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

ABSTRACT 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.