Identification of Immune-Inflammatory Endotypes in Early COPD Risk: A Cluster Analysis of Age-Associated Biomarkers.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a highly heterogeneous syndrome rather than a single disease entity. Identifying biologically distinct endotypes is essential for early risk stratification and precision prevention. Immunosenescence-the age-related remodeling of the immune system-has been associated with COPD pathogenesis, but its heterogeneity remains poorly characterized. METHODS: We employed a two-stage discovery‑validation design. The discovery cohort included 439 healthy adults (2019-2020), in whom age‑associated immune biomarkers were identified using Spearman correlation. The validation cohort comprised 89 community‑dwelling adults (2023-2024), including 34 healthy controls and 55 individuals at high risk for COPD (COPD‑SQ ≥ 16, preserved lung function). Biomarkers that were both age‑associated and differentially expressed between groups were selected for further analysis. To investigate the inherent heterogeneity of immune‑inflammatory profiles, we performed unsupervised k‑means clustering and principal component analysis (PCA) on these selected biomarkers in the validation cohort. The association between cluster membership and COPD high‑risk status was assessed using logistic regression. RESULTS: Four cytokines (IL‑4, IL‑5, IL‑6, IL‑12p70) were significantly correlated with age and differentially elevated in the high‑risk group. Unsupervised clustering identified three distinct immune‑inflammatory endotypes: a high‑inflammatory endotype (n = 13, 100% high‑risk), a moderate‑inflammatory endotype (n = 29, 89.7% high‑risk), and a low‑inflammatory endotype (n = 45, 35.6% high‑risk). Using the low‑inflammatory endotype as reference, both high‑inflammatory (unadjusted OR = 21.4, 95% CI: 3.2-∞) and moderate‑inflammatory (OR = 8.5, 95% CI: 2.8-25.7) endotypes were significantly associated with COPD high‑risk status (both p < 0.001). After adjustment for age and sex, the associations remained significant (high‑inflammatory OR = 17.2, 95% CI: 4.7-63.0; moderate‑inflammatory OR = 7.1, 95% CI: 2.2-22.8; both p < 0.001). CONCLUSION: This study identifies three distinct immune‑inflammatory endotypes in a community‑based population at risk for COPD, with the high‑ and moderate‑inflammatory endotypes showing strong, independent associations with high‑risk status. These findings reveal the biological heterogeneity of immunosenescence and provide a framework for endotype‑based risk stratification in early COPD. The results highlight the potential of cluster‑derived immune profiles to inform targeted prevention strategies.