Early studies of CRS heterogeneity and indicators of underlying endotypes
Studies based on histology quantitated the numbers of eosinophils, mast cells and neutrophils 17-22. In the West, CRSwNP patients had higher numbers of eosinophils and mast cells while CRSsNP expressed relatively higher levels of neutrophils. Heterogeneity of histology made it clear that there were multiple overlapping processes 23,24. Specifically, many CRSwNP cases were associated with both eosinophilic and neutrophilic infiltrates, while CF polyps demonstrated a predominance of neutrophils 25. Furthermore, a subset of CRSsNP cases exhibited elevated eosinophil counts 26. Changes in remodeling including polypoid edema, glandular hypertrophy and fibrosis have been used to subdivide CRS 27-29. The combination of tissue remodeling changes together with effector cell infiltrates has recently been proposed in a structured histopathologic classification system of CRS 30,31. Histological phenotyping to distinguish endotypes is only as good as the specificity of inflammatory cell counts or tissue structural changes evaluated. For example, while current evidence indicates that polyposis reflects formation of a fibrin matrix, this feature can result from at least 3 distinct inflammatory pathways32-34. Although tissue eosinophilia and remodeling are probably of value, histopathologic features have not been defined in guidelines and remain experimental.
Early molecular studies indicated that IL-5 and IgE are important biomarkers in eosinophilic CRS while IL-8 is found in neutrophilic CRS35-39. Recognition of a T cell cytokine expression pattern was first made by Bachert and colleagues 40. Interestingly, Asian CRSsNP expressed high levels of type 1 cytokines41 similar to Caucasians, but Asian CRSwNP frequently expressed type 3 and type 1 cytokines, as in contrast to the type 2 skewing in Caucasian polyps (see below for discussions of the three types) 42. A landmark first attempt to define the CRS endotypes was an international study that utilized a cluster analysis of the presence of pre-selected biomarkers to distinguish 10 endotypes43. The strength of the study was the differential association of these endotypes with the phenotypic presence of asthma or nasal polyposis. The 10 endotypes were further subdivided into 3 groups based on high IL-5, low IL-5 or absence of IL-5 44. Although the study did not associate endotype with outcome data, it was an important starting point, and this publication accelerated the search for biomarkers that could, at least in theory, define endotypes that would respond uniquely to endotype-specific therapeutics. 25%