Relationship between lung volumes and heterogeneity in the response to elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease

Background The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with CF (pwCF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, but predictors of FEV1 change after treatment are still missing. Research Question Which ventilatory parameters are involved in the heterogeneity of FEV1 change after 12-month ETI treatment in pwCF with advanced lung disease? Study Design: and Methods This was a multicenter, observational, prospective cohort study at two major CF centers in Italy. We enrolled 47 adults with CF and advanced lung disease (FEV1 <40% or actively listed for lung transplant) who started ETI treatment between December 2019 to December 2021. At treatment initiation and after 12 months, patients underwent body plethysmography. Values were compared at the two time points. To assess the relationship between baseline plethysmography measurements and treatment-induced changes in FEV1, we used the Spearman’s rank correlation coefficient (r) and median quantile regressions. Results After 12 months of ETI treatment, there was a significant increase in percent predicted FEV1 (ppFEV1) from a median (25th-75th percentiles) value of 36.0 (33 – 39) to 52 (43 – 61) (P<0.001). IC/TLC ratio also increased from 32.0 (28.6 - 36.9) to 36.3 (33.4 - 41.3) (P<0.001). sRaw decreased from 263 (182 - 405) to 207 (120 - 258) (P<0.001). FRC/TLC ratio decreased from 68.2 (63.3 - 71.9) to 63.9 (58.8 - 67.1) (P<0.001), and RV/TLC ratio decreased from 53.1 (48.3 - 59.4) to 45.6 (39.4 - 49.8) (P<0.001). Changes in ppFEV1 negatively correlated with baseline FRC/TLC ratio (r= -0.38, P= 0.009) and RV/TLC ratio (r= -0.42, P= 0.004). After adjustment for age at treatment initiation and CFTR genotype, we estimated that for each 10-unit increase in baseline RV/TLC ratio the expected median change in FEV1 decreased by 2.3 (95% CI: -5.8; -0.8). Interpretation ETI was associated with improvements in both static and dynamic volumes in pwCF and advanced lung disease. Heterogeneity in ppFEV1 change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.