High Radiological Severity in CRSwNP Is Associated With a Mixed Type 2/Type 3 Epithelial Inflammatory Signature

Background Severe chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with a substantial clinical burden and frequently exhibits resistance to standard therapies. However, the precise inflammatory profiles driving disease severity remain incompletely understood, limiting the development of targeted interventions. Methods We prospectively recruited 48 participants, including 38 patients with CRSwNP. Patients were stratified based on their preoperative Lund–Mackay Score (LMS) into low (LMS ≤ 12, n = 27) and high (LMS > 12, n = 11) severity groups; 10 healthy controls were also enrolled. Clinical data were analyzed alongside histopathological characteristics of nasal polyp tissues. Additionally, sinus mucosal brushings underwent RT‐qPCR to profile inflammatory gene expression. Results Patients in the high LMS group demonstrated a significantly greater clinical burden, as indicated by endoscopic scores, nasal symptom scores, and peripheral eosinophil counts. Histological analyses revealed that high LMS correlated with extensive tissue remodeling, including basement membrane thickening, goblet cell hyperplasia, and pronounced mixed eosinophilic and neutrophilic infiltration. Molecular profiling identified a distinct mixed inflammatory signature in the high LMS group: in addition to the expected elevation of Type 2 markers (e.g., IL‐5, IL‐13, and CCL26), Type 3 inflammatory genes (e.g., CXCL2, IL‐1β, and IL‐8) were also significantly upregulated. Conclusion Severe CRSwNP, characterized by a high LMS, exhibits a mixed Type 2/Type 3 epithelial inflammatory signature. The co‐activation of Type 3 pathways alongside Type 2 responses is associated with severe tissue remodeling. These findings further elucidate the complex inflammatory landscape of CRSwNP and suggest that high radiological scores may reflect distinct molecular heterogeneity in patients exhibiting extensive sinus opacification.