Introduction
The importance of vaccines in ending the global coronavirus disease 2019 (COVID-19) pandemic is immense [1]. Vaccines have markedly decreased the risk of infection and the progression to severe COVID-19, thus preventing severe outcomes, including mortality [2]. Therefore, vaccination is strongly advised for individuals at high risk of severe COVID-19, such as the elderly and those with pre-existing health conditions [3]. Among these conditions, COVID-19 vaccination is particularly emphasized for individuals with various chronic respiratory diseases [4].
Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of death worldwide and incurs a substantial economic burden [5,6]. COPD constitutes a significant chronic respiratory condition for which COVID-19 vaccination is strongly advised [7]. Current evidence presents mixed findings concerning the effects of COVID-19 vaccination on the acute exacerbation of COPD (AECOPD). In one study, fully vaccinated COPD patients exhibited a higher rate of exacerbations compared with those not fully vaccinated (70.5% vs. 55.3%) [8]. Conversely, another study reported significantly fewer severe and moderate COPD exacerbations in vaccinated patients compared with unvaccinated ones during a 6-month period post-vaccination [9]. Additionally, evidence suggesting worse COVID-19 outcomes in COPD patients complicates the understanding of associations among COVID-19 vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [10], and AECOPD. As the COVID-19 pandemic transitions to an endemic phase, it is essential to understand these relationships.
To explore these complex associations, this study aimed to evaluate the risk of AECOPD based on COVID-19 vaccination status and COVID-19 status in individuals with COPD.
Materials and Methods
1. Data source
We conducted a retrospective cohort study using data from the Korean National Health Insurance System (NHIS) [11-13]. The NHIS, a government-operated universal insurance program, covers approximately 97% of the population, encompassing around 50 million individuals. The NHIS database has been extensively utilized in numerous epidemiological studies associated with COVID-19 and its subsequent complications [14-18].
During the COVID-19 pandemic in 2020 and 2021, the Korean government actively promoted testing by subsidizing diagnostic procedures for those presenting symptoms indicative of the virus. It also provided financial aid for treating individuals diagnosed with COVID-19 (NHIS-2022-1-623). The NHIS-SARS-CoV-2 database, which includes test results for all individuals tested for the virus, was established based on these data.
2. Study population
The inclusion criteria identified individuals over the age of 20 with previously diagnosed COPD before February 26, 2021, and individuals who contracted COVID-19 prior to March 31, 2022. Exclusion criteria were lack of available health examination data, vaccination following COVID-19 diagnosis, diagnosis of COPD after COVID-19 infection, and death before the index date or December 31, 2021. We excluded individuals who died before December 31, 2021, to prevent the assignment of index dates to those who had not been vaccinated.
COPD was defined by a minimum of two prescriptions in 1 year for medicines specific to COPD, under the International Classification of Diseases 10th Revision (ICD-10) codes J43.1, J43.2, J43.8, J43.9, or J44. This included several types of bronchodilators, as detailed in our previous studies [19]. The index date was defined as the vaccination date for vaccinated subjects, and a corresponding matched date for unvaccinated subjects.
In the COVID-19 vaccination-COPD cohort, we performed propensity score (PS) matching employing a 1:1 ratio between vaccinated and unvaccinated individuals, considering variables such as age, sex, body mass index (BMI), smoking status, alcohol consumption, economic status, residential area, regular physical activity, one or more severe exacerbations in the previous year, and comorbid conditions including hypertension, diabetes, dyslipidemia, chronic kidney disease (CKD), and asthma (Figure 1).
3. Exposure: COVID-19 vaccination
The exposure for this study was vaccination against COVID-19, which began in South Korea on February 26, 2021. By October 23, 2021, over 70% of individuals had received at least two doses of the COVID-19 vaccine [20].
4. AECOPD
AECOPD was identified by either emergency room visits or hospitalizations for COPD-related ICD-10 codes along with the concurrent prescription of systemic steroids [21]. Study participants were monitored from the index date until the first exacerbation occurrence, censoring, or the conclusion of the 90-day follow-up period post-vaccination.
5. Post hoc analysis
We conducted a post hoc analysis to assess the impact of COVID-19 on AECOPD among both vaccinated and unvaccinated groups. The exposure considered in this analysis was SARS-CoV-2 infection, characterized by a COVID-19 diagnosis confirmed through reverse transcription polymerase chain reaction tests on nasal or pharyngeal swabs, as identified by the ICD-10 code (U07.1) [16].
6. Covariates
BMI was calculated by dividing weight by the square of height (kg/m2). BMI was categorized into five groups according to recommendations for Asians: underweight (<18.5 kg/m2); normal weight (18.5-22.9 kg/m2); overweight (23.0-24.9 kg/m2); obese (25-29.9 kg/m2); and highly obese (≥30 kg/m2) [22,23]. Smoking status was categorized into current smokers, former smokers, and never smokers [24]. Economic status was defined based on personal income, with high income representing the top 30%, low income encompassing the bottom 30% and recipients of medical aid, and middle income covering the remaining population. Regular physical activity was defined as moderate activity for more than 30 minutes on most days of the week or vigorous activity for more than 20 minutes on more than 3 days per week. Alcohol consumption was categorized into four levels: none, 1-2 times per week, 3-4 times per week, and almost daily [25]. A history of AECOPD was defined as either an emergency room visit or hospitalization involving the use of systemic steroids and associated with ICD-10 codes for COPD within the past year. Asthma was identified using ICD-10 codes J45-J46 and the prescription of asthma-related medications, which include systemic steroids, bronchodilators, leukotriene receptor antagonists, and xanthine derivatives [14,16]. Other comorbidities, such as hypertension, diabetes mellitus, dyslipidemia, and CKD, were identified using corresponding ICD-10 codes [13,26-33].
7. Statistical analysis
Categorical and continuous variables were respectively presented as numbers (percentages) and median (interquartile range). The chi-square test was utilized to compare categorical variables across study groups. The incidence of exacerbation was reported as the number of exacerbation events per 10,000 person-years (PY). Kaplan-Meier curves were employed to visualize the incidence of AECOPD by vaccination status, with statistical significance determined using the logrank test. Initially, Cox proportional hazards regression models evaluated the risk of AECOPD without adjustment, as all variables demonstrated a standardized mean difference (SMD) <0.25 [34]. However, in the post hoc analysis, due to some variables not satisfying the SMD < 0.25 criterion, additional adjustments were made, including factors such as age, sex, BMI, smoking status, alcohol consumption, economic status, residential area, regular physical activity, one or more severe exacerbations in the previous year, and comorbidities such as hypertension, diabetes, dyslipidemia, CKD, and asthma. A two-sided p<0.05 was considered statistically significant. 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).
8. Ethics approval
The study protocol was approved by the Institutional Review Board of Hanyang University Hospital (No. HYUH 2023-11-049). The requirement for informed consent was waived due to the anonymization of all patient records prior to their use.
9. Data sharing 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.
Results
1. Baseline characteristics
The selection process for individuals included in the analysis is depicted in Figure 1. Out of the 4,758,546 individuals in the NHIS-SARS-CoV-2 database, 4,713,157 were excluded due to the absence of health examination data, 810 were vaccinated after a COVID-19 infection, 71 were diagnosed with COPD post-COVID-19 infection, and 4,004 died before the index date or December 31, 2021. Consequently, 40,504 individuals with COPD were enrolled in the COVID-19 vaccination-COPD cohort. Of these, 3,602 were selected following 1:1 PS matching.
Baseline characteristics of the study population are detailed in Table 1. The majority of individuals were male (62.9%) and aged between 60 and 79 years (63.1%). No significant differences in baseline characteristics were observed between vaccinated and unvaccinated individuals.
2. Risk of AECOPD
Throughout the study period, the incidence of AECOPD was notably lower in vaccinated individuals (1,683/10,000 PY) compared to unvaccinated individuals (3,410/10,000 PY). As indicated in Table 2, the risk of AECOPD was significantly decreased in vaccinated compared to unvaccinated individuals (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.41 to 0.72). This finding was corroborated by cumulative incidence plots (log-rank p<0.001) (Figure 2).
3. Post hoc analysis
The results of the post hoc analysis are detailed in Table 3. The post hoc analysis revealed a COVID-19 diagnosis rate of 3.9% among vaccinated individuals and 8.0% among unvaccinated individuals. Despite the general similarity in the clinical characteristics of infected and uninfected individuals, residents of metropolitan cities exhibited a higher susceptibility to COVID-19, irrespective of their vaccination status (Supplementary Table S1).
COVID-19 was associated with an elevated risk of AECOPD in unvaccinated individuals, even after adjustments were made (adjusted HR, 2.06; 95% CI, 1.28 to 3.33). Conversely, the risk of AECOPD in vaccinated individuals was not significantly different between those with and without COVID-19 infection (adjusted HR, 1.35; 95% CI, 0.42 to 4.36).
Discussion
In this nationwide cohort study, vaccinated individuals with COPD had a significantly lower risk of AECOPD compared to unvaccinated individuals. COVID-19 increased the risk of AECOPD in the unvaccinated group, whereas vaccinated individuals had a similar risk of exacerbation regardless of COVID-19 status. These findings underscore the protective benefits of COVID-19 vaccination in individuals with COPD.
Individuals with COPD who experience exacerbations are at increased risk of subsequent AECOPD events [35,36]. Additionally, recurrent exacerbations frequently lead to hospital readmissions following an AECOPD episode [37]. A recent systematic review and meta-analysis reported readmission rates of 11% at 30 days, 17% at 90 days, and 37% at 1 year [38]. These data highlight the critical need for interventions to mitigate the risk of recurrent exacerbations. Proposed measures include pulmonary rehabilitation and nutritional supplementation after an AECOPD event [39,40], yet proactive strategies to prevent AECOPD are still limited.
The role of respiratory infections in triggering AECOPD is well established [41]. Particularly, viral infections influence the lung microbiota and host immune responses, thereby increasing the risk of AECOPD [42,43]. Consequently, vaccination against respiratory infections could offer protection against AECOPD. Several studies support this hypothesis, reporting that influenza and pneumococcal vaccines reduce the risk of AECOPD [44,45]. Similarly, vaccination against COVID-19 might help prevent recurrent exacerbations. However, the available information on this matter is limited [46], and conflicting outcomes have been documented. While one study identified an increased risk of AECOPD following COVID-19 vaccination [8], another indicated that the vaccine may protect against AECOPD [9]. The reasons for these conflicting results are not fully understood; however, it is theorized that a complex interaction among COVID-19 vaccination, susceptibility to COVID-19, and subsequent AECOPD in individuals with COPD could explain these findings.
This study observed a decreased incidence of AECOPD in vaccinated individuals, emphasizing the potential benefits of COVID-19 vaccination in mitigating exacerbations among individuals with COPD. AECOPD is associated with healthcare utilization increase, accelerated decline in lung function, and diminished quality of life [36]. Given the substantial morbidity and healthcare burden linked to AECOPD, it is imperative for clinicians to recognize COVID-19 vaccination as an essential component of preventive care strategies for these patients. Further research is needed to clarify the specific mechanisms behind the observed benefits and to assess the potential long-term effects of vaccination on COPD outcomes.
A plausible explanation for these findings is that vaccination decreases the risk of symptomatic COVID-19 infection, hospitalization, and severe illness in individuals with COPD. This is corroborated by our post hoc analysis, which indicated that unvaccinated individuals were more likely to contract COVID-19 and also faced an elevated risk of AECOPD. Although this study is observational and cannot establish causality, these results offer indirect evidence that vaccination may decrease the future risk of AECOPD in individuals with COPD.
There are limitations to our study. First, the diagnosis of COPD was based on ICD-10 codes, which may lead to under- or over-diagnosis. Second, potential confounding factors affecting the risk of AECOPD, such as etiology, pulmonary function, and other laboratory findings, could not be controlled due to the absence of this data in the dataset [47,48]. Third, most of the study period occurred before the emergence of the Omicron variant of COVID-19, and during this time, social restrictions were relatively stringent. Certain unaccounted factors, including social distancing, may influence the study outcomes [49]. Fourth, as this study was conducted in a single Asian country, caution should be exercised when generalizing the findings.
In conclusion, COVID-19 vaccination may decrease the risk of AECOPD in individuals with COPD.
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