Abstract
Background
The coronavirus disease 2019 (COVID-19) vaccination is suggested to be effective in improving outcomes of chronic obstructive pulmonary disease (COPD). However, real-world evidence on long-term mortality among individuals with COPD, accounting for both vaccination and COVID-19 infection status, remains sparse.
Methods
A retrospective cohort study was conducted using datasets from the Korean National Health Insurance system. Through two-step propensity score matching, 716 individuals with COPD were included in the analysis and classified into four groups according to COVID-19 vaccination and severe acute respiratory syndrome coronavirus 2 infection status: 125 COVID-19 vaccinated/uninfected, 125 vaccinated/infected, 233 unvaccinated/uninfected, and 233 unvaccinated/infected. A multivariable Cox proportional hazards regression analysis was conducted to assess the risk of mortality following COVID-19 vaccination and SARS-CoV-2 infection status.
Results
The median follow-up period was 420 days, during which 79.6% of study participants completed follow-up. Mortality rates were lowest in the vaccinated/uninfected individuals (281/10,000 person-years), followed by the vaccinated/infected individuals (661/10,000 person-years) and unvaccinated/uninfected individuals (2,106/10,000 person-years) and highest in unvaccinated/infected individuals (4,510/10,000 person-years). Compared with vaccinated/uninfected individuals, unvaccinated/infected individuals had a significantly higher annual risk of mortality (adjusted hazard ratio [aHR] = 13.51, 95% confidence interval [CI] = 4.91–37.13). The annual mortality risk was also significantly higher among unvaccinated/uninfected individuals (aHR = 6.01, 95% CI = 2.15–16.81). On the other hand, vaccinated/infected individuals (aHR = 2.32, 95% CI = 0.71–7.55) did not exhibit a significantly increased annual mortality risk compared with vaccinated/uninfected individuals.
Conclusion
COVID-19 vaccination is associated with reduced long-term COPD-related mortality, whereas mortality risk was higher in unvaccinated/uninfected individuals than in vaccinated/infected individuals. Vaccination-related factors may confer broader benefits on COPD outcomes beyond direct protection against COVID-19.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-025-03470-9.
Keywords: Chronic obstructive pulmonary disease, Respiratory disease, Vaccination, COVID-19, Mortality
Introduction
The devastating coronavirus disease 2019 (COVID-19) pandemic has transitioned into a global endemic phase [1]. However, with ongoing waves of COVID-19, the need for regular COVID-19 vaccination in vulnerable populations is essential [2]. Governments and chronic obstructive pulmonary disease (COPD) guidelines recommend COVID-19 vaccination for individuals with COPD [3–5]. Nonetheless, some COPD patients exhibit vaccine hesitancy [6]. Despite vaccination being provided free of charge in Korea, concerns about the safety of the vaccine and its potential effects on their prognosis have contributed to continued hesitancy [7, 8].
Post-COVID-19 condition can manifest as persistent or new symptoms appearing at least three months after the initial infection; therefore, several studies have investigated the long-term effects of COVID-19 [9, 10]. COVID-19 vaccination is known to effectively reduce long-term health consequences in the general population [11, 12]. Although COVID-19 vaccination is associated with reduced long-term healthcare use among people living with COPD, including severe exacerbations and hospitalization [13, 14], its effects on long-term mortality remain insufficiently explored. For example, a population-level study conducted in Italy reported a reduction in COPD-related mortality following the initiation of the COVID-19 vaccination campaign [15]; however, the design of that study limited its ability to attribute the observed decline solely to vaccination because other confounding factors may have contributed [16]. The absence of explicit data on both COVID-19 vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status in many studies complicates comprehensive assessment of the effects of COVID-19 vaccination in individuals with COPD [17].
Therefore, further investigation using a longitudinal cohort study design is warranted to determine whether COVID-19 vaccination decreases COPD-related mortality. In this study, we used a nationwide cohort dataset to evaluate the long-term annual mortality risk in individuals with COPD based on COVID-19 vaccination and SARS-CoV-2 infection status.
Methods
Study population
This retrospective cohort study used data derived from claims data in the Korean National Health Insurance System (NHIS) database. The NHIS is a government-managed universal insurance provider encompassing nearly 97% of the Korean population, approximately 50 million individuals [18]. The NHIS database has been widely adopted in epidemiological research associated with COVID-19 and post-COVID complications [19–22].
This study included individuals older than 20 years who had a confirmed diagnosis of COPD before February 26, 2021, as well as healthy control participants. Infected participants were required to have experienced COVID-19 between October 8, 2020, and March 31, 2022. The following individuals were excluded: 1) those lacking health examination records, 2) vaccinated after COVID-19 diagnosis, 3) diagnosed with COPD after COVID-19, or 4) died before the index date or February 26, 2021. We excluded individuals vaccinated after a COVID-19 diagnosis to avoid reverse causality and misaligned exposure windows, and those diagnosed with COPD after COVID-19 to ensure we evaluated outcomes among individuals with pre-existing COPD [23].
COPD was defined as requiring at least two prescriptions within one year for COPD-specific medications under International Classification of Diseases, 10th Revision (ICD-10) codes for COPD (J43–J44, excluding J43.0) [14]. The list of COPD-specific medications included long-acting muscarinic antagonists, long-acting beta-2 agonists (LABAs), inhaled corticosteroid/LABA combinations, short-acting muscarinic antagonists (SAMAs), short-acting beta-2 agonists (SABAs), SAMA/SABA combinations, methylxanthines, and systemic beta-agonists. The index date was determined as follows: the date of COVID-19 diagnosis for COVID-19 cases; the date of vaccination for vaccinated individuals; and a date matched to that of vaccinated patients for uninfected and unvaccinated individuals.
From the NHIS-SARS-CoV-2 database, which included 8,771,237 individuals from 2020 to 2021, exclusions were applied to establish the final analytic cohort. First, 4,713,210 individuals without health examination data were excluded, followed by 3,948,792 individuals without COPD, 823 individuals vaccinated after contracting COVID-19, 4,572 individuals diagnosed with COPD after COVID-19, and 1,805 individuals who died prior to the index date. As a result, the final cohort consisted of 42,035 individuals with COPD. A two-step propensity score (PS) matching process was applied based on age, sex, body mass index (BMI), smoking status, alcohol consumption, economic status, residential area, and comorbidities (hypertension, diabetes, dyslipidemia, chronic kidney disease, and asthma). Using this approach, an analytic cohort of 716 individuals with COPD was established (Fig. 1).
Fig. 1.
Flow chart of the study population. Abbreviations: COPD = chronic obstructive pulmonary disease, COVID-19 = coronavirus disease 2019, PS = propensity score
Ethics statement
The study protocol was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH-2024-10-002). The requirement for informed consent was waived because all patient records were anonymized before use.
Exposure: COVID-19 vaccination and infection status
The Republic of Korea initiated its COVID-19 vaccination campaign on February 26, 2021. By October 23, 2021, more than 70% of the population had received at least two doses of the BNT162b2, mRNA-1273, or AZD1222 vaccine [24].
In Korea, nationwide COVID-19 screening and diagnostic testing were implemented early under the government’s proactive strategy during the study period for symptomatic individuals, high-risk individuals, or contacts [25]. All COVID-19 diagnoses were confirmed through real-time reverse transcription-polymerase chain reaction tests of nasal or pharyngeal swabs, coded under ICD-10 as U07.1 [19]. Nasopharyngeal or oropharyngeal swabs were mainly collected at public health centers, community screening clinics, or designated hospitals sites. The Korean government actively promoted testing during the pandemic and extended health insurance coverage to all citizens diagnosed with COVID-19 (NHIS-2022-1-623). Severe cases of COVID-19 were identified based on the need for advanced medical interventions during hospitalization. These interventions included oxygen therapy, admission to the intensive care unit, mechanical ventilation, or treatment with extracorporeal membrane oxygenation [19–21].
Outcome: mortality
The primary outcome evaluated in the study was the long-term annual risk of all-cause mortality. Participants were followed from the index date until death or the end of the follow-up period (420 days after the index date). The follow-up of 420 days was determined by the availability of mortality data in the dataset.
Covariates
The BMI was determined by dividing an individual’s weight (kg) by the square of height (m²) and was classified following guidelines specific to Asian populations: underweight (< 18.5 kg/m²), normal (18.5–22.9 kg/m²), overweight (23.0–24.9 kg/m²), obese (25.0–29.9 kg/m²), and severely obese (≥ 30 kg/m²) [26]. Economic status was categorized by income level: individuals in the top 30% were classified as high income; those in the bottom 30% or receiving medical aid were considered low income; and the remaining individuals were in the middle-income category. Regular physical activity was defined as moderate exercise for more than 30 min at least five times per week or vigorous exercise for more than 20 min at least three times weekly [27, 28]. Alcohol consumption was grouped into four levels: none, 1–2 times weekly, 3–4 times weekly, and nearly daily. A history of severe exacerbation of COPD was identified through emergency room visits or hospitalizations with systemic steroid treatment under the ICD-10 COPD codes within the previous year. Asthma was diagnosed through ICD-10 codes J45–J46 and confirmed by prescriptions for asthma treatments, including inhaled or systemic steroids, bronchodilators, leukotriene receptor antagonists, or xanthine derivatives [20]. Hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease were defined by corresponding ICD-10 codes [27, 28].
Statistical analysis
The data are presented as number with percentage for categorical variables and either mean ± standard deviation or median with interquartile range (IQR) for continuous variables depending on the normality of the distribution. Categorical variables were compared using the χ2 test, and continuous variables were compared using t-tests. Mortality rates were determined by dividing the number of deaths by the overall follow-up period, expressed per 10,000 person-years (PY). Cumulative incidence curves were used to compare mortality rates based on vaccination and COVID-19 status, and statistical significance was assessed using the log-rank test. Cox proportional hazards regression models were used to estimate the annual mortality risk. Adjustments were made for all variables involved in the PS matching process to account for residual intergroup differences. A subgroup analysis was performed based on age, dividing participants into younger individuals (< 65 years) and older individuals (≥ 65 years) [29]. A sensitivity analysis was conducted for severe COVID-19 cases to assess the effects of vaccination. Time-dependent analysis was conducted to investigate early (< 60 days) and late (≥ 60 days) risk for mortality. A two-sided p-value less than 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline characteristics
Table 1 presents the baseline characteristics of the study population. Among the entire study population, 64.8% of participants were male, and 62.0% were aged between 60 and 79 years. Among the vaccinated participants, 96.8% received two or more doses. No significant differences were observed between groups with respect to sex, smoking status, economic status, or comorbidities, as indicated by standardized mean differences less than 0.25.
Table 1.
Baseline characteristics of the study population
| Vaccinated/Infected (n = 125) |
Vaccinated/ Uninfected (n = 125) |
Unvaccinated/ Infected (n = 233) |
Unvaccinated/ Uninfected (n = 233) |
SMD | |
|---|---|---|---|---|---|
| Age, years | 0.340 | ||||
| 20–49 | 5 (4.0) | 13 (10.4) | 26 (11.2) | 17 (7.3) | |
| 50–59 | 12 (9.6) | 11 (8.8) | 16 (6.9) | 18 (7.7) | |
| 60–69 | 44 (35.2) | 28 (22.4) | 66 (28.3) | 66 (28.3) | |
| 70–79 | 46 (36.8) | 55 (44.0) | 64 (27.5) | 75 (32.2) | |
| ≥ 80 | 18 (14.4) | 18 (14.4) | 61 (26.2) | 57 (24.5) | |
| Sex, male | 84 (67.2) | 81 (64.8) | 145 (62.2) | 154 (66.1) | 0.057 |
| BMI | 0.268 | ||||
| Low, < 18.5 kg/m2 | 5 (4.0) | 9 (7.2) | 17 (7.3) | 18 (7.7) | |
| Normal, 18.5–22.9 kg/m2 | 37 (29.6) | 46 (36.8) | 78 (33.5) | 87 (37.3) | |
| Overweight, 23.0–24.9 kg/m2 | 36 (28.8) | 26 (20.8) | 42 (18.0) | 42 (18.0) | |
| Obese, 25.0–29.9 kg/m2 | 39 (31.2) | 42 (33.6) | 81 (34.8) | 69 (29.6) | |
| Highly obese, ≥ 30 kg/m2 | 8 (6.4) | 2 (1.6) | 15 (6.4) | 17 (7.3) | |
| Regular physical activity | 49 (39.2) | 51 (40.8) | 51 (21.9) | 44 (18.9) | 0.31 |
| Smoking status | 0.136 | ||||
| Never smoker | 58 (46.4) | 59 (47.2) | 127 (54.5) | 125 (53.6) | |
| Former smoker | 46 (36.8) | 44 (35.2) | 78 (33.5) | 82 (35.2) | |
| Current smoker | 21 (16.8) | 22 (17.6) | 28 (12.0) | 26 (11.2) | |
| Alcohol consumption | 0.316 | ||||
| None | 86 (68.8) | 87 (69.6) | 198 (85.0) | 202 (86.7) | |
| 1–2 times/week | 23 (18.4) | 22 (17.6) | 22 (9.4) | 21 (9.0) | |
| 3–4 times/week | 11 (8.8) | 13 (10.4) | 7 (3.0) | 5 (2.1) | |
| Almost every day | 5 (4.0) | 3 (2.4) | 6 (2.6) | 5 (2.1) | |
| Economic status | 0.221 | ||||
| Low | 23 (18.4) | 29 (23.2) | 69 (29.6) | 79 (33.9) | |
| Middle | 63 (50.4) | 53 (42.4) | 101 (43.3) | 91 (39.1) | |
| High | 39 (31.2) | 43 (34.4) | 63 (27.0) | 63 (27.0) | |
| Residential area | 0.184 | ||||
| Metropolitan cities | 10 (8.0) | 8 (6.4) | 27 (11.6) | 29 (12.4) | |
| Mid-size and small cities | 20 (16.0) | 21 (16.8) | 51 (21.9) | 54 (23.2) | |
| Rural areas | 95 (76.0) | 96 (76.8) | 155 (66.5) | 150 (64.4) | |
| Previous severe exacerbations | 25 (20.0) | 22 (17.6) | 61 (26.2) | 58 (24.9) | 0.124 |
| Vaccination dose | 3.560 | ||||
| One | 7* (5.6) | 1 (0.8) | |||
| Two or more | 118 (94.4) | 124 (99.2) | |||
| Comorbidities | |||||
| Hypertension | 55 (44.0) | 46 (36.8) | 103 (44.2) | 102 (43.8) | 0.076 |
| Diabetes mellitus | 30 (24.0) | 21 (16.8) | 59 (25.3) | 59 (25.3) | 0.11 |
| Chronic kidney disease | 3 (2.4) | 1 (0.8) | 14 (6.0) | 15 (6.4) | 0.187 |
| Dyslipidemia | 18 (14.4) | 25 (20.0) | 27 (11.6) | 24 (10.3) | 0.151 |
| Asthma | 56 (44.8) | 56 (44.8) | 89 (38.2) | 106 (45.5) | 0.074 |
Data are shown as mean (SD) or number (%), as appropriate
Abbreviations: COVID-19 coronavirus disease 2019, SMD standardized mean difference, interval, SD standard deviation, BMI body mass index
*one of the seven was vaccinated with Ad26.COV2.S, which was authorized as a single-dose vaccination
Effects of vaccination on mortality
The median follow-up period was 420 days, during which 79.6% of study participants completed follow-up. Mortality rates were lowest among vaccinated/uninfected individuals (281/10,000 PY), followed by vaccinated/infected (661/10,000 PY) and unvaccinated/uninfected (2,106/10,000 PY) individuals, and they were highest among unvaccinated/infected individuals (4,510/10,000 PY).
As indicated in Table 2, compared with vaccinated/uninfected individuals, unvaccinated/infected individuals had the highest annual mortality risk (adjusted hazard ratio [aHR] = 13.51, 95% confidence interval [CI] = 4.91–37.13), followed by unvaccinated/uninfected individuals (aHR = 6.01, 95% CI = 2.15–16.81). The vaccinated/infected individuals did not have a significantly higher annual mortality risk compared to vaccinated/uninfected individuals (aHR = 2.32, 95% CI = 0.71–7.55). Cumulative incidence plots illustrate these findings (Fig. 2, log-rank p < 0.001).
Table 2.
Long-term mortality risk based on COVID-19 vaccination and infection status
| COVID-19 vaccination |
COVID-19 infection | N | Number of deaths | Mortality rate (per 10,000 person-years) |
Unadjusted HR (95% CI) |
Adjusted HR (95% CI) |
|---|---|---|---|---|---|---|
| Yes | No | 125 | 4 | 281 | Ref. | Ref. |
| Yes | Yes | 125 | 9 | 661 | 2.32 (0.71–7.54) | 2.32 (0.71–7.55) |
| No | No | 233 | 49 | 2106 | 7.12 (2.57–19.73) | 6.01 (2.15–16.81) |
| No | Yes | 233 | 84 | 4510 | 14.50 (5.32–39.55) | 13.51 (4.91–37.13) |
| Age < 65 | ||||||
| Yes | No | 32 | 0 | 0 | - | - |
| Yes | Yes | 35 | 1 | 251 | Ref.* | Ref. * |
| No | No | 62 | 4 | 583 | 2.29 (0.26–20.52) | 2.36 (0.22–25.07) |
| No | Yes | 75 | 15 | 2083 | 7.91 (1.04–59.87) | 13.20 (1.44–120.89) |
| Age ≥ 65 | ||||||
| Yes | No | 93 | 4 | 379 | Ref. | Ref. |
| Yes | Yes | 90 | 8 | 832 | 2.16 (0.65–7.16) | 2.03 (0.61–6.77) |
| No | No | 171 | 45 | 2747 | 6.79 (2.44–18.89) | 5.12 (1.82–14.41) |
| No | Yes | 158 | 69 | 6047 | 14.02 (5.11–38.42) | 11.54 (4.17–31.93) |
Data are shown as number or ratio (95% CI), as appropriate
Abbreviations: COPD chronic obstructive pulmonary disease, COVID-19 coronavirus disease 2019, HR hazard ratio, CI confidence interval
*In the subgroup analysis of individuals aged under 65 years, vaccinated/infected individuals were used as the reference group, as there were no mortality cases among the vaccinated/uninfected individuals
Fig. 2.
Kaplan-Meier curve for mortality based on COVID-19 vaccination and infection statuses. Abbreviations: COVID-19 = coronavirus disease 2019
Subgroup analyses by age showed consistent patterns. In individuals aged < 65 years, unvaccinated/infected individuals had the highest mortality risk (aHR = 13.20, 95% CI = 1.44–120.89), while comparison between vaccinated/uninfected and unvaccinated/uninfected groups was not feasible due to the absence of deaths in the former. Among those aged ≥ 65 years, the highest risk was also observed in unvaccinated/infected individuals (aHR = 11.54, 95% CI = 4.17–31.93), followed by unvaccinated/uninfected individuals (aHR = 5.12, 95% CI = 1.82–14.41).
Effects of COVID-19 vaccination on mortality among severe COVID cases
As shown in Fig. 3, among individuals who experienced severe COVID-19, vaccination decreased the risk of mortality by approximately 70% (aHR = 0.29, 95% CI = 0.11–0.76, log-rank p = 0.005). Specifics on the causes of severe COVID-19 were shown in Supplementary Table 1.
Fig. 3.
Kaplan-Meier curve for mortality among severe COVID-19 cases. Abbreviations: COVID-19 = coronavirus disease 2019, aHR = adjusted hazard ratio, CI = confidence interval
Time-dependent analysis
Table 3 presents the results of the time-dependent analysis. There were no mortality cases among 125 vaccinated/uninfected individuals within 60 days, and unvaccinated/infected individuals showed the highest mortality risk (aHR = 11.12, 95% CI = 3.42–36.18) compared with vaccinated/infected individuals. Beyond 60 days, the elevated risk persisted (aHR = 4.38, 95% CI = 1.53–12.55), although the magnitude of the association was attenuated.
Table 3.
Time-dependent analysis for mortality
| COVID-19 vaccination | COVID-19 infection | N | Mortality cases | aHR (95% CI) | ||
|---|---|---|---|---|---|---|
| < 60 days | ≥ 60 days | < 60 days | ≥ 60 days | |||
| Yes | No | 125 | 0 | 4 | N/A | Ref. |
| Yes | Yes | 125 | 3 | 6 | Ref.* | 1.58 (0.44–5.65) |
| No | No | 233 | 15 | 28 | 2.34 (0.66–8.23) | 5.00 (1.73–14.46) |
| No | Yes | 233 | 56 | 34 | 11.12 (3.42–36.18) | 4.38 (1.53–12.55) |
Abbreviations: COVID-19 coronavirus disease 2019, aHR adjusted hazard ratio, CI confidence interval
*In the time-dependent analysis of less than 60 days, vaccinated/infected individuals were used as the reference group, as there were no mortality cases among the vaccinated/uninfected individuals
Discussion
To our knowledge, this is the first study to suggest that COVID-19 vaccination might lower the long-term annual mortality risk in individuals with COPD. Using this nationwide, long-term dataset of COVID-19-related information, we report the following. First, unvaccinated individuals who had COVID-19 had more than a 10-fold increase in the annual risk of death compared with vaccinated individuals who did not have COVID-19. Second, COVID-19 did not significantly increase the annual risk of death among individuals who received the COVID-19 vaccine. Third, COVID-19 vaccination reduced the annual mortality risk among individuals without COVID-19. Fourth, COVID-19 vaccination decreased the mortality risk associated with severe COVID-19 by approximately 70%.
The detrimental effects of COVID-19 on individuals with COPD are well-documented. Individuals with COPD face a higher risk of COVID-19-related hospitalization, intensive care unit admission, mechanical ventilation, and mortality than those without COPD [30, 31]. Beyond those acute phase risks, as the world transitions to managing COVID-19 in the endemic phase, attention has shifted to addressing the long-term outcomes of COVID-19. Individuals with COPD have been identified as a high-risk group for long COVID and its associated complications [13, 14, 22]. Pulmonary rehabilitation has been proposed as a potential intervention [32]; however, the availability of effective therapies remains limited, highlighting the importance of preventive strategies (e.g., COVID-19 vaccination) to mitigate the long-term consequences of COVID-19.
We found that COVID-19 vaccination is associated with reduced annual mortality, suggesting its effectiveness as a preventive measure against related long-term adverse outcomes. COPD patients had a more than 10-fold increased risk of death from COVID-19 if they were unvaccinated. This risk was more pronounced in the early phase after infection, but the trend persisted, though its magnitude was reduced. Furthermore, COVID-19 infection did not significantly increase the annual risk of death among individuals who had received the COVID-19 vaccine. Interestingly, COVID-19 vaccination was also linked to a decreased annual mortality risk even in individuals without confirmed infection. Undetected asymptomatic or mild infections can still provoke COPD exacerbations, similar to influenza, and vaccination both reduces exacerbations and improves outcomes [33]. Thus, COVID-19 vaccination might lower the long-term annual mortality risk by preventing exacerbations or reducing the risk of fatal events, such as cardiovascular disease, related to COVID-19 [34, 35].
To address the possibility that the observed mortality gradient reflects differences in age structure, we conducted subgroup analyses by age. These analyses demonstrated that the pattern persisted within each age group: unvaccinated/infected individuals consistently had the highest mortality risk, followed by unvaccinated/uninfected, and then vaccinated/uninfected individuals. Notably, among younger individuals, the excess risks remained substantial, indicating that differences in age composition alone do not account for the findings. This suggests that vaccination may be associated with lower long-term mortality in COPD, beyond the confounding effects of age. Nevertheless, unvaccinated individuals tended to be older than vaccinated individuals. Since age is the most significant factor associated with mortality, our results should be interpreted considering the impact of age [36]. Further studies on the role of vaccination in the super-aged population would be beneficial.
Another important finding of our study is that COVID-19 vaccination reduced the risk of COVID-19-related death by 70% among individuals with COPD who had severe COVID-19. Considering that severe COVID-19 is the driving cause of the increase in long-term annual risk of death in individuals with COPD [22], our study results suggest that COVID-19 vaccination plays a role in attenuating long-term sequelae in individuals who had severe COVID-19. Because our study is observational, we cannot provide a plausible explanation for this phenomenon. However, it is likely that the severity of COVID-19 might be lower in the vaccinated population than the unvaccinated population because the enhanced immunity against the virus provided by vaccination leads to reduced lung damage. Also, cross-protective immunity against common COPD exacerbation triggers (e.g., other coronaviruses) might also be linked to the reduced risk of future exacerbations after initial recovery from severe COVID-19 [37]. Future studies are needed to explain this phenomenon.
The current Global Initiative for Chronic Obstructive Lung Disease recommendations advocate for COVID-19 vaccination in individuals with COPD [3]. Despite the potential benefits of COVID-19 vaccination on long-term COPD-related mortality, direct evidence supporting the survival benefit of COVID-19 vaccination in the COPD population is lacking. Based on our study results, stronger recommendations for COVID-19 vaccination should be provided to individuals with COPD to promote their long-term health.
Our study has several limitations that should be acknowledged. First, the diagnosis of COPD was based on ICD-10 codes and prescribed medications in the absence of spirometry and clinical data, which might have led to under- or overdiagnosis. Also, the claim data-based approach is further limited in identifying the duration of COPD diagnosis, which could affect the prognosis. Second, a relatively high proportion of never-smoker COPD patients was observed in this study. This pattern may partly reflect the characteristics of the Korean population, such as smoking rate and other risk factors (e.g., prior pulmonary tuberculosis and biomass exposure) which also contribute to COPD development [38, 39]. Nevertheless, previous studies using the same nationwide claims have consistently reported a substantial fraction of never-smoker COPD cases, supporting that this finding is not unique to our study but reflects the epidemiologic context of COPD in Korea [40]. Third, cause-of-death data were not available in our dataset, which limited further exploration of COVID-19-related or respiratory-specific mortality. Future studies including detailed cause-of-death information would be valuable to identify specific risk factors for mortality in individuals with COPD. Fourth, because the etiotypes, endotypes, and phenotypes of COPD were not fully considered, our study population might have been heterogeneous [41]. Fifth, the study was conducted during the COVID-19 pandemic, when public health interventions and social restrictions might have influenced the outcomes. Lastly, because the findings are derived from data collected in a single nation, their generalizability to other populations might be limited.
In conclusion, COVID-19 vaccination decreased the long-term annual mortality risk in individuals with COPD, including those with severe COVID-19. Meanwhile, mortality risk was higher in unvaccinated/uninfected individuals than in vaccinated/infected individuals. Vaccination-related factors may confer broader benefits on COPD outcomes beyond direct protection against COVID-19.
Supplementary Information
Acknowledgments
Not applicable.
Clinical trial number
Not applicable.
Abbreviations
- aHR
Adjusted Hazard Ratio
- BMI
Body Mass Index
- CI
Confidence Interval
- COPD
Chronic Obstructive Pulmonary Disease
- COVID-19
Coronavirus Disease 2019
- ICD-10
International Classification of Diseases, 10th Revision
- IQR
Interquartile Range
- LABA
Long-Acting Beta-2 Agonist
- mRNA
Messenger Ribonucleic Acid
- NHIS
National Health Insurance System
- PS
Propensity Score
- PY
Person-Years
- RNA
Ribonucleic Acid
- RT-PCR
Reverse Transcription-Polymerase Chain Reaction
- SABA
Short-Acting Beta-2 Agonist
- SAMA
Short-Acting Muscarinic Antagonist
- SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
- SD
Standard Deviation
Authors’ contributions
H.L. and J.-Y.M. are the guarantors of the manuscript and take responsibility for its content, including the data and analysis. All authors contributed to the conception of the study and were involved in data collection. S.H.K., J.S.K., M.G.K., H.L., and J.-Y.M. contributed to the design of the study. S.H.K., J.S.K., M.G.K., H.L., and J.-Y.M. were involved in data interpretation. J.S.K., M.G.K., and M.J.K. were involved in the statistical analyses. S.H.K., J.S.K., M.G.K., H.L., and J.-Y.M were major contributors to the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2025-00557268 and RS-2025-00514175), by the research fund of Hanyang University (HY-202500000001668), and by the Biomedical Research Institute at Jeonbuk National University Hospital. This work was supported by the Research Program funded by the Korea National Institute of Health (Fund CODE 2016ER670100, 2016ER670101, 2016ER670102, 2018ER670100, 2018ER670101, 2018ER670102, 2021ER120500, 2021ER120501, 2021ER120502, 2024ER120100, 2024ER120101, and 2024ER120102)
Data availability
The data that support the findings of this study are available from the Korea NHIS but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Korea NHIS.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH-2024-10-002). The requirement for informed consent was waived because all patient records were anonymized before use.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Sang Hyuk Kim, Jong Seung Kim and Min Gu Kang contributed equally as co-first authors.
Ji-Yong Moon and Hyun Lee contributed equally as co-corresponding authors.
Contributor Information
Ji-Yong Moon, Email: respiry@gmail.com.
Hyun Lee, Email: namuhanayeyo@naver.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the Korea NHIS but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Korea NHIS.