Inflammatory Signatures Beyond Th1/Th2 Endotypes Provide Insights Into Postoperative Recurrence in Chronic Rhinosinusitis

Background Chronic rhinosinusitis (CRS) represents a spectrum of inflammatory endotypes, driven by distinct T helper (Th) immune responses. The high rate of recurrent disease despite appropriate medical and surgical interventions highlights the need for improved characterization beyond the traditional type 2 and non‐type 2 phenotypes to better inform personalized treatment. Methods Sinonasal tissue samples were obtained from 105 CRS patients undergoing endoscopic sinus surgery. Histopathologic evaluation classified inflammatory patterns by predominant cell type and severity. Levels of Th1, Th2, and Th17‐ and epithelial‐derived cytokines were quantified using a multiplex immunoassay targeting 12 markers. Clinical, radiologic, and follow‐up data were correlated with inflammatory patterns and cytokine profiles. Results Type 2 CRS, identified in 65 patients (62%), was associated with higher levels of IL‐5, IL‐13, and TSLP ( p = 0.0002, <0.0001, and 0.02, respectively), whereas IL‐8 was elevated in non‐type 2 disease ( p = 0.022). Recurrence occurred in 22 patients (21%) and was associated with asthma ( p = 0.002), anosmia ( p = 0.006), prior steroids use ( p = 0.044), lymphoplasmacytic inflammatory pattern ( p = 0.022), higher IL‐13 ( p = 0.045), and IL‐33 ( p = 0.031). Recurrence rates did not differ between inflammatory profiles (Th2, Th1/Th17, and mixed). Asthma remained the only independent predictor of recurrence in multivariable Cox model (HR 2.48, 95% CI 1.003–8.042, p = 0.049). Conclusion Elevated IL‐33 levels and lymphoplasmacytic inflammation were associated with postoperative recurrence, underscoring the role of epithelial‒immune signaling in persistent mucosal inflammation, whereas comorbid asthma remained the only independent predictor of refractory CRS.