Impact of Elexacaftor/Tezacaftor/Ivacaftor (ETI) on Airway and Aystemic Inflammation in Cystic Fibrosis: A Systematic Review

Background Elexacaftor/tezacaftor/ivacaftor (ETI) has transformed clinical outcomes in people with cystic fibrosis (PwCF), but its impact on airway and systemic inflammation is less well defined. Methods We systematically searched PubMed, Embase and CENTRAL (January 1, 2019–September 30, 2025) for full-text human studies of pwCF treated with ETI that reported at least one inflammatory biomarker before and after ETI initiation. Because of heterogeneity in study design, sample type, biomarker panels and assays, we did not perform a meta-analysis but instead conducted a structured narrative synthesis, grouping biomarkers by compartment (systemic vs airway); when reported, we also recorded associations between biomarker changes and clinical outcomes. Results Thirty-two observational studies (8-272 participants) met inclusion criteria; 25 evaluated systemic and 10 airway biomarkers, with follow-up up to 30 months. ETI was associated with substantial reductions in sputum neutrophil elastase, IL-1β and IL-8, and in systemic C-reactive protein, other acute-phase reactants, circulating neutrophils and selected Th17-related cytokines, indicating an overall reduction in inflammatory burden, although residual inflammation relative to healthy controls was common. Th1-associated markers and immune-cell activation phenotypes showed heterogeneous changes, while Th2/eosinophilic markers showed less consistent modulation with ETI. Just over half of studies examined biomarker-outcome relationships; in these, reductions in neutrophil-associated markers, CRP, fibrinogen and selected cytokines were often associated with improvements in ppFEV1 or other clinical measures. Conclusion ETI is associated with substantial but incomplete reductions in airway and systemic inflammation in pwCF, with the most consistent effects in neutrophil and acute-phase pathways and more variable changes across other immune markers. Persistent low-grade inflammation in many cohorts suggests that adjunctive anti-inflammatory strategies may still be relevant and that further longitudinal studies are needed to link residual biomarker abnormalities with long-term clinical and structural outcomes.