Bronchial segmental heterogeneity of responsiveness to modulator therapy in cystic fibrosis: linking structural improvements on CT to Inflammation in Bronchoalveolar lavage fluid

Background Although Elexacaftor–tezacaftor–ivacaftor (ETI) improves lung function and reduces exacerbations in cystic fibrosis (CF), airway inflammation and bronchial wall thickening do not completely resolve. Characterizing regional heterogeneity in bronchial wall thickness before and after ETI may provide insight into residual disease. We investigated whether bronchial wall thickening during ETI reflects ongoing inflammation, mucus burden, and infection at the segmental level. Methods In this prospective observational cohort study, paired pre-ETI and 1.5-year post-ETI chest CT scans and bronchoalveolar lavage (BAL) samples were analyzed from five preselected lung segments in nine adults with CF. An AI-based pipeline generated automated segmental bronchus–artery metrics, including bronchial wall area (B wa /B oa ), wall thickness (B wt /A), inner diameter (B in /A), and outer diameter (B out /A) ratios, as well as mucus plug number and volume. These metrics were correlated with segment-matched BAL markers of inflammation, mucus burden, and Pseudomonas aeruginosa infection. Results Responses to ETI were heterogeneous both between and within subjects. Across 176 segments, 91.3% ( sd 19.1) showed reductions in B wa /B oa , 86.7% ( sd 18.4) reductions in B wt /A, and 77.1% ( sd 20.9) increases in B in /A, whereas B out /A remained stable. However, differences in the magnitude of these changes were observed at the segmental level within subjects. Pre-ETI, bronchial wall thickness was most strongly associated with neutrophil elastase. Post-ETI, this association weakened but persisted, while sialic acid emerged as an additional predictor of residual wall thickness. P. aeruginosa burden was also associated with wall thickness post-ETI but explained less of the variance than inflammatory and mucus markers. Conclusions ETI produces significant but variable improvements at the segmental level in bronchial dimensions. Persistent segmental heterogeneity suggests that local inflammation, mucus retention, and infection continue to shape residual structural lung disease. Automated segmental CT analysis may enable more individualized monitoring and management in the era of CFTR modulation.