Inflammatory Factors and Chronic Rhinosinusitis: An Umbrella Review.

Chronic rhinosinusitis (CRS) is a common inflammatory disorder of the nasal mucosa and paranasal sinuses characterized by persistent sinonasal symptoms and objective endoscopic and imaging evidence of the disease. CRS is broadly described as a disease with two different phenotypes: without (CRSsNP) or with nasal polyps (CRSwNP), but substantial heterogeneity in clinical presentation and underlying mechanisms complicates classification and treatment selection. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted an umbrella review supported by a systematic literature search in Scopus and PubMed, screening publications from May 1968 to August 2025 and ultimately including 64 studies, with findings synthesized qualitatively. The evidence supported the concept that the inflammatory pathways in CRS reflect distinct, and sometimes overlapping, immune patterns dominated by T helper cells (Th1, Th2, Th17, Th22), and T regulatory cells (Treg). Type 1 inflammation, more commonly associated with CRSsNP, is characterized by interferon-gamma and interleukin (IL)-12 signaling and often shows prominent neutrophilic inflammation. Type 2 inflammation, particularly relevant to CRSwNP, involves epithelial-derived mediators such as thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 and is defined by the presence of Th2 cytokines (IL-4, IL-5, and IL-13) and eosinophilic infiltration; downstream effects include increased mucus-related gene activity and changes in epithelial transport that may interact with other inflammatory programs. Type 3 (type 17) inflammation has been linked to increased IL-17 and IL-22 and is relevant to host defense against bacteria and fungi, including fungal rhinosinusitis and allergic fungal rhinosinusitis. Comorbid conditions, including aspirin-exacerbated respiratory disease and cystic fibrosis, further influence CRS endotypes and clinical severity. Biologic therapies, including dupilumab, highlight the potential of endotype-driven management, but additional work is needed to refine inflammatory classification, identify treatment-responsive subgroups, and reduce reliance on repeated surgery while mitigating progression to lower airway disease.