Association of Epithelial Alarmins and Th2 Cytokines with Disease Severity in Non-Cystic Fibrosis Bronchiectasis

Background and Objectives: Alarmins and Th2-driven inflammatory pathways may contribute to disease severity, exacerbation frequency, and mortality; however, their role in non-cystic fibrosis bronchiectasis remains insufficiently defined. This study aimed to investigate the association between alarmins, Th2 inflammation, disease severity, exacerbations, and mortality in patients with non-cystic fibrosis bronchiectasis. Materials and Methods: A total of 79 adult patients with stable state non-cystic fibrosis bronchiectasis were prospectively enrolled. Demographic characteristics, comorbidities, pulmonary function tests, radiological findings, and disease severity scores (Bronchiectasis Severity Index [BSI] and FACED score [FEV1, age, chronic colonization, extension, dyspnea]) were recorded. Serum levels of IL-25, IL-33, thymic stromal lymphopoietin (TSLP), IL-4, IL-5, IL-13, and IL-17A were measured using enzyme-linked immunosorbent assay. Associations between cytokine levels, disease severity, exacerbations, hospitalizations, and mortality were analyzed using correlation and logistic regression analyses. Results: The mean age of the patients was 50.19 years (range: 19–80). Etiological analysis revealed that 40.5% of cases were post-infectious, 22.8% were related to COPD, and 34.2% were associated with asthma. Pulmonary function tests showed obstructive patterns in 38% of patients, while 32.9% had normal findings. Increased IL-25 and IL-5 levels were associated with higher exacerbation frequency, emergency department visits, and hospitalizations. IL-25 levels showed significant correlations with IL-33 and TSLP. According to FACED classification, disease severity increased in parallel with IL-25 and IL-5 levels, whereas no significant association was observed between BSI scores and cytokine levels. Logistic regression analysis identified elevated IL-25 levels, recent hospitalizations, and emergency department admissions as independent risk factors for mortality and morbidity at 1-year follow-up. Agreement between FACED and BSI scores was modest (κ = 0.273). Conclusions: Alarmins, particularly IL-25, and Th2-driven inflammation may have a significant association with disease severity and clinical outcomes in non-cystic fibrosis bronchiectasis. Elevated IL-25 and IL-5 levels may serve as clinically relevant biomarkers. Combined use of FACED and BSI scores may improve risk stratification, and targeting alarmin-mediated inflammatory pathways could offer novel therapeutic opportunities.