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Increasing incidence associated with herpes zoster infection in British Columbia, Canada Marra, Fawziah; Chong, Mei; Najafzadeh, Mehdi Oct 20, 2016

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RESEARCH ARTICLE Open AccessIncreasing incidence associated with herpeszoster infection in British Columbia, CanadaFawziah Marra1,4* , Mei Chong2 and Mehdi Najafzadeh3AbstractBackground: Recent studies have shown an increasing incidence of herpes zoster (HZ) infection, which may berelated to the introduction of varicella vaccination programs in children. We examined the epidemiology andtreatment costs of HZ and post-herpetic neuralgia (PHN) over time in British Columbia, Canada.Methods: The cohort consisted of all cases with HZ infection from January 1, 1997 and December 31, 2012.Incident zoster was defined as a case (ICD-9 053 or ICD-10 B02) without a previous episode of HZ or PHN in theprevious 12 months. We determined the incidence for HZ and PHN and the age-sex standardized rate for theoverall population. We determined the association between the varicella vaccination program and increased HZrates by evaluating the rate ratios in the publicly-funded varicella vaccine period compared to the non-publiclyfunded period in a regression model. We evaluated the hospitalization rates, treatment by GPs and their associatedyearly costs for HZ and PHN.Results: HZ incidence increased for the entire study period from 3.2 per 1000 population in 1997 to 4.5 in 2012. HZrates were higher for females than males and all age groups had an increased incidence rate, except the 0–9 yearolds, where the rate decreased. Crude and age-sex standardized incidence rates of PHN demonstrated very similarpatterns to HZ incidence. Based on the regression model, rates of HZ were higher in the older individuals. Nosignificant increase with HZ incidence was seen during the publically funded varicella vaccination programcompared to the non-publicly funded period. From 1997 to 2012, the annual HZ-related costs associated withhospitalizations and GP visits were over $CDN4.9 million and $CDN537,286, respectively; treatment costs forhospitalizations have increased significantly over time. Majority of PHN-related cases are managed by GPs, with asteady increase over time in number of cases and associated annual costs.Conclusions: The incidence of zoster and PHN is increasing with time, particularly in the elderly population andthe risk is greater in the over 65 year olds. Treatment costs for both HZ and PHN represent a significant burden onthe Canadian healthcare system.Keywords: Herpes zoster, Incidence, Post-herpetic neuralgia, EpidemiologyBackgroundVaricella zoster virus (VZV) infection or chickenpox typic-ally occurs in children and manifests as a diffuse itchy rash.The rates of infection are high with approximately 95 % ofthe population testing seropositive for VZV [1, 2]. Reactiva-tion of the varicella virus later in life is known as herpeszoster (HZ) infection [3], and is triggered when an individ-ual’s immune system, cellular immunity in particular,decreases due to the process of aging [4] or becomes im-munocompromised [5]. Other risk factors for developmentof HZ include race (Caucasians are at higher risk thanAfrican Americans), gender (most studies show a higher in-cidence among women), stress, trauma, and diabetes [6–8].Herpes zoster infection manifests itself as a unilateral, ves-icular, painful rash [9], and can lead to complications suchas post-herpetic neuralgia (PHN) [10, 11] in approximately20 % of people.Recent studies from Europe [12] and North America[13] have shown a trend of increased zoster infectionrates over time. Scientists are unclear as to the reason* Correspondence: fawziah@mail.ubc.ca1University of British Columbia, Vancouver, BC, Canada4University of British Columbia, 2405 Wesbrook Mall, Vancouver, BritishColumbia V6T 1Z3, CanadaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Marra et al. BMC Infectious Diseases  (2016) 16:589 DOI 10.1186/s12879-016-1898-zfor its increase, but Hope-Simpson in his original studieshad hypothesized that viral latency after infection withVZV is maintained by “immunosurveillance”, which isboosted by periodic subclinical reactivations and expos-ure to exogenous virus [3, 14, 15]. Thus, HZ clinicallymanifests itself when “immunosurveillance” falls below acertain threshold [3]. Some have hypothesized that theintroduction of widespread childhood varicella vaccin-ation programs could lead to less wild type virus boost-ing for adults [16–18], leading to an increase in zosterrates. Alternatively, the aging population and presenceof larger numbers of immunocompromised individuals(due to autoimmune diseases, transplants and largernumbers on medications such as corticosteroids,DMARDS and biologics) [19] could also account for theincrease in zoster rates seen around the world [12, 13].Given that it has been a decade since Canada evalu-ated its rates of zoster infection [20, 21], we undertookthis study to determine the trends over time in age andsex-specific herpes zoster and PHN rates. We further ex-amined the rates of hospitalization and costs associatedwith HZ and PHN over time. Finally, although not ourprimary objective, we looked at the impact of varicellavaccination on herpes zoster rates.MethodsData sourceWe used population-based data available from Population-DataBC® which houses several health-related databases,including the Medical Services Plan (MSP) [22] andDischarge Abstract Database (DAD) [23]. These databasesuse the International Classification of Diseases, NinthRevision (ICD-9) or Tenth Revision (ICD-10) to code formedical billing. These two databases were linked to the out-patient prescription database (PharmaNet) [24] and vitalstatistics for cause of death (see Additional file 1: Table S1for additional information on the data holdings). Individualconsent was not required for the records, however thepatient records/information was anonymized and de-identified prior to analysis. Ethics approval for the studywas obtained from the University of British Columbia’sEthics Committee.Study populationIndividuals were eligible for inclusion in the cohort if theywere a resident of British Columbia between January 1,1997 to December 31, 2012 with incident HZ. To improvecoding accuracy, we excluded visits or admissions with co-existent codes for varicella (ICD-9 052 and ICD-10 B01).An incident zoster case was defined as an enrollee with aHZ ICD-9 (053) or ICD-10 (B02) code in the primary orsecondary position (i.e., all other) without any evidence ofHZ or PHN within 12 months prior to this incidence. All25 diagnostic codes (primary as well as secondary codes)in the hospitalization data were used to identify cases. Ifthe first position (or diagnosis) was the primary reason foradmission, all other positions from 2nd to 25th, if any,were categorized as the secondary diagnostic codes. Toidentify incident cases, we only included the firstoutpatient visit or hospitalization during the study periodfor each individual. In order to further ensure we wereobtaining incident zoster cases only, enrollees with onlyPHN-specific ICD-9 (053.12, 053.13) or ICD-10 (B02.22,B02.23) were excluded. We conducted a sensitivity ana-lysis and used the methodology proposed by Zhang et al.to increase positive predictive value of a HZ diagnosis inan administrative data source by defining incident herpeszoster as the presence of an ICD-9 or −10 code for herpeszoster plus receipt of antivirals, acyclovir, valacyclovir,famciclovir, within 7 days before or after the diagnosticcode for HZ [25].PHN was identified as those individuals with a first epi-sode of zoster with a further zoster diagnostic code after90 days with a relevant prescription for analgesia, anticon-vulsant, or antidepressant therapy on the same day as therecorded consultation [26]. The presence of codes for non-specific neuralgia or for neurological complications ofzoster after 90 days was also consistent with PHN.Immunosuppression status was identified by the presenceof two diagnostic ICD-9 or ICD-10 codes on different daysas an outpatient or inpatient within one year prior to theinitial HZ diagnosis date. The following patients wereconsidered as immunosuppressed: hematopoietic stem cellor solid organ transplantation; hematological malignanciessuch as Hodgkin’s lymphoma, multiple myeloma, acuteleukemia, non-Hodgkin’s lymphoma; other hematologicaldiseases, such as aplastic anemia, agranulocytosis, myelo-dysplastic syndrome; AIDS, advanced HIV infection; cancer,and other disorders involving immunodeficiency (seeAdditional file 1: Table S2 for ICD-9 and ICD-10 codes).Statistical analysisFor our primary analysis, we calculated incidence as thenumber of incident cases divided by the BC population.The overall crude annual incidence rates (number ofevents per 1000 population) of HZ and PHN was calcu-lated by year and age group. We standardized the inci-dence by age and sex using the 2006 Canadian censusdata.Varicella vaccines were introduced in Canada in 1998but were implemented as part of routine immunizationprograms in British Columbia in September 2004 andJanuary 2005 for susceptible kindergarten (age 6)/grade6 students (age 12) and infants greater than or equal to12 months of age, respectively [27]. At that time it was aone-dose program, but was later changed to a two-doseprogram January 1, 2012 [28]. The HZ vaccine, a liveattenuated vaccine containing the Oka/Merck strain ofMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 2 of 13varicella-zoster virus, was marketed in 2008 in Canada[29, 30]. We used a negative binomial regression model toassess the impact of varicella vaccination on zoster inci-dence during the three periods of the varicella vaccinationprogram: the pre-licensure period (1997–1998), the periodwhen the vaccine was available privately (1999–2004) andthe publicly funded one-dose vaccination period(2005–2012). The model included age group, sex, im-munosuppression status, indicator variables for varicellavaccine implementation, and calendar year. Interactioneffects were assessed and sensitivity analysis was alsoperformed for those aged 65 years or older. To evaluaterisk factors for HZ, we calculated adjusted rate ratios forage, sex, immunosuppression status and varicella vaccineavailability period using the regression model.Finally, we evaluated the number and costs associatedwith hospitalizations, General Practioner (GP) visits, andtreatment of HZ and PHN. Treatment for HZ was obtainedby linking the prescription database to the hospitalizationor GP office visit on that day and looking for antivirals,analgesics, antidepressants, corticosteroids within 90 dayspost-initial HZ visit. Each hospitalization inpatient recordwas assigned at least one methodology-specific resource in-tensity weight (RIW). The cost associated with acute carehospitalization was estimated by multiplying the highestRIW to the provincial estimates of the cost per weighted-case (CPWC) (i.e., hospitalization cost = RIW*CPWC). Thecost associated with a GP visit was obtained from theamount paid in the MSP billing system. Treatment costwas defined as the total of drug cost submitted and thepharmacy professional fee submitted (i.e., PharmaNet cost= submitted drug cost + submitted professional fee). Allcosts were inflated by multiplying the ratio of the BritishColumbia consumer price index (CPI) for health care withthe base year of 2013.All statistical tests were two-tailed and p = 0.05 usedto determine statistical significance. All analyses wereundertaken using SAS 9.4 (SAS Institute Inc., Cary, NC)[31]. Bonferroni correction was applied in multiplecomparisons and confidence intervals constructions,wherever applicable.ResultsHerpes zoster casesFrom 1997 to 2012, there were 238,295 incident cases ofherpes zoster in our study population, after excluding201 cases with either co-existing varicella codes (n = 68)or only PHN specific codes (n = 133) (Table 1). Themean age of the zoster cases increased from 49.6 yearsin 1997 to 53.2 years in 2012 and there were morefemales than males (n = 138,855; 58.3 %). Among theherpes zoster cases, 9526 (4.0 %) were immunosup-pressed at the time of diagnosis; only 0.2 % (n = 516)were vaccinated in our cohort.Herpes zoster incidenceCrude HZ incidence increased with time from 2.9 per1000 population in 1997 to 4.7 per 1000 population in2012. As shown in Fig. 1, the age-sex standardized HZrates also illustrated the increasing trend between 1997(3.2 per 1000 population) and 2012 (4.5 per 1000population) (see Additional file 1: Table S3).HZ incidence rates were strongly age-related (Fig. 2).In 2012, the incidence in children and adolescents(<20 years) was 1.3/1000 population (95 % CI: 1.2–1.4),while in adults aged ≥50 years the incidence was 8.2/1000 population (95 % CI: 8.1–8.4). This trend wasmaintained each year during the whole study period.Over time, zoster incidence increased in all age groups,except 0–9 year age group which indicated a 50 %decrease since 2004 from 1.6 to 0.8 per 1000 population(Fig. 2). The highest increases in incidence from 1997 to2012 were seen in age groups 40–49 years (2.4 to 3.9 per1000 population, 63 % increase) and 60–69 years (5.4 to8.7 per 1000 population, a 61 % increase). Although agegroup 80 years and up had the highest incidence rate,this age group experienced the lowest increase of 21 %from 9.2 to 11.1 per 1000 population.The incidence was significantly higher among femalescompared to males across all the years (females: 3.35;95%CI: 3.27, 3.43 vs males: 2.53; 95%CI: 2.46, 2.60 in1997 and females: 5.48; 95%CI: 5.39, 5.58 vs males: 3.90;95%CI: 3.82, 3.98 in 2012). This significant higher rate ofzoster infection in females persisted in almost all agegroups. There was a 19.3 % and 21.8 % increase in HZduring the publicly funded varicella vaccine period(3.869 per 1000 population) as compared to the privatelyfunded period (3.244 per 1000 population) and thepre-licensure period (3.175 per 1000 population),respectively (Table 2).In order to increase specificity for the HZ casedefinition, we conducted a sensitivity analysis of the casedefinition, which was HZ accompanied with antiviraltaken within 7 days of diagnosis; the analysis of HZincidence showed a similar pattern to the primaryanalysis (Fig. 1 and Additional file 1: Table S3).PHN incidenceCrude and age-sex standardized incidence rate of PHNdemonstrated very similar patterns to the HZ incidence(see Additional file 1: Table S2 for the crude analysis).Figure 3 shows that the standardized rates increased al-most 3-fold from 0.128 to 0.343 per 1000 population forPHN defined within 90 days post HZ diagnosis. We sawa similar result for our sensitivity analysis where PHNwas defined within 30 days post HZ diagnosis (ageadjusted rates increased from 0.104 to 0.296 per 1000population (Fig. 3). All age groups showed increasingincidence over the years (Fig. 4). The highest increase inMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 3 of 13PHN incidence within 90 days post initial HZ from 1997to 2012 was found in age groups 40–49 years (5.6-foldfrom 0.04 to 0.2 per 1000 population) and 10–19 years(4.5-fold from 0.004 to 0.02 per 1000 population).Although the age group of 80 years and up had the high-est incidence rate, this age group experienced the lowestincrease (2.1-fold from 0.8 to 1.6 per 1000 population).The incidence was significantly higher among femalescompared to males across all the years (females: 0.14;95%CI: 0.12, 0.15 vs males: 0.08; 95%CI: 0.07, 0.10 in1997 and females: 0.42; 95%CI: 0.40, 0.45 vs males: 0.32;95%CI: 0.30, 0.34 in 2012). Although females had higherrates than males across all age groups, their differenceswere not significant across the years. Similar patternswere shown in our sensitivity analysis defined as PHNwithin 30 days post HZ diagnosis.Rate ratios comparisons on the impact of varicellavaccine availability on HZ incidenceIn our univariate analysis, the standardized mean annualHZ incidence rates were significantly higher during thepublicly funded varicella vaccine period as compared toprivately funded period (rate ratio 1.193; 95 % CI: 1.180,1.205) and pre-licensure period (rate ratio 1.218; 95 % CI:1.199, 1.238) (Additional file 1: Table S4). However, in ourmultivariate analysis, the risk of HZ during the publiclyfunded varicella vaccine period was not statistically differ-ent from the non-publicly funded period after controllingfor the effects of age, gender and immunosuppressive sta-tus (Fig. 5, Additional file 1: Table S5). No significantinteraction effects were found. Age remained as having asignificant effect on the rate of HZ - the risk of HZ forthose 65 years of age and over was 2 times (1/0.5) higherTable 1 Profile of Herpes Zoster Cases by Varicella Vaccine Availability, BC 1997–2012Pre-licensure Privately Funded Publicly Funded Overall1997–1998 1999–2004 2005–2012 1997–2012Age0–9 1577 (6.7 %) 4562 (5.9 %) 3619 (2.6 %) 9758 (4.1 %)10–19 1422 (6 %) 4649 (6.1 %) 6995 (5.1 %) 13066 (5.5 %)20–29 2073 (8.8 %) 6314 (8.2 %) 11706 (8.5 %) 20093 (8.4 %)30–39 2952 (12.5 %) 8743 (11.4 %) 13304 (9.7 %) 24999 (10.5 %)40–49 3098 (13.1 %) 10550 (13.7 %) 17872 (13 %) 31520 (13.2 %)50–59 3332 (14.1 %) 12544 (16.3 %) 25707 (18.7 %) 41583 (17.5 %)60–69 3397 (14.4 %) 11306 (14.7 %) 25270 (18.3 %) 39973 (16.8 %)70–79 3682 (15.6 %) 11049 (14.4 %) 19552 (14.2 %) 34283 (14.4 %)80+ 2089 (8.8 %) 7149 (9.3 %) 13738 (10 %) 22976 (9.6 %)Unknown 12 (0.1 %) 24 (0 %) 8 (0 %) 44 (0 %)Mean (IQR) 49.6 (33–69) 50.2 (34–69) 53.2 (39–69) 51.9 (36–69)GenderMale 10141 (42.9 %) 32247 (41.9 %) 56917 (41.3 %) 99305 (41.7 %)Female 13453 (56.9 %) 44579 (58 %) 80823 (58.7 %) 138855 (58.3 %)Unknown 40 (0.2 %) 64 (0.1 %) 31 (0 %) 135 (0.1 %)Health AuthorityInterior 4040 (17.1 %) 13659 (17.8 %) 24215 (17.6 %) 41914 (17.6 %)Fraser 7470 (31.6 %) 24894 (32.4 %) 43316 (31.4 %) 75680 (31.8 %)Vancouver Coastal 5684 (24.1 %) 17632 (22.9 %) 33518 (24.3 %) 56834 (23.9 %)Island 4264 (18 %) 14231 (18.5 %) 26046 (18.9 %) 44541 (18.7 %)Northern 1174 (5.0 %) 3667 (4.8 %) 7902 (5.7 %) 12743 (5.4 %)Unknown 1002 (4.2 %) 2807 (3.7 %) 2774 (2 %) 6583 (2.8 %)Immunosuppression Status (Any)Yes 905 (3.8 %) 3121 (4.1 %) 5500 (4.0 %) 9526 (4.0 %)No 22729 (96.2 %) 73769 (95.9 %) 132271 (96.0 %) 228769 (96.0 %)Zoster VaccinatedYes NA NA 516 (0.4 %) 516 (0.2 %)No 23634 (100 %) 76890 (100 %) 137255 (99.6 %) 237779 (99.8 %)Marra et al. BMC Infectious Diseases  (2016) 16:589 Page 4 of 13than for those in age group 45–64 years, and 4.5 times (1/0.22) higher than for those in age group 10–44 years. Al-though females show a 16 % higher risk of HZ than males,the effect was not statistical significant. We conducted asimilar analysis restricted to those aged 65 years and overand the results were similar (data not shown).Hospital admissions, GP visits and treatment related toHZ and PHNTable 3 shows that between 1997 and 2012, on a yearlybasis, 2 % of the initial cases were diagnosed throughhospitalization records, while the majority of HZ episodeswere non-hospitalized. The trend over time is a slightdecrease in the number of hospitalizations for treatment ofHZ, and a slight increase in the number of GP visits peryear with time. For those who were hospitalized the averageage was 73.0 years (SD: 18.3), with a median age of 78 years.Majority of the patients were women (60.6 %), 2.7 % werepediatric (i.e., 0–19 years), 14.3 % were adults (20–59 years)and 82.9 % were 60 years and older. In contrast, the pa-tients who visited their GPs, were younger - the average agewas 60.2 years (SD: 19.2), with a median age of 63 years.Fifty eight percent were women, 3.9 % were pediatric (0–19years), 38.7 % were adults (20–59 years) and 57.4 % were60 years and older.The annual cost of hospitalizing patients with HZ isapproximately $4.9 million, compared to $537,286 forGP visits, resulting in an average cost per case of$16,389 for hospitalization and $37 for GP-related visit.Treatment was initiated in 53.4 % of the cases seen byGPs and the majority of the cases (95 %) received antivi-rals, thus when including costs associated withFig. 1 Crude and Age-Sex Standardized Herpes Zoster Incidence Rate and 95 % Confidence Interval by Year. The crude and age-sex adjusted rateof herpes zoster and 95 % confidence interval between 1997 and 2012 using two different definitions of incident zoster: as defined by ICD9/10code and as the presence of an ICD-9/10 code for herpes zoster plus receipt of antivirals within 7 days before or after the diagnostic code for HZMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 5 of 13treatment, the annual cost per case of a GP-related visitwould increase by an additional $123 per case for initialtreatment of zoster infection. Subsequent visits to theGP or hospitalization within 90 days of the initial HZdiagnosis were very few. From 1997 to 2012, only 0.6 %of cases were re-admitted into the hospital, with anannual readmission cost of $12,149 per admission. Incontrast, on average, 26.4 % of cases re-visited their GPwithin 90 days of their initial HZ diagnosis, costing anadditional $253,768 per year to the healthcare system.Between 1997 to 2012, there were a total of 588(0.2 %) cases with at least one hospitalization related toPHN whereas the majority of the cases (total N= 14,054;(5.9 %)) were seen by GPs. On a yearly average, therewere 39 hospitalizations and 1421 GP visits related toPHN. The number of hospital admissions per year overtime has remained steady, but the annual number of GPvisits for treatment of PHN has increased with time. Forthose who were hospitalized, the average age was76.5 years (SD: 13.5), with a median age of 80 years and62.9 % of the patients were women, 0.3 % were pediatric(0–19 years), 9.7 % were adults (20–59 years) and 90.0 %were 60 years and older. For patients who visited theirGPs, the average age was 66.7 years (SD: 14.8), with amedian age of 69 years and 60.4 % of the patients werewomen, 0.6 % were pediatric (0–19 years), 27.5 % wereadults (20–59 years) and 71.9 % were 60 years and older.Between 1997 and 2012, the total annual cost forPHN-related hospitalization and GP visits were over$552,740 and $12,709, respectively. Total costs per yearfor PHN that is treated in by a GP have risen signifi-cantly, from $5,693 to $19,048 per year. Prescriptioncosts associated with outpatient treatment of PHN wereestimated at $1.0 million (overall average $62,800/year)and again have risen considerably over time, from$17,011 to $91,544 per year. In contrast to HZtreatment, medications used for PHN were primarilyanticonvulsants (61.7 %) and antidepressants (27.9 %).DiscussionIn our study, over the 16 year period, we saw a 1.5-foldincrease in HZ incidence regardless of the definitionsTable 2 Age-Sex Standardized Mean Annual Incidence Rate by Varicella Vaccine Availability PeriodsAge-Sex Standardized Incidence Rate per 1000 Population (95 % Confidence Interval)Pre-licensure(1997–1998)Privately Funded(1999–2004)Publicly Funded(2005–2012)Overall(1997–2012)HZ 3.175(3.134, 3.217)3.244(3.221, 3.267)3.869(3.849, 3.890)3.575(3.561, 3.589)HZ with Antiviral 1.678(1.648, 1.709)1.926(1.908, 1.944)2.571(2.554, 2.587)2.242(2.231, 2.254)PHN within 90 days 0.127(0.119, 0.135)0.169(0.164, 0.175)0.271(0.266, 0.277)0.221(0.217, 0.224)PHN within 30 days 0.104(0.097, 0.112)0.141(0.136, 0.146)0.232(0.227, 0.237)0.187(0.184, 0.191)Fig. 2 Herpes Zoster Incidence Rate, by Age Group and Year. The rate of herpes zoster between 1997 and 2012, by various age groupsMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 6 of 13used to identify herpes zoster. For young childrenbetween the ages of 0 and 9 years, the HZ incidencedecreased abruptly from 1.8 to 0.8 per 1000 populationin 2004, and has been steadily declining, likely reflectingthe start of the publicly-funded varicella vaccinationprogram which targeted children in kindergarten (age6 years). Interestingly, despite the introduction of thevaricella vaccination program in 2004 for 12 year olds,the age-specific HZ incidence held steady but did notdecline for those within the 10–19 year old category.This is probably related to the fact that most of themwill have had varicella infection already and have goodimmunity; for now too little time has elapsed to show adecrease in this age groups of HZ rates. Alternatively,the lack of effect on HZ rates may be related to a lowervaccine uptake rate in this age group than the kindergar-teners or the fact that the vaccine effectiveness wasreduced with the one dose program. On the positiveside, zoster rates have not increased either, as they havefor all other age categories after the age of 19 years.Although we saw a slight increase in zoster incidence inthe 20–39 year old age groups, the largest increases wereseen in the 40–49 (63 %) and the 60–69 year olds(61 %). The 80 year old group had the highest incidenceFig. 3 Age-Sex Standardized PHN Incidence Rate and 95 % Confidence Interval by Year. The age-sex adjusted rate of post-herpectic neuralgia between1997 and 2012 using two different definitions of PHN: PHN diagnosed within 90 days post HZ diagnosis and within 30 days post HZ diagnosisFig. 4 Post-herpectic Neuralgia Incidence Rate, by Age Group and Year. The rate of post-herpectic neuralgia between 1997 and 2012, by variousage groupsMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 7 of 13in 2012 (11/1000 population), although their increasewas only 21 % between 1997 and 2012. Our finding thatHZ incidence increases with age has been reported inother studies and is thought to be related to immunose-nescence, that is, decreasing ability to respond to thereactivated virus as the body ages [4, 19]. Pinchinat andcolleagues [12] in their review of studies looking at theincidence of HZ across Europe showed that HZ incidenceincreases sharply with age, from around 1/1 000 children<10 years up to 10/1 000 people over 80 years of age.Similarly Kawai et al. found that age-specific incidencewas similar across countries and rose sharply after the ageof 50 years; their rates were similar to our study as theyfound rates of 6-8/1000 person-years at age 60 years and8-12/1000 person-years at age 80 years [13].Our observation of a higher zoster incidence in womenhas also been seen in other studies [7, 32–34]. Originally,investigators believed this difference was not a realphenomenon and it was likely due to women havinggreater health-seeking behavior. However, given that thedifference between females and males occurs in all agegroups, including children, and has been seen consistentlyin many studies using different methodologies, it isunlikely that this phenomenon is due to differentialhealth-seeking behaviours. The biological reason behindthis effect is unclear; it may be related to symptomaticzoster being more common in women, or genderdifferences in immune responses to the varicella antigenand loss of immunity over time [7, 35, 36].In our study, the standardized rates seen in 2012 forzoster were within the range reported in other NorthAmerican and European studies [12, 13]. In their system-atic review Kawai et al. included 130 studies conducted in26 countries. They found the incidence of HZ rangedfrom 3 to 5 per 1000 person-years [13]. Although themethodology used in these studies varied from prospectivesurveillance to use of retrospective administrative data todetermine incidence, most of the studies showed atemporal increase in the incidence of HZ and PHN in thepast several decades. The authors also observed that thosestudies which evaluated all age groups (rather thanrestricting the analyses to those over 60 years of age) andwere conducted in the 50s to early 90s, showed lower HZrates (HZ incidence of North American studies ranged1.31 to 2.40 per 1000) [37, 38] than studies conducted2000s (HZ incidence of North American studies ranged3.82 to 5.79 per 1000) [35, 36, 39–41].In our secondary analysis we evaluated the impact ofthe introduction of the publicly funded varicella vaccin-ation program. Between 2007 and 2012, the average cover-age rates in the 2 year old, kindergarden (6 year old) andgrade 6 (12 year old) children was 83 %, 74 %, and 63 %,respectively [42]. Despite these uptake rates, a vaccine ef-fect was not seen after adjusting for potential confounderswhich would have an effect on HZ incidence, includingage, sex, and immunosuppression status. Previous olderstudies using survey data and modeling had suggested thatthe introduction of a routine varicella vaccinationprogram could potentially increase the incidence of zosterinfections due to less boosting of immunity by the wildtype virus [16, 18, 19, 43, 44]. However, North Americanstudies conducted in the last 5 years, using large databaseshave shown that although age-specific HZ incidenceis increasing, it started increasing before the introductionof widespread varicella vaccination. Hales et al. [45]conducted a retrospective study using Medicare claims toexamine the link between herpes zoster incidence in theUS population older than 65 years and childhood varicellavaccination. They found that age and sex standardized HZincidence increased 39 % from 10.0 per 1000 person-yearsFig. 5 Rate Ratio on Herpes Zoster Incidence and 95 % Confidence Interval Using a Regression Model. The reference groups for the analysesincluded publicly funded period, age 65+ years and male genderMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 8 of 13Table 3 Hospitalizations, General Practitioner Visits, and Treatment Costsa Associated with HZ and PHNPre-licensure Privately Funded Publicly Funded Overall1997–1999 1999–2004 2005–2012 1997–2012(3 years) (6 years) (8 years) (16 years)Initial HZ Cases Identified Based on Hospitalization or GP VisitsHospitalization (Annual count, %) 409 (3.5 %) 296 (2.3 %) 276 (1.6 %) 300 (2 %)Annual Cost $4,747,242 $4,290,917 $5,428,559 $4,916,779Cost/hospitalization Case $11,607 $14,505 $19,678 $16,389GP Visit (Annual count, %) 11408 (96.5 %) 12519 (97.7 %) 16946 (98.4 %) 14593 (98 %)Annual Cost $451,523 $475,046 $605,407 $537,286Cost/GP Case $40 $38 $36 $37Number of Cases Treated (Annual count, %)b 4889 (41.4 %) 6281 (49 %) 9987 (58 %) 7960 (53.4 %)Annual Treatment Costs $750,370 $896,161 $1,091,457 $975,585Cost/Rx Case $153 $143 $109 $123Overall Annual Cost $5,949,134 $5,662,124 $7,125,422 $6,429,649Overall Cost/Case $503 $442 $414 $432HZ Related Hospitalization or GP Visits within 90 days Post Initial HZ DiagnosisHospitalizationAnnual Casesc with ≥1 admission 109 (0.9 %) 84 (0.7 %) 93 (0.5 %) 91 (0.6 %)Annual Cases with 0 admission 11708 (99.1 %) 12732 (99.3 %) 17129 (99.5 %) 14802 (99.4 %)Annual Cost $1,164,402 $963,319 $1,381,308 $1,197,449Cost/Admission $9,785 $10,763 $13,779 $12,149GP VisitsAnnual Casesc with ≥1 Visit 3207 (27.1 %) 3316 (25.9 %) 4588 (26.6 %) 3938 (26.4 %)Annual Cases with 0 Visit 8610 (72.9 %) 9500 (74.1 %) 12634 (73.4 %) 10956 (73.6 %)Annual Visits 8168 7602 12659 10201Annual Visits with Rxd 1289 1458 2925 2170Annual Visit Cost $219,145 $218,276 $289,042 $253,768Annual Rx Cost $112,653 $122,106 $219,036 $169,389Annual Cost (Visit + Rx) $331,798 $340,382 $508,078 $423,157Cost/Visit (including Rx cost) $41 $45 $40 $41PHN Related Hospitalization or GP Visits within 90 days Post Initial HZ DiagnosisHospitalizationAnnual Casesc with ≥1 admission 39 (0.3 %) 35 (0.3 %) 37 (0.2 %) 37 (0.2 %)Annual Cases with 0 admission 11778 (99.7 %) 12780 (99.7 %) 17184 (99.8 %) 14857 (99.8 %)Annual Admission 43 38 40 39Annual Cost $360,725 $539,429 $610,727 $552,740Cost/Admission $8,488 $14,196 $15,364 $14,016GP VisitsAnnual Casesc with ≥1 Visit 416 (3.2 %) 614 (4.8 %) 1192 (6.9 %) 878 (5.9 %)Annual Cases with 0 Visit 11410 (96.6 %) 12201 (95.2 %) 16029 (93.1 %) 14015 (94.1 %)Annual Visits 606 901 2015 1421Annual Visits with Rxe 478 751 1514 1098Annual Visit Cost $5,693 $6,596 $19,048 $12,709Annual Rx Cost $17,011 $39,874 $91,544 $62,851Annual Cost (Visit + Rx) $22,704 $46,470 $110,592 $75,560Cost/Visit $37 $52 $55 $53Marra et al. BMC Infectious Diseases  (2016) 16:589 Page 9 of 13in 1992 to 13.9 per 1000 person-years in 2010. They usedPoisson regression analysis to compare HZ trends during3 periods of varicella vaccination program implementa-tion: preimplementation (1992 to 1995), early implemen-tation (1996 to 1999), and full implementation (2000 to2010). The authors also found that the rise in HZ inci-dence predated 1996, when the U.S. Advisory Committeeon Immunization Practices first recommended routinevaricella vaccination for children aged 12 to 18 months,and HZ incidence did not accelerate after full implemen-tation of the varicella vaccination program, when vaccinecoverage reached 90 % and varicella incidence decreasedby 90 %. The authors of this paper also looked at HZ inci-dence in US states that had low varicella vaccine coveragerates compared to high coverage rates; they found thatstate varicella vaccination coverage had no effect on HZincidence concurrently or 10 years later (RR, 0.9998 [CI,0.9993 to 1.0003]) after adjusting their model for sex, age,and calendar year [44]. Using medical claims data, Leungand colleagues [38] evaluated HZ incidence in all personsenrolled in the MarketScan® databases (Thomas Reuters,Ann Arbor, MI). They used similar definitions as ourstudy and defined incident HZ as an enrollee of any age inthe MarketScan® database with an outpatient claim bear-ing a HZ ICD-9 code (053.xx) in the primary or secondarydiagnostic position. From 1993 through 2006, HZincidence also increased 98 % from 1.7 (95%CI: 1.6-1.7) in1993 to 4.4 (95 % CI: 4.3-4.4) in 2006. The increasesoccurred among all age strata and both sexes, although itincreased more rapidly among females. Their resultssuggested greater increase in HZ rates between 1993 and1996, prior to introduction of the varicella vaccinationprogram. They also did not find any variation in HZincidence by state varicella vaccination coverage rates. Aninteresting observation by the authors was that adults withdependents less than 12 years of age had lower HZ inci-dence at the outset of the varicella vaccination programcompared with adults without dependents. However, theincidence in both groups became similar as the programprogressed, suggesting that the introduction of thevaricella vaccination program has not influenced HZ inci-dence in the general population, but it may have affectedspecific groups or households. In a recent Canadian epide-miologic study, Russell et al. [40] used multiple linkeddatasets to determine the incidence of HZ in Alberta,Canada and the impact of the varicella vaccination pro-gram, which has been publicly funded since 2002. Similarto our study, they showed that crude rates of medicallyattended HZ episodes increased over the interval of1994–2010. Herpes zoster rate was 3.5 per 1000 person-years in 1994, 3.8/1000 person-years in 1998, 4.0/1000person-years in 2001 and 4.5/1000 person-years by 2010.Rates were higher among females than males over theentire interval, and increased more rapidly for femalesthan males. As in our study, prior to the publicly-fundedvaricella vaccination program in 2002, all age groups expe-rienced increasing annual rates of HZ, but a sharp declinewas seen in those less than 10 years of age for 2002–2010,the period in which varicella vaccination was publiclyfunded by the government. Other recent studies con-ducted in Australia [46], Japan [47] and Taiwan [48, 49]also have found that zoster rates were increasing beforethe introduction of their varicella vaccination programs.Although our study findings is in agreement with thesestudies, our data should be interpreted with caution. Thevaricella impact model we used may not capture the influ-ence on zoster of varicella vaccination, because time pe-riods we used were based on time of varicella vaccinationpolicy changes and we did not allow for the impact of thatvaccination on chickenpox rates to be seen. Because wedid not allow for a lag time to see reductions in childhoodvaricella rates after introduction of a new vaccination pro-gram, we may have missed the true impact of childhoodvaricella vaccination program on HZ rates.In our study we saw a very low PHN incidence of0.343 per 1000 persons compared to the SPS trial [29],which showed the PHN incidence to be 1.38 per 1000 inthe placebo group. In the systematic review conductedby Kawai et al., the risk of developing PHN rangedwidely from 5 % to 30 % because of the different defini-tions used by researchers to classify duration, severity ofpain and also because of differing comorbid illnesses,age and other underlying risk factors from one study toanother [13]. The low incidence of PHN seen in ourstudy is comparable to other studies using administrativedatabases to estimate PHN incidence; these studies aremore likely to report a lower estimated risk of PHNcompared with prospective studies (2.6 % to 6.9 %)[50–53]. This is likely the result of misclassification biaswhen using billing codes rather than actual medical re-cords to delineate PHN. Further, the definition of PHNvaries widely from one study to another and therefore,the incidence varies depending on whether the studyuses the 90 day or 30 definition, making the directaAll Costs were adjusted to 2013 British Columbia Consumer Price Index, Health and Personal CarebPrescriptions on the same day of GP visits related to initial HZ treatment were antivirals (94.5 %), anticonvulsants (5.5 %), antidepressants (3.9 %), corticosteroids(2.6 %), NSAIDS (2.5 %), immunosuppressants (0.1 %), non-NSAID analgesia (0.0 %)cCase refers to the number of patients with at least one related PHN or HZ hospital admission or GP visits 90 days after initial HZ diagnosisdPrescriptions on the same day of GP visits related to HZ treatment were anticonvulsants (40.3 %), antivirals (38.6 %), antidepressants (18.3 %), NSAIDS (6.8 %),corticosteroids (6.5 %), immunosuppressants (0.2 %), non-NSAID analgesia (0.1 %)ePrescription on the same day of GP visits related to PHN were anticonvulsants (61.7 %), antidepressants (27.9 %), NSAIDS (9.8 %), corticosteroids (8.7 %), antivirals(7.5 %), non-NSAID analgesia (0.2 %), immunosuppressant (0.2 %)Marra et al. BMC Infectious Diseases  (2016) 16:589 Page 10 of 13comparison difficult across studies. Regardless of thedefinition, we did see a significant increase in theincidence of PHN between 1997 and 2012. Given thatthe definition of PHN included a diagnosis of zoster, wehad expected to see a rise in PHN incidence but themagnitude of a 3-fold increase was a surprise. Althoughsome of this increase is likely real and the result of theincrease in HZ rates, we feel it may also be related toincreasing recognition and awareness by the public andmedical community about PHN being a common com-plication of zoster. Like previous studies, we also showedthat the highest incidence of PHN was in the older indi-viduals, especially those over the ages of 70 years, but interms of increasing incidence with time, we saw thelargest increase in those 40–49 years and 10–19 years.Understanding of the risk factors for PHN has evolvedover the years; not only are older age, greater pain andrash severity, and presence of a prodrome known to berisk factors for PHN, but newer evidence would suggestimmunosuppression, diabetes and trauma to also be riskfactors for PHN [4, 54]. It may be that the youngercohort are more immunosuppressed due to specificdiseases or medications, or the proportion of youngadults with diabetes is increasing, or perhaps they ortheir parents are more prone to seeking medicalattention for PHN symptoms than the elderly.Between 1997 and 2012, only 0.6 % (6 per 1000 popu-lation) of our HZ cases were hospitalized, and over timewe saw a slight decrease in the hospitalization rate from0.9 % in 1997 to 0.5 % in 2012. Studies that have re-ported on hospitalization rates for HZ show a wide vari-ation with reported rates ranging from 2 to 25/100 000person-years in studies examining all ages [13]; the vari-ation is probably related to differing admission criteriaand whether studies used the HZ primary code or allcodes for diagnosis. In our study, we saw that the meanage of patients hospitalized was higher and in themid-seventies compared to those being seen by theirGPs. Although we did not breakdown our data by age,studies have shown that hospitalization rates increasewith age. For example, Jackson et al. reportedhospitalization rates of 10 per 100,000 in adults 60–69years of age but 65 per 100,000 in adults 80 years old orabove [55]. Rates of hospitalization, in an Australianstudy, showed similar increases from 13 per 100,000 to96 per 100,000 in adults 60–64 years of age and those≥80 years of age respectively [56].In our dataset, despite seeing a slight decrease in thenumber of hospitalizations for the treatment of HZ, wesaw a significant increase in hospitalization costs overtime. We believe, this may be related to more compli-cated cases being admitted for treatment while uncom-plicated cases are being treated as outpatients, as wealso saw an increase in the number of cases seen peryear by GPs with HZ. Ninety-five percent of our HZpatients were treated with antivirals, which is similar torates seen in studies conducted in Germany (71 %) [57],Italy (79 %) [51], and France (94 %) [58]. In general percase treatment costs of inpatients with HZ are approxi-mately $16,000 and outpatients is around $40 per GPvisit (an additional $123 if you include medications).With respect to PHN, we saw that most PHN cases werebeing treated on an outpatient basis, again with anincrease over time with respect to the number of casesbeing seen by GPs. Like HZ, we saw an increase in thetreatment costs associated with PHN. Costs associatedfor PHN treatment in the hospital is approximately$14,000 per case and for outpatients is $53 per visit.Given the numbers of patients who have a diagnosis ofPHN, the annual cost of visiting a GP and receivingtreatment is $75,560 to the healthcare system. It isdifficult to compare cost data to other studies as the ap-proaches used to calculate costs are so different; somestudies look at direct and indirect costs while others, likeours look at direct costs only; some look at outpatientvisits only, while other studies look at all medicalexpenses. Gauthier et al. estimated the mean total costin their study of inpatient to be £103 ($206) per HZ caseand £397 ($794) per HZ case for outpatient care [36].This is in contrast to our study which showed higherhospitalization costs rather than outpatient costs. In anItalian study, the mean inpatient treatment costs for HZwas €2592 ($4147) while outpatient costs were €123($197) [51]. While the trends are similar to our study –higher costs for hospital visits – our costs were muchhigher for HZ hospitalization ($16,389) but similar foroutpatient costs ($160).Although our data with respect to the increase in HZand PHN rates over time agree with previously reportedstudies, this may be an artifact given that ours is an epi-demiological study using large datasets, and we were notable to directly access the accuracy of the administrativedatabase claims through record reviews. As with allstudies using administrative data, we used billing codesmeant for physician billing as our basis to delineatezoster and PHN diagnosis. Because of this, changes incoding or coding errors could have led to an over- orunder-estimation of the results. To try and overcomesome of these issues and increase specificity, we usedalternative definitions and found similar results to ourmain analysis. Our study was limited by the dataavailable in the databases so if patients did not approacha medical facility for their zoster infection or PHN treat-ment, we would not have captured these events or theircosts in our analyses, thereby underestimating their inci-dence; this may be particularly true around PHN-relatedcosts as patients could have had alternative treatmentsfor pain control. It is also possible that increasing HZMarra et al. BMC Infectious Diseases  (2016) 16:589 Page 11 of 13and PHN rates are simply due to improved coding andawareness. This may be especially true after the herpeszoster vaccine was marketed in 2008 as both the publicand the medical community have been better educatedon signs and symptoms of herpes zoster, the use of anti-virals and analgesics for its treatment and complicationsarising from zoster infection, particularly PHN. Aroundthe time the zoster vaccine was marketed in Canada,pharmacists received the authority to immunize and oneof the vaccines they are heavily promoting to theirclients is the herpes zoster vaccine, further enhancingawareness of the disease. However having said that, weknow that between 2008 and 2012, the herpes zostervaccine was marketed as a freezer-stable product andthe uptake rate of the vaccine was less than 10 %.Although we adjusted for age and sex, we are not able tocontrol for all the potential confounders which may haveaffected the HZ and PHN rates. In particular, the pro-portion of the population which has comorbidities suchas diabetes mellitus (a known risk factor for HZ), andimmunocompromising conditions such as solid organtransplants, cancer, leukemia/lymphoma, or being onmedications that decrease T-cells (TNF-alpha inhibitors,DMARDS, corticosteroids) has increased over time,leading to increased numbers of patients being at riskfor HZ/PHN [59]. Finally, as with all epidemiologicalstudies, there may be additional risk factors for zosterand PHN that we are unaware of at the present timeand these would not have been adjusted for in our study.ConclusionsIn conclusion, we found the incidence of zoster andPHN is increasing with time. Although there are wellknown risk factors, such as age, female gender and beingimmunocompromised, which are contributing to the in-creased incidence seen with time, there are obviouslyrisk factors present which are more difficult to tease out,such as trauma, psychological stress, race, and familyhistory. Understanding the epidemiology and risk factorsof HZ is critical for better targeting of treatment andprevention strategies.Additional filesAdditional file 1: Table S1. Description of the datasets used for datalinkage. Table S2. Definitions for immunosuppression. Table S3. Crudeand Age-Sex Standardized Incidence Rate and 95 % Confidence Intervalby Year. Table S4. Rate Ratio of Age-Sex Standardized Mean Annual Inci-dence Rate and 95 % Confidence Interval with Bonferroni Correction forMultiple Comparison. Table S5. Rate Ratio on Herpes Zoster Incidenceand 95 % Confidence Interval Using a Regression Model. (DOCX 28 kb)AcknowledgementsWe would like to thank the Ministry of Health and PopulationDataBC forproviding us the dataset to analyze for this study and to Drs Simon Dobsonand Carlo Marra for reviewing the manuscript.FundingThis work was supported by a grant to the University of British Columbiafrom Merck Canada. The University of British Columbia’s UILO office hadensured that the study investigators had complete autonomy with respectto development of the protocol (including case definitions and outcomes toevaluate), carrying out the analyses and interpreting the results. The authorsreceived no financial support or other form of compensation related to thedevelopment of the manuscript or dissemination of the results.Availability of data and materialThe datasets supporting the conclusions of this article are available in thePopulationDataBC repository. However, the data cannot be shared withanyone except the PI for the study and the biostatistician, as per policies setby the data holders, Population DataBC and the BC Ministry of Health.Authors’ contributionsFM was responsible for the design, implementation, interpretation anddrafted the manuscript. MC was responsible for the study design, carried outthe statistical analysis and wrote the results portion of the manuscript. MNhelped with data interpretation and helped to draft the manuscript. Allauthors read and approved the final manuscript.Competing interestsNone of the authors have received reimbursements, fees, or salary from anorganization that may in any way gain or lose financially from thepublication of the manuscript, either now or in the future. None of theauthors hold stocks, shares or patents in an organization that may in anyway gain or lose financially from the publication of the manuscript.Consent for publicationOur manuscript does not contain data from any individual person, andtherefore this section is not applicable.Ethics approval and consent to participateEthics approval was obtained for this study from the University of BritishColumbia’s Behavioural Ethics Committee.Author details1University of British Columbia, Vancouver, BC, Canada. 2JC2 Answers,Vancouver, BC, Canada. 3Brigham and Women’s Hospital, Harvard MedicalSchool, Boston, USA. 4University of British Columbia, 2405 Wesbrook Mall,Vancouver, British Columbia V6T 1Z3, Canada.Received: 24 June 2016 Accepted: 5 October 2016References1. Miller E, Marshall R, Vurdien J. Epidemiology, outcome and control ofvaricella-zoster infection. Rev Med Microbiol. 1993;4(4):222e30.2. Heininger U, Seward JF. Varicella. Lancet. 2006;368(9544):1365–76.3. Hope-Simpson RE. 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