Varicella among Adults: Data from an Active Surveillance Project,

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1 SUPPLEMENT ARTICLE Varicella among Adults: Data from an Active Surveillance Project, Mona Marin, 1 Tureka L. Watson, 1 Sandra S. Chaves, 1 Rachel Civen, 2 Barbara M. Watson, 3 John X. Zhang, 1 Dana Perella, 3 Laurene Mascola, 2 and Jane F. Seward 1 1 Centers for Disease Control and Prevention, Atlanta, Georgia; 2 Los Angeles County Department of Health, Los Angeles, California; 3 Philadelphia Department of Health, Philadelphia, Pennsylvania We report detailed population-based data on varicella among adults. In 2 US varicella active surveillance sites with high vaccine coverage among young children, the incidence of varicella among adults declined 74% during A low proportion (3%) of adults with varicella had been vaccinated, with no improvement over the decade of program implementation, suggesting that the decline was likely secondary to herd-immunity effects. Compared with children, adults had more severe varicella in terms of both clinical presentation and frequency of complications. However,!30% of adults with varicella were treated with acyclovir. Among adolescents, illness severity was intermediate between that in children and adults. Varicella cases are preventable through vaccination. As we enter the second decade of the varicella vaccination program in the United States, we need to ensure that susceptible adolescents and adults are adequately protected from varicella by vaccination and that those who acquire varicella are appropriately treated with effective antiviral treatment. In the prevaccine era, varicella was primarily considered to be a childhood disease. More than 90% of cases occurred in persons!15 years of age [1]. However, the low proportion of cases in adults resulted in disproportionate morbidity and mortality [2 5]. In the United States, before implementation of the varicella vaccination program in 1995, adults 20 years of age with varicella were 13 times as likely to be hospitalized and 25 times as likely to die, compared with children [2, 3]. Nonetheless, for adults, there are few populationbased reports on age-specific incidence and risks of certain varicella complications [6 9], and there are no published data on clinical features of disease. Potential conflicts of interest: L.M. is on the Merck speakers bureau. B.M.W. received research funding from Merck during , at The Children s Hospital of Philadelphia, and has served on Merck advisory boards during the past 5 years. All other authors report no potential conflicts. Financial support: supplement sponsorship is detailed in the Acknowledgments. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention, US Department of Health and Human Services. Reprints or correspondence: Dr. Mona Marin, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS A-47, Atlanta, GA (mmarin@cdc.gov). The Journal of Infectious Diseases 2008; 197:S by the Infectious Diseases Society of America. All rights reserved /2008/19705S2-0013$15.00 DOI: / Concerns have been raised that the implementation of a childhood vaccination program could result in a shift in the age distribution of varicella cases that would lead to increases in varicella incidence among adults and in overall morbidity [10, 11]. A population-based active surveillance project for varicella provided the opportunity to (1) describe the epidemiology of varicella among adults during the first 11 years of the US varicella vaccination program and (2) characterize the clinical presentation, treatment, and risks of complications for varicella among adults, compared with those among children. METHODS Project description. Data were collected through the Varicella Active Surveillance Project (VASP) during 1 January December 2005 in 2 sites: Antelope Valley, California, and West Philadelphia, Pennsylvania. In 1995, the combined population of the 2 sites was 576,000. Detailed methods for VASP have been described elsewhere [12]. Briefly, varicella cases are reported to the sites from a variety of sources, including preschools, schools, universities, private and public health care providers, emergency departments, hospitals, employers with 1500 employees, correctional fa- S94 JID 2008:197 (Suppl 2) Marin et al.

2 cilities, homeless shelters, and households. Reported cases are investigated by telephone interviews or home visits, and those whose conditions meet the case definition (see below) are enrolled. To capture additional household cases, follow-up calls are made after the initial case investigation. Information collected on each case patient includes demographic characteristics, clinical features of the disease, underlying medical conditions, complications, and treatment. Complications are self-reported as illnesses occurring within 2 weeks of onset of varicella. Medical charts are reviewed for hospitalizations. Definitions. A varicella case is defined as an illness with acute onset of generalized maculopapulovesicular rash without other known cause. Cases in which rash onset occurs 142 days after vaccination are considered to be breakthrough varicella cases. A varicella hospitalization is defined as an admission to an inpatient ward or an emergency department for 18 h within 14 days of rash onset or after 14 days after rash onset if the condition requiring hospitalization was a recognized complication of varicella. Data analysis. We analyzed data by use of SAS (version 9.01; SAS Institute). We present findings for 0 14, 15 19, and 20-year age groups. The youngest age group was examined with and without infants 0 1 year of age; because we found no statistically significant difference, we present these data together for the 0 14 age group. We used population estimates from the US Census Bureau to calculate annual agespecific incidence rates of reported varicella cases per 1000 population. Because the number of breakthrough cases among adults ( n p 10) was insufficient to provide accurate estimates regarding disease characteristics in this population, for the analysis of clinical characteristics and complications we restricted data to unvaccinated persons with varicella, also excluding persons who reported a history of varicella. Disease severity was evaluated using 5 features: fever, number of skin lesions ( severe cases were considered to be those with the highest reported numbers of lesions: 1250 lesions during and 1500 lesions during ), complications, hospitalization, and medical encounter. We calculated 95% confidence intervals (CIs) for rates of complications under the assumption of a Poisson distribution of variables. Results for risk ratios (RRs) are reported with 95% limits for CIs. In the preliminary analysis, we used a multiple logistic regression model to calculate odds ratios (ORs) adjusted for variables that can influence disease severity (preexisting immunocompromising conditions and exposure in the household). Because we found minimal differences between crude ORs and adjusted ORs in the model, we present RRs, which better express the burden of disease. To compare proportions, we used Fisher s exact test. All P values are calculated by use of a 2-sided test. RESULTS Case characteristics and epidemiology. A total of 17,233 varicella cases were reported by the 2 surveillance sites from January 1995 to December Of these, 15,657 (91%) were among children 0 14 years of age, 529 (3%) were among adolescents years of age, and 1047 (6%) were among adults 20 years of age (table 1). The proportion of cases that occurred among males was lower for adults than for children: 41% versus 50% ( P!.0001). Also, compared with children, a higher proportion of adults reported a history of varicella (21% vs. 8%) ( P!.0001), but a lower proportion had been vaccinated (3% vs. 14%) ( P!.0001). The household as source of exposure was more commonly reported by adults than by children (68% vs. 42%) ( P!.0001). During , varicella age-specific incidence rates significantly declined for both children and adults ( P!.0001) (figure 1). Among children 0 14 years of age, the incidence declined by 90%, from cases/1000 population in 1995 to 2.80 cases/1000 population in Among adults 20 years of age, the incidence declined by 74%, from 0.50 to 0.13 cases/ 1000 population. The proportion of adults 20 years of age among all reported varicella cases increased during , from 5% in 1995 to 10% in 2002, with variations between 6% and 12% during ( P!.0001 for the 11-year trend). Table 1. Selected characteristics of reported varicella case patients, by age group, Antelope Valley, California, and West Philadelphia, Pennsylvania, Characteristic 0 14 years years 20 years Reported cases, no. 15, Age, median, years Male 7875 (50) 261 (49) 431 (41) History of varicella 1000 (8) 105 (26) 167 (21) Preexisting immunocompromising conditions 1800 (12) 70 (13) 139 (13) Exposure in the household 5299 (42) 183 (52) 472 (68) Vaccinated 2022 a (14) 24 (5) 30 (3) NOTE. Data are no. (%) of cases for which data were available, unless otherwise indicated. a Data are for children 1 14 years of age. Surveillance for Varicella among Adults JID 2008:197 (Suppl 2) S95

3 Figure 1. Varicella age-specific incidence rates, Antelope Valley, California, and West Philadelphia, Pennsylvania, (logarithmic Y-axis) Information on vaccination status was available for 98% of both children and adults. Among the total varicella cases in children eligible for vaccination (1 14 years of age), the proportion of breakthrough cases increased steadily, beginning in 1998, and reached 61% by 2005 (figure 2). Among adults 20 years of age, the proportion of breakthrough cases varied by year between 0% and 3%, with no increase over time. Overall, disease was more severe in unvaccinated adults than in unvaccinated children (table 2). Adults had a 1.8 and 1.9 times higher risk of having 1250 ( ) or 1500 ( ) skin lesions, respectively; a 2.0 times (95% CI, ) higher risk of developing a complication; and a 6.2 times (95% CI, ) higher risk of being hospitalized. Treatment of varicella with antivirals and administration of antibiotics were significantly more common among adults than among children (RR, 7.5 [95% CI, ] and 1.6 [95% CI, ], respectively). Adults had a 1.6 times (95% CI, ) higher risk than children of consulting a health care provider and a 1.9 Figure 2. Proportion of breakthrough varicella cases, by age group, Antelope Valley, California, and West Philadelphia, Pennsylvania, S96 JID 2008:197 (Suppl 2) Marin et al.

4 Table 2. Comparison of disease presentation in and treatment of unvaccinated varicella case patients, by age group, Antelope Valley, California, and West Philadelphia, Pennsylvania, Characteristic 0 14 years years 20 years RR a (95% CI) Unvaccinated case patients, no. 12, Fever 8240 (66) 261 (67) 622 (75) 1.1 ( ) Duration of fever, median (range), days 2 (1 21) 3 (1 15) 2 (1 14) No. of lesions In b! (37) 20 (20) 62 (27) Reference (45) 52 (52) 85 (37) 1.1 ( ) (18) 28 (28) 81 (36) 1.8 ( ) In ! (36) 58 (24) 126 (25) Reference (54) 142 (60) 279 (56) 1.2 ( ) (10) 38 (16) 94 (19) 1.9 ( ) Complications 1476 (12) 70 (18) 198 (24) 2.0 ( ) Hospitalization 65 (0.5) 7 (1.8) 27 (3.2) 6.2 ( ) Antiviral (acyclovir) use 425 (3) 41 (11) 211 (26) 7.5 ( ) Antibiotic use 949 (8) 36 (9) 98 (12) 1.6 ( ) Health care provider seen or consulted by phone 3711 (38) 135 (48) 385 (60) 1.6 ( ) NOTE. Data are no. (%) of cases for which data were available, unless otherwise indicated. CI, confidence interval; RR, risk ratio. a RR for comparison of presentation among adults 20 years of age vs. children 0 14 years of age. b Data are for Antelope Valley only. times higher risk of visiting the health care provider. Nonspecific general symptoms (including nausea, vomiting, headache, fatigue, dizziness, and appetite loss) were also more prevalent among adults (1 in 17 adult cases vs. 1 in 116 child cases). Fever was slightly more common among adults than among children (RR, 1.1 [95% CI, ]), but the median duration of fever was 2 days regardless of the age group. For all variables examined, adolescents were intermediate between children and adults in terms of disease characteristics and treatment (P!.001 for trend by age for each characteristic in table 2). Complications and hospitalizations. The most commonly reported varicella complications were diarrhea, pharyngitis, skin/soft tissue infections, and otitis media among both adults and children, with no significant differences in the respective rates between the 2 groups (table 3). Dehydration and pneumonia occurred more frequently among adults than children (RR, 5.4 and 10.6 respectively; P!.001 for both) but these were infrequent complications (6 60/10,000 cases). No neurologic complications were reported among adults, whereas 6 neurologic complications were reported among children (4 cases of acute cerebellar ataxia and 2 cases of encephalitis). None of the patients with pneumonia or neurologic complications died or had apparent long-term sequelae. The hospitalization rate among adults 20 years of age was 32.4/1000 reported cases, 16 times higher than among children 0 14 years of age (5.2/1000 cases) ( P!.001). The median length of hospital stay was 3.5 days (range, 1 9 days) for adults and 3 days (range, 0 16 days) for children ( P p.9). For adults, the most common causes of hospitalization were pneumonia (27%), dehydration (15%), and severe nausea and vomiting (12%); for children, they were skin/soft tissue infections (42%), dehydration (11%), and neurologic complications (9%). DISCUSSION In 2 US varicella active surveillance sites where high vaccine coverage has been achieved in young children, the incidence of varicella among adults has declined 75% from 1995 to This decline is likely secondary to protection provided by indirect vaccination (herd immunity) effects in the population. Most adults acquire immunity through natural infection. However, in our study, the extremely low proportion of adults with varicella who were vaccinated suggests that vaccination coverage is very low among susceptible adults [13]. This is concerning, because varicella is more severe among adults than among children, and varicella vaccine is highly effective in preventing the severe consequences of varicella [14]. Reduced opportunities for exposure to children with varicella will increase susceptibility among adolescents and adults unless they are protected through vaccination. Physicians caring for patients in these age groups should routinely screen them for evidence of varicella immunity (history or laboratory evidence of varicella disease, serological evidence of immunity, receipt of 2 doses of varicella vaccine, or birth in the United States before 1980) and Surveillance for Varicella among Adults JID 2008:197 (Suppl 2) S97

5 Table 3. No. and rate of specific complications among unvaccinated varicella case patients, by age group, Antelope Valley, California, and West Philadelphia, Pennsylvania, Complication 0 14 years of age years of age 20 years of age No. Rate (95% CI) b No. Rate (95% CI) b No. Rate (95% CI) b Any complication ( ) ( ) ( ) 2.3 ( ) Skin/soft tissue infection ( ) 3 77 (25 237) ( ) 1.4 ( ) Pneumonia (3 12) (25 133) 10.7 ( ) Acute cerebellar ataxia (1.2 9) 0 0 Other varicella encephalitis (0.4 6) 1 26 ( ) 0 Viral meningitis ( ) 1 12 (1.7 85) Diarrhea ( ) ( ) ( ) 1.1 ( ) Otitis media ( ) (85 375) ( ) 0.8 ( ) Pharyngitis ( ) ( ) ( ) 1.6 ( ) Asthma exacerbation (21 40) 3 77 (25 237) 3 36 (12 112) 1.2 ( ) Dehydration (7 19) (25 144) 5.4 ( ) NOTE. Rates were calculated as the no. of complications per 10,000 varicella cases. CI, confidence interval; RR, risk ratio. a For comparison of complication rates between adults 20 years of age and children 0 14 years of age. b 95% CIs calculated under the assumption of a Poisson distribution of variables. offer vaccine (2 doses administered 4 8 weeks apart) to those without evidence of immunity [15]. Every opportunity in which adolescents and adults access health care should be used for this purpose, including primary health care offices, obstetrician and gynecologist offices, sports clinics, and sexually transmitted disease clinics. In our study, 68% of adults had been exposed in the household. Although preexposure vaccination is the optimal prevention strategy, postexposure vaccination (ideally within 3 days but up to 5 days after exposure) is recommended for healthy persons without evidence of immunity, to prevent or modify disease [16]. To our knowledge, this is the largest population-based series reporting on clinical presentation and treatment of varicella among unvaccinated adults. Our study s findings support previous reports that varicella disease is more severe among adults than among children [6 7, 9, 17]. Additionally, we showed that adolescents had illness severity intermediate between the severity in children and adults. Given this increased severity, it is concerning that only 11% of adolescents and a quarter of adults with varicella were treated with acyclovir, treatment that is routinely recommended for all adolescents and adults with varicella [18 19]. There are limited published data on varicella characteristics and complications among adults with which to compare our data. Our findings of diarrhea, pharyngitis, skin/soft tissue infections, and otitis media as the most common varicella-related complications among both adults and children and of dehydration being a more frequent complication among adults have not, to our knowledge, been previously described. Pneumonia has previously been noted as the most common severe complication of varicella among adults resulting in hospitalizations and physician office visits [4, 7, 9, 20]. Smoking has been RR a postulated as a risk factor for varicella pneumonia [21 23] and may explain, in part, why pneumonia is more common in adults than in children. Pregnancy has also been reported as possible risk factor for varicella pneumonia, but these observations have come mainly from case reports, and findings have not been consistent across studies [21, 24]. Other studies have reported that the highest risk of hospitalization is in adults 120 years of age (6 15 times higher risk, on average, compared with children) [2, 4, 5, 7, 9]. We found an increased risk of hospitalization in the lower end of this range, possibly because our study, being community-based, captured a broader spectrum of disease and not only cases among persons who sought health care. This may also explain the higher rates of complications we found, both overall and for specific complications such as skin/soft tissue infections, compared with previous studies [7, 9]. We did not capture any serious neurologic complication among adults, but the number of adult cases in our study was too small to capture rare events. The estimates for varicellarelated complications among adolescents are based on a small number of cases and are, therefore, unstable. Although the focus of our analysis was to describe the characteristics of varicella disease among adults and compare them with those among children, this study provided the opportunity to describe rarer complications among children!15 years of age. In this age group, we report rates of pneumonia and acute cerebellar ataxia of 5.6 and 3.4/10,000 cases, respectively, which are in the same range as those previously reported [7, 9]. Our estimate for the rate of encephalitis (1.6/10,000 cases) is higher than a previously described estimate (0.3/10,000 cases) [7]. However, both estimates were based on only 1 or 2 encephalitis cases in the population under study. In another article in this supplement, Chaves et al. [25] report a lower rate of pneumonia S98 JID 2008:197 (Suppl 2) Marin et al.

6 and a higher rate of cerebellar ataxia among children 1 14 years of age, but our estimates (which include infants 0 1 year and more years of data) are likely to be more robust, being based on twice the number of cases. A quarter of persons 15 years of age with varicella reported a previous episode of varicella, which would have precluded them from vaccination. Second cases of varicella have been documented to occur in healthy persons, with laboratory confirmation of both first and second episodes in some cases [26, 27]. How commonly a second infection occurs is not well understood. A study from Antelope Valley, California, one of the active varicella surveillance sites, suggested that second infections might be more common than previously thought, with a previous episode of varicella being reported in 4.5% 13.3% of cases [28]. Another explanation for the high percentage of adult cases in which a history of varicella is reported could be erroneous 2nd varicella disease diagnosis or erroneous history of the previous episode. However, a recent community-based study showed that, in the postvaccine era, a history of varicella was highly predictive (99% 100%) of serologic evidence of immunity among persons years of age but not among children [29]. A high predictive value (97% 99%) of a positive varicella history was also documented among adult health care workers in the prevaccine era [30, 31]. Recording the history of varicella in medical records is beneficial to avoid recall bias and misclassification and assess susceptibility. As varicella disease burden decreases, laboratory confirmation of cases will be needed to accurately diagnose the disease. Several limitations need to be considered when interpreting the findings of our study. Data on disease characteristics and complications were self-reported. However, interviews were conducted by trained staff using a standardized case investigation form, which likely reduced self-reporting bias; some complications were physician verified; and hospitalizations were ascertained through chart review. There were some slight recording variations over the years and by site. The high proportion of adult cases secondary to household exposure might be a consequence of active follow-up of cases in households. However, the follow-up was not differential by age. West Philadelphia did not collect information on varicella history from 1995 to Given that only 8% of child cases and 21% of adult cases involved a reported history of varicella and that West Philadelphia data constituted 24% of all reported cases, it is unlikely that this limitation had a significant impact on the findings presented. The new 2-dose varicella vaccination program in children has the potential to further decrease varicella in the community. As we enter the second decade of the varicella vaccination program in the United States, we need to ensure that adolescents and adults without evidence of immunity are adequately protected from varicella by vaccination and that those who acquire varicella are appropriately treated with effective antiviral therapy. Acknowledgments Supplement sponsorship. This article was published as part of a supplement entitled Varicella Vaccine in the United States: A Decade of Prevention and the Way Forward, sponsored by the Research Foundation for Microbial Diseases of Osaka University, GlaxoSmithKline Biologicals, the Sabin Vaccine Institute, the Centers for Disease Control and Prevention, and the March of Dimes. References 1. Wharton M. The epidemiology of varicella-zoster virus infections. Infect Dis Clin North Am 1996; 10: Galil K, Brown C, Lin F, Seward JF. Hospitalizations for varicella in the United States, 1988 to Pediatr Infect Dis J 2002; 21: Meyer PA, Seward JF, Jumaan AO, Wharton M. 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