Extracellular vesicle surface markers inform on COPD severity and mortality in COSYCONET

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of global morbidity and mortality, and its heterogeneity demands better biomarkers of severity and progression risk. Extracellular vesicles (EVs) are promising blood-based biomarkers, but have not been examined for COPD severity and outcomes in a large multicentre cohort. Methods: We analysed 600 COSYCONET participants (up to 54 months of follow-up). EV surface markers were profiled with the MACSPlex EV Kit IO. Cross-sectional associations with severity (GOLD, FEV1) were primary (ordinal and linear regression); longitudinal trajectories and all-cause mortality were prespecified exploratory endpoints. Results: Six EV markers showed robust associations with cross-sectional severity: CD29, CD49e and CD31 increased with severity (a cell-adhesion/matrix-remodelling signal), whereas CD81 and CD8 decreased; HLA-ABC (increasing) was less specific. No marker was linked to FEV1 decline. After FDR correction, lower levels of three markers with higher 54-month mortality (all HR<1): CD25 (HR 0.77, 95% CI 0.65-0.90, q=0.018), CD56 (HR 0.75, 95% CI 0.63-0.89, q=0.018) and CD142 (HR 0.74, 95% CI 0.60-0.90, q=0.024). CD25 and CD142 also improved reclassification, CD56 did not; a CD25 + CD69 combination showed the largest incremental signal ({Delta}C 0.017, 95% CI 0.002-0.032, p=0.027). Conclusion: Circulating EV surface markers are associated with cross-sectional COPD severity. Exploratory analyses nominate CD25, CD142 and CD25 + CD69 as candidate prognostic markers requiring external validation, suggesting minimally invasive EV profiling could complement clinical assessment in COPD.