Revisiting Type 2 Inflammation and Airway Hyper-responsiveness in COPD

Airway hyper-responsiveness (AHR) is well established in asthma but remains under-recognized in chronic obstructive pulmonary disease (COPD). The recognition of COPD heterogeneity, particularly eosinophilic COPD and asthma COPD overlap, has increased interest in AHR as a clinical marker of type 2 (T2) inflammation. This phenotype is present in 20% to 40% of patients with COPD and has become a focus of clinical trials exploring biologics targeting IL-4, IL-5, IL-13, and thymic stromal lymphopoietin. We aim to review current evidence on AHR in COPD, its relationship with inflammatory phenotypes, diagnostic modalities, and therapeutic implications. AHR in COPD reflects both structural and inflammatory mechanisms. Direct challenges such as methacholine predominantly assess airway geometry, whereas indirect challenges such as mannitol reflect more activity of T2 inflammation and correlates consequently with eosinophils and fractional exhaled nitric oxide. Patients with AHR may derive greater benefit from inhaled corticosteroids than AHR-negative patients. Although AHR reduction has been demonstrated with biologics in asthma, no study has evaluated their effects on AHR in COPD. AHR represents a clinically relevant and promising treatable trait in COPD, particularly in T2-high phenotypes. Standardized challenges combined with the integration of inflammatory markers and targeted trials of biologics are needed to clarify its role in personalized COPD management and therapeutic decision-making.