Incidence of Herpes Zoster AmongChildren: 2003–2014Sheila Weinmann, PhD,a Allison L. Naleway, PhD,a Padma Koppolu, MPH,a Roger Baxter, MD,b† Edward A. Belongia, MD,c

Simon J. Hambidge, MD, PhD,d Stephanie A. Irving, MHS,a Michael L. Jackson, PhD,e Nicola P. Klein, MD, PhD,b Bruno Lewin, MD,f

Elizabeth Liles, MD,a Mona Marin, MD,g Ning Smith, PhD,a Eric Weintraub, MPH,g Colleen Chun, MDh

abstractBACKGROUND AND OBJECTIVES: After the 1996 introduction of routine varicella vaccination in theUnited States, most studies evaluating pediatric herpes zoster (HZ) incidence reported lowerincidence over time, with varying degrees of decline. Using the combined databases of 6integrated health care organizations, we examined HZ incidence in children over a 12-yearperiod in the varicella vaccine era.

METHODS: This study included children aged 0 through 17 years from 2003 through 2014. Usingelectronic medical records, we identified HZ cases through International Classification ofDiseases, Ninth Revision diagnosis code 053. We calculated HZ incidence rates per 100 000person years of health plan membership for all children and among children who werevaccinated versus unvaccinated. We calculated rates for the 12-year period and examinedtemporal trends. Among children who were vaccinated, we compared HZ rates by month andyear of age at vaccination.

RESULTS: The study included 6 372 067 children with $1 month of health plan membership. Forthe 12-year period, the crude HZ incidence rate for all subjects was 74 per 100 000 personyears, and the rate among children who were vaccinated was 38 per 100 000 person years,which was 78% lower than that among children who were unvaccinated (170 per 100 000person years; P , .0001). Overall HZ incidence declined by 72% (P , .0001) from 2003through 2014. Annual rates in children who were vaccinated were consistently lower than inchildren who were unvaccinated.

CONCLUSIONS:With this population-based study, we confirm the decline in pediatric HZ incidenceand the significantly lower incidence among children who are vaccinated, reinforcing thebenefit of routine varicella vaccination to prevent pediatric HZ.

WHAT’S KNOWN ON THIS SUBJECT: Herpes zoster (HZ)is caused by wild-type or vaccine-strain varicellazoster virus. In previous studies, authors evaluatedtrends in pediatric HZ incidence since the varicellavaccination program began in 1996; most have shownlower incidences with varying degrees of decline.

WHAT THIS STUDY ADDS: In this study involving 6million children, children vaccinated against varicellahad a 78% lower HZ incidence than children who wereunvaccinated, and the overall HZ incidence ratedeclined 72%. Two-dose vaccine recipients had lowerHZ incidence than 1-dose recipients.

To cite: Weinmann S, Naleway AL, Koppolu P, et al. Incidenceof Herpes Zoster Among Children: 2003–2014. Pediatrics.2019;144(1):e20182917

aCenter for Health Research, Kaiser Permanente Northwest, Portland, Oregon; bVaccine Study Center, KaiserPermanente Northern California, Oakland, California; cMarshfield Clinic Research Institute, Marshfield, Wisconsin;dDenver Health, Denver, Colorado; eKaiser Permanente Washington, Seattle, Washington; fKaiser PermanenteSouthern California, Pasadena, California; gCenters for Disease Control and Prevention, Atlanta, Georgia; andhDivision of Pediatric Infectious Diseases (Emeritus), Department of Pediatrics, Northwest Permanente, Portland,Oregon

Drs Weinmann and Chun conceptualized and designed the study, drafted the initial manuscript, andreviewed and revised the manuscript; Ms Koppolu and Dr Smith provided substantial contributionsto analysis and interpretation of the data and critically revised the manuscript for intellectualcontent; Drs Baxter, Belongia, Hambidge, Jackson, Klein, Lewin, Liles, Marin, and Naleway, Ms Irving,and Mr Weintraub provided substantial contributions to the design of the study and interpretationof the data and critically revised the manuscript for intellectual content; and all authors approvedthe final manuscript as submitted and agree to be accountable for all aspects of the work.†Deceased.

DOI: https://doi.org/10.1542/peds.2018-2917

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In 1996, the Advisory Committee onImmunization Practices (ACIP)recommended routine administrationof the varicella vaccine to children inthe United States aged 12 through18 months. In 2007, the ACIPrecommended the first varicellavaccine dose at ages 12 through15 months with a second dose at ages4 through 6 years. Similar towild-type varicella zoster virus (VZV)infection, a vaccine-strain virus mayestablish a latent infection that canreactivate, causing herpes zoster(HZ).1–6 HZ from wild-type orvaccine-strain VZV can occur inchildren after varicella vaccination.

In a 2013 study at Kaiser PermanenteNorthwest (KPNW)7 involvingchildren ,18 years of age withlaboratory-confirmed HZ, wereported that children who werevaccinated had a 79% lowerincidence of HZ than children whowere unvaccinated (48 vs 230 per100 000 person years). However,among children aged 1 and 2 years,incidence was significantly higheramong children who were vaccinated(100 per 100 000 vs 10 per 100 000person years; P = .01). Given theseresults, we considered it importantto examine, in a larger pediatricpopulation, HZ incidence overall andin subgroups.

Using the databases of 6 integratedhealth care organizations containingthe health information of almost6.4 million children, we characterizedthe annual incidence of HZ amongchildren aged 0 through 17 yearsfrom 2003 through 2014 by varicellavaccination status, age at HZdiagnosis, immunosuppressed status,sex, and other factors.

METHODS

This study included children,18 years of age at any time fromJanuary 1, 2003, to December31, 2014, who were members of1 of the health care organizationsparticipating in the Centers for

Disease Control and Prevention–sponsored Vaccine Safety Datalink:the Kaiser Permanente regions ofNorthwest, Northern California,Southern California, Colorado, andWashington and the Marshfield Clinicin Wisconsin.8 All sites’ institutionalreview boards approved the studyprotocol.

We identified cases of HZ using theInternational Classification ofDiseases, Ninth Revision (ICD-9)diagnosis code 053 in outpatient,inpatient, and emergencydepartment visits and claims fromoutside providers. We includedthose for whom there was no HZdiagnosis within the previous6 months (and a 6-month period in2002 for calculation of 2003 rates).We validated this ICD-9 code inearlier studies at KPNW, findinga positive predictive value of 96.8%among 0- to 17-year-olds.9 We didnot include children whose only HZ-related ICD-9 codes were 053.12(postherpetic trigeminal neuralgia)or 053.13 (postherpeticpolyneuropathy) because these maynot represent incident cases.Children vaccinated #4 days beforetheir first birthday were consideredvaccinated 12-month-olds inaccordance with ACIP guidelines.10

Varicella vaccination status wasobtained from electronic medicalrecords.8 We excluded childrenwhose only documented varicellavaccination was before vaccinelicensure in 1995 (N = 6298) andchildren whose only documentedvaricella vaccination was before11 months of age (N = 4267). Ifa child had a recorded varicellavaccination before 1995 or before11 months of age followed by anothervaricella vaccination (n = 13 480children), we considered the latter tobe the first dose.

Immunosuppressed status wasdefined as an immunosuppressivecondition or a condition treated withimmunosuppressive drugs at any

time during the study period. Weidentified these children through aniterative process, reviewinga published list of 200 ICD-9 codes4

and conditions associated witha comprehensive list ofimmunosuppressive medications11

and adding codes from additionalliterature review. One author (E.L.)reviewed 300 patient chartsidentified by these codes, and 2authors (E.L. and C.C.) reviewed thefinal list of selected codes.

Incidence rates were calculated bydividing the number of cases in eachperiod by the number of person yearsin the population during that periodand were expressed as cases per100 000 person years. All P valueswere 2 sided.

Overall HZ Incidence Rates

For calculation of overall HZincidence rates, children contributedperson time beginning at birth,health care organization entry, orJanuary 1, 2003 (whichever camelast). Person time ended whenchildren reached 18 years of age,died, or left their health careorganization or at the end of thestudy period (whichever came first).We included children who left andrejoined their health careorganizations but factored only theenrolled periods into the person-time calculations. A child could havemultiple HZ diagnoses; the 180 daysafter each HZ diagnosis wereexcluded from person time to ensurethat only new diagnoses wereincluded in incidence calculations.Varicella vaccination status wasassessed at the time of HZ diagnosis.For children who were unvaccinated,person-time calculation started onJanuary 1, 2003; at enrollment; or atbirth (whichever came last) andcontinued through 20 days after thefirst varicella vaccination, the child’s18th birthday, death, disenrollmentin the health care organization, orthe end of the study period(whichever came first). In calculating

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incidence rates for children whowere vaccinated, we started theperson-time calculation 21 days afterthe first varicella vaccination or onJanuary 1, 2003 (whichever camelater). The 21-day windowallowed time for the recipient todevelop immunity to the vaccine andavoid the interval during whicha localized vaccine-related rashcould occur. A child could contributeunvaccinated and vaccinatedperson time.

Children who wereimmunosuppressed were included inthese rates. We calculated crudeincidence rates by calendar year forall ages combined, by vaccinationstatus, and in all children regardlessof vaccination status. We alsocalculated crude HZ incidence ratesfor the 12-year period by varicellavaccination status, age at HZ, sex,immunosuppressed status, site, andnumber of doses (1 vs $2). Thedose-number analysis was limited tochildren $4 years of age to allow

comparison of similar-aged children.Not all HZ ICD-9 codes are accuratelyassigned, so we created a “laboratoryconfirmation–adjusted rate” bymultiplying crude rates by theproportion of cases that had skinlesions with VZV detected bypolymerase chain reaction (PCR)in our earlier study.7 Confidenceintervals were computed assuminga Poisson distribution.12 Weevaluated linear trends in annualincidence rates using Poissonregression analysis.

HZ Incidence After VaricellaVaccination

To estimate HZ incidence rates asa function of time since the firstvaricella vaccination, we includedonly subjects who were vaccinated in2003 or later while they weremembers of the health careorganizations; this analysis waslimited to children with 1 dose.Person-time calculation began21 days after the first varicellavaccination and ended on the date of

the second dose, first HZ diagnosis,disenrollment from the health careorganization, or study end date(December 31, 2014; whichevercame first). We calculated HZincidence by age in years atvaccination (ages 1–7 years) and byage in months at vaccination (ages11–36 months). To examine possiblechanges in HZ incidence over timeafter vaccination, we also calculatedHZ incidence for each 1-year periodafter varicella vaccination up to6 years. Because age at varicellavaccination may be related toa variety of immunosuppressingmedical conditions, we excludedsubjects who wereimmunosuppressed from theseanalyses. We evaluated linear trendsusing Poisson regression analysis.

RESULTS

A total of 6 372 067 children wereincluded in the analyses: 3 186 732(50%) were vaccinated for some orall of the study period, and 3 185 335

TABLE 1 Crude and Laboratory Confirmation–Adjusted HZ Incidence Rates by Selected Demographic and Clinical Characteristics, 2003–2014

Characteristics No. Children in theStudy Population

Person y HZCases

Incidence Rates(Crude) per 100 000

Person y

Proportion KPNW Study ParticipantsPositive for VZV by PCR per No. Adequate

Specimens(N = 309), n (%)a

Incidence Rates(Adjusted) per 100 000

Person y(95% CI)

Sexb

Male 3 232 096 9 864 319 6894 70 120 of 155 (77.4) 54 (41–70)Female 3 139 609 9 449 629 7489 79 134 of 154 (87.0) 69 (54–87)

ImmunocompromisedYes 31 655 65 669 271 413 4 of 5 (80.0) 330 (295–368)No 6 340 412 19 248 702 14 122 73 250 of 305 (82.2) 60 (46–77)

Vaccination statusUnvaccinated 3 185 335 5 311 456 9044 170 174 of 194 (89.7) 153 (128–179)Vaccinated 3 186 732 14 002 915 5339 38 80 of 115 (69.6) 27 (17–39)

SiteA 468 373 1 061 893 1296 122 254 of 309 (82.2) 100 (81–122)B 395 715 944 341 991 105 254 of 309 (82.2) 86 (69–106)C 136 481 487 965 492 101 254 of 309 (82.2) 83 (66–102)D 2 241 579 7 463 212 4866 65 254 of 309 (82.2) 54 (41–70)E 378 400 968 230 1010 104 254 of 309 (82.2) 86 (69–106)F 2 751 519 8 388 730 5728 68 254 of 309 (82.2) 56 (42–73)

Age group, y1–2 N/A 1 872 775 763 41 25 of 32 (78.1) 32 (22–45)3–9 N/A 7 373 895 2943 40 38 of 56 (67.9) 27 (18–39)10–17 N/A 10 067 701 10 677 106 191 of 221 (86.4) 92 (74–113)

All subjects 6 372 067 19 314 371 14 383 74 254 of 309 (82.2) 61 (47–78)

CI, confidence interval; N/A, not applicable.a These laboratory confirmation proportions were calculated for each category from the Weinmann et al7 study at KPNW. The overall proportion, calculated by combining the previousstudy’s vaccinated and unvaccinated groups, was applied to each of the site-specific groups.b Reported numbers of boys and girls omit 362 children without documented sex.

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(50%) were not vaccinated againstvaricella during this period. The totalpopulation was 49% girls and 51%boys. Among children aged 1 to17 years, the proportion with $1dose of varicella vaccine ranged from27% to 52% in 2003 and from 82%to 91% in 2014 by Vaccine SafetyDatalink site.

Overall HZ Incidence Rates

The crude HZ incidence rate forall subjects was 74 per 100 000person years (laboratoryconfirmation–adjusted rate: 61 per100 000 person years; Table 1).When stratified by varicellavaccination status, the crude rateamong children who were vaccinatedwas 38 per 100 000 person years;this was 78% lower than the rate of170 per 100 000 person years inchildren who were unvaccinated(82% lower with the laboratoryconfirmation–adjusted rate; P ,.0001). HZ incidence rates werehigher in girls than in boys (P ,.0001) and 5 to 6 times higher inchildren who wereimmunosuppressed than in thosewho were not immunosuppressed.Crude HZ rates by study site rangedfrom 65 per 100 000 to 122 per100 000 person years (Table 1).

The overall HZ incidence ratedeclined by 72% to its lowest rate in2014 (P , .0001 for the trend overthe 2003–2014 period; Fig 1). Therate among children who werevaccinated declined over time(P , .0001) and was consistentlylower than that among those whowere unvaccinated. The rate amongchildren who were unvaccinatedclimbed from 2003 to 2007(P , .001) and then declined sharplythrough the end of the study period(P , .0001). By site, HZ rates amongthose who were vaccinated wereremarkably similar over time,whereas rates among those who wereunvaccinated varied considerably andfrom year to year (data not shown).Crude HZ incidence rates by age

FIGURE 1Crude HZ incidence rates among children aged 0 to 17 years who were varicella vaccinated andunvaccinated from 6 Vaccine Safety Datalink sites (United States; 2003–2014).

FIGURE 2Crude HZ incidence rates by age group (each group includes subjects who were varicella vaccinatedand unvaccinated) from 6 Vaccine Safety Datalink sites (United States; 2003–2014). The decreasingtrend in incidence from 2008 to 2014 is significant for all 3 age groups (P , .0001).

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groups of 1 to 2, 3 to 9, and 10 to17 years are presented in Fig 2. In thegroup aged 1 to 2 years, theconfirmation-adjusted HZ rate amongchildren who were vaccinated was70% higher than among those whowere unvaccinated (P , .0001; Fig 3).In the 2 older age groups, HZ rateswere significantly higher in childrenwho were unvaccinated than in thosewho were vaccinated (P , .0001 foreach group).

When stratifying by individual year ofage at HZ diagnosis (Fig 4), 1-year-olds who were vaccinated hada 140% higher risk of HZ than 1-year-olds who were unvaccinated (P ,.0001). This higher risk in those whowere vaccinated disappeared by age 2(P = .59). For those aged 5 to17 years, HZ rates were much lowerin children who were vaccinated thanin those who were unvaccinated.

Among children $4 years of age whowere vaccinated, the crude HZincidence rate was 28.47 cases per100 000 person years for those

who received 1 vaccine dose and14.11 cases per 100 000 personyears for those who received 2doses (P , .0001).

HZ Incidence After VaricellaVaccination

To examine whether age atvaccination was associated witha higher rate of HZ, we calculated HZrates by year of age at vaccination upto 7 years (Fig 5). The HZ incidencerates for children aged 2 and 3 yearsat vaccination were approximatelyhalf the rates for 1-year-olds (P = .06for comparison between 1 and2 years of age). HZ rates for childrenvaccinated at .3 years of age werenot statistically different from thosefor 1-year-olds. When HZ rates werestratified on individual month of ageat varicella vaccination between 12and 36 months, no clear patternemerged (Fig 6). Vaccination at11 months of age was associated withan HZ rate more than triple the otherrates presented; however, the personyears (1637) and HZ cases (n = 3)were small in this group.

We examined HZ incidence over timeafter varicella vaccination at 12 to18 months of age to further explorerisk of HZ in early childhood(Table 2). For rates calculated byusing the entire study period, the risk

FIGURE 3Laboratory confirmation–adjusted HZ incidence rates by age group and varicella vaccination statusfrom 6 Vaccine Safety Datalink sites (United States; 2003–2014).

FIGURE 4Crude HZ incidence rates by age (years) and varicella vaccination status from 6 Vaccine SafetyDatalink sites (United States; 2003–2014).

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of HZ was highest the first year aftervaccination, dropping off sharplyover the subsequent 5 years(P , .0001).

DISCUSSION

With this population-based study, weconfirm that there was a decline inHZ incidence (72%) from 2003 to2014 among children ,18 yearsof age. HZ incidence among childrenwho were vaccinated wassignificantly lower than amongchildren who were unvaccinated.Because the population used tocalculate these HZ rates includeda small percentage of children whowere immunosuppressed, for whomhigher HZ incidence rates have beenreported,7,11,13,14 the rates amongchildren who wereimmunocompetent are lower thanthose presented in Fig 1. Weobserved a significant decrease in

HZ incidence among children whowere unvaccinated beginning in2010, 4 years after the introductionof a routine second varicella vaccinedose; however, the rate amongchildren who were unvaccinatedremained significantly higher thanamong children who were vaccinatedthroughout the study. The trend ofdecreasing HZ incidence amongchildren who were unvaccinated islikely due to a lack of primary VZVinfection resulting from herdimmunity in a highly vaccinatedpopulation. We also report thatamong children .4 years of age,children who were unvaccinated hadmuch higher HZ rates than childrenwho were vaccinated.

Although HZ incidence among 1- to2-year-olds who were vaccinatedwas higher than among theircounterparts who were unvaccinated,the laboratory confirmation–adjusted

rate from this study (34 per 100 000person years) is only one-third of thatreported for vaccinated 1- to 2-year-olds in our smaller 2005–2009 KPNWstudy.7 The rate in the current studyis still higher than rates reported in2 other studies. Black et al15 reportedan HZ incidence of 15 per 100 000person years in vaccinated 1- to 2-year-olds in 1995–1996. However, inthat study, only 10 of 23 reportedcases were evaluated by a physician;2 of the 10 cases were identified asHZ and used to calculate theincidence rate. Tseng et al16 reporteda rate of 29 per 100 000 person yearsfor the group aged 1.0 to 1.5 yearsand 14 per 100 000 for the groupaged 1.6 to 5 years during2002–2008; after chart review, 46%of electronically identified cases wereincluded in the reported rates.

During the period between the firstand second varicella vaccinations, wedid not find statistically significantdifferences in HZ rates by age atvaccination for 12- to 36-month-olds.However, the HZ incidence rates forchildren aged 2 and 3 years atvaccination were approximately halfthe HZ rate for 1-year-olds.

Among the small number of childrenvaccinated at 11 months of age(for whom the vaccine is notrecommended), the HZ incidence ratewas significantly higher than inchildren vaccinated at $1 year of age.Similarly, children who contract wild-type varicella infection at #1 year ofage also have a higher risk of HZ(relative risk: 13.5; 95% confidenceinterval 9.6–18.8).17 The immatureadaptive T-cell response in children,1 year of age appears less able tocontain VZV as a latent infectioncompared with older children. Ourfindings for 11-month-olds who werevaccinated should be interpreted withcaution because this populationincluded only 3 cases of HZ and couldhave included children participatingin a prelicensure study with a vaccineformulation different from Varivax.

FIGURE 5Crude HZ incidence rates by age (years) at first varicella vaccination and before second vaccinedose from 6 Vaccine Safety Datalink sites (United States; 2003–2014). Excludes children vaccinatedbefore 2003 and those classified as immunosuppressed during the study period.

FIGURE 6Crude HZ incidence rates by age (months) at first varicella vaccination and before second vaccinedose from 6 Vaccine Safety Datalink sites (United States; 2003–2014). Excludes children vaccinatedbefore 2003 and those classified as immunosuppressed during the study period.

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Comparing epidemiological studies ofHZ in the vaccine era is complicatedby children having received 0 to2 vaccine doses, the decreasingincidence of varicella disease, theaccumulation of more children whoare vaccinated, and different timeintervals since vaccination. Beforeroutine varicella vaccination,reported HZ incidence rates among 0-to 19-year-olds varied: rates were 42per 100 000, 160 per 100 000, and220 per 100 000 person years in theUnited States,13 Iceland,18 andFrance,19 respectively. Anotherreported rate among US 0- to14-year-olds before vaccineintroduction was 46 per 100 000.20

In our study, pediatric HZ incidencerates in the unvaccinated rangedfrom 160 per 100 000 to 213 per100 000 person years in the earlystudy period.

Authors of a study of HZ incidencefrom 1992 to 2002 among the GroupHealth Cooperative populationreported that the HZ incidence amongchildren and adolescents aged 0 to19 years remained stable before andafter introduction of routinechildhood varicella vaccination.21

During 2000–2006 in AntelopeValley, California, the reported HZrate for children ,10 years of agewho were vaccinated was 19.2 per100 000 person years,22 similar to therates among vaccinated 3- to 9-year-olds in the 2005–2009 KPNW study7

and in this study. Similar to ourcurrent findings (Fig 2), a follow-upstudy from Antelope Valley during2000–2010 reported a continueddecreasing trend of HZ incidenceamong children ,10 years, which by2010 had declined 84% comparedwith 2000.23 Among 10- to 17-year-olds, we report a plateau in HZincidence during 2003–2007followed by a steady decline to 2014,whereas the Antelope Valley studyreported an increase from 2003 to2006 and a trend toward lowerincidence from 2007 to 2010.23

Authors of studies from Canadadescribing the impact of routinevaricella vaccination on pediatric HZincidence report mixed results. Also,the amount of Oka strain VZV perdose differed from the Varivax(1350 plaque-forming units[PFUs]/dose; Merck) andProQuad (9772 PFUs as part of

measles-mumps-rubella-varicellavaccine; Merck) vaccinesadministered in the United States. Apopulation-based study from Alberta,Canada, during 1994–2010 (Varivax[Merck], 1350 PFUs/dose; Priorix-Tetra [GlaxoSmithKline], 1995PFUs/dose; ProQuad, 9772 PFUs/dose) revealed a significant decreasein HZ incidence among children,10 years of age after the 2002introduction of a routine, publiclyfunded vaccine dose at 12 monthsof age. Comparing 2002–2010 with1994–2001, authors reported anannual percent change in HZ rates forboys and girls ,10 years of age of210% (P , .0001 for each sex)attributed to introduction ofvaccination.24 In contrast, authorsof a study from Ontario, Canada,reported HZ incidence during1992–2010, spanning theintroduction of a privately fundedVZV vaccine in 1999 and a publiclyfunded routine 2-dose vaccination in2005. The authors of that studyreported an overall HZ incidence of128 per 100 000 among 0- to 9-year-olds and 154 per 100 000 for 10-to 19-year-olds. There was nosignificant decrease in HZ ratesduring the study period from theprevaccine years to 5 years afterthe introduction of routine 2-dosevaccination.25

A higher overall HZ incidence amonggirls than among boys has beenreported in multiple studies beforeand after the introduction of routinevaricella vaccination of children.4,7,24–26

This was also our finding. Thereis no known biological or behavioralbasis for this excess risk in girls.4

To examine changes in HZ incidencepostvaccine, Tseng et al16 reportedthat children vaccinated at 12 to18 months of age from 2002 to 2008had annual HZ incidence rates thatgradually increased during thesubsequent 4 years (43.2 per100 000 after 4 years) and decreasedthereafter, suggesting a period ofrelatively higher incidence in early

TABLE 2 Crude HZ Incidence Rates per 100 000 Person Years for Each Year After the First Dose ofVaricella Vaccine at 12–18 Months of Age and Before Administration of a Second Dose

Vaccination ya Time Since Vaccination, y

,1 1–,2 2–,3 3–,4 4–,5 5–,6

2003 37 17 13 9 7 42004 44 29 18 10 3 02005 57 36 17 11 7 132006 73 28 14 7 8 142007 66 25 6 9 9 182008 79 24 9 6 5 02009 56 21 10 8 0 02010 32 14 10 1 0 —

2011 46 15 8 2 — —

2012 44 10 2 — — —

2013 28 9 — — — —

2014 24 — — — — —

All yb 50 21 11 7 5 6

Excludes children vaccinated before 2003, children vaccinated at 11 months of age, and those classified as immuno-suppressed during the study period. —, not applicable.a Each row of the table reveals annual HZ incidence rates over the subsequent 6-year period for the cohort of childrenvaccinated in that calendar year; follow-up for calendar years 2010–2014 is truncated at December 31, 2014, studyend date.b Annual HZ incidence rates over the 6-year period after varicella vaccination for all study years combined (2003–2014;P , .0001).

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childhood. In contrast, in our largerstudy, we found a consistent decreasein HZ rates during the first 5 yearsafter vaccination of 12- to 18-month-olds.

Our study has several strengths,including many subjects and12 years of data from comprehensivehealth care plans with electronicmedical records. Although our healthplans were generally large andgeographically diverse, there was anunequal distribution of the studypopulation across sites. Theavailability of information ondiagnoses associated withimmunosuppression andimmunodeficiencies allowed us toexclude children who wereimmunosuppressed from selectedanalyses to better reflect HZ rates inchildren who were notimmunosuppressed.

Limitations of the study include thelack of historical data to determinepre–vaccine-era HZ rates in ourpopulation and inadequateinformation to calculate HZ rates byrace or ethnicity. Varicellavaccination requirements variedacross states in this multicenterstudy, which impacted theproportion of children who werevaccinated by site. We were unableto assess the unvaccinated group’s

underlying risk for HZ because wedid not collect serological or medicalrecord evidence of previous VZVinfection. As the US varicellavaccination program matured overthe study period, the likelihood ofexposure to wild-type VZVdecreased. Also, our study waslimited to HZ in children who soughtmedical care. Cases did not oftenhave PCR or culture confirmation ofVZV, so some non-HZ rashes couldhave been included. To address thelack of VZV confirmation, we appliedthe laboratory confirmationadjustment based on our earlierstudy involving 322 subjects from 1health plan. The retrospective natureof this study did not allow for HZvirus typing. Finally, ourclassification of children asimmunosuppressed (yes or no) usingICD-9 codes was conservative;children who wereimmunosuppressed for only part ofthe study period were included inthe immunosuppressed category. Wedid not exclude children who wereimmunosuppressed withcontraindications for vaccination.

CONCLUSIONS

With this study, we reinforce thebenefit of HZ prevention amongchildren through varicella

vaccination. Despite an increased HZincidence among vaccinated 1-year-olds, the overall HZ risk in childrenwho are vaccinated is significantlylower than among children who areunvaccinated. HZ incidence waslower in children who received2 doses of varicella vaccine than 1dose. Future pediatric HZ rates maybe lower than those reported hereduring a maturing 2-dose varicellavaccination program.

ACKNOWLEDGMENTS

We acknowledge the contributions ofMara Kalter and Katie Essick(KPNW), Erica Scotty (MarshfieldClinic Research Institute), and CherylCarlson, Sungching Glenn, MichaelMarcy, and Lina Sy (KaiserPermanente Southern California).

ABBREVIATIONS

ACIP: Advisory Committee onImmunization Practices

HZ: herpes zosterICD-9: International Classification

of Diseases, Ninth RevisionKPNW: Kaiser Permanente

NorthwestPCR: polymerase chain reactionPFU: plaque-forming unitVZV: varicella zoster virus

Accepted for publication Mar 20, 2019

Address correspondence to Sheila Weinmann, PhD, Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, Portland, OR 97227. E-mail:

sheila.weinmann@kpchr.org

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by the US Centers for Disease Control and Prevention (Task Order 200-2012-53584-0006). The findings and conclusions in this report are those

of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

POTENTIAL CONFLICT OF INTEREST: Dr Weinmann has received research funding from GlaxoSmithKline for unrelated studies; Dr Naleway has received research

funding from Pfizer, MedImmune (AstraZeneca), and Merck for unrelated studies; Dr Baxter has received research support for unrelated studies from Pfizer, Merck,

Protein Sciences Corporation (now Sanofi Pasteur), MedImmune, and Dynavax Technologies; Ms Irving has received research funding from MedImmune

(AstraZeneca) for an unrelated study; Dr Klein has received research funding from Merck, GlaxoSmithKline, Pfizer, Sanofi Pasteur, Protein Sciences Corporation

(now Sanofi Pasteur), MedImmune, and Dynavax Technologies; the other authors have indicated they have no potential conflicts of interest to disclose.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2018-3561.

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