Systematic Literature Review on the Incidence of Herpes Zoster in Populations at Increased Risk of Disease in the EU/EEA, Switzerland, and the UK

A systematic review of the literature was performed, following Cochrane Collaboration [17] and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [18] for performing and reporting systematic reviews. The search was performed in Medline (via PubMed) and Embase, for publications in English, German, Dutch, French, Spanish, and Italian, from January 1, 2002 to January 1, 2022, and combined search terms for HZ, incidence, high-risk populations, and countries of interest (see Supplemental file 1). Study designs of interest were prospective and retrospective observational studies e.g., cohort studies, passive surveillance studies and other controlled/uncontrolled studies.

The grey literature was also searched using disease search terms (e.g., zoster, shingles), in international health websites [19‐24] and websites of the Ministries of health, national statistics and national public health institutes of six key countries for which limited data were published i.e., France, Portugal, Norway, Switzerland, Denmark, and Finland.

During the abstract and title screening (selection step 1), studies were included based on relevant outcomes (i.e., HZ incidence in the high-risk population) and excluded based on population (i.e., not IC patients); study design (i.e., models, sample size smaller than 30, phase I, II and III trials); geography (i.e., country out of scope); and type of publication (i.e., letters, editorials, comments). Two researchers independently performed this step and discussed any discrepancies (N.V., H.V.). Fewer than 5% of the abstracts required review and discussion.

During full-text screening of articles selected in step 1, studies that answered the review question were included. Exclusion criteria related to populations (i.e., non-relevant high-risk populations, combined relevant and non-relevant high-risk populations without stratified data, unclear if secondary VZV infection only); country (i.e., combined relevant and non-relevant countries without country-specific data, country not stated); methods (i.e., no quantitative data or only data in figures, insufficient methodological details, insufficient methodological quality); and reporting (i.e., narrative review, no methods section). Two researchers independently checked the first 10% of full-text articles for relevancy (N.V., H.V.). There was agreement on all selections.

To ensure reproducibility, the study selection process was documented in an EndNote Library with the reasons for exclusion of full-text publications in an MS Excel table.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data were extracted into an Excel database by one researcher (N.V.) and reviewed by another (H.V.). Standard evidence tables were used to extract data on: First author, publication year, journal; Country; Study design; Study period and setting; Study population (inclusion and exclusion criteria, sample size, age groups, gender, ethnicity, underlying high-risk conditions; Methodology (IC definition, HZ case detection, HZ case definition, type of patients and incidence denominator); HZ incidence (defined as incidence rate [incidence per 1000 person-years], cumulative incidence [incidence per 1000 persons], or relative incidence [number of cases as a percentage of study population]) by year, gender, age, ethnicity, high-risk population, and treatment option; Comments or quality issues from authors; and Quality assessment tool. The primary outcomes were HZ incidence rate and cumulative incidence, while the relative incidence was a secondary outcome.

The methodological quality of studies was assessed based on representativeness of the target population, validity of the HZ case definition, and use of a properly defined incidence denominator. Most of the included studies were surveillance studies, non-comparative studies, or comparative studies that are not cohort or case–control studies. As there are no formal validated checklists available for these study types, a previously-developed quality assessment tool was used to critically appraise and describe the methodological quality of incidence and prevalence studies. This tool was adapted further, in collaboration with an HZ expert, to focus specifically on HZ incidence studies [16] (see Supplemental file 2).

Feasibility of conducting a meta-analysis was assessed according to Cochrane criteria [17]. From an overview of studies that reported on the same outcome measure with a corresponding 95% confidence interval (95% CI), the comparability of the studies and similarity of the results was discussed to decide on the feasibility of a meta-analysis. As many included studies were non-comparative observational studies, the assessment mainly focused on comparability of study characteristics (i.e., setting, period, definition of HZ and high-risk disease) and of population characteristics (i.e., type of high-risk disease, age, gender, antiviral prophylaxis; or other medications).

GlaxoSmithKline Biologicals S.A. (VEO-000054) funded this literature review and all costs related to the development of the publication, including the journal’s Rapid Service Fee.

Seven studies [30, 34, 37, 38, 41, 47, 48] reported HZ incidence rates in the subgroup of solid organ transplant recipients, all studies focused on adult patients (≥ 18 years). The HZ incidence rate per 1000 person-years ranged from 12.1 in a mixed group of solid organ transplant patients [48] to 78.8 in kidney transplant patients [30].

A retrospective study (N = 1033) reported incidence rates by type of solid organ transplantation [34]. The highest incidence was found in patients with a lung transplant (38.8), followed by heart transplant (30.7), liver transplant (22.7), and kidney transplantation patients (14.5) [34]. Another retrospective study in lung transplant patients (N = 119) reported similar incidence rates (38.2 [47] vs. 38.8 [34]). A prospective study (N = 444) [30] and a retrospective study (N = 450) [38] in kidney transplant patients reported higher incidence rates (20.6 [38] and 78.8 [95% CI 54–104] [30]). All three studies in kidney transplant patients [30, 34, 38] included adult outpatients with HZ diagnosed based on clinical signs. In one of these studies, incidence was found to be higher in patients ≥ 60 years (43) versus < 60 years of age (16.7) [38]. Three studies [37, 41, 48] reported incidence rates in a group of combined solid organ transplant patients (i.e., ranging from 12.1 [48] to 14.5 [41] in transplant patients versus, for non-IC patients, 4.6 [95% CI 4.6–4.7] in Spain [37], 5.9 [95% CI 5.8–5.9] in Germany [41], and 6.2 [95% CI 6.1–6.3] in England [48]). Higher incidence rates were found in the older age categories (e.g., 17.0 in 60–69 years and 17.3 in ≥ 80 years versus 6.0 in 18–29 years of age in Spain [37], and 16.9 in ≥ 80 years versus 11.0 in 18–49 years of age in England [48]).

Three studies [37, 41, 48] reported HZ incidence rates in stem cell transplantation patients aged ≥ 18 years, ranging from 37.2 (95% CI 32.0–43.0) [41] in in- and outpatients in Germany receiving stem cell transplantation (including HSCT) to 56.1 (95% CI 48.9–64.0) [37] in HSCT patients in Spain. Incidence rates were significantly lower in non-IC patients (e.g., 5.9 [95% CI 5.8–5.9] in Germany [41], 4.6 [95% CI 4.6–4.7] in Spain [37], and 6.2 [95% CI 6.1–6.3] in England [48].)

Incidence rates reported peaked in 50–59 year-olds (69.2 vs. 5.5 in non-IC patients) in Spain [37] and 60–64 year-olds (60.3 vs. 6.9 in non-IC patients) in England [48]. Lower rates were reported in younger age groups (42.4 in 18–29 year-olds [37] and 34.1 in 18–49 year-olds [48], vs. 2.1–2.3 in non-IC patients [37, 48]), as well as in older age groups (52.0 in 70–79 year-olds [37] and 47.0 in 65–69 year-olds [48], vs. 8.6–9.3 in non-IC patients [37, 48]).

Four studies [25, 37, 43, 48] reported HZ incidence rates in a mixed group of hematological malignancies [37, 48], in myelofibrosis (MF) [25], and chronic lymphocytic leukemia (CLL) [43].

The lowest incidence rate was reported in the Swedish Cancer Registry for CLL in- and outpatients (N = 8989), who had an 11.3 (95% CI 8.4–15.3) times greater risk of HZ versus controls (2.94 vs. 0.26) [43]. In a multinational study in MF patients (N = 462), HZ incidence was increased in ruxolitinib users versus non-ruxolitinib users (3) i.e., incidence varied in long-term (37), short-term (29), new (59) users and patients who switched to ruxolitinib during the study (43) [25]. In the mixed group of hematological malignancy patients in Spain [37] and England [48], the incidence rate in adults ≥ 18 years was 12.0 (95% CI 11.5–12.5) versus 4.6 (95% CI 4.6–4.7) in non-IC controls [37] and 15.2 (95% CI 14.5–16.0) [48] versus 6.2 (95% CI 6.1–6.3) in non-IC controls, and increased with age to 18.4 (95% CI 16.1–21.0) vs. 6.9 (95% CI 6.6–7.2) [48] in 60–64 year-olds, and to 20.1 (95% CI 18.4–21.9) vs. 9.3 (95% CI 9.2–9.4) [37] in 70–79 year-olds.

Ten studies [26, 31, 37, 39‐42, 44, 46, 48] reported the HZ incidence rates in patients with rheumatoid arthritis (RA), ranging from 0.41 in adult UK in- and outpatients using rituximab [40] to 21.5 in German outpatients of all ages treated with Janus kinase-inhibitors (JAK-inhibitors) [39]. There was heterogeneity across HZ case definitions used (clinical diagnosis versus MedDRA), study populations, and medication types. This heterogeneity might explain the broad range of HZ incidence rates.

Four studies reported the HZ incidence rate by type of medication (Table 2), with the high rates in patients treated with JAK-inhibitors (21.5) [39], infliximab (20.0) [31], etanercept and anti-TNF agents (both 16.0) [31], adalimumab (13.0) [31], B-cell-targeted therapies (10.3) [39] and infliximab/adalimumab (11.1) [44]. A second UK study [40] focusing on serious opportunistic infections (OIs) in RA patients starting on biologic therapies (mean age 56.7 years [SD 12.3]) reported that HZ was the most common OI with an overall incidence rate of 0.59 (based on 61 HZ cases, from 2001 to 2016) [40]. The considerably lower incidence rate in this study may be due to the inclusion of severe cases only, as the other UK study [31] identified 320 HZ cases using the same database (British Society for Rheumatology’s Biologics Register) over a shorter duration (2001–2009).

HZ incidence was compared in males versus females with RA, and found to be comparable (7.7 vs. 7.9) [44]. In a retrospective matched cohort study in Germany, HZ incidence in RA patients followed over 10 years appeared to be stable over time (2008: 10.0; 2018: 10.5) [26]. In a passive surveillance study in Germany, HZ incidence in RA versus polymyalgia rheumatica patients was comparable (16.2 vs. 15.8) [41].

Three studies reported HZ incidence rates in adults aged ≥ 18 years with systemic lupus erythematosus (SLE) [37, 41, 48] and one with lupus erythematosus [41].

Incidence rates in SLE patients were 11.0 (95% CI 9.8–12.3) vs. 6.2 (95% CI 6.1–6.3) in non-IC patients in a matched cohort study in England [48], and 13.4 vs. 4.6 in non-IC patients in a retrospective study in Spain [37]. Higher rates were reported in older age groups (7.9–12.8 in < 70 years vs. 17.2–18.1 in ≥ 70 years (compared with non-IC patients, 2.1–8.6 in < 70 years and 11.0 in ≥ 70 years) [48]; and 8.4–9.8 in < 50 years vs. 17.2–21.8 in ≥ 50 years (compared with non-IC patients, 2.3–2.8 in < 50 years and 5.5–9.5 in ≥ 50 years) [37]. Comparable incidence rates were reported from a passive surveillance study in Germany, in patients with SLE versus lupus erythematosus (SLE 16.5 [95% CI 14.4–18.9] vs. lupus erythematosus 16.2 [95% CI 14.6–17.9]), compared with non-IC patients (5.9 [95% CI 5.8–5.9]) [41].

Five studies in HIV patients [32, 33, 37, 41, 48] reported HZ incidence rates, ranging from 11.8 [48] in England to 13.0[41] in Germany among adults (≥ 18 years), compared with 5.9 (95% CI 5.8–5.9) in non-IC patients in Germany [41].

Three studies reported incidence by age groups [33, 37, 48]. A higher incidence rate was reported among patients ≥ 40 years (13.4–13.5) versus younger age groups (4.8–12.0) in a prospective comparative study in Germany, with the risk of HZ remaining significantly higher than in the general population (incidence of 1.5–3.3 reported in Western countries) [33]. Incidence rates were 12.9 (95% CI 12.0–14.0) versus 4.6 (95% CI 4.6–4.7) in non-IC patients in a retrospective study in Spain [37], and 11.8 (95% CI 9.5–14.4) vs. 6.2 (95% CI 6.1–6.3) in non-IC patients in a matched cohort study in England [48]. In a passive surveillance study in France [32], the incidence rate was found to be lower in the period 2009–2011 versus 1992–1996 (6.3 vs. 29.5), while remaining significantly higher than incidence in the general population (2.7 [95% CI 2.6–2.9]) [32].

In a passive surveillance study in HIV and AIDS patients in Spain, incidence was higher in females versus males (15.2 vs. 11.6) [29].

Five studies [26‐29, 36] reported HZ incidence rates in asthma and COPD patients, ranging from 4.7 in adult asthma patients treated with inhaled corticosteroids [27] to 11.2 (95% CI 9.9–12.5) in elderly asthma patients [28] and from 7.4 in COPD patients aged 50–59 years using no inhaled corticosteroids to 14.2 in COPD patients ≥ 80 years on inhaled corticosteroids [36]. In studies reporting HZ incidence rates in both asthma and COPD patients, rates were higher in COPD patients i.e., 6.9 vs. 11.4 (passive surveillance study in Spain) [29] and 5.9–7.2 vs. 8.2–8.7 (range of annual rates from German retrospective matched cohort study over 10 years [26]).

In adult asthma patients, the HZ incidence rate was 1.2–1.4 times higher than in controls [26, 28, 29], and up to 1.5 times higher in asthma patients on oral versus inhaled corticosteroids [27]. The HZ incidence rate in Spain (N = 4476, passive surveillance, primary care data 2009–2012) was 6.9 for asthma patients (adjusted incidence rate ratio [IRR] 1.3 [95% CI 1.3–1.4] versus controls) and was higher in women versus men (8.1 vs. 4.9) [29]. A similar incidence rate of 7.2 was reported in Germany (retrospective matched cohort, hospital data 2018) versus 5.3 in matched controls (adjusted odds ratio [aOR] 1.2 [95% CI 1.2–1.3]) [26]. The incidence rate was higher in elderly asthma patients in England (primary care and hospital data 2013–2016): 11.2 (95% CI 9.9–12.5) versus 9.3 (95% CI 8.8–9.9) in general population controls [28]. A study in the UK (N = 4432, primary care and hospital data 2000–2015) found that HZ incidence rates were higher for asthma patients who have used oral corticosteroids (6.1, adjusted IRR 1.3 [95% CI 1.2–1.4]) or are using oral corticosteroids (7.2, adjusted IRR 1.5 [95% CI 1.4–1.7]) versus those on inhaled corticosteroids alone (4.7) [27].

In adult COPD patients, the HZ incidence rate was 1.1–1.5 times higher [26, 29, 36], and up to 1.6 times higher for COPD patients on inhaled corticosteroids [36], versus controls without COPD. The HZ incidence rate in Spain (N = 2894, passive surveillance, primary care data 2009–2012) was 11.4 for COPD patients (adjusted IRR 1.3 [95% CI 1.2–1.3] in men and 1.2 [95% CI 1.2–1.3] in women versus controls) and was higher in women versus men (12.9 vs. 10.8) [29]. HZ incidence rate was also higher for COPD patients in Germany versus controls (8.7 vs. 7.3, OR 1.1 [95% CI 1.0–1.1] based on hospital data for 2018 (retrospective matched cohort) [26]. In Spain (N = 5793, passive surveillance, primary care and hospital data 2009–2014), HZ incidence rates were higher for COPD patients aged ≥ 50 years (adjusted relative risk [aRR] 1.5 [95% CI 1.4–1.5], and even higher for COPD patients on inhaled corticosteroids (aRR 1.6 [95% CI 1.5–1.7]) versus patients without COPD [36]. Incidence rates for non-COPD controls, COPD patients not on inhaled corticosteroids, and COPD patients on corticosteroids, respectively, increased with age from 5.3, 7.4 and 10.6 (aged 50–59 years) to 8.6, 12.8 and 14.2 (aged ≥ 80 years), respectively [36].

One Italian study (N = 1553, hospital data 2013–2015) reported 2-year HZ cumulative incidence per 1000 persons (6.8) in COPD patients aged ≥ 50 years versus 4.7 in patients not at risk of HZ (p < 0.01) [50]. In this study, patients at risk of HZ were defined according to the Italian National Vaccine Prevention Plan (2017–2019) i.e., cardiovascular disease, COPD, diabetes, immunosuppression [50].

Three studies [29, 37, 48] reported HZ incidence rates, ranging from 8.8 [48] to 11.0 [37], in patients aged ≥ 18 years with various solid organ malignancies versus 4.6–6.2 in non-IC controls. Higher incidence rates [95% CI] were reported in older age groups versus non-IC controls (among patients aged 50–59 years: 10.2 [9.7–10.9] vs. 5.5 [5.4–5.6] in Spain [37] and 6.8 [6.4–7.3] vs. 4.9 [4.7–5.1] in England [48]; among patients aged ≥ 80 years: 12.0 [11.4–12.6] vs. 9.5 [9.4–9.7] in Spain [37] and 11.6 [11.1–12.2] vs. 11.0 [10.6–11.4] in England [48]), and in females versus males (10.8 vs. 9.0) [29].

Three studies [37, 41, 48] reported HZ incidence rates in adults ≥ 18 years with IBD [37, 48], Crohn’s disease [41] and ulcerative colitis (UC) [41] that were 1.1–1.8 times higher than in non-IC patients.

In Spain, IBD patients ≥ 18 years (N = 28,700, hospital and primary care data 2009–2014) had significantly higher HZ incidence rates versus non-IC patients (8.3 [95% CI 7.8–8.8] vs. 4.6 [95% CI 4.6–4.7]). Incidence rates increased with age from 4.8 (95% CI 3.7–6.3) versus controls 2.3 (95% CI 2.2–2.3) in younger adults aged 18–29 years, to 16.2 (95% CI 13.2–19.7) versus controls 9.5 (95% CI 9.4–9.7) in older adults aged ≥ 80 years [37].

In a matched cohort study in England (N = 31,884, hospital and primary care data 2000–2012), HZ incidence rate was 7.0 (95% CI 6.6–7.4) in IBD patients ≥ 18 years versus 6.21 (95% CI 6.1–6.3) in controls. Incidence rates increased with age from 4.0 (95% CI 3.6–4.5) versus controls 2.1 (95% CI 2.0–2.2) in patients aged 18–49 years, to 13.9 (95% CI 11.6–16.4) versus controls 11.0 (95% CI 10.6–11.4) in older adults aged ≥ 80 years [48].

From German claims data (hospital data 2012), HZ incidence rates in adults ≥ 18 years were 10.8 (95% CI 10.2–11.4) for UC and 10.7 (95% CI 9.9–11.4) for Crohn’s disease versus 5.9 (95% CI 5.8–5.9) for non-IC patients [41].

Three studies [26, 29, 35, 37] reported HZ incidence rates in patients with DM, ranging from 4.3–6.3 in T1DM to 7.0–7.9 in T2DM (between 2008 and 2018) [26], and ranging from 6.7 in DM patients (type not specified) aged 50–59 years old to 10.6 in those aged ≥ 80 years [35].

A retrospective matched cohort study in Germany [26] reported HZ incidence rates in T1DM and T2DM per year from hospital data between 2008 and 2018: incidence rates ranged from 4.3 to 6.3 in patients with T1DM versus 4.4 to 5.0 in controls, and from 7.0 to 7.9 in patients with T2DM versus 6.7–7.5 in controls. In 2018, HZ incidence was higher in T1DM (5.8 vs. 4.6, adjusted OR 1.01 [95% CI 0.98–1.04]) and T2DM (7.9 vs. 7.5, adjusted OR 0.99 [95% CI 0.91–1.08]) versus controls [26].

Two passive surveillance studies in DM patients in Spain included primary care data and reported significantly higher HZ incidence in DM patients versus controls (from hospital and primary care data in Valencia [N = 397,940 aged ≥ 50 years[35], and N = 491,210 aged ≥ 18 years [37]] and from primary care data in Madrid [N = 284,895] [29]). Incidence rates in DM adults ≥ 18 years were significantly higher than controls without DM (i.e., 9.4, adjusted IRR 1.13 [95% CI 1.09–1.17] in men and 1.04 [95% CI 1.01–1.08] in women [29]). Similarly, in DM adults ≥ 50 years, incidence rates were 9.3 (95% CI 9.1–9.4) versus 6.8 (95% CI 6.8–6.9) in controls (aRR 1.20 [95% CI 1.17–1.22]), and increased with age from 6.7 (50–59 years), to 9.1 (60–69 years), to 10.1 (70–79 years) and to 10.6 (≥ 80 years) [35]. HZ incidence was significantly higher in women versus men (aRR 1.36 [95% CI 1.33–1.38] [35]), and in older age groups versus patients aged 50–59 years (aRR for 60–69 years 1.38 [95% CI 1.35–1.41], 70–79 years 1.53 [95% CI 1.49–1.57] and ≥ 80 years 1.50 [95% CI 1.46–1.54]) [35].

Two studies [49, 50] reported HZ cumulative incidence per 1000 persons in DM patients (type not specified). Two-year HZ incidence in DM patients ≥ 50 years (N = 591,765, hospital data 2013–2015) was 5.6 versus 4.7 (p < 0.01) in controls not at risk of HZ, in Italy (at risk of HZ based on Italian National Vaccine Prevention Plan) [50]. In Spain (N = 26,793, primary care data 2006), HZ incidence in DM patients ≥ 30 years was also significantly higher versus controls i.e., overall incidence 15.3 (aRR 2.1 [95% CI 1.9–2.4]). Incidence increased significantly with age versus patients aged 30–44 years (7.0); 45–59 years (9.0, aRR 2.3 [95% CI 2.0–2.7]); 60–74 years (14.7, aRR 4.0 [95% CI 3.5–4.6]; ≥ 75 years (21.3, aRR 4.6 [95% CI 4.0–5.4]) and in women versus men (18.7 vs. 12.4, aRR 1.3 [95% CI 1.2–1.4]) [49].

A retrospective matched cohort study reported the HZ incidence rate in adults in Germany with depression over a 10-year timeframe versus non-IC controls; incidence was 7.2 vs. 5.5 [2008] and 7.6 vs. 6.2 [2018]) [26]. The adjusted OR (all ages) was 1.3 (95% CI 1.2–1.3) in 2008 and 1.2 (95% CI 1.1–1.2) in 2018; with higher ORs seen in adults aged 50–59 years (i.e., 1.4 [1.3–1.5] in 2008 and 1.3 [1.2–1.4] in 2018) [26].

Two studies [37, 48] reported HZ incidence rates in MS patients aged ≥ 18 years i.e., 5.7 (95% CI 5.1–6.4) in a matched cohort study in England [48], and 6.3 (95% CI 5.3–7.5) in a passive surveillance study in Valencia, Spain [37]. Incidence rates increased with age from 4.1–7.2 in < 60 years (vs. 2.2–5.5 in non-IC patients) to 11.0–12.3 in ≥ 60 years (vs. 8.1–9.5 in non-IC patients) in Spain[37]; and from 3.7–6.0 in < 60 years (vs. 2.1–4.9 in non-IC patients) to 6.9–10.2 in ≥ 60 years (vs. 6.9–11.0 in non-IC patients) in England [48].

Four studies [37, 41, 45, 48] reported HZ incidence rates in adults ≥ 18 years with psoriasis, ranging from 5.3 (95% CI 5.2–5.5) in a matched cohort study in England [48] to 6.1 (95% CI 5.9–6.3) in a passive surveillance study in Valencia, Spain [37]. In these two studies, incidence rates increased with age from 3.0–3.7 in < 50 years to 7.6–12.4 in ≥ 50 years (compared with non-IC patients, from 2.3–2.8 to 5.5–9.5) in Spain[37], and from 2.6–5.5 in < 60 years to 7.4–12.2 in ≥ 60 years (compared with non-IC patients, from 2.1–4.9 to 6.9–11.0) in England [48]).

The incidence rate was higher in patients with moderate to severe psoriasis (6.5 [95% CI 5.9–7.1]) versus mild psoriasis (5.4 [95% CI 5.2–5.5]) in a UK prospective matched cohort study (N = 199,700) [45].

Two studies [28, 41] reported HZ incidence rates in grouped IC populations.

In a passive surveillance study in Germany [41], the grouped HZ incidence rate was 11.3 (95% CI 11.1–11.5) in 2006 and 11.5 (95% CI 11.4–11.6) in 2012, among IC patients with HIV, malignant neoplasms, organ transplantation, stem cell transplantation, SLE, UC, Crohn’s disease, lupus erythematous, and RA. HZ incidence in non-IC patients was 5.9 (95% CI 5.8–5.9) [41].

In a UK retrospective comparative study, the HZ incidence rate in older IC patients (born in 1934–1946) with immunocompromising conditions was 15.5 (12.2–18.8) versus 14.2 (10.9–17.6) in patients immunosuppressed due to medication [28]. HZ incidence was 9.3 (95% CI 8.8–9.9) in the general population. Conditions included hematological malignancy, HIV/AIDS, cellular immune deficiencies or HSCT. Immunosuppressive or immunomodulating therapies included chemotherapy, radiotherapy, solid organ transplantation, immunosuppressive therapy, biological therapy, short-term high-dose corticosteroids, long-term lower-dose corticosteroids, and non-biological oral immune-modulating drugs.

One study [50] reported an HZ cumulative incidence of 3.5, in patients immunosuppressed due to medication and/or IC conditions.

The feasibility of conducting a meta-analysis was explored for the 11 studies that reported incidence rates with 95% CIs. These studies included 11 different subgroup populations (i.e., chronic respiratory diseases, hematological malignancy, HIV/AIDS, IBD, SLE, RA, MS, psoriasis, solid organ malignancy, solid organ transplant, and stem cell transplantation). However, data across different subgroups could not be meaningfully pooled. There were at least two studies with data for each subgroup population, however, the number of studies was considered too few for the meta-analysis to add value. Moreover, for subgroups with a somewhat larger number of studies, the criterium of comparability of study/population characteristics was not met (see Appendix Table 3).

There was great variability in the incidence rates reported across populations at increased risk of HZ and across subgroups, due to heterogeneity in study designs, populations and HZ case definitions, or as shown for RA, due to different immunosuppressive medications (Table 3). For study quality, 13/26 studies were of sufficient quality regarding representativeness of the target population, 14/26 regarding validity of HZ case definition, and 17/26 had a properly defined denominator. Overall, 19% of studies met all three quality criteria, 39% met two criteria and 65% met one criterion.