Lung Clearance Index Improves in People with Cystic Fibrosis not Achieving a Clinical Important Difference in Forced Expiratory Volume in One Second After Elexacaftor/Tezacaftor/Ivacaftor Therapy

Abstract

Purpose: In people with cystic fibrosis (pwCF), elexacaftor/tezacaftor/ivacaftor (ETI) therapy is associated with an average improvement in FEV₁ of 10-14%. However, a subset of individuals fails to achieve a clinically meaningful increase in spirometric indicators. In this study, we aimed to assess whether the lung clearance index (LCI_2.5), a more sensitive indicator of lung involvement, improves following ETI initiation in this population.

Methods: We conducted a prospective observational study in a specialized CF center in Italy. PwCF performed a spirometry and a multiple breath nitrogen washout test the day they initiated ETI therapy and after 6 and 12 months. They were grouped according to the 12-month change in FEV₁ into two groups: Individuals who experienced a change in FEV₁ ≥ a minimal clinically important difference (MCID) of 3% and those who did not. Mean changes in LCI_2.5 were estimated using generalized estimating equations.

Results: The study included 129 pwCF who initiated ETI at our center (Age Range: 12-36 years). In 20 subjects (15.5%), the FEV₁ change was < MCID. These individuals had better baseline pulmonary function than those with FEV₁ changes ≥ MCID (Median FEV₁: 102.5 vs 87.0%), with the majority (90%) having FEV₁ values ≥ 90%. Mean changes in LCI_2.5 at 12-month follow-up visit were - 1.44 units (95% CI: - 2.12; - 0.75) in individuals with changes in FEV₁ < MCID and - 2.64 units (95% CI: -3.05; -2.23) in those with values ≥ MCID.

Conclusion: LCI_2.5 is a useful measure to monitor the effectiveness of ETI in pwCF with normal spirometry and limited FEV₁ change following treatment initiation.

Keywords: CFTR modulators; Cystic fibrosis; Elexacaftor/tezacaftor/ivacaftor; Heterogeneity of response; Lung clearance index; Personalised medicine; Response to treatment.