Endotyping

Endotyping is a framework for classifying a disease into subtypes, or endotypes, defined by distinct underlying biological mechanisms or etiologies rather than solely by observable traits. The goal is to link clinical features to specific pathophysiology to better predict disease course and response to therapy.

Endotypes are conceptually distinct from phenotypes. Phenotypes describe outward characteristics such as symptoms, onset age, or imaging findings, while endotypes seek to explain why those features arise by pointing to shared mechanisms. This approach is used to illuminate heterogeneity within conditions and to support precision medicine.

Endotyping has particular relevance in heterogeneous, common diseases. In asthma, for example, endotypes include Type 2 (Th2-high) and non-Type 2 endotypes. Type 2 endotypes typically show eosinophilic inflammation and responsiveness to corticosteroids and biologics targeting IL-4 or IL-13 pathways; non-Type 2 endotypes involve alternative inflammatory circuits and may require different therapies. In COPD, eosinophilic endotypes may guide corticosteroid use. In sepsis and cancer, transcriptomic or molecular endotypes disclose hyperinflammatory, immunosuppressive, or oncogenic pathways that influence treatment choices and prognosis.

Methods to identify endotypes combine biomarkers, omics data (genomics, transcriptomics, proteomics, metabolomics), and functional assays with data-driven clustering and longitudinal analysis. Challenges include temporal instability of endotypes, overlap between mechanisms, variability across populations, and the need for validated, accessible biomarkers to translate endotyping into routine care.