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.