Improved ventilation inhomogeneity and lower LCI variability under ETI: Retrospective analysis in a pediatric cohort

Elexacaftor/tezacaftor/ivacaftor (ETI) has transformed cystic fibrosis (CF) therapy, yet observational clinical data in children with preserved spirometry remain limited. The lung clearance index (LCI) is used to monitor treatment response, but exhibits considerable short-term variability, affecting the interpretation of two-point comparisons.

We retrospectively analysed longitudinal clinical data from a typical pediatric CF cohort. Multiple measurements per patient within 12 months before and after ETI initiation enabled LCI variability assessment and comparison of mean LCI before and under treatment. We assessed the LCI response to ETI, its association with baseline LCI, FEV₁ z-score, sweat chloride, genotype, and changes in within-patient LCI variability.

Mean LCI in 59 patients (median age 11.6y) decreased from 7.9 (IQR 6.9-9.4) to 6.4 (6.1-7.0) (p < 0.001), with a significant reduction in within-patient LCI variability from 7.9% (4.3-10.2%) to 4.9% (3.4-6.7%). LCI improvement strongly correlated with baseline LCI (r = 0.73) and weakly with baseline FEV₁ (r = -0.36). In multivariable analysis, baseline LCI, homozygous F508del genotype, baseline FEV₁ and sweat chloride were significant predictors of LCI change. LCI response was more variable in patients with baseline LCI >10.

ETI reduces ventilation inhomogeneity in children with CF, the magnitude of LCI reduction is strongly dependent on baseline disease severity. Within-patient LCI variability is reduced, indicating greater disease stability. LCI is a sensitive marker, improvements upon ETI treatment are well predictable particularly in early disease stages, observational data support its routine use in clinical monitoring of pediatric patients.