Definition of phenotype and endotype
To understand clinically observed variability in presentation and outcomes, many chronic diseases have been classified by genotype, phenotype and/or endotype. Genotypic classification subdivides disease based upon genetic polymorphisms and has been of limited utility in CRS 1, aside from identifying related monogenic conditions like cystic fibrosis 2 or ciliary dysmotility 3. Phenotypic classifications utilize clinically observable characteristics and have helped advance understanding of natural history and treatment outcomes. In CRS, phenotypic classification has utilized endoscopically observed features, presence of comorbid or systemic illness and timing of disease onset. Classification of CRS by the presence (CRSwNP) or absence (CRSsNP) of nasal polyps has been the most widely applied phenotyping of CRS. CRSwNP is viewed as a diffuse inflammatory process, while CRSsNP is linked, at least in part, to sinus outflow obstruction with secondary inflammation and infection, suggesting presence of a mechanical process4. Subclassification by the presence or absence of common comorbidities such as asthma 5 or allergies6,7 has been used. Other phenotypic subclassification has embraced recognized presentations such as Aspirin Triad (AERD, NERD), Allergic Fungal Rhinosinusitis (AFRS), Eosinophilic Granulomatosis with Polyangiitis (EGPA) 8, Granulomatosis with Polyangiitis (GPA), sinonasal sarcoidosis and CRS with immunodeficiency 9, although these phenotypes are relatively rare and variably defined.
There has been a growing appreciation that establishment of endotype, which initially involved classification by histologic features such as presence of neutrophilia, eosinophilia, fibrosis, glandular hypertrophy and epithelial dysmorphosis, can provide insight into treatment response or pathobiology. Classification based on the presence of fungi or bacteria, has stimulated debate but not led to emergence of widely used clinical protocols 10-14. Recent efforts seek to define CRS endotypes based upon specific molecular biomarkers or mechanisms. It is gratifying that endotypes have strong associations with phenotypes and histologic findings. Endotypic disease classification is challenging because considerable tissue is required, pathologist interpretations are variable, endotype assays are not readily accessible and results may be influenced by treatment or unstable 15. Nonetheless, there is an inexorable shift of interest towards the molecular pathways that underlie endotypes that drive inflammation, remodeling and clinical phenotype16. In conjunction with new, specific and powerful interventions targeting molecular pathways, study of endotype holds great promise.