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.

慢性鼻窦炎（CRS）是一种异质性疾病，其特征为上呼吸道的局部炎症。CRS包括两种主要表型，即伴有鼻息肉的慢性鼻窦炎（CRSwNP）和无鼻息肉的慢性鼻窦炎（CRSsNP）。基于表型的分类方法无法反映病理机制。基于内型的分类方法已越来越受到研究者的关注。它主要分为2型和非2型内型。目前尚不清楚驱动非2型炎症发病机制的机制。在本综述中，通过检索PubMed和Web of Science数据库，对过去十年内发表的关于CRS中非2型炎症发病机制的代表性文献进行了批判性分析。本综述总结了可能导致非2型炎症发病机制的最新证据。这是从免疫学角度分析发病机制的主要方法。基因组学和蛋白质组学技术为发病机制的研究提供了新的途径。由于种族、环境、地理和生活方式的差异，非2型炎症的发生存在差异，这增加了理解CRS中非2型炎症发病机制的难度。研究证实，非2型内型在亚洲患者中更为常见。重叠和不分类的内型的出现推动了CRS异质性的研究。此外，作为炎症细胞的来源和炎症反应的起始部位，鼻黏膜下上皮组织中的微血管和微淋巴管参与炎症反应和组织重塑。关于CRS患者是否影响SARS-CoV-2感染的风险尚无定论。此外，非2型CRS与COVID-19的病理生理机制尚需进一步研究，值得考虑如何为具有非2型炎症的CRS患者选择适宜的生物制剂。