Unravelling COVID-19 in COPD - Evidence from Population-Based Analyses

Abstract

Background: Individuals with chronic obstructive pulmonary disease (COPD) are considered a high-risk group for adverse outcomes from viral infections such as the coronavirus disease 2019 (COVID-19). However, knowledge of risk factors for mild and severe COVID-19, and the potential cardiovascular consequences in this population has been limited. This thesis comprises four studies investigating factors influencing COVID-19 risk and prognosis in individuals with COPD, including general risk factors (Study I), inhaled corticosteroid treatment (Study II), smoking (Study III) and the association between COVID-19-related COPD exacerbations and cardiovascular outcomes (Study IV). Methods: Studies I, II and IV were primarily conducted on COPD patients identified in the Swedish National Airway Register (SNAR) or the National Patient Register. Study II also included individuals from the general Swedish population aged ≥40 years. Study III used patient data from SNAR, national cardiovascular and diabetes quality registers in Sweden and a general population cohort from Norway. Covariate data recorded on or before 2020 from several nationwide registers were then linked for each individual. Follow-up began in January 2020 for COVID-19 outcomes (Studies I-III), and for cardiovascular outcomes (Study IV). Statistical analyses included descriptive summaries, incidence rate calculations, and hazard ratios (HRs) with 95% confidence intervals (CIs) estimated using multivariable Cox proportional hazards regression, applying covariate adjustment and propensity score methods to confounding control. Results: In Study I (N=87,472), demographic factors such as older age (e.g., ≥50 vs 40-49 years, significant HR >1.9), being male, lower education level, being born abroad, and clinical factors such as comorbidities, obesity, and poor lung function were strongly predictive of different COVID-19 outcomes. The importance of specific factors varied by outcome, e.g., respiratory comorbidity was particularly associated with infection and hospitalization, metabolic disease with intensive care, and cardiovascular disease with mortality. In Study II (general population N=5,243,479; COPD patients N=133,372), inhaled corticosteroid therapy was associated with slightly increased risk of COVID-19 outcomes in both the overall population and the COVID-19 diagnosed sub-cohort [HRs range 1.02-1.10, 95%CIs include 1.0], but showed potential benefit to hospitalized COPD patients [HR 0.82, 95%CI 0.67-0.99]. In Study III (Sweden N=506,745; Norway N=155,333), both former and current smoking were associated with increased risk of COVID-19 death [HRs >1.0, albeit non-significant], whereas current smoking showed paradoxical inverse associations with less severe COVID-19 outcomes (infection, diagnosis, and hospitalization, [HRs range 0.88-0.93, 95%CI exclude 1.0]). In Study IV (N=266,273 exacerbations among 64,437 COPD patients), COVID-19-related COPD exacerbations, particularly moderate ones, were associated with higher risks of cardiovascular events including pulmonary embolism [HRs range 1.88-2.26, 95%CIs exclude 1.0] and mortality [HR 4.58, 95%CI 4.06-5.17] than other exacerbations. Conclusions and implications: This thesis identifies key demographic, clinical, and behavioral factors influencing COVID-19 risk in COPD patients, suggests a potential benefit of inhaled corticosteroids in hospitalized patients, highlights inconsistent associations with smoking for non-severe but not for severe outcomes, and shows that COVID-19-related exacerbations markedly increase cardiovascular and mortality risk. These findings provide clinically relevant knowledge to support improved risk stratification and management of COPD and may be relevant for future viral or seasonal infectious outbreaks. This thesis also highlights the value of population-based register research for addressing complex clinical and public health questions and in advancing the clinical and epidemiological understanding of COPD and chronic respiratory disease in the context of emerging infectious threats.