Beyond Blood Eosinophils: Target-Tier Heterogeneity and Patient Enrichment in COPD Type 2 Inflammation

Chronic obstructive pulmonary disease (COPD) exhibits considerable clinical and biological heterogeneity, and frameworks centered on symptom burden, airflow limitation, and exacerbation risk do not fully explain variation in inflammatory pathways or responses to targeted therapies. Blood eosinophils (blood EOS) provide an accessible clinical biomarker for estimating inhaled corticosteroid (ICS) benefit, stratifying exacerbation risk, and enriching biologic trials in COPD. We position blood EOS as an entry biomarker within a target- and context-dependent framework because peripheral counts incompletely represent airway epithelial activation, local chemotaxis, mucus pathology, tissue EOS activation, or mixed inflammatory microenvironments. This focused narrative review integrates biologic trials, biomarker analyses, and human airway and lung-tissue studies to map type 2-related signals across target tiers. IL-5/IL-5R targeting tests the EOS effector-cell compartment. IL-4Rα blockade supports the therapeutic relevance of an IL-4/IL-13-associated epithelial-chemokine-tissue response program in selected enriched populations. IL-33/ST2 evidence supports therapeutic relevance in COPD, although efficacy remains intervention- and context-dependent, whereas TSLP evidence remains exploratory. Collectively, the evidence supports interpreting COPD type 2 inflammation through target tier, tissue pathway, and patient context. Future studies should test target-directed composite enrichment and prospectively link target perturbation, pathway readouts, and clinical responses.