valley compared to rates reported in historical studies. Additionally, increases in school-related stress and expanding use of immunosuppressive modalities may account, in part, for higher incidence rates of HZ in this study compared to studies conducted prior to the widespread development of these trends. A limitation in this study, as in all previous studies of HZ incidence as well as in trials of antiviral drugs, is that HZ disease was not laboratory confirmed; however, the expected low rate among vaccinated children serves as a control indicating cases of HZ are not generally being misdiagnosed. We postulate that due to the evidence that asymptomatic reactivations occur more frequently in OKA-strain VZV compared to wild-type VZV [28], the HZ incidence rate among vaccinees is not as sensitive to decreased exogenous boosting as is the wild-type virus. Thus, the HZ incidence rate among vaccinees in the postlicensure period has thus far been unaffected by the fact that incidence of wild-type varicella is no longer high in the community. The poor reporting of HZ cases by healthcare providers under active surveillance highlights the importance of having another source (schools) for case ascertainment and demonstrates why application of capture recapture methods are critical for incidence estimation [8,9]. The largest HMO in the study population (Kaiser) did not participate in the bimonthly reporting of HZ cases to the VASP. Based on a computer search of medical records for cases of HZ over a 6-month-period from January through June 2002, it is estimated that this HMO would have contributed some 60 cases among individuals <20 and 400 cases in adults during the 2-year study period. These additional cases suggest the estimated reporting completeness of HZ cases is reasonable and the capture recapture assumptions of source independence and homogeneity of the source populations are plausible. Physicians and healthcare providers are encouraged to report any suspected adverse events that occur after varicella vaccination to the Vaccine Adverse Events Reporting System (VAERS) established by the US. Department of Health and Human Services. However, since immunized individuals are not the same ones that experience the deleterious effects (in terms of increased incidence of HZ), VAERS is unsuitable for reporting such adverse events concerning interaction of varicella and HZ epidemiology. Furthermore, there is no legal precedent requiring a vaccine manufacturer to perform studies on individuals that have not been immunized with their product. Thus, postmarketing surveillance for such deleterious effects remains an important tool in assessing varicella vaccine safety. This study highlights the importance of continued HZ monitoring. The results of this study will serve as a useful baseline for further studies of HZ in the Antelope Valley. It may also encourage other investigators to examine HZ rates on a longitudinal basis, not only among vaccine recipients, but also among those who have not received vaccine [29]. If a clear vaccine-associated increase in HZ is demonstrated by longitudinal data and is confirmed in further studies in broader populations, this should be considered by public health authorities in evaluating vaccine use strategies. Acknowledgements We wish to thank the healthcare providers, school nurses, child care center directors, and other professionals and members of the Antelope Valley community who reported cases of HZ in 2000 and The Varicella Active Surveillance Project under the Los Angeles County Department of Health Services (LACDHS), Acute Communicable Disease Control unit, is supported by a grant provided by the Centers for Disease Control and Prevention (CDC, Atlanta Georgia). References [1] Seward JF, Watson BM, Peterson CL, et al. Varicella disease after introduction of varicella vaccine in the United States, JAMA 2002;287(5): [2] Wise RP, Salive ME, Braun MM, et al. Postlicensure safety surveillance for varicella vaccine. JAMA 2000;284(10): [3] Vazquez M, LaRussa PS, Gershon AA, Steinberg SP, Freudigman K, Shapiro ED. The effectiveness of the varicella vaccine in clinical practice. N Engl J Med 2001;344: [4] Spingarn RW, Benjamin JA. Universal vaccination against varicella. N Engl J Med 1998 March (Letter);338(10):683. [5] Hope-Simpson RE. The nature of herpes zoster: a long-term study and a new hypothesis. Proc R Soc Med 1965;58:9 20. [6] Asano Y. Varicella vaccine: the Japanese experience. J Infect Dis 1996;174(Suppl 3):S310 3.

7 G.S. Goldman / Vaccine 21 (2003) [7] Regal RR, Hook EB. Goodness-of-fit based confidence intervals for estimates of the size of a closed population. Stat Med 1984;3: [8] Hook EB, Regal RR. The value of capture recapture methods even for apparent exhaustive surveys: the need for adjustment for source of ascertainment intersection in attempted complete prevalence studies. Am J Epidemiol 1992;135: [9] McCarty DJ, Tull ES, Moy CS, Kwoh CK, LaPorte RE. Ascertainment corrected rates: applications of capture recapture methods. Int J Epidemiol 1993;22: [10] Hook EB, Regal RR. Effect of variation in probability of ascertainment by sources ( variable catchability ) upon capture recapture estimates of prevalence. Am J Epidemiol 1993;137: [11] Seber GAF. Closed population: single mark release. In: The estimation of animal abundance and related parameters. London, England: Charles Griffin & Company Limited; 1973, Chapter 3. p [12] Robson DS, Regier HA. Sample size in Petersen mark recapture experiments. Trans Am Fish Soc 1964;93(3): [13] Vaccination and Immunization Education: a teleconference series. Strategic Institute for Continuing Health Care Education. Strategic Implications International; p. 45. [14] Glynn C, Crockford G, Gavaghan D, Cardno P, Price D, Miller J. Epidemiology of shingles. J R Soc Med 1990;83: [15] Hellgren L, Hersle K. Statistical and clinical study of herpes zoster. Geront Clin 1966;8:70 6. [16] Hook EB, Regal RR. Capture recapture methods (Letter). Lancet 1992;339:742. [17] Guess HA, Broughton DD, Melton LJ, Kurland LT. Epidemiology of herpes zoster in children and adolescents: a population-based study. Pediatrics 1985;76: [18] Donahue JG, Choo PW, Manson JE, Platt R. The incidence of Herpes Zoster. Arch Intern Med 1995;155: [19] Miller E, Marshall R, Vurdien J. Epidemiology, outcome and control of varicella-zoster infection. Rev Med Microbiol 1993;4: [20] Joseph CA, Noah ND. Epidemiology of chickenpox in England and Wales, Br Med J 1988;296: [21] Terada K, Hirago U, Kawano S, Kataoka N. Incidence of herpes zoster in pediatricians and history of reexposure to varicella-zoster virus in patients with herpes zoster. Kansenshogaku Zasshi 1995;69(8): [22] Arvin A, Korpchak C, Wittek A. Immunologic evidence of reinfection with varicella-zoster virus. J Infect Dis 1983;148: [23] Solmon BA, Kaporis AG, Glass AT, Simon SI, Baldwin HE. Lasting immunity to varicella in doctors study (L.I.V.I.D. study). Am Acad Dermatol 1998;38: [24] Brisson M, Gay NJ, Edmunds WJ, Andrews NJ. Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine 2002;20(19 20): [25] Thomas SL, Wheeler JG, Hall AJ. Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. The Lancet, 2 July 2002; com/extras/01art6088web.pdf. [26] Levin MJ, Muray M, Zerbe GO, White CJ, Hayward AR. Immune responses of elderly persons 4 years after receiving a live attenuated varicella vaccine. J Infect Dis 1994;170: [27] Straus SE, Ostrove JM, Inchauspe G. Varicella-zoster virus infections: biology, natural history, treatment, and prevention. Ann Intern Med 1988;108: [28] Krause PR, Klinman DM. Varicella vaccination: evidence for frequent reactivation of the vaccine strain in healthy children. Nat Med 2000;6(4): [29] Krause PR, Klinman DM. Efficacy, immunogenicity, safety, and use of live attenuated chickenpox vaccine. J Pediatr 1995;127: