Clinical Characteristics and Risk Factors for Severe Exacerbation in Never-Smokers with Chronic Obstructive Pulmonary Disease: A Retrospective Cohort Study

<b>Background:</b> Chronic obstructive pulmonary disease (COPD) in nonsmokers is increasingly recognized, yet its clinical profile and outcomes remain less well defined compared to smoking-related COPD. The aim of this study was to compare the clinical characteristics, comorbidities, and risk factors associated with severe exacerbations in nonsmoking COPD patients versus smokers. <b>Methods:</b> We conducted a prospective cohort study including 2376 patients with a diagnosis of COPD from the Lleida Health Region (Catalonia, Spain). Patients were followed for 2 years (2021-2022). Severe exacerbation was defined as hospital admission due to worsening COPD symptoms. Clinical variables were collected at baseline, and logistic regression analysis was performed to identify risk factors for severe exacerbation in the COPD-NS subgroup. <b>Results:</b> A total of 2376 COPD patients were included, of whom 966 (40.7%) were never-smokers. During the two-year follow-up, 165 patients (6.9%) required hospitalization for a severe exacerbation, nearly half of whom were never-smokers (48.5%). In multivariate analysis restricted to COPD never-smokers, the following independent predictors of hospitalization were identified: atrial fibrillation (OR: 2.35; 95% CI: 1.37-3.93), bronchiectasis (OR: 1.91; 95% CI: 1.08-3.28), and lower lung function measured by FVC (OR: 0.64; 95% CI: 0.45-0.89) and FEV1/FVC ratio (OR: 0.64; 95% CI: 0.45-0.89). Female gender was associated with a lower risk (OR: 0.44; 95% CI: 0.21-0.88). The predictive model demonstrated moderate discrimination (AUC = 0.71). <b>Conclusions:</b> COPD-NS patients represent a large proportion of the COPD population and present distinct clinical features. Although the incidence of severe exacerbation is similar to that of smokers/ex-smokers, risk factors such as atrial fibrillation and bronchiectasis have a stronger impact in this subgroup. Early identification of these factors may help guide more targeted clinical management strategies.