Article Text

Herpes zoster burden in patients with asthma: real-world incidence, healthcare resource utilisation and cost
  1. David Singer1,
  2. Philippe Thompson-Leduc2,
  3. Siyu Ma3,
  4. Deepshekhar Gupta4,
  5. Wendy Y Cheng5,
  6. Aruna Muthukumar4,
  7. Francesca Devine6,
  8. Manasvi Sundar7,
  9. Michael Bogart8,9,
  10. Ella Hagopian5,
  11. Sara Poston1,
  12. Mei Sheng Duh5 and
  13. John J Oppenheimer10
  1. 1GSK, Philadelphia, Pennsylvania, USA
  2. 2Analysis Group Inc, Montreal, Quebec, Canada
  3. 3GSK/Tufts Medical Center, Boston, Massachusetts, USA
  4. 4Analysis Group Inc, Menlo Park, California, USA
  5. 5Analysis Group Inc, Boston, Massachusetts, USA
  6. 6Analysis Group Inc, New York, New York, USA
  7. 7Analysis Group Inc, Los Angeles, California, USA
  8. 8GSK, Research Triangle Park, North Carolina, USA
  9. 9Gilead Sciences, Foster City, California, USA
  10. 10Rutgers New Jersey Medical School, Newark, New Jersey, USA
  1. Correspondence to Dr David Singer; david.a.singer{at}gsk.com

Abstract

Background Herpes zoster (HZ) is a painful condition caused by reactivation of the varicella-zoster virus. The objectives of this study were to compare HZ incidence in adults with asthma versus adults without asthma and to compare healthcare resource use as well as direct costs in adults with HZ and asthma versus adults with asthma alone in the USA.

Methods This retrospective longitudinal cohort study included adults aged ≥18 years across the USA. Patients were identified from Optum’s deidentified Clinformatics Data Mart Database, an administrative claims database, between 1 October 2015 and 28 February 2020, including commercially insured and Medicare Advantage with part D beneficiaries. Cohorts of patients with and without asthma, and separate cohorts of patients with asthma and HZ and with asthma but not HZ, were identified using International Classification of Diseases 10th Revision, Clinical Modification codes. HZ incidence, healthcare resource use and costs were compared, adjusting for baseline characteristics, between the relevant cohorts using generalised linear models.

Results HZ incidence was higher in patients with asthma (11.59 per 1000 person-years) than patients without asthma (7.16 per 1000 person-years). The adjusted incidence rate ratio (aIRR) for HZ in patients with asthma, compared with patients without asthma, was 1.34 (95% CI 1.32 to 1.37). Over 12 months of follow-up, patients with asthma and HZ had more inpatient stays (aIRR 1.11; 95% CI 1.02 to 1.21), emergency department visits (aIRR 1.26; 95% CI 1.18 to 1.34) and outpatient visits (aIRR 1.19; 95% CI 1.16 to 1.22), and direct healthcare costs that were US dollars ($) 3058 (95% CI $1671 to $4492) higher than patients with asthma without HZ.

Conclusion Patients with asthma had a higher incidence of HZ than those without asthma, and among patients with asthma HZ added to their healthcare resource use and costs.

  • Asthma
  • Asthma Epidemiology
  • Health Economist
  • Viral infection

Data availability statement

The data that support the findings of this study are available from Optum, but restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. GSK makes available anonymised individual participant data and associated documents from interventional clinical studies which evaluate medicines, upon approval of proposals submitted to www.clinicalstudydatarequest.com. To access data for other types of GSK sponsored research, for study documents without patient-level data and for clinical studies not listed, please submit an enquiry via the website.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Herpes zoster occurs when the virus that causes chickenpox becomes active again in someone who previously had the virus.

WHAT THIS STUDY ADDS

  • This study compared herpes zoster incidence in patients with asthma versus patients without asthma, and healthcare resource use and costs in patients with asthma and herpes zoster versus patients with asthma without herpes zoster.

  • Patients with asthma were 1.34 times more likely to have herpes zoster than patients without asthma.

  • Patients with asthma who also had herpes zoster had more inpatient stays, more emergency department visits, more outpatient visits and healthcare costs more than $3000 higher over 1 year compared with patients with asthma who did not have herpes zoster.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Strategies to prevent herpes zoster in patients with asthma may help to reduce healthcare costs.

Introduction

Primary infection with the varicella-zoster virus (VZV) causes varicella (chickenpox). The virus remains dormant in the sensory nerve ganglia after primary infection, where it may reactivate later to cause herpes zoster (HZ), also known as shingles.1 HZ is characterised by a painful blistering skin rash, typically presenting unilaterally. Almost everyone born in the USA before 1980 has been infected with VZV and is at risk for HZ.2 Approximately one in three people in the USA will develop HZ during their lifetime, and the risk increases markedly after the age of 50 years.2

The most common complication of HZ is postherpetic neuralgia (PHN), generally defined as pain that persists for >90 days after rash onset. PHN occurs in approximately 10%–13% of HZ patients aged ≥60 years and may persist for weeks, months or years.2 HZ, and particularly PHN, severely affects patients’ quality of life across multiple domains, including negative effects on sleep, emotional functioning, physical functioning, activities of daily living, social functioning and work3 and may result in loss of independence in some older individuals.4 There is no reliable treatment for PHN.1 Vaccination with recombinant zoster vaccine (RZV) to prevent HZ and its complications is currently recommended in the USA for adults aged ≥50 years.5 The Global Initiative for Chronic Obstructive Lung Disease recognised the Centers for Disease Control and Prevention recommendation of HZ vaccination for adults with chronic obstructive pulmonary disease (COPD).6

Asthma is a chronic respiratory disease characterised by episodes of impaired breathing.7 In 2020, asthma prevalence in the USA was 7.8% or 25.3 million people, of whom 21.0 million were adults aged ≥18 years and 4.2 million were children and adolescents aged <18 years.8 Healthcare resource utilisation (HRU) for asthma is substantial, with 13.9 million visits to physicians’ offices, 1.4 million outpatient visits, 1.75 million emergency department visits and 456 000 asthma hospitalisations in the USA in 2007.7 In the period 2008–2013, the cost of asthma in the USA was estimated at US dollars ($) 81.9 billion per year, including $3 billion in lost work and school days, $29 billion due to asthma-related deaths and $50.3 billion in medical costs.9 In a retrospective database analysis in US working adults in 2003–2006, direct medical costs in people with asthma were $1785 higher than in matched people without asthma.10

Evidence suggests that patients with asthma may be at higher risk for HZ. A small case–control study conducted in Minnesota, USA, found that a history of asthma was significantly associated with an increased risk of HZ after controlling for confounders (adjusted OR) 1.70; 95% CI 1.20 to 2.42, p=0.003),11 and two meta-analyses reported an elevated risk of HZ in patients with asthma.12 13 These studies have some limitations, as the meta-analyses synthesised data from multiple studies around the world, many of which were not conducted in the USA, and the case–control study was conducted in a geographically limited population with a relatively small sample. The reason for increased risk of HZ in patients with asthma is unclear, although oral corticosteroid use has been associated with an increased incidence of HZ in older adults14 and people with COPD,15 and may be a possible mechanism. No study has yet been published investigating the association between asthma and HZ in a large geographically diverse population sample across the USA. Furthermore, no previous studies have investigated HRU and healthcare costs of HZ in populations who also have asthma.

The objectives of this study were to provide up-to-date estimates of HZ incidence in US patients with asthma compared with patients without asthma, and to estimate HRU and costs in patients with HZ and asthma compared with asthma alone.

Methods

Study design

This was a retrospective longitudinal cohort study conducted in the US using administrative claims data. For the comparison of HZ incidence in patients with and without asthma, two cohorts of adult patients aged ≥18 years were defined: a cohort with asthma and a cohort without asthma. For the comparison of HRU and costs, two separate cohorts of adult patients aged ≥18 years who were diagnosed with asthma were independently defined: a cohort with asthma and HZ; and a cohort with asthma and without HZ.

This study complied with all applicable laws regarding patient privacy. No direct patient contact or primary collection of individual patient data occurred. Study results are presented as aggregate analyses that omit patient identification, and, therefore, informed consent, ethics committee, or Institutional Review Board approval were not required.

Data sources

The study used data from 1 October 2015 to 28 February 2020 in Optum’s deidentified Clinformatics Data Mart Database (CDM). The end date was selected to minimise confounding effects from the COVID-19 pandemic. CDM is derived from a database of administrative healthcare claims for members of a large national managed care company and includes approximately 15–19 million annual covered lives. Administrative claims submitted for payment by providers and pharmacies are verified, adjudicated, adjusted and deidentified prior to inclusion. The claims data include commercial and Medicare Advantage health plan data and the included population spans all 50 US states. The database includes medical claims, pharmacy claims and inpatient confinements. CDM applies standard pricing algorithms to the claims data in order to create prices that reflect allowed payments for all provider services across regions. CDM is statistically deidentified under the Expert Determination method consistent with the Health Insurance Portability and Accountability Act (HIPAA). Data directly measuring disease severity and progression, patient-reported outcomes and physician notes are not available in the database.

Study population

The study population was selected from adults aged ≥18 years identified from CDM between 1 October 2015 and 28 February 2020. For the cohorts in the incidence comparison analysis, all patients had to have ≥6 months of continuous enrolment before the index date (this time period was the baseline period) and were excluded if they had a claim associated with HZ diagnosis or HZ complications or had received HZ vaccine before or on the index date, or if they had a claim associated with a COPD diagnosis during the baseline period. HZ-related complications included PHN, HZ ophthalmicus, disseminated HZ and HZ-related meningoencephalitis. Patients in the cohort with asthma had to have ≥2 claims associated with asthma diagnoses (International Classification of Diseases 10th Revision, Clinical Modification (ICD-10-CM) codes J45, J46 or J82.83) on separate dates during the period of continuous enrolment. This case definition for asthma was consistent with previous real-world studies and intended to provide some confirmation of diagnosis.16 17 Patients also had to have ≥1 prescription claim for an asthma medication during the baseline period or within the 30 days after the index date. This allowed incident asthma patients to be included in the cohort, who would not reasonably be expected to have asthma medication before their first asthma diagnosis. The index date was the later of the first claim associated with a diagnosis of asthma or the 6-month mark following the beginning of continuous enrolment. For the cohort without asthma, patients were excluded if they had a claim associated with an asthma diagnosis and the index date was defined as 6 months after the start of continuous enrolment. The observation period was the time between the index date and first HZ event, HZ vaccination or end of data availability (online supplemental figures 1 and 2).

The cohorts in the HRU and cost comparison were constructed independently of the cohorts in the incidence comparison analysis. Patients had to have ≥12 months of continuous enrolment before the index date, ≥1 month of continuous enrolment following the index date and ≥2 claims on separate dates associated with an asthma diagnosis (ICD-10-CM codes J45, J46 and J82.83) between the beginning and end of continuous enrolment, with ≥1 claim for asthma and ≥1 asthma prescription claim during the baseline period (the 12 months before the index date). Patients with HZ vaccination before or on the index date or a claim for COPD (ICD-10-CM codes J41–44) during the baseline period were excluded. For the cohort with HZ, patients also had to have ≥1 claim associated with a HZ diagnosis (ICD-10-CM code B02, excluding patients for whom the first HZ diagnosis was ‘HZ with other nervous system involvement’ (ICD-10-CM code B02.2)), and the index date was defined as the date of the first HZ claim. In the cohort without HZ, patients were excluded if they had a claim associated with HZ diagnosis or HZ complications during the period of continuous enrolment, and an ‘index date’ was randomly imputed based on the distribution of time between the beginning of continuous enrolment and the index dates in the cohort with HZ. In both cohorts, the period from the index date to the end of data availability was defined as the observation period (online supplemental figures 3 and 4). Patient cohorts and sample selection steps are summarised in online supplemental figure 5.

Measures

Baseline measures/covariates

Demographic characteristics (age, gender, race/ethnicity and type of insurance plan) were reported for all patients. Age was stratified as follows: 18–29 years; 30–39 years; 40–49 years; 18–49 years; 50–64 years; ≥65 years; 50–59 years; 60–69 years; 70–79 years and ≥80 years. Clinical characteristics were measured during the baseline period, including Charlson-Quan Comorbidity Index score18 (modified to exclude chronic pulmonary disease) as a measure of general comorbidity burden, presence of comorbidities potentially associated with HZ, presence of immunosuppressive conditions and asthma-related treatment use.

Outcomes

For incidence analyses, cases of HZ and/or PHN (PHN defined as ICD-10-CM code B02.2) were identified. For HRU and cost analyses, all-cause and HZ-related HRU were measured during the observation period, including number of visits and proportion of patients with each type of visit, for care settings of inpatient, emergency department and outpatient. All-cause and HZ-related direct costs were recorded during the observation period, divided into pharmacy costs (defined as costs from pharmacy claims) and medical costs (the sum of costs from claims for care in settings of inpatient, emergency department, outpatient and any other settings of care on the medical benefit). HZ-related HRU and costs were identified using medical claims with a HZ diagnosis in any position and did not include costs from pharmacy claims.

Statistical analysis

Descriptive analyses were conducted for demographic and clinical characteristics, with mean and SD reported for continuous variables, and frequencies and proportions for categorical variables. Baseline characteristics were compared between cohorts using standardised differences. Standardised differences of 20%, 50% and 80% represented small, medium and large differences, respectively.19

To account for baseline differences between cohorts, multivariable comparative analyses were performed using doubly robust propensity score (PS) adjustment. PS adjustment has advantages over PS matching in that it allows all patients in the sample to be retained, is more robust to model misspecification relative to multivariable models and reduces the number of terms that must be included in the multivariable outcome model.20

For the cohorts in the HZ incidence comparison analysis, incidence rates of HZ were calculated as the number of patients with an HZ diagnosis divided by patient months of observation. Adjusted incidence rate ratios (aIRR) and 95% CIs were calculated using a generalised linear regression model (GLM) with a Poisson distribution, adjusting for patients’ PS and relevant baseline characteristics and used to compare the incidence rate of HZ between patients with asthma versus patients without asthma, overall and stratified by age and asthma medication use category at the end of the observation period. The odds of developing PHN within 6 and 12 months after the incident HZ event were compared using a multivariable logistic regression model adjusting for patients’ PS and relevant baseline characteristics.

For the cohorts in the HRU and cost comparison analysis, incidence rates for visits of each type (inpatient, emergency department and outpatient visits) were compared between the cohorts with or without HZ using aIRRs. Costs were adjusted to 2021 US dollars using the medical care component of the Consumer Price Index and compared between the cohorts with and without HZ using two-part GLMs (adjusting for patients’ PS and relevant baseline characteristics) to estimate adjusted cost differences.

More details are provided in online supplemental material.

All statistical analyses were conducted using the statistical software SAS Enterprise Guide V.7.1 and SAS Studio (SAS Institute, Cary, North Carolina).

Patient and public involvement

There was no specific patient and public involvement in planning or execution of the study.

Results

Incidence

A total of 38 113 848 patients were identified from CDM between 1 October 2015 and 28 February 2020. Of these, 684 869 individuals met the criteria for inclusion in the asthma cohort (Asthma+) and 21 717 258 individuals met the criteria for inclusion in the cohort without asthma (Asthma−).

Table 1 shows the demographic and baseline characteristics for the two cohorts. The asthma cohort had a higher average age (53.0 years vs 48.8 years) and a higher proportion of women (67.3% vs 50.1%) compared with the cohort without asthma.

Table 1

Baseline demographic and clinical characteristics used for the HZ incidence comparison analysis, and for the healthcare resource use and cost comparison analysis

In the asthma cohort, there were 14 498 HZ events over the 1 250 573 person-years of follow-up, giving an incidence rate of 11.59 per 1000 person-years. In the cohort without asthma, there were 2 67 280 HZ events over the 37 332 678 person-years of follow-up, giving an incidence rate of 7.16 per 1000 person-years.

The incidence rates for HZ in each cohort and the aIRR values overall and stratified by age are shown in online supplemental table 1 and as a Forest plot in figure 1. The incidence of HZ was significantly higher in the cohort with asthma, compared with the cohort without asthma, overall and in all age groups, even after adjusting for differences in baseline characteristics. The overall aIRR comparing HZ incidence in patients with versus without asthma was 1.34 (95% CI 1.32 to 1.37). For those aged 18–49 years, the aIRR was 1.40 (95% CI 1.35 to 1.45) and for those aged ≥50 years the aIRR was 1.27 (95% CI 1.24 to 1.29).

Figure 1

Crude incidence rate and adjusted incidence rate ratio (aIRR) for HZ in cohorts with and without asthma. aIRR, adjusted incidence rate ratio; HZ, herpes zoster.

HZ incidence and aIRR stratified by asthma medication use category are shown in online supplemental figure 6. The overall aIRR for HZ was highest in patients receiving oral corticosteroids (aIRR 2.36, 95% CI 2.27 to 2.46).

Table 2 shows the proportion of patients developing PHN within 6 or 12 months of HZ diagnosis among patients with and without asthma for those with sufficient follow-up at each time point. It also shows adjusted OR comparing likelihood of PHN in patients with asthma who had HZ to those without asthma who had HZ, accounting for differences in the baseline characteristics of the populations. Among patients who had HZ, those with asthma were significantly more likely to develop PHN than those without asthma at both time points. The adjusted OR for PHN was 1.16 (95% CI 1.10 to 1.23) at 6 months and 1.16 (95% CI 1.08 to 1.24) at 12 months (table 2).

Table 2

Likelihood of PHN in the periods 6 and 12 months after HZ diagnosis*

Healthcare resource use and costs

Of the 38 113 848 patients of any age identified from CDM between 1 October 2015 and 28 February 2020, a total of 2 571 003 (6.7%) had ≥1 claim associated with a diagnosis of asthma at any time during this period. Among these patients, 8129 met the eligibility criteria for the cohort with HZ and asthma (Asthma+/HZ+), and 334 404 met the eligibility criteria for the cohort with asthma and without HZ (Asthma+/HZ−). Baseline demographic and clinical characteristics are reported for both cohorts in table 1. The cohort with asthma and HZ was older than the cohort with asthma and without HZ (mean age 61.4 years vs 52.9 years) and had a higher proportion of women (76.4% vs 67.2%). Baseline costs were generally higher in the cohort with asthma and HZ than in the cohort with asthma and without HZ (mean total healthcare costs $37 175 vs $25,680) (table 1, online supplemental table 2). During the observation period, after adjusting for baseline differences between cohorts, HRU was significantly higher for patients with asthma and HZ than patients with asthma and without HZ, for all types of medical encounters at all time points (table 3). At 1 month, the aIRR was 2.75 (95% CI 2.44 to 3.09) for inpatient visits, 2.82 (95% CI 2.59 to 3.06) for emergency department visits and 1.86 (95% CI 1.81 to 1.90) for outpatient visits. At 3 months, the aIRR was 1.60 (95% CI 1.48 to 1.74) for inpatient visits, 1.69 (95% CI 1.58 to 1.82) for emergency department visits and 1.41 (95% CI 1.38 to 1.44) for outpatient visits. At 12 months, the aIRR was 1.11 (95% CI 1.02 to 1.21) for inpatient visits, 1.26 (95% CI 1.18 to 1.34) for emergency department visits and 1.19 (95% CI 1.16 to 1.22) for outpatient visits. Similar results were found for HRU in the first month and the first 3 months of follow-up from patients with a full year of follow-up (online supplemental table 3).

Table 3

All-cause healthcare resource use and all-cause healthcare cost in cohorts with asthma and with or without HZ

Adjusted costs were significantly higher in patients with asthma and HZ versus patients with asthma without HZ at all time points (table 3). At 1 month, the adjusted cost difference between patients with asthma and HZ versus patients with asthma without HZ was $1807 (95% CI $1516 to $2114), at 3 months, it was $2145 (95% CI $1605 to $2653), and at 12 months, it was $3058 (95% CI $1671 to $4492). Similar findings were reported for all-cause healthcare costs in the first month and the first 3 months of follow-up from patients with a full year of follow-up (online supplemental table 4).

Table 4 shows HZ-related healthcare costs for patients with asthma and HZ with 1 month, 3 months and 12 months of follow-up. Average HZ-related costs were $1870 per patient over 12 months of follow-up. HZ-related costs were driven by inpatient costs, which averaged $1172 per patient per year and accounted for 63% of total average HZ-related costs. While inpatient costs were the main driver of overall costs, relatively few patients had HZ-related inpatient costs over 1 year of follow-up (3.4% of patients). Outpatient visits were more commonly observed in the cohort but at a lower average cost. HZ-related outpatient costs were incurred by 93.5% of patients within a year.

Table 4

HZ-related healthcare costs in patients with asthma and HZ (Asthma+/HZ+)

Discussion

This retrospective claim database study investigated the incidence of HZ in adult patients with asthma compared with those without asthma, and compared HRU and costs in patients with asthma and HZ versus patients with asthma without HZ. Patients with asthma had higher incidence of HZ than those without asthma, and those with asthma and HZ had higher HRU and costs than those with only asthma.

The incidence of HZ was significantly higher in patients with asthma than in patients without asthma (11.59 per 1000 person-years vs 7.16 per 1000 person-years, IRR 1.34; 95% CI 1.32 to 1.37). This is consistent with findings from previous studies.11–13 A population-based cohort study in Taiwan found that in patients with newly diagnosed asthma, the risk of HZ was 1.48-fold higher than in non-asthmatic patients,21 although this study differed from the present analysis as it was conducted in a non-US population. Our study builds on previous publications by providing data on the increased incidence of HZ in patients with asthma in a large sample covering all 50 US states. It also reports novel data showing that the likelihood of PHN was significantly higher in patients with asthma than in patients without asthma among those who have HZ. The results of the present study also suggested that the population of patients with asthma receiving oral corticosteroids had an elevated risk of HZ compared with the overall population with asthma. This may reflect an increased risk of HZ due to oral corticosteroid use or that increased asthma severity may be associated with increased HZ risk. However, this finding has limitations, as medication category was based on medication use at the end of the observation period and did not account for variations in medication use over time. It is, therefore, only a surrogate for asthma severity and an imperfect measure of overall medication exposure. These results should be interpreted with caution and further research may help understand the mechanism behind this observed association.

HRU was significantly higher in patients with HZ and asthma compared with patients who had asthma without HZ. This higher HRU translated into significantly higher direct healthcare costs for patients with HZ and asthma compared with asthma alone. Patients with asthma and HZ had higher use of all types of healthcare resources studied, including more inpatient stays, more emergency department visits and more outpatient visits, at all time points studied (1 month, 3 months and 12 months of follow-up), compared with patients who had asthma without HZ. As the adjusted analysis accounted for baseline costs and resource utilisation patterns, the difference in resource use is expected to be due directly or indirectly to HZ, although some residual confounding may remain and the results should be interpreted in this context. Asthma is associated with an increased susceptibility to microbial infections, which may be related to impairments in immune function.22 Respiratory viral infections, most frequently rhinovirus, are associated with a high proportion of asthma exacerbations.23 The potential impact of other infections that may be more prevalent in patients with asthma could be an important area for future research. Adjusted incremental direct costs for patients with asthma and HZ were $3058 per patient in the year after the first HZ diagnosis, compared with patients with asthma alone. The highest proportion of adjusted incremental costs over the 1 year observation period occurred during the first month after HZ onset. This reflects the acute nature of HZ, which would be expected to require the highest intensity of care soon after diagnosis in most patients.

The additional burden of HZ in patients with asthma suggests a need to consider measures to prevent HZ in this population. RZV vaccination for HZ prevention is indicated in the US for adults aged ≥50 years and immunocompromised adults aged ≥18 years.24 Efficacy of RZV in older adults and immunocompromised adults has been demonstrated in pivotal clinical trials,25–28 and studies have shown effectiveness and a well-tolerated safety profile in real-world settings.29 Based on data from the National Health Interview Survey, RZV coverage (≥2 doses) in the USA in 2021 was 15.4% in adults aged ≥50 years and 18.5% in adults aged ≥60 years, both higher than in 2020.30 While these coverage estimates show suboptimal overall vaccination in these age groups, chronic comorbidities including COPD and chronic pulmonary disease have been found to be associated with lower vaccination completion rates in adults aged ≥50 years in the USA,31 32 suggesting potentially important additional gaps in coverage for these populations.

To our knowledge, this is the first study to investigate and quantify the effect of HZ on HRU and direct costs in patients with asthma. While there are no previous data on these outcomes in patients with asthma and HZ, our findings are consistent with those of previous studies in other chronic diseases. The nearest comparator is likely to be a study of HZ HRU and costs in 2013–2018 in US patients with COPD, another chronic respiratory disease, which used a similar design to the present study.33 Patients aged ≥50 years with HZ and COPD had higher HRU and healthcare costs than patients with COPD but without HZ. The mean adjusted cost difference was $313 per person per month during the first year.33 If the findings in our analysis of incremental costs over 1 year of follow-up are reported monthly as per patient per month, this would result in an estimate of $255 per patient per month, a somewhat lower cost than observed in patients with COPD, possibly reflecting disease differences between COPD and asthma. This could reflect differences in inflammation associated with asthma and COPD, and that patients with COPD are typically older and have more comorbidities than patients with asthma. It may also reflect the higher age of the patients in the HZ and COPD study.33 The mean age was 73.2 years in patients with COPD and HZ and 72.4 years in patients with COPD without HZ, compared with mean age of 61.4 years in patients with asthma and HZ and 52.9 years in patients with asthma without HZ in the present study. Like the present study, the majority of the cost difference in patients with HZ and COPD occurred in the first month.33 Another retrospective claims database study in the US assessed HZ incidence and HRU and cost in patients with and without type 2 diabetes mellitus in 2012–2018. The incidence of HZ was higher in patients with than without type 2 diabetes mellitus (adjusted IRR 1.84; 95% CI 1.82 to 1.85), consistent with our findings. Patients with HZ and type 2 diabetes mellitus also incurred higher healthcare costs than patients with type 2 diabetes mellitus but without HZ; at 12 months, the incremental all-cause healthcare cost for patients with type 2 diabetes mellitus and HZ was $5216 compared with PS-matched patients who had type 2 diabetes mellitus but without HZ.34 This study of HZ and type 2 diabetes mellitus differed from the present study in that it compared costs in propensity-matched populations,34 whereas the present study used propensity scoring adjustment to estimate adjusted cost differences. In addition, US claims database studies have also reported higher HZ incidence in patients with rheumatoid arthritis compared with patients without rheumatoid arthritis, and more frequent hospitalisations and emergency department visits in patients with HZ and rheumatoid arthritis than patients with rheumatoid arthritis without HZ.35 36

Key strengths of this study include its large sample size and its broad geographical representation of the USA. It provides more recent data (2015–2020) than previous research examining HZ incidence in patients with asthma in the USA (2010–2011)11 and also report novel findings indicating that patients with HZ and asthma were significantly more likely to develop PHN than patients with HZ and without asthma. Furthermore, to our knowledge, this is the first study to report all-cause and HZ-related HRU and costs in a population with asthma and HZ.

Nevertheless, the study has a number of limitations. The CDM database may not be generalisable to populations not covered by the included commercial and Medicare Advantage insurance programmes, such as those covered by Medicaid or without insurance. Although we aimed to exclude patients from analyses who had previously received HZ vaccination, patients’ medical histories were retrieved only for the 6 months or 12 months before index in the incidence and HRU/cost analyses, respectively. It is, therefore, possible that some patients who received HZ vaccination before this period may have been misclassified as not having received HZ vaccination. Similarly, the limited medical history may have affected our aim of excluding patients with COPD to capture a population that had asthma, not COPD and not both diseases. The potential for misdiagnosis of asthma is recognised, with estimates that 30%–35% of patients with physician-diagnosed asthma may not have current asthma.37 This is a potential limitation of any retrospective database analysis in asthma, although these estimates of misdiagnosis are based on results from research conducted outside the USA and may not generalise to the US setting. In the present study, we attempted to mitigate the risk of misclassification by requiring ≥2 claims associated with asthma diagnoses on separate dates. A possible minor limitation is that the HRU and cost data only included care received within plans captured by the database and may have underestimated total HRU and cost if care received from other sources was missed. HRU and costs may also have been underestimated if HZ-related costs were incurred before the patient’s HZ diagnosis during a prodromal disease phase. It is also possible that using a single claim associated with a HZ diagnosis code may not accurately estimate the incidence of HZ. Finally, while claims data provide relatively complete capture of healthcare use and associated costs, this type of data source is used for billing purposes and does not provide detailed clinical information. This limits the ability of database analyses to measure important quality of life outcomes and details of patients’ clinical condition, which may lead to unmeasured confounding.

Conclusion

This study provides a valuable update on the increased incidence of HZ in patients with asthma versus those without asthma and supports previous findings. In addition to the higher incidence of HZ in patients with asthma, those who had HZ and asthma were more likely to develop PHN versus patients who had HZ but no asthma. Furthermore, patients with asthma and HZ also had significantly higher HRU and costs than asthma patients without HZ. This additional burden of HZ in patients with asthma suggests a need to consider measures to prevent HZ in this population.

Data availability statement

The data that support the findings of this study are available from Optum, but restrictions apply to the availability of these data, which were used under license for the current study and so are not publicly available. GSK makes available anonymised individual participant data and associated documents from interventional clinical studies which evaluate medicines, upon approval of proposals submitted to www.clinicalstudydatarequest.com. To access data for other types of GSK sponsored research, for study documents without patient-level data and for clinical studies not listed, please submit an enquiry via the website.

Ethics statements

Patient consent for publication

Ethics approval

Not applicable.

Acknowledgments

The authors thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Carole Nadin (Fleetwith Ltd, on behalf of GSK) provided medical writing support.

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors All authors participated in the design or implementation or analysis, and interpretation of the study; and the development of this manuscript. All authors had full access to the data and gave final approval before submission. DS is the guarantor.

  • Funding GlaxoSmithKline Biologicals SA funded this study (GSK study identifier: VEO-000257) and was involved in all stages of the study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also took in charge all costs associated with the development and publication of this manuscript. All authors had full access to the data and agreed with the submission of the publication.

  • Competing interests DS and SP are employed by and hold shares in GSK. PT-L, DG, WYC, AM, FD, MS, EH and MSD are/were employees of Analysis Group, Inc., a consulting firm that received funding from GSK for the conduct of this study. SM declares a postdoctoral fellowship grant from GSK for the conduct of this study. MB was employed by and held shares in GSK at the time of the study. JO received consulting fees for adjudication committees, data and safety monitoring boards or study design from GSK, AstraZeneca, Amgen, Sanofi, and Regeneron, Aquestive Therapeutics, and Aimmune; is a member of the advocacy council of the American Board of Internal Medicine and a member of the American Board of Allergy and Immunology; is a reviewer for UpToDate; and was Executive-Editor of Annals of Allergy, Asthma & Immunology.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer-reviewed.

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