Preventive Role of <scp>COVID</scp>‐19 Vaccination on Future Severe Exacerbation of Asthma According to Severe COVID‐19 Status: A Nationwide Population‐Based Cohort Study

Contrary to initial concerns, previous studies have revealed that individuals with asthma are not at an increased risk of severe COVID-19 unless they have not been recently hospitalized or have not used systemic corticosteroids [1, 2]. However, regarding long-term consequences, severe COVID-19 may affect the future disease course of asthma. Since vaccination could provide long-term benefit from severe COVID-19, we aim to examine the impact of COVID-19 vaccination and severe COVID-19 status on the risk of asthma exacerbations using a nationwide population-based cohort. We conducted a retrospective cohort study using claims data from the Korean National Health Insurance Service (NHIS) SARS-CoV-2 database. The inclusion criteria, definitions of index date, asthma, severe COVID-19, and severe exacerbation, and details on follow-ups were provided in Table S1. This study included 3380 individuals, who were categorized by COVID-19 vaccination and severe COVID-19 status into four groups (Figure S1). Definitions of covariates were provided in Table S2. Kaplan–Meier curves and Cox proportional hazards regression models were used to estimate severe exacerbation risks. To explore the impact of post-COVID-19 conditions on severe exacerbation risks, we performed stratified analyses across two time windows (0–30 vs. 31–240 days). Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). The baseline characteristics of the study population are summarized in Table 1. The four groups were well-balanced. As shown in Figure 1, the lowest risk was observed in vaccinated/uninfected individuals (hazard ratio [HR] = 0.28, 95% confidence interval [CI] = 0.19–0.43), followed by unvaccinated/uninfected individuals (HR = 0.44, 95% CI = 0.29–0.67). Notably, vaccinated/infected individuals also had a significantly lower risk of severe exacerbations compared to unvaccinated/infected individuals (HR = 0.63, 95% CI = 0.43–0.94). In the stratified analyses based on post-COVID-19 period, the direction of effect was similar in both periods, but a statistically significant decrease in severe exacerbations was observed only in vaccinated/uninfected individuals during 31–240 days (Table S3). We found that vaccinated individuals had a significantly lower risk of subsequent severe exacerbations of asthma compared to unvaccinated individuals who experienced severe COVID-19, even among those who did not experience severe COVID-19. Compared to the unvaccinated/infected individuals, the risk of severe exacerbations of asthma decreased by 72%—the greatest reduction—in vaccinated/uninfected individuals. Furthermore, vaccinated/infected individuals also exhibited a 37% reduction in the risk of severe exacerbations. Our findings provide real-world evidence of the long-term protective effects of COVID-19 vaccination against post-COVID-19 exacerbations of asthma, particularly in severe cases. An altered immune system and physical deconditioning following severe COVID-19 may make individuals with asthma more vulnerable to severe exacerbations of asthma [3, 4], and vaccination may exert a protective effect. Clinicians should proactively encourage annual booster vaccinations as part of routine asthma management. There are some limitations in this study. First, using ICD-10 codes to define asthma could result in under- or overdiagnosis. Second, our study duration may be limited to evaluate the long-term effect of vaccination, and thus, a future study extending the study period would be necessary. Third, SARS-CoV-2 variants could not be considered. Fourth, unassessed confounding factors, such as reasons for systemic corticosteroid use, blood eosinophil count, and adherence to inhaled corticosteroids, may exist. For example, early events could represent post-COVID-19 respiratory complications rather than asthma exacerbations, and exacerbations may have resulted from poor medication adherence. Fifth, the lack of specific virus pathogen data introduces uncertainty regarding the exact causes of exacerbations. In conclusion, COVID-19 vaccination decreased the risk of severe exacerbations of asthma during the COVID-19 pandemic. Our findings highlight the importance of COVID-19 vaccination in asthma management and provide evidence supporting clinical recommendations. Jong Seung Kim and Hyun Lee are the guarantors of the manuscript and take responsibility for the content of the manuscript, including the data and analysis. All authors contributed to the conception of the study and were involved in data collection. Hyun Lee and Jong Seung Kim contributed to the design of the study. Sang Hyuk Kim and Jong Geol Jang were involved in the interpretation of the data. Min Gu Kang was involved in statistical analyses. Sang Hyuk Kim and Jong Geol Jang were major contributors to the writing of the manuscript. All authors have read and approved the final manuscript. The study protocol was approved by the Institutional Review Board of Hanyang University Hospital (no. HYUH 2024-11-053-003). The requirement for informed consent was waived because all patient records were anonymized before use. The authors declare no conflicts of interest. The data that support the findings of this study are available from Korea NHIS. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from https://nhiss.nhis.or.kr/ with the permission of Korea NHIS. Table S1: The inclusion and exclusion criteria, and definition of index date, asthma, severe COVID-19, and severe exacerbation. Table S2: Definition of covariates. Table S3: Risk of severe exacerbations of asthma according to COVID-19 vaccination and infection status in two windows. Figure S1: Flow chart of study population selection. COVID-19, coronavirus disease 2019; PS, propensity score. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.