Impact of COPD on Susceptibility and Severity of Viral Infections

Introduction: Chronic Obstructive Pulmonary Disease (COPD) is linked to worse outcomes in respiratory viral infections, especially COVID-19. Understanding genetic and mechanistic connections may improve risk assessment and treatment strategies. Aim: To investigate the genetic and biological links between COPD and respiratory viral infections. Materials and Methods: Using three COVID-19 outcomesSARS-CoV-2 infection, COVID-19 hospitalisation, and critical COVID-19 as representative cases. In parallel, we conducted literature-based functional pathway analysis to identify and map shared molecular, cellular, and tissue/organ-level mechanisms linking COPD to both COVID-19 and viral infections more broadly, enabling visualisation of biologically plausible pathways contributing to disease susceptibility and severity. Results: Our Mendelian Randomisation (MR) analysis revealed a genetic predisposition in individuals with COPD to an increased risk of severe COVID-19 {Odds Ratio (OR)=1.16, 95% CI: 1.01–1.34, p=0.033}, while no reverse causal effect of COVID19 on COPD was observed (p>0.37). Functional pathway analysis highlighted key overlapping molecular players- such as Transmembrane Serine Protease (TMPRSS2), AngiotensinConverting Enzyme 2 (ACE2), Tumour Necrosis Factor (TNF), Interleukin (IL)-6, Interferons (IFNs), Dipeptidyl Peptidase-4 (DPP4) and Human Leukocyte Antigen (HLA) alleles- and dysregulated biological processes, including inflammation, oxidative stress, apoptosis, coagulation, angiogenesis, and immune responses. These findings support a model where SARS-CoV-2 infection exacerbates pre-existing pathological pathways in COPD, contributing to more severe disease outcomes. Conclusion: This study provides genetic and mechanistic evidence supporting the heightened vulnerability of COPD patients to severe COVID-19 and general viral infections. The identified shared molecular pathways may inform future therapeutic targets and guide clinical risk stratification in chronic respiratory disease management.