Graphical abstract
Overview of the study.
Abstract
Background Asthma is a common respiratory disease, which may be associated with an increased risk of herpes zoster (HZ), often a debilitating disease associated with severe pain. This is the first systematic review with the objective of summarising evidence on HZ burden in adults with asthma.
Methods A global systematic literature review and meta-analysis was conducted (MEDLINE and Embase, 2003–2024) on HZ burden (incidence, risk and complications) in adults (≥18 years) with asthma.
Results There were 19 studies included on HZ outcomes in adults with asthma. Pooled HZ incidence per 1000 person-years was 5.71 (95% CI 4.68–6.96) in adults aged ≥18 years (4.20 (95% CI 3.09–5.70) in those aged <60 years versus 10.33 (95% CI 9.17–11.64) in those aged ≥60 years). The pooled rate ratio for developing HZ was 1.23 (95% CI 1.11–1.35) in those aged ≥18 years and 1.36 (95% CI 1.15–1.61) in those aged ≥50 years. The risk of HZ was higher in people with asthma using systemic corticosteroids, long-acting β-agonists plus inhaled corticosteroids and “add-on therapy”. Asthma was also associated with an increased risk of post-herpetic neuralgia (OR 1.21, 95% CI 1.06–1.37) and HZ ophthalmicus (OR 1.9, 95% CI 1.1–3.2). Differences in study design, setting, case definitions and follow-up durations led to heterogeneity.
Conclusions This systematic literature review and meta-analysis found that adults with asthma have an increased risk of HZ, with higher risks in older age groups and in those on certain treatments, such as oral corticosteroids. HZ vaccines are available for adults, including those with comorbidities such as asthma, and can be considered as part of integrated respiratory care.
Shareable abstract
This systematic review and meta-analysis found that adults with asthma have an elevated risk of herpes zoster (HZ, shingles), increasing in older age groups and with certain asthma treatments. HZ vaccination may help to reduce this burden. https://bit.ly/3KQgd7G
Highlights
A global systematic review and meta-analysis assessed herpes zoster (HZ) burden and risks in adults with asthma.
Pooled HZ incidence per 1000 person-years was 5.71 (95% CI 4.68–6.96) in adults ≥18 years with asthma, increasing to 10.33 (95% CI 9.17–11.64) in adults ≥60 years (age cut-off based on included studies).
Asthma was identified as a risk factor for developing HZ, with a pooled rate ratio of 1.23 (95% CI 1.11–1.35) in adults ≥18 years, increasing to 1.36 (95% CI 1.15–1.61) in adults ≥50 years.
The risk of HZ was higher in asthma patients using systemic corticosteroids, long-acting β-agonists plus inhaled corticosteroids and “add-on therapy”.
Some studies showed that adults with asthma also had a higher chance of developing HZ complications (post-herpetic neuralgia and HZ ophthalmicus) than those without asthma; however, more data are needed.
Introduction
Several common chronic conditions have been associated with an increased risk of herpes zoster (HZ; also known as shingles), including diabetes, chronic renal disease, COPD and asthma [1–3]. Asthma is one of the most common chronic respiratory diseases, affecting over 300 million adults and children globally [4]. The Global Initiative for Asthma (GINA) defines asthma as a “heterogenous disease, usually characterized by chronic airway inflammation … history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation” [5]. Although the underlying mechanisms in asthma are not fully understood, an impaired innate or adaptive immune response could increase susceptibility to viral infections [6]. Furthermore, certain asthma treatments, such as frequent use of systemic/oral corticosteroids (OCS), may also contribute to reduce immunity against HZ [7].
Following primary infection, the highly infectious varicella zoster virus (VZV) causes varicella (chickenpox) and mainly affects children. By adulthood, >90% of the population has been infected with VZV [8]. The virus becomes latent in sensory ganglia and may be re-activated to cause HZ [9, 10], a painful and often debilitating disease that significantly impairs quality of life [11, 12]. HZ generally presents as rash characterised by painful erythematous maculo-papular lesions and vesicles in one or two adjacent dermatomes, and lasts for 2–4 weeks [13, 14]. Acute pain associated with HZ has been described by patients as burning, sharp/shooting, extreme/intense, sensitive to touch and pain that interrupts sleep [12]. The most common complication, affecting up to 30% of people with HZ [15], is post-herpetic neuralgia (PHN), i.e. chronic nerve pain that persists for at least 90 days after the onset of HZ rash and can last from months to years. Around 10% of adults with HZ develop other serious non-PHN complications, which can be systemic or localised, including encephalitis, HZ ophthalmicus (HZO), stroke, Ramsay Hunt syndrome and disseminated HZ, which occur more frequently in high-risk populations [11, 12, 16–18]. HZ and its complications result in significant healthcare resource utilisation and have an important socioeconomic impact on patients and caregivers [16, 19].
A decline in VZV cell-mediated immunity is thought to be the most common reason for virus re-activation and can result from an age-related decline in immunity or immunosuppressive diseases and therapies. HZ incidence rates are between 3 and 5 per 1000 person-years for all ages, and increase sharply from the age of 50 years [15]. At ages 60 and 80 years, HZ incidence rates are estimated to increase to around 6–8 and 8–12 per 1000 person-years, respectively [15], with higher rates in women versus men [20].
Three systematic literature reviews on HZ risk factors found that the risk of developing HZ was around 25% higher in asthma patients versus controls [1, 21, 22]. There are currently no published systematic literature reviews on the asthma-specific or respiratory-specific risk of HZ. Therefore, the aim of this systematic literature review was to summarise the current global evidence on the burden of HZ in adults with asthma, including evidence on incidence and prevalence, morbidity and mortality, PHN and other complications, and asthma as a risk factor for HZ. This paper summarises the findings related to adults with asthma.
Patients and methods
A systematic literature review was conducted according to the Cochrane guidelines [23] and PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines for performing and reporting systematic reviews [24]. The review is registered in the PROSPERO database (CRD42024513214).
Search strategy
MEDLINE (accessed via PubMed) and Embase databases were searched, combining disease-specific terms for HZ with asthma terms (supplementary file S1). To keep the search broad, no outcome-specific terms were included. Publications in any country, published in English, French, German, Spanish and Italian, from 1 January 2003 until the search date of 17 February 2024 were included.
Screening and selection
The records identified from the search were imported and deduplicated in Rayyan [25]. The process of selection and inclusion/exclusion of articles was registered in an Endnote library by one researcher.
Two researchers (I.T. Sepúlveda-Pachón and H. Vroling) independently screened all titles and abstracts, and then selected full-text articles (30% in duplicate). Articles excluded during the full-text screening were grouped by reason of exclusion (supplementary file S2). Hand searching of reference lists from identified systematic literature reviews was performed to identify and include any missed studies that met the selection criteria.
Selection criteria were based on the population, outcomes and study design of interest. The population of interest was adults ≥18 years with asthma. Outcomes of interest were incidence and risk of HZ, HZ-associated complications (i.e. PHN, disseminated zoster, encephalitis, HZO or pneumonia), hospitalisation, mortality, healthcare resource use and costs, and exacerbations of asthma due to HZ. Study designs included were observational studies and phase 3 clinical trials. Other study designs were excluded (e.g. reviews, modelling studies and phase 1/2 trials), as well as studies with a sample size of less than 30 patients and publication types such as letters to the editor, editorials, conference abstracts and comments.
Data extraction
Key data were extracted from the included articles into standardised tables in Microsoft Excel, including the citation; study methods (design, study period, setting and country); population (inclusion/exclusion criteria, size, age group, gender, type of patients (in/outpatients)); follow-up time, denominator; HZ case detection, HZ and PHN case definition; asthma case definition, severity, duration of disease, treatments; outcomes (by year, gender, age and treatment); comments or quality issues from authors as well as researchers. If relevant data were only presented in a figure, the authors were contacted to request the full data.
Data extraction was performed by one researcher and 30% of articles were checked by a second researcher.
Quality assessment
Methodological quality assessment was conducted for all included full-text articles using specific checklists developed by the Joanna Briggs Institute (University of Adelaide, Adelaide, Australia) for cohort studies, case–control studies and incidence/prevalence studies (supplementary file S3). Any items on the checklist that were not met were reported in the comments section of the data extraction tables.
Data synthesis
Data were summarised descriptively by outcome and, where possible, by age and medication use. The feasibility of conducting a meta-analysis was assessed using the following Cochrane criteria [23]. 1) All outcomes are comparable and can be pooled meaningfully. 2) The correct data are available for the included studies. For outcomes reported as proportions or rates (e.g. incidence per 1000 person-years), either the numerator or the denominator value needs to be available to be able to pool results. 3) All interventions and comparators are the same or similar enough to be combined meaningfully. For observational studies, the assessment of this criterion focuses on the comparability of study characteristics (i.e. setting, period, and definitions of HZ and of asthma) and population characteristics (i.e. age, gender and medication). Three studies were considered sufficient for a meta-analysis, provided they could be meaningfully pooled and their results were sufficiently similar.
Meta-analysis methods
A random effects meta-analysis was used to summarise the following outcomes that could be pooled according to feasibility assessment: 1) the incidence of HZ in asthma patients and 2) asthma as a risk factor for developing HZ. A random effects model was chosen as characteristics of study design, population and setting differed between studies.
For asthma as a risk factor for HZ, a rate ratio was the preferred metric. Nested case–control studies reporting odds ratios were included in the meta-analysis because odds ratios in nested case–control studies estimate the rate ratio [26, 27]. Other case–control studies reporting odds ratios based on incident HZ, conducted in dynamic and stable populations, were also included in the meta-analysis, as these odds ratios also provide an estimate of the rate ratio [27–29]. Studies reporting hazard ratios and relative risks were also included in the meta-analysis. Odds ratio results of classical case–control studies were not included, as these can only be interpreted as rate ratios in case of rare disease (typically <10%) [30], which is not the case for HZ.
In case a study only reported stratified incidence estimates, an overall incidence was calculated using the reported numerator and/or denominator, if available.
The level of heterogeneity was assessed using Cochran's Q statistics and I2. Forest plots were used to present the pooled estimates with 95% confidence intervals and prediction intervals, and to explore age as a source of heterogeneity in subgroup analyses, if feasible. In the subgroup analysis, the pooled estimate in each subgroup and within-group heterogeneity were obtained. Publication bias was assessed, if at least 10 studies were included in each analysis, using funnel plots and the Egger test. Data analysis was performed using R version 4.3.1 (www.r-project.org).
Results
The search identified 610 unique records from MEDLINE and Embase, and an additional four from hand searches; overall, 44 underwent full-text screening. Rayyan identified and removed all duplicates prior to screening. There were 19 studies included on HZ in adults with asthma (figure 1). A list of excluded studies with reasons for exclusion can be found in supplementary file S2.
PRISMA flowchart showing the results of the search and selection process, with 19 studies included for asthma. SLR: systematic literature review.
Study characteristics
The study characteristics of the 19 included studies are summarised in table 1 (see supplementary table S1 for more details).
Summary of included studies
Most studies were conducted in Europe, including the UK [31–34], Spain [2, 35], Belgium [36], Denmark [37], Finland [38], France [39], Germany [40] and Sweden [41]. Four studies were conducted in Asia: from Japan [42, 43], Republic of Korea [44] and Taiwan [45]. Two studies were conducted in the USA [46, 47] and one in Australia [48].
The majority of studies were comparative observational studies, using either a case–control design (n=9) [33, 35–37, 39, 44, 46–48] (with two not matched [35, 48]), a cohort design (n=6) [32, 38, 40, 42, 43, 45] (with four not matched [31, 32, 42, 43]) or a combination design (n=1, cohort with nested case–control) [31]. The three remaining observational studies were classified as retrospective surveillance studies [2, 34, 41].
The International Classification of Diseases (ICD) or equivalent codes were used to define HZ, except in two studies (one used a general practitioner diagnosis [39] and the other did not describe how HZ was defined [35]). Studies defined asthma cases using ICD or equivalent codes (some also required prescriptions for asthma medication [31, 33, 34, 37, 42–45]), except for four studies: one used extensive clinical criteria [47], another used drug reimbursements followed by physician diagnosis [38] and two did not report how asthma cases were defined [35, 39]. The studies did not report whether cases were allergic versus non-allergic, childhood versus adult-onset asthma or the number of years since diagnosis.
Most studies reported on asthma as a risk factor for HZ (n=14) [2, 31, 33, 35–40, 43–45, 47, 48] and 10 studies also reported HZ incidence rates [2, 31–33, 38, 40–43, 45]. The risk of HZ complications (PHN and HZO) in asthma patients was investigated in three studies [34, 35, 46]. No studies were found reporting on any of the other outcomes of interest.
The quality of the studies was assessed (supplementary file S3). Four [33, 36, 46, 47] of eight case–control studies were of high quality. Lower quality related to definitions of asthma or HZ used, and in one study [39] also to limited statistical analysis and follow-up. The eight cohort studies did not specify if follow-up was complete or did not provide reasons for loss to follow-up. Lower quality also related to definitions of asthma and HZ used, limitations in statistical analyses, and in one study, only capturing hospitalised HZ cases [38]. Two of the three retrospective surveillance studies were of high quality [2, 34].
HZ incidence in adults with asthma
The HZ incidence (per 1000 person-years) was reported in nine studies [2, 31–33, 38, 40, 42, 43, 45], while one study reported incidence per 1000 population (supplementary table S2) [41]. There was an increasing trend in HZ incidence rates between 2008 and 2018 in Germany in people with asthma [40]. Higher rates were reported in women versus men in Spain [2], but not in Japan [43]. Generally, HZ incidence rates were consistent across studies in different countries, except for a study in Finland based on hospitalised HZ cases alone [38], which reported a lower HZ incidence. HZ incidence increased with age [32, 33, 41–43, 45] and was significantly higher in adults with asthma who were prescribed OCS (e.g. prednisolone) compared with those who were prescribed inhaled corticosteroids (ICS) only [31].
Six studies had sufficiently similar characteristics to conduct a meta-analysis: four were included in the overall (age ≥18 years) analysis [2, 31, 33, 45] and four in an age-stratified analysis [32, 33, 42, 45]. Four studies were not included in the meta-analysis, due to missing numerators and denominators [40, 43], an outlier study with only hospitalised HZ captured [38], and incidence reported per 1000 population [41]. The pooled HZ incidence per 1000 person-years in adults aged ≥18 years with asthma was 5.71 (95% CI 4.68–6.96) (figure 2a). There were too few studies to assess publication bias.
Meta-analysis of herpes zoster (HZ) incidence (per 1000 person-years) in a) adults with asthma ≥18 years and b) adults with asthma by age groups (younger (18–74 years) and older (≥60 years)).
As HZ incidence is known to increase with age, separate meta-analyses were performed for the HZ incidence in younger (<60 years) versus older (≥60 years) adults with asthma. The categorisation of studies age cut-off was informed by the stratification groups used in the studies; for the younger population, this included two studies with ages up to 60 years and one study with an age group of 18–74 years. The latter study was included given that the mean±sd age in the asthma group was 36.91±11.89 years with 97.2% of the overall study population <65 years of age.
The pooled HZ incidence (per 1000 person-years) for younger adults with asthma was 4.20 (95% CI 3.09–5.70) compared with 10.33 (95% CI 9.17–11.64) for older adults with asthma (figure 2b). The difference in HZ incidence between these age groups was statistically significant (p<0.01). Given the low number of studies included in the meta-analysis, a post-hoc sensitivity analysis was conducted using the Sidik–Jonkman method to estimate τ2 and the Hartung–Knapp approach for confidence intervals (HKSJ methods). The updated τ2 estimates were similar with slightly wider confidence intervals, and the pooled HZ incidence in both younger and older adults remained significantly high for adults with asthma (supplementary file S4).
Risk of HZ in adults with asthma
There were 14 studies [2, 31, 33, 35–40, 43–45, 47, 48] that investigated the risk of HZ in adults with asthma versus no asthma (supplementary table S3).
The overall adjusted OR (aOR) for adults aged ≥18 years with asthma developing HZ varied between 1.11 and 1.67 (all 95% CIs were >1) [33, 35, 40, 44]. One study from Japan in adults aged 18–74 years with asthma found a similar but non-significant result (adjusted HR (aHR) 1.11, 95% CI 0.95–1.31) [43]. Two studies were outliers: one reporting an aOR of 0.78 (95% CI 0.38–1.58; p=0.492) in France with asthma diagnosis based on self-report [39] and one reporting an aHR of 6.18 (95% CI 1.21–31.6; p<0.05) in Finland among hospitalised HZ cases only [38]. Both of these studies included small numbers of asthma patients (e.g. 11 [39] and 14 [38], respectively). In other studies, asthma was a significant risk factor for developing HZ, regardless of study age group [33, 40, 44, 45], sex [2, 44] or HZ definition used [37].
Three studies [33, 40, 44] had sufficiently similar characteristics to conduct a meta-analysis for asthma as a risk factor for HZ in adults aged ≥18 years. One study reported results by year from 2008 to 2018; given the global trend of increasing HZ incidence over time [20], for this study results from the middle period (2013) were used [40]. Studies were excluded from the meta-analysis due to only presenting medication-stratified results [31] or sex-stratified results [2], only including hospitalised HZ [38], presenting an odds ratio which could not be converted to a rate ratio (classical case–control study) [39], lack of details about asthma and HZ definition and follow-up period to judge similarity with other studies [35], and other age groups not covering all adults [36, 37, 43, 45, 47, 48]. To test the robustness of results, a prespecified sensitivity analysis was conducted with broader inclusion of articles, including the Japanese population aged 18–74 years old [43] and the Spanish study with insufficient reporting of relevant methodology aspects [35].
The pooled rate ratio of developing HZ was 1.23 (95% CI 1.11–1.35) in adults aged ≥18 years with asthma (figure 3a). Heterogeneity was high (95%). In the prespecified sensitivity analysis (broader inclusion of studies) (figure 3b), the significant association between asthma and HZ remained (pooled rate ratio 1.28, 95% CI 1.11–1.49), with a wider confidence interval and higher heterogeneity (99%).
a) Meta-analysis of asthma (versus non-asthma) as a risk factor for herpes zoster in adults ≥18 years and b) prespecified sensitivity analysis in adults ≥18 years.
As HZ incidence is known to increase with age, a separate meta-analysis was performed in adults in older age groups. This analysis included four studies with a population ≥50 years [47], ≥60 years [40], the age group ≥61 years from [45] and ≥70 years [33]. The pooled rate ratio of developing HZ was 1.36 (95% CI 1.15–1.61) in adults with asthma aged ≥50 years (figure 4). While heterogeneity was lower than in the population aged ≥18 years discussed above, it was nonetheless high (83%). Of note, the risk of developing HZ was also increased in adults with asthma aged ≥40 years (rate ratio 1.28, 95% CI 1.13–1.44) (meta-analysis not shown). There were too few studies to assess publication bias. In post-hoc sensitivity analysis (using the HKSJ methods; see supplementary file S4), all estimates of HZ risk remained significantly higher in adults with asthma, except for the analysis (figure 3a) with a narrow inclusion of three studies in adults ≥18 years.
Meta-analysis results of asthma (versus non-asthma) as a risk factor for herpes zoster in a population ≥50 years old.
It was not possible to conduct a meta-analysis of results by asthma treatment. In a German study in adults ≥18 years, the overall aOR for developing HZ was 1.22 (95% CI 1.18–1.26), which was higher for adults with asthma using systemic corticosteroids (aOR 1.33, 95% CI 1.25–1.42) versus no systemic corticosteroids (aOR 1.17, 95% CI 1.12–1.21) [40]. A UK study found an association between oral prednisolone and HZ for current (aOR 1.32, 95% CI 1.19–1.48), recent (aOR 1.29, 95% CI 1.13–1.47) and past prednisolone use (aOR 1.13, 95% CI 1.05–1.21) versus no prednisolone use [31]. No difference in HZ risk was observed with ICS alone [31, 47], with short-acting β-agonists (SABA) or short-acting muscarinic antagonists (SAMA) [31]. However, HZ risk was increased with long-acting β-adrenoceptor agonist (LABA) plus ICS (aOR 1.15, 95% CI 1.07–1.25) and with “add-on therapy” (i.e. theophylline, leukotriene receptor antagonists or omalizumab; no outcomes by type of add-on therapy were provided) (aOR 1.24, 95% CI 1.06–1.46) (supplementary table S3) [31].
HZ complications in adults with asthma
It was not possible to conduct a meta-analysis of the risk of HZ complications due to the limited number of studies identified.
The aOR of developing PHN after HZ was 1.21 (99% CI 1.07–1.38) in UK adults aged ≥18 years with asthma compared with no asthma; however, in older age groups (>60 and >70 years), the results were not significantly different. Antiviral treatment had no effect on PHN risk in adults with asthma [34]. In Spain, while asthma was associated with significant increase in HZ risk (aOR 1.67, 95% CI 1.63–1.71), the risk of PHN was inexplicably found to be lower (aOR 0.91, 95% CI 0.90–0.92) [35]. In this study, the definition of PHN (pain duration following HZ) was not reported.
Asthma as a risk factor for HZO was reported in a case–control study [46] investigating the association between atopy and HZO, in 137 HZO cases and 541 age- and sex-matched controls. An association between asthma and an increased risk of HZO was found (OR 1.9, 95% CI 1.1–3.2; p=0.02); however, this study included a small sample size (22 and 50 adults with asthma included in the HZO cases and control group, respectively) [46].
Discussion
This global systematic literature review and meta-analysis included 19 observational studies on HZ outcomes in adults with asthma, including HZ incidence, risk and complications.
HZ incidence (per 1000 person-years) in adults with asthma was comparable across most studies, with higher rates in older age groups, in women versus men and in OCS versus ICS users. The pooled HZ incidence was 5.71 (95% CI 4.68–6.96) in adults aged ≥18 years with asthma and increased with age (4.20 (95% CI 3.09–5.70) in adults aged <60 years versus 10.33 (95% CI 9.17–11.64) in adults aged ≥60 years). 14 studies investigated HZ risk in adults with versus without asthma. The pooled rate ratio for developing HZ was 1.23 (95% CI 1.11–1.35) in adults with asthma aged ≥18 years and 1.36 (95% CI 1.15–1.61) in those aged ≥50 years. These findings are comparable to the literature, where asthma was associated with a significantly increased risk of HZ (rate ratio 1.25, 95% CI 1.13–1.39) from a systematic literature review on risk factors for HZ in adults (studies published in 2003–2017) [21], rate ratio 1.24 (95% CI 1.16–1.31) from a systematic literature review (1966–2019) of HZ risk factors in all ages [1] and OR 1.30 (95% CI 1.19–1.42) from a systematic literature review of HZ risk factors in all ages (studies published 2003–2022) [22]. To further test the robustness of the results, a post-hoc sensitivity analysis was conducted using the HKSJ methods. Although considered a conservative approach [49], HZ risk in asthma patients remained significant with the exception of the pooled HZ risk in adults ≥18 years, due to the wider confidence intervals. However, all individual studies in this conservative analysis showed a significant association between asthma and HZ, and the pooled HZ risk remained significant in adults ≥18 years in the broader sensitivity meta-analysis (including more studies), supporting the association between asthma and HZ in adults. The results among adults aged ≥50 years remained consistent and robust in all sensitivity analyses.
Results stratified by treatment showed that the odds ratio for developing HZ was higher in adults with asthma using OCS [31, 40], for LABA with an ICS and for “add-on therapy” [31]. Use of these treatments is likely to indicate that these patients suffer from more severe asthma. Asthma severity alone may be associated with an increased risk of HZ; however, none of the studies assessed this. Thus, it was not possible to establish to what extent the increase in HZ risk was associated with asthma disease/severity versus treatment. The medications used are unlikely to fully account for the association between asthma and the risk of HZ as it is likely confounded by asthma severity and/or control status. This should be explored in future studies designed for this purpose. Future studies should also assess whether use of newer biologics may be associated with an increased risk of HZ and how their individual risk potentially varies. Nevertheless, the OCS results are consistent with what one might expect. For example, a prospective study found a six-fold increase in HZ risk in the first month after a single prescription of OCS, with greater risks for adults on higher doses [50]. No association with HZ development was found for use of ICS alone [31, 47], SABA or SAMA [31] in adults with asthma. ICS are generally locally targeted, which could explain why no increased HZ risk was observed. However, higher doses of ICS have been known to result in systemic side-effects [51], which could explain the higher HZ risk seen in adults using LABA with an ICS. More data are needed in this area. Adults with asthma had an increased odds of HZ complications of PHN (OR 1.21, 99% CI 1.06–1.37) [34] and HZO (OR 1.9, 95% CI 1.1–3.2) [46], except in one study where HZ risk was significantly higher but PHN risk was lower [35]. As this study [35] was lacking methodology details (definitions of asthma, HZ, PHN and unclear follow-up time), it was not possible to compare this result with other studies and it should be interpreted with caution. Overall, the findings of this systematic literature review were comparable to results from other literature reviews [1, 21, 22].
The potential mechanisms linking asthma to HZ development remain unknown; however, several studies have suggested that the impaired innate and adaptive immunity in asthma patients (both necessary to prevent VZV re-activation) may lead to re-activation of VZV resulting in HZ [6, 47, 52]. For instance, asthma is associated with a T-helper (Th) 1 immune deficiency and elevated Th2, both of which have been observed in HZ patients; Th1 cell-mediated immunity is believed to be important in preventing the re-activation of VZV. Low Th1 activity, along with impaired innate immune pathways in people with asthma, may increase the risk of HZ [7]. In addition, corticosteroid treatment (in particular OCS) has an immunosuppressive effect, which may increase the risk of HZ [7]. As biological treatments become more widely used in people with asthma, this risk might increase further, as some biologics have been associated with a higher risk of infections (e.g. anti-interleukin-5) [53, 54].
Vaccines are available to prevent against HZ and increased uptake may help to reduce the disease burden among adults with asthma. The recombinant zoster vaccine (RZV) provides effective protection against HZ, with evidence in adults aged ≥50 years and in patients aged ≥18 years at increased risk of HZ [55–58]. RZV demonstrated >90% efficacy against HZ, PHN and non-PHN complications in adults aged ≥50 years in the pivotal phase 3 ZOE trials and provided durable protection (>80% efficacy) for up to 10 years after initial vaccination [59–61]. In a post-hoc pooled analysis, the efficacy and safety profile of RZV in patients with selected medical conditions at enrolment, including asthma, were consistent with the overall population [62]. The GINA strategy currently recommends influenza and coronavirus disease 2019 vaccination for people with asthma, and has not yet given recommendations on the place of HZ vaccination in this patient group [5].
This systematic literature review has some limitations. Data were obtained from electronic databases using ICD/equivalent coding, without information on disease severity, lifestyle factors or other comorbidities, thus limiting adjustment for confounders. Electronic databases only capture patients who seek healthcare and general practitioner databases generally do not capture institutionalised people, potentially underestimating HZ incidence in the oldest age groups. Uninsured people are not included in health insurance databases and may be in worse health than insured people, potentially affecting HZ results. Disease definitions used ICD/equivalent codes with some studies also including treatment prescriptions. This may result in inclusion of more severe cases (e.g. of asthma) and an underestimation of HZ incidence if less severe HZ cases not requiring medication were excluded. Methodological variations were observed among studies, making comparison between studies difficult. The pooled estimates were based on small numbers of studies, resulting in high heterogeneity and wide prediction intervals, warranting cautious interpretation. Studies had varied settings (single regions to nationwide studies) and sample sizes (677 to >7 million overall and 39 to >400 000 asthma patients), which affects generalisability and comparability of results. The study periods also differed (from 1994 to 2021), affecting comparability of results as, over time, HZ incidence tends to increase [63] and HZ and asthma treatments may change. Lastly, the age and gender distribution of the study populations varied, which can all influence HZ occurrence [63]; nevertheless, results were consistent with previous studies. Asthma is recognised as a heterogenous disease, from a clinical and immunological perspective. The data available in this systematic literature review did not provide specific HZ risks according to these features.
This systematic literature review identified some gaps in the literature. The majority of studies were conducted in Europe and none were conducted in South America or Africa, thus more data are needed from low- and middle-income countries. More data are needed on the risk of HZ by dose of treatment and/or asthma severity, for the many new biologics for asthma patients, and on the risk of various HZ complications (e.g. cutaneous and vascular) in people with asthma. There is a need for more research on the risk of HZ hospitalisation and mortality, and healthcare resource use and costs, as limited evidence was identified in adults with asthma, and HZ is known to be associated with significant morbidity and to impose an economic burden [6].
Conclusions
This is the first systematic literature review and meta-analysis to specifically investigate the association between asthma and HZ. Results show that adults with asthma have an increased risk of HZ, with higher risks in older age groups and for patients on certain asthma treatments (e.g. OCS). HZ imposes a significant burden on patients as well as health systems. HZ vaccines are available for adults, including those with comorbidities such as asthma, and can be considered as part of integrated respiratory care.
Supplementary material
Supplementary Material
Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material ERJ-00462-2024.Supplement
Shareable PDF
Supplementary Material
This one-page PDF can be shared freely online.
Shareable PDF ERJ-00462-2024.Shareable
Acknowledgements
The authors would like to thank Business & Decision Life Sciences Medical Communication Service Centre for editorial assistance and manuscript coordination; and Kavi Littlewood (Littlewood Writing Solutions, Houten, The Netherlands) for medical writing support, on behalf of GSK.
Footnotes
Author contributions: A.A. Cruz, A. Jorga, C. Williams, H. Vroling, I.T. Sepúlveda-Pachón and K.J. Mortimer were involved in the design of the study. H. Vroling and I.T. Sepúlveda-Pachón collected or generated the data. A.A. Cruz, A. Jorga, C. Williams, H. Vroling, I.T. Sepúlveda-Pachón and K.J. Mortimer analysed and interpreted the data. All authors participated to the development of this manuscript and in its critical review with important intellectual contributions. All authors had full access to the data and gave approval of the final manuscript before submission. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This article has an editorial commentary: https://doi.org/10.1183/13993003.01300-2024
Conflict of interest: A. Jorga and C. Williams are employed by GSK. A. Jorga holds shares in Pfizer and GSK. H. Vroling and I.T. Sepúlveda-Pachón are employees of P95/Pallas. P95/Pallas received funding from GSK for the submitted work. P95/Pallas holds/held contracts with AstraZeneca, GSK, Pfizer, Sanofi, Seqirus, Merck, Takeda, Orchard, Biomarin, Daiichi, Bavarian Nordic and Bayer (work for the non-GSK companies was not related to HZ). K.J. Mortimer declares grants and sponsorship from AstraZeneca and GSK to support the Global Asthma Network, consulting fees from AstraZeneca and GSK on asthma and COPD-related advisory boards, and honorarium from GSK for lectures on improving vaccine access for people with asthma, outside the submitted work. A.A. Cruz declares grants and sponsorship from GSK to support the ProAR Foundation, and consulting or lecture fees from Abdi-Ibrahim, AstraZeneca, Boehringer Ingelheim, Chiesi, Crossject, Eurofarma, Farmoquimica, Glennmark, GSK, Mylan, Novartis and Sanofi on asthma-related activities. The authors declare no other financial or non-financial relationships and activities or conflicts of interest.
Support statement: GlaxoSmithKline Biologicals S.A. funded this study and all costs related to the development and publication of this manuscript. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 6, 2024.
- Accepted June 12, 2024.
- Copyright ©The authors and/or their employers 2024.
This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0. For commercial reproduction rights and permissions contact permissions{at}ersnet.org
References
