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%