Incidence and Burden of Herpes Zoster in Sweden: A Regional Population-Based Register Study

We conducted a retrospective, observational, non-interventional database study based on medical records in Sweden for patients registered with a diagnosis of HZ or associated complications. Medical data were obtained from the VEGA database, which contains anonymised patient-level healthcare information for all contacts registered within the VGR healthcare system from 2005 onwards. In our analyses, we identified all registered incident cases of HZ in the VGR population, including cases with HZ complications and cases with high-risk conditions, based on the International Classification of Diseases 10th revision (ICD-10) codes and drug prescriptions (as applicable) (Tables S1, S2, S3 and S4) [24].

We used national data from Statistics Sweden [25], the Swedish National Board of Health and Welfare [26], the Swedish Social Insurance Agency [27‐29] and the Swedish National Diabetes Register [30]. Regional data for VGR were obtained from the VEGA database, which contains primary care, secondary/specialised care and inpatient care data, as well as from the Digitalis register, which contains data on prescribed medicines. The Swedish Ethical Review Authority deemed that informed consent was not required for this study.

The study population comprised individuals ≥ 18 years old residing in VGR between 2005 and 2021. The population of VGR was considered representative of the national population, with a comparable profile of age, gender and proportion of the population born outside Sweden (Fig. S1).

A new case of HZ was defined as an entry with the ICD-10 code B02 and that had at least one registered primary or secondary diagnosis between 2005 and 2021 (Table S1). In addition, an HZ case was considered to be a new episode if the individual had no prior HZ diagnosis during the preceding 365 days. The incidence analysis used a moving window approach, with a washout period of 365 days to prevent double counting of prevalent cases of HZ and to differentiate between recurrent and existing cases. HZ with complications was defined as any HZ episode with subsequent complications within 365 days of the initial diagnosis. Cases with cerebral and cardiovascular complications were defined by a registered care event within 1 year after the HZ index event and a diagnosis involving the specific ICD-10 codes described in Table S3. Data for the incidence of cerebral and cardiovascular complications in the general population were obtained from the Swedish National Board of Health and Welfare statistics database [26]. Analysis of HZ complications also included cases of PHN, where PHN was defined as pain persisting for > 90 days following rash onset or cutaneous healing. The PHN cases were identified based on one of two ICD-10 codes, B02.2 or G53.3 (Table S2) [24]. To investigate potential cases of PHN in the absence of a specific PHN diagnosis, disease episodes with a drug prescription for neuropathic pain were also included. Such cases were included if the index HZ event occurred in 2017 (with follow-up until 31 December 2019). This particular time period was chosen to ensure that we had sufficient PHN cases for the analysis and to describe the duration of PHN. We included cases of patients who had been prescribed analgesics for neuropathic pain with the following Anatomical Therapeutic Chemical (ATC) codes: N01BX04 (capsaicin), N03AX12 (gabapentin), N03AX16 (pregabalin), N06AA09 (amitriptyline) and N06AX21 (duloxetine) [31, 32]. Patients with an HZ episode that included a prescription for these drugs in 2016 or prior to an index event in 2017 were excluded.

Cases in high-risk groups were defined as at least one healthcare visit with a registered high-risk diagnosis (defined by ICD-10 code) prior to the HZ index event and after 2005 (Table S4). Inclusion in the solid organ tumour group required at least two healthcare visits with a solid organ tumour diagnosis within a 1-year washout period prior to the HZ index event. Prevalence data for risk groups within the general population were collected from the Swedish Diabetes Register for diabetes type 1 and 2, COPD and asthma and from the Swedish National Board of Health and Welfare statistics database for the remaining high-risk conditions. An episode with a drug prescription for high-risk groups included both an index event and an analgesics prescription in 2019. Patients in a high-risk group with an analgesic prescription in 2018 or prior to an index event were excluded.

The standardised cumulative risk of HZ was estimated according to the previously published standardised lifetime risk-method [33]. The municipalities with the five highest and lowest incidence rates of HZ in 2019 were used to define the range of lifetime risk in VGR (excluding recurrences).

The recurrence analysis was based on two cohorts with index events in 2011/2012 and 2014/2015, with a washout period of 365 days and a follow-up period until the end of 2021 and 2019, respectively. Time to first recurrence was calculated based on the time between the first index event to the first recurrent index event.

The characteristics of patients diagnosed with HZ were stratified by age, sex, geography and diagnosis based on ICD-10 codes and drug prescriptions. Specifically, age groups were divided into 18–49, 50–59, 60–64, 65–69, 70–79 and ≥ 80 years old. Complications following an HZ episode were based on ICD-10 codes and included PHN, cerebral and cardiovascular complications among others (Table S2 and S3). The incidence rates of those non-PHN complications were estimated and compared between HZ patients and the general population of VGR. A comparison between patients with HZ and the general population of VGR was performed to estimate the incidence of other non-PHN complications. The average standardised cumulative risk of HZ, incidence rates for each high-risk group and the individual risk of HZ recurrence in different age groups were estimated. High-risk groups included patients with predefined/pre-identified immunocompromised conditions, comorbidities and autoimmune conditions (Table S4).

We utilised descriptive statistics such as the mean (standard deviation) for continuous variables and proportions/percentages for qualitative variables. Incidence rates (95% confidence intervals [CI]) were calculated as the ratio of HZ cases to the total person-years (PY) in VGR county during the same time period. Similarly, the incidence of PHN (95% CI) was calculated as the ratio of HZ cases with PHN to the total PY in VGR county during the same time period. Additionally, in some analyses, the incidence rates of PHN were calculated as a proportion of all HZ cases. Non-PHN complications were included as a percentage of the total number of cases. The incidence rates were stratified by sex and age at diagnosis in the categories 18–49, 50–59, 60–64, 65–69, 70–79 and ≥ 80 years. The standardised cumulative risk including recurrent cases was estimated using 5-year age groups (apart from the youngest age group, 18–24, which was 7 years) as previously described by Sasieni and Adams (1999) [33]. Additionally, incidence rates for each high-risk group and the individual risk of HZ recurrence in different age groups were estimated.

We adjusted for socioeconomic status using the Care Need Index (CNI) score [34]. The score is based on a weighted population grouping of the following variables: level of education, share of foreign-born individuals, unemployment, single parents, newly moved-in individuals, children 0 to 5 years old and single-household elderly. We obtained CNI scores from Statistics Sweden for each primary care unit in VGR. The CNI scores and age at diagnosis scores were used in a univariate regression model, with occurrence of HZ as the dependent variable. Calculations were made for cases diagnosed during 2019 to avoid the subsequent disruptions to healthcare visits and diagnoses caused by the coronavirus disease 2019 (COVID-19) pandemic. We used R software to perform the statistical analyses [35].

We identified a total of 75,538 individuals who were diagnosed with HZ (excluding recurrent cases) in VGR between 2005 and 2021. When recurrent cases were included, 82,712 cases of HZ were identified for the same period. The overall incidence of HZ episodes (including recurrent cases) from 2005 to 2021 for all age groups ≥ 18 years old in Sweden was 3.77 episodes per 1000 PY (95% CI 3.74–3.79). In the same period, the overall incidence of PHN (including recurrent cases) was 0.24 episodes per 1000 PY (95% CI 0.23–0.24). Notably, cumulative incidence of all HZ episodes increased from 2.50 (95% CI 2.4–2.6) in 2005 to 4.20 (95% CI 4.1–4.3) in 2021 per 1000 population, respectively (Fig. 1). During the period 2005 to 2013, incidence increased rapidly followed by a plateauing trend. From 2014 to 2019, in the pre-COVID-19 pandemic period, overall average incidence was 4.20 (95% CI 4.1–4.3) per 1000 population, with a temporary drop to 3.90 (95% CI 3.8–4.0) in 2020. Approximately 14.0% of all HZ episodes were diagnosed with complications (Fig. S2). During the study period of 2005–2021 there was a 5-fold increase in PHN in overall incidence rate, raising from 0.07 in 2005 (95% CI 0.05- 0.08) to 0.37 in 2021 (95% CI 0.35–0.40) (Fig. 2B). During the same period, the portion of patient with HZ developing PHN increased 3-fold, raising from 2.80% in 2005 to 8.74% of the cases in 2021 (Fig. 1), From 2019 to 2021, the incidence rate of PHN remained stable with 0.36, 0.39 and 0.37 cases per 1000 PY in 2019, 2020 and 2021, respectively.

Overall, 58.6% of all patients with a diagnosis of HZ were women (Fig. S3). When the results were stratified by age group, we observed that from 2005 to 2021 the incidence of HZ increased among individuals ≥ 50 years old (Fig. 2A, B). Specifically, the incidence of HZ in those aged 50–59 years increased from 2.43 to 4.01 per 1000 PY between 2005 and 2021. For the same period, HZ incidence among the ≥ 80-year age group increased from 7.2 to 11.7 per 1000 PY. Overall, the cumulative incidence of HZ for those aged 50–59 years was 3.59 per 1000 PY (95% CI 3.52–3.65), which peaked at 9.94 per 1000 PY (95% CI 9.77–10.10) for the ≥ 80-year age group (Table S5). When analysing PHN complications between 2005 and 2021, stratified by age groups, we observed that 83.1% of PHN cases occurred in individuals aged ≥ 60 years. Non-PHN complications were most common in the two oldest age groups (70–79- and ≥ 80-year age groups) (Fig. S4).

When analysing the proportion of HZ patients with neuropathic pain based on PHN diagnosis or an HZ diagnosis plus a prescription for an analgesic, 19.1% (95% CI 18.0–20.2%) of all patients diagnosed with HZ in 2017 developed neuropathic pain between their diagnosis and 2019 (the end of the follow-up period). This proportion increased to 21.8% (95% CI 20.7–23.5%) when analysing the ≥ 50-year age groups. The overall incidence of PHN based on diagnosis and analgesic prescriptions increased from 0.36 cases per 1000 PY (PHN diagnosis only) in 2017 to 0.58 cases per 1000 PY in 2019 when diagnosis and an analgesic prescription against neuropathic pain with a duration of > 90 days was considered.

In terms of age groups, we observed that the share of HZ episodes with a PHN diagnosis and/or an analgesic prescription that lasted for > 90 days increased with increasing age. The corresponding rates among the 50–59, 60–64, 65–69, 70–79 and ≥ 80 year age groups were 10.7%, 10.8%, 11.3%, 17.1% and 24.5%, respectively (Fig. 3). Across all age groups, 13.6% (95% CI 12.6–14.5%) of HZ patients (15.7% of HZ patients ≥ 50 years old) received either a diagnosis of PHN or an analgesic prescription that lasted for > 90 days (without a PHN diagnosis).

When comparing the incidence of cerebral and cardiovascular complications between patients with HZ and the general population (within the 2012 to 2020 period), we found that incidence of both complications increased among patients with HZ, and also with an increase in age. The highest incidence was observed among those ≥ 80 years old who developed cerebrovascular disease (1.4% among patients with HZ versus the baseline incidence rate of 0.18% among the general population) (Table S6).

The prevalence of HZ was analysed by geographical municipality for the year 2019 (but not for 2020 or 2021 because of the disruption caused by the COVID-19 pandemic) among individuals ≥ 18 years old and those ≥ 65 years old. Among those ≥ 18 years old, large geographical differences in HZ prevalence were observed, with more than twice as many cases in Bengtsfors (7.4 per 1000 inhabitants) than in Mölndal (3.2 per 1000 inhabitants) (Fig. 4A). Among those ≥ 65 years old, a similar difference in HZ prevalence was observed between the municipalities with the highest (Bengtsfors, 14.0 per 1000 inhabitants) and lowest prevalence (Hjo, 6.4 per 1000 inhabitants) (Fig. 4B).

We did not observe any meaningful correlation between HZ incidence and socioeconomic status based on our analysis of data from 2019 (R² coefficient of the CNI score = 0.15). In VGR, the average lifetime risk of HZ (excluding recurrent episodes) between 2014 and 2019 was estimated to be 36.5% (95% CI 35.5–37.4%). Lifetime risk (excluding recurrent episodes) ranged from 34.4% (95% CI 32.4–36.4%) to 43.6% (95% CI 40.0–47.3%) in the municipalities with the five lowest and highest incidences, respectively (Fig. S5). For the 2019 period, we observed that the lifetime risk of HZ (excluding recurrences) in municipalities with the highest HZ incidence varied between 40.6% and 50.1%.

We analysed treatment rates for 2019, based on time to prescription and collection in terms of the number of days from an HZ index event. Among those ≥ 50 years old, 69% of HZ cases were prescribed antivirals within 3 days of the date of the index event, while 67% of HZ cases collected their medication within 3 days of the date of the index event. Between 2014 and 2019, approximately 8% of patients with HZ seen in specialised outpatient care were treated at an infection clinic compared with 5% in 2020.

For the 2014–2019 period, we identified a total of 1449 cases of HZ among patients with a high-risk diagnosis in the 18–49-year age group, 2799 in the 50–64-year age group and 9446 in 65 +-year age group (excluding HIV). Most patients had diabetes (n = 3057), followed by autoimmune diseases (n = 2291). The incidence rate for HZ was highest among those with inflammatory system diseases (ICD-10 codes M33-M35), incidence rate (IR) = 105.4 (95%CI 99.0–111.8) for individuals ≥ 18 years, IR = 20.7 (95% CI 14.7–26.7) in the 18–49-year age group, IR = 46.1 (95% CI 37.9–54.4) in 50–64-year age group and IR = 173.9 (95% CI 162.3–185.4) in the 65 +-year age group, per 1000 PY, respectively. All patients with comorbid conditions had considerably higher incidence rates compared with patients without such conditions (Table 1A and B) and HZ prevalence was highest among the oldest age group. Notably, among those with multiple sclerosis and HIV, younger individuals were more affected by HZ (Fig. S6).

The proportion of PHN cases (registered diagnosis only) within high-risk groups was calculated for 2012–2020. The highest proportion of HZ cases with PHN was observed in patients with COPD and in patients with SLE (15%, respectively). This shows a much higher occurrence of PHN complication in these populations compared to the general population where 8% of patients with HZ had PHN complications. The share of HZ cases with PHN based on analgesics prescriptions and a diagnosis of PHN among high-risk patients varied from 12% for patients with a diagnosis of psoriasis to 27% for patients diagnosed with SLE (Fig. S7).

The recurrence of HZ in VGR was calculated from two cohorts, namely the 2011/2012 cohort with follow-up until 2021 (10.5 years follow-up) and the 2014/2015 cohort with follow-up until 2019 (5.5 years follow-up). The recurrence rate of HZ was observed to be 9.1% and 8.7%, respectively. For the 2011/2012 cohort, the average time from an index event to first recurrence was 1590 days (range: 365–3959 days) with an average of 1.3 recurrences per patient; for the 2014/2015 cohort, it was 946 days (range: 365–1960 days) with an average of 1.1 recurrences. When stratified by age group, HZ patients in the 2011/2012 cohort aged ≥ 50 years had higher recurrence rates than those aged 18–49 years (5.3%). Similarly, for the 2014/2015 cohort the recurrence rate among patients with HZ who were ≥ 50 years old was higher than in the 18–49-year age group (4.6%) (Table 2).