Limited impact of Elexacaftor/Tezacaftor/Ivacaftor on CPET outcomes in an Italian cohort of people with cystic fibrosis: reinforcing the essential role of exercise training

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is changing life quality and expectancy of people with Cystic Fibrosis (pwCF). Exercise has a pivotal role in improving health of pwCF and proved to be a reliable indicator of health status. This study aims at describing the effects of 6 months of ETI therapy on pwCF exercise-related health and giving insight on the conditions predisposing to better treatment response. Methods: In this observational prospective multicentric study were consecutively enrolled pwCF aged ≥16 who started ETI between May 2021 and April 2022 at Milan Children and Adult CF centres. Exercise performance at Cardiopulmonary Exercise Test (CPET), indicated by maximum workload (Wmax), and other functional outcomes were assessed before starting and after 6 months of ETI. Results: 101 pwCF were enrolled in the study, mean age 28.4 (8.7) years, 38.6 % females. 20.8 % were affected by CF-related diabetes (CFRD) and 46.5 % had a previous exposure to CFTR modulators. Wmax significantly improved across timepoints (151.0 [38.6] W to 156.6 [41.1] W, p = 0.008), baseline characteristics associated with such improvement were being more physically active, male sex, CFRD, higher lung clearance index, baseline exercise limitation. No significant change in peak oxygen consumption was observed, while patients experienced an overall improvement in functional outcomes. Fitted regression model showed male subjects and those affected by CFRD are expected to have better exercise performance. Conclusion: While participants who started ETI treatment experienced some improvement in exercise capacity, the gains were limited. Therefore, integrating physical exercise training remains an essential and impactful strategy to enhance physical fitness.