Type 2 Endotypes in Airway Diseases

Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent chronic inflammatory airway diseases worldwide, significantly affecting patients' quality of life and mortality and imposing a substantial socioeconomic burden. Increasing insights into their pathophysiology have led to the recognition of both conditions as complex syndromes encompassing distinct pheno-endotypes. Asthma patients can be broadly stratified into type 2 (T2)-high and T2-low phenotypes based on biomarker expression and clinical features. More than half of asthma patients exhibit a T2-high phenotype, which includes two principal endotypes: allergic eosinophilic and non-allergic eosinophilic asthma. In COPD, traditionally associated with type 1 and type 3 immune responses and neutrophilic inflammation, around 20-30% of patients display a marked T2 signature, defining a novel T2-COPD endotype. In both diseases, epithelial and innate immune cells cooperate to orchestrate adaptive and effector T2 responses characterized by blood and airway eosinophilia and elevated fractional exhaled nitric oxide (FeNO). In asthma, 6 biologics targeting key T2 inflammatory pathways are approved as add-on treatment (omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab and tezepelumab). In T2 COPD, 2 biologics have recently been approved (dupilumab and mepolizumab) and others are under clinical evaluation. Other emerging strategies, including next-generation allergen-specific immunotherapy and trained immunity-based vaccines, offer promising new therapeutic avenues. A better understanding of the molecular mechanisms driving T2-high asthma and T2 COPD endotypes is essential to identify reliable biomarkers and novel therapeutic targets. Such advances will improve patient stratification, optimize disease management, and foster the development of preventive and precision medicine approaches in chronic airway diseases.