Endotyping Chronic Rhinosinusitis Based on Olfactory Cleft Mucus Biomarkers.

ABSTRACT Background Although chronic rhinosinusitis (CRS) is considered the most treatable form of olfactory dysfunction (OD), there has been relatively little clinical attention focused on assessing endotypes as they pertain to olfactory loss. Objective The goal of this study was to explore inflammatory endotypes in CRS using an unsupervised cluster analysis of olfactory cleft (OC) biomarkers in a phenotype-free approach. Methods Patients with CRS were prospectively recruited and psychophysical olfactory testing, Questionnaire of Olfactory Dysfunction (QOD-NS), and bilateral OC endoscopy were obtained. Mucus was collected from the OC and evaluated for 26 biomarkers using principal component analysis (PCA). Cluster analysis was performed using only OC biomarkers and differences in olfactory measures were compared across clusters. Results 198 subjects (128 with CRS and 70 controls) were evaluated. Evaluation of OC biomarkers indicated 6 principal components, explaining 69.50% of the variance, with Type 2, mixed Type1/Th17, growth factor, and neutrophil chemo-attractant inflammatory signatures. A total of 10 clusters were identified which differed significantly in frequency of controls, CRSsNP, and CRSwNP across the clusters (LRT χ2(18)=178.64, p Conclusion Clustering based solely on OC biomarkers can organize patients into clinically meaningful endotypes that discriminate between CRS and controls. Validation studies are necessary to confirm these findings and further refine olfactory endotypes. Clinical implications Olfactory biomarkers can be utilized to organize chronic rhinosinusitis into endotypes that reflect underlying inflammation. These endotypes are likely to be the foundation of personalized treatment for CRS-related olfactory dysfunction.