Different Inflammatory Phenotypes and Immune Endotypes Drive Disease Heterogeneity in Asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are highly heterogeneous airway disorders that cannot be adequately understood or managed as single disease entities. Instead, both encompass a wide spectrum of inflammatory phenotypes and immune endotypes that differ in pathobiological mechanisms, clinical presentation, exacerbation risk, and therapeutic responsiveness. In asthma, the classical type 2-high eosinophilic phenotype is typically driven by T helper 2 (Th2) cells, group 2 innate lymphoid cells (ILCs), and the canonical cytokines interleukin (IL)-4, IL-5, and IL-13, whereas non-type 2 asthma includes neutrophilic, mixed granulocytic, and paucigranulocytic patterns associated with Th17-related inflammation, epithelial dysfunction, and relative corticosteroid resistance. In COPD, neutrophil-dominant inflammation mediated by macrophages, Th1/Tc1 cells, and, in some patients, Th17-associated pathways has long been considered the dominant immunopathological pattern. However, growing evidence indicates that a substantial subset of patients with COPD exhibit eosinophil-associated, type 2-skewed inflammation with important implications for inhaled corticosteroid responsiveness and biologic therapy. In this review, we distinguish the concepts of phenotype and endotype, summarize the major inflammatory and immune subtypes of asthma and COPD, and discuss their underlying cellular and molecular mechanisms. We further examine clinically relevant biomarkers, including blood and sputum eosinophils, IgE, and fractional exhaled nitric oxide (FeNO), as well as the expanding therapeutic landscape encompassing anti-IgE, anti-IL-5, anti-IL-4Rα, anti-thymic stromal lymphopoietin (anti-TSLP), macrolides, phosphodiesterase-4 inhibitors, and emerging endotype-directed strategies. By comparing asthma and COPD within a unified immunological framework, this review highlights both shared and disease-specific mechanisms of heterogeneity and argues that mechanistically informed phenotyping and endotyping are central to advancing precision medicine in chronic airway disease.