INTRODUCTION. The heterogeneity of the ventilatory response to elexacator/tezacaftor/ivacaftor (ETI) and its magnitude are the side of the coin that has remained largely unexplored, especially in patients with cystic fibrosis (CF) and severe lung disease.

METHODS. We conducted a multicenter, observational, prospective study from 2019 to 2021 at two CF Centers in Italy enrolling consecutive adults with CF and ppFEV1 <40% undergoing treatment with ETI. Each participant underwent body plethysmography with diffusing lung capacity before ETI and after 12 months. We compared the 12-month change in ppFEV1 across different levels of pre-treatment indicators, defined by terciles of their distribution.

RESULTS. We included 50 patients [50% males; median age: 37 (17 - 52) years; median pre-treatment ppFEV1: 36% (13%; 52%); F/MF: 37 patients (74%)]. Patients with a low pre-treatment RV/TLC ratio showed higher responses after 12 months of ETI (Table 1). Median changes in ppFEV1 were: +20%, +13.5% and +9% among patients with low, intermediate and high pre-treatment RV/TLC ratios, respectively.

CONCLUSIONS. For the first time, we investigated the heterogeneity of ppFEV1 change following ETI in patients with CF and advanced lung disease. Higher RV/TLC before treatment correlated with lower increase in ppFEV1, suggesting that baseline hyperinflation limited the change in dynamic volumes. This work contributes to identify hyperinflation as a novel lesion and a potential new treatable trait in CF patients with advanced lung disease.