Abstract
Epidemiologic studies suggest that COPD is associated with an increased risk of poor outcome in patients with COVID-19, although they failed to demonstrate COPD as a risk factor for acquiring COVID-19. However, most data have come from a limited global population. In this nationwide cohort study based on the Korean national health insurance claims-based database, COPD is associated with increased risk for COVID-19 and having COPD does not seem to confer substantial risk for severe COVID-19 and mortality. These findings indicate that heterogeneity in the populations across many countries may complicate the net effects of COPD on the COVID-19-related outcomes.
Keywords: COPD, COVID-19, National health insurance service, Severe acute respiratory syndrome coronavirus 2
To the Editor:
In the period up to April 2021, the coronavirus disease (COVID-19) pandemic associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected approximately 143,000,000 people globally with over 3,000,000 deaths, and poses a great threat to patients with chronic lung diseases [1]. However, evaluating the excess risk of chronic obstructive pulmonary disease (COPD) for COVID-19 and, in particular, for more severe disease, is challenging [2]. Initially, the prevalence of COPD among hospitalized patients with COVID-19 was reported to be lower than in the general population and in those reported with other comorbidities [3], a finding contrary to the common speculation that COPD may be more susceptible to contracting respiratory viruses. Paradoxically, COVID-19 in COPD is increasingly being reported to be associated with critical illness of COVID-19 [2,4]. A nationwide analysis on the comorbidity of 1590 COVID-19 patients in China showed that COPD was a risk factor for reaching the composite end points related to poorer clinical outcomes [5]. These findings indicate the heterogeneity of clinical COVID-19 cohorts across different nations and the clinical severity with diverse comorbidities [2].
The aim of this study is to determine whether COPD influences the occurrence and clinical severity of COVID-19. This large-scale cohort covers individuals who underwent SARS-CoV-2 testing in South Korea from January 1, 2020 to May 1, 2020 supported by the Korean Centers for Disease Control and the National health insurance service (NHIS2 ). For each patient who underwent SARS-CoV-2 testing, we combined medical data on COVID-19-related outcomes during the hospitalization with claim-based data from January 1, 2015 to May 1, 2020, including personal data (age, sex, region of residence, and socioeconomic status) and health care records of inpatients and outpatients throughout the past 5 years (including health care visits, prescriptions, diagnoses, and procedures), retrospectively. SARS-CoV-2 infection was defined by a positivity on a real-time RT–PCR assay of nasal or pharyngeal swabs [6]. A history of COPD (J43-J44, apart from J430), diabetes mellitus (E10-14), ischemic heart disease (I20-25), cerebrovascular disease (I60-64, I69, and G45), hypertension (I10-13 and I15), or chronic kidney disease (N18-19) was defined by physician diagnosis of at least two claims within 1 year during this 5-year study period according to the appropriate International Classification of Disease, Tenth Revision (ICD-10) code [7]. In this study, “exposure” comprised the development of COPD; the “primary outcome” was test positivity for SARS-CoV-2 among all patients who underwent SARS-CoV-2 testing, and the “secondary outcome” was severe disease or mortality of patients who tested positive for SARS-CoV-2. The definition of severe disease included: 1) requirement for oxygen supplementation, 2) intensive care unit (ICU) admission, 3) intubation with mechanical ventilation, or 4) application of extracorporeal membrane oxygenation (ECMO) [8,9].
We performed two rounds of propensity score (PS) matching to balance the baseline characteristics and reduce potential confounders. We evaluated each propensity score matching in a 1:1 ratio using the ‘greedy nearest-neighbor’ algorithm and calculated the predicted probability of (a) individuals with a history of COPD versus individuals without a history of COPD among all patients who underwent SARS-CoV-2 testing (n 129,120); (b) individuals with a history of COPD versus individuals without a history of COPD among patients with confirmed COVID-19 (n 8,070). The adequacy of matching was evaluated by comparing the distributions of propensity score and standardized mean differences (SMDs). After utilizing a multivariate logistic regression model adjusted for history of angina, any type of cancer, hypertension (HTN), congestive heart failure (CHF), chronic kidney disease (CKD), cerebrovascular disease (CVD), diabetes mellitus (DM), hepatitis, and myocardial infarction (MI), estimation of the adjusted odds ratios (aORs) with 95% CIs was performed. Patient-related data were anonymized and the protocol was approved by the Institutional Review Board of Jeonbuk National University Hospital [2020-04-067].
Among 129,120 patients who underwent SARS-CoV-2 testing (mean age SD, 41.7 19.6 years), we identified 8,070 (6.25%) patients who tested positive (all SMDs 0.1). There were 4,800 patients (62.4 ± 15.6 years) with a history of COPD in the entire cohort (n 129,120) (Table 1 ). Then, we performed 1:1 propensity score matching in the full-unmatched cohort and identified 4,800 patients without a history of COPD (all SMDs 0.05). Among all patients tested, the positivity rate of SARS-CoV-2 testing in patients with COPD was 7.3% (350/4800), compared with 4.8% (230/4800) in those without COPD (aOR, 1.54; 95% CI, 1.3–1.83) (Fig. 1 ). Furthermore, we identified 350 patients with COPD among the patients who tested positive for SARS-CoV-2 (n 8,070). We also performed 1:1 propensity score matching in the full-unmatched cohort and identified 350 patients with no history of COPD (all SMDs 0.1). The rate of severe disease in patients with COPD was 28.9% (101/350) among patients who tested positive for SARS-CoV-2, compared with 25.1% (88/350) in those without COPD (aOR, 1.23; 95% CI, 0.85–1.76). In particular, among patients confirmed to have COVID-19, the rate of mortality in patients with COPD was 17.7% (62/350), compared with 13.7% (48/350) in those without COPD (aOR, 1.39; 95% CI, 0.87–2.23) (Fig. 1).
Table 1.
Baseline demographics for all severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tested patients and propensity score-matching group (no previous COPD versus COPD groups) with laboratory confirmed COVID-19 in South Korea (N = 129,120). Minimally adjusted OR (adjusted by age and sex), Fully adjusted OR (adjusted by age, sex, economic status and underlying diseases).
| Patients who underwent SARS-CoV-2 test (total n = 129120) |
Patients who tested positive for SARS-CoV-2 test (total n = 8070) |
||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
COPD |
COPD |
||||||||||||||||
| Characteristic | No | Yes | SMD | No | Yes | SMD | |||||||||||
| Total, n (%) | 4800 | 4800 | 350 | 350 | |||||||||||||
| Age, meanSD | 62.7 | 15.6 | 62.4 | 15.6 | 0.018 | 62.515.5 | 62.315.9 | 0.011 | |||||||||
| Sex, n (%) | 0.024 | 0.040 | |||||||||||||||
| Male | 2427 | (50.6) | 2484 | (51.7) | 166 (47.4) | 173(49.4) | |||||||||||
| Female | 2373 | (49.4) | 2316 | (48.3) | 184 (52.6) | 177 (50.6) | |||||||||||
| Social economic status, n (%) | 0.006 | 0.050 | |||||||||||||||
| Low | 3048 | (63.5) | 3061 | (63.8) | 252 (72.0) | 244 (67.7) | |||||||||||
| High | 1752 | (36.5) | 1739 | (36.2) | 98 (28.0) | 106 (30.3) | |||||||||||
| History of angina, n (%) | 1307 | (27.2) | 1290 | (26.9) | 0.008 | 98 (28.0) | 104 (29.7) | 0.038 | |||||||||
| History of cancer, n (%) | 1145 | (23.9) | 1188 | (24.8) | 0.021 | 86 (24.6) | 81 (23.1) | 0.034 | |||||||||
| History of HTN, n (%) | 1065 | (22.2) | 1064 | (22.2) | 0.001 | 92 (26.3) | 95 (27.1) | 0.019 | |||||||||
| History of CHF, n (%) | 482 | (10.0) | 518 | (10.8) | 0.001 | 39 (11.1) | 43 (12.3) | 0.036 | |||||||||
| History of CKD, n (%) | 993 | (20.7) | 999 | (20.8) | 0.025 | 79 (22.6) | 84 (24.0) | 0.034 | |||||||||
| History of CVD, n (%) | 1010 | (21.0) | 994 | (20.7) | 0.003 | 79 (22.6) | 82 (23.4) | 0.020 | |||||||||
| History of diabetes mellitus, n (%) | 652 | (13.6) | 674 | (14.0) | 0.008 | 46 (13.1) | 46 (13.1) | 0.001 | |||||||||
| History of hepatitis, n (%) | 1402 | (29.2) | 1401 | (29.2) | 0.013 | 82 (23.4) | 93 (26.6) | 0.073 | |||||||||
| History of MI, n (%) | 371 | (7.7) | 406 | (8.5) | 0.001 | 36 (10.3) | 44 (12.6) | 0.072 | |||||||||
| History of smoking, n (%) | 1077 | (22.5) | 1078 (22.5) | 0.001 | 40 (11.4) | 41 (11.7) | 0.003 | ||||||||||
| History of ICS, n (%) | 1223 | (25.4) | 1226 (25.5) | 0.001 | 96 (27.4) | 98 (28.0) | 0.002 | ||||||||||
| COVID-19, n (%) | 230 | (4.79) | 350 | (7.29) | |||||||||||||
| Minimally adjusted OR (95% CI) | Reference | 1.55 (1.3–1.83)*** | |||||||||||||||
| Fully adjusted OR (95% CI) | Reference | 1.54 (1.3–1.83)*** | |||||||||||||||
| Severe clinical outcomes of COVID-19 | 88 (25.1) | 101 (28.9) | |||||||||||||||
| Minimally adjusted OR (95% CI) | Reference | 1.22 (0.85–1.74) | |||||||||||||||
| Fully adjusted OR (95% CI) | Reference | 1.23 (0.85–1.76) | |||||||||||||||
| Death | 48 (13.7) | 62 (17.7) | |||||||||||||||
| Minimally adjusted OR (95% CI) | Reference | 1.35 (0.87–2.11) | |||||||||||||||
| Fully adjusted OR (95% CI) | Reference | 1.39 (0.87–2.23) | |||||||||||||||
Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; CVD, cerebrovascular disease; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; ICS, intranasal corticosteroid; SMD, standardized mean difference; OR, odds ratio. ***: Statistically significant (p < 0.001).
Fig 1.
Propensity score-matched association of chronic obstructive pulmonary disease (COPD) with test positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (primary outcome) among all patients who underwent SARS-CoV-2 testing (n 129,120) and the association of COPD with severe disease and mortality (secondary outcome) among patients with confirmed coronavirus disease (COVID-19) (n 8,070). Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; CVD, cerebrovascular disease; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction; SES, socioeconomic status.
Herein, we have identified that COPD is associated with an increased risk for COVID-19. Moreover, having COPD does not seem to confer a substantial risk for severe disease and mortality. These findings are interesting in that the results from numerous epidemiologic studies have suggested that COPD is associated with an increased risk of poor outcome in patients with COVID-19, although they failed to clearly demonstrate COPD as a risk factor for acquiring COVID-19 [2,4]. Since most data so far that can potentially explain the relationship between COPD and SARS-CoV-2 in the emergence of COVID-19 has come from a limited global population, the data will inevitably involve patients having different proportions of medical comorbidities due to the variability in testing and admission strategies [2], and this may obscure the effect of COPD on contracting COVID-19. Indeed, increased angiotensin-converting enzyme-2, an entry protein for SARS-CoV-2, was observed in the airways of COPD patients who smoke, a similar finding that favors the potential implication of COPD as a risk factor for COVID-19 [10]. However, in this study, the adjusted ORs of smoking in a PS-matched cohort (test positivity, severity, mortality) were as follows; 1.69 (95% CI: 1.29–1.92), 1.37 (95% CI: 0.53–3.53), and 1.15 (95% CI: 0.38–3.48), respectively, all of which suggest that smoking did not change the effect of COPD on the primary and secondary outcomes of the current study. A similar phenomenon was observed regarding the effects of prescribed inhaled corticosteroid (ICS) on those outcomes (Table 1, Fig. 1). All of these data suggest that COPD may be an independent risk factor for contracting COVID-19, not explained by other factors such as cigarette smoke or prescribed ICSs.
Furthermore, once a host has become infected with SARS-CoV-2 in the airways, a unique phenotype of systemic immune/inflammatory responses has been reported to be associated with COVID-19 acute respiratory distress syndrome (ARDS) compared to their non-COVID-19 counterparts, although patients with COVID-19 had less severe ARDS initially [11]. In the same context, excluding respiratory diseases, most comorbidities were associated with an increased risk of COVID-19-related death [12]. These findings suggest that systemic general medical conditions shaping overall immune/inflammatory responses are critically implicated in the regulation of the clinical course of COVID-19, to an even greater extent than the medical conditions involving the respiratory tract itself.
Despite the limitations of the current study concerning the inherent characteristics of claim-based data (only comprises hospitalization date, diagnosis code, treatment history during hospitalization, medication history, and death information) and the inconsistency with regard to the previously suggested role of COPD in the occurrence of severe COVID-19 illnesses [13], our findings demonstrate that COPD may be associated with an increased risk for COVID-19, and having COPD does not seem to confer a substantial risk for severe COVID-19 and mortality.
Declaration of all sources of funding
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2020R1A2C2101942; Y.C.L.), and by the fund of Biomedical Research Institute, Jeonbuk National University Hospital. No competing financial interests exist.
CRediT authorship contribution statement
Jae Seok Jeong: conceived and designed the research, interpreted the data, and wrote the manuscript. Jong Seung Kim: conceived and designed the research, collected the data and performed the analysis. Yeon Seok You: Data curation, Formal analysis. Sang Woo Yeom: Data curation, Formal analysis. Yong Chul Lee: conceived and designed the research, interpreted the data, and edited the manuscript.
Declaration of competing interest
No conflict of interest related to this article.
Footnotes
NHIS-2020-1-479.
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