Nasal Lavage IL-4 and IL-13 in Cystic Fibrosis-Related Chronic Rhinosinusitis: Associations With Disease Severity and Potential Implications for Targeted Therapies.

BACKGROUND: Chronic rhinosinusitis (CRS) is highly prevalent in patients with cystic fibrosis (CF) and has traditionally been considered a predominantly neutrophilic condition. Emerging evidence, however, suggests that type-2 inflammatory pathways may contribute to disease heterogeneity. Data linking local inflammatory mediators with objective sinonasal disease severity and olfactory dysfunction in CF-associated CRS remain limited. METHODS: In this cross-sectional study, 42 adults with CF-associated CRS (22 with nasal polyps and 20 without) underwent assessment of disease severity using the nasal polyp score (Meltzer classification) (NPS-MS), modified Lund-Kennedy score (mLKS), and Lund-Mackay score (LMS), together with olfactory testing (Sniffin' Sticks Identification Test) and quality-of-life evaluation (22-item Sinonasal Outcome Test [SNOT-22]). Nasal lavage concentrations of IL-4, IL-13, and IL-8 were quantified by ELISA. RESULTS: IL-4 and IL-13 were significantly associated with objective measures of sinonasal disease severity, including NPS-MS and LMS (all p < 0.05), whereas IL-8 did not show consistent associations with disease severity. In multivariable models, IL-4 remained independently associated with mLKS (p = 0.025), LMS (p = 0.047), and olfactory dysfunction (p = 0.002). IL-13 was primarily associated with NPS-MS (p = 0.007) and LMS (p = 0.005). Lung transplantation modified cytokine-severity relationships. Exploratory analyses showed lower IL-4 levels in elexacaftor/tezacaftor/ivacaftor-treated patients (p = 0.036), with no significant effects for IL-8 or IL-13. CONCLUSIONS: CF-associated CRS exhibits a heterogeneous inflammatory profile in which type-2 cytokines, particularly IL-4 and IL-13, are linked to disease severity and olfactory dysfunction. Nasal lavage cytokines may represent promising compartment-specific biomarkers to support inflammatory endotyping and targeted therapeutic strategies.