Supplementary Material for: A Decade of Pathogenesis Advances in non-Type 2 Inflammatory Endotypes in Chronic Rhinosinusitis: 2012-2022

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by localized inflammation of the upper airways. CRS includes two main phenotypes, namely CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). The phenotype-based classification method cannot reflect the pathological mechanism. The endotype-based classification method has been paid more and more attention by researchers. It is mainly divided into type 2 and non-type 2 endotypes. The mechanism driving the pathogenesis of non-type 2 inflammation is currently unknown. In this review, the Pubmed and Web of Science databases were searched to conduct a critical analysis of representative literatures on the pathogenesis of non-type 2 inflammation in CRS published in the past decade. This review summarizes the latest evidence that may lead to the pathogenesis of non-type 2 inflammation. It is the main method that analyzing the pathogenesis from the perspective of immunology. Genomics and proteomics technique provide new approaches to the study of the pathogenesis. Due to differences in race, environment, geography, and living habits, there are differences in the occurrence of non-type 2 inflammation, which increases the difficulty of understanding the pathogenesis of non-type 2 inflammation in CRS. Studies have confirmed that non-type 2 endotype is more common in Asian patients. The emergence of overlap and unclassified endotypes has promoted the study of heterogeneity in CRS. In addition, as the source of inflammatory cells and the initiation site of the inflammatory response, microvessels and microlymphatic vessels in the nasal mucosal subepithelial tissue participate in the inflammatory response and tissue remodeling. It is uncertain whether CRS patients affect the risk of infection with SARS-CoV-2. In addition, the pathophysiological mechanism of non-type 2 CRS combined with COVID-19 remains to be further studied and it is worth considering how to select the befitting biologics for CRS patients with non-type 2 inflammation.