Relationship Between Lung Volumes and Heterogeneity in the Response to Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease

Andrea Gramegna; Gianfranco Alicandro; Chiara Premuda; Francesca Lucca; Lucia Pinali; Mariangela Retucci; Valentina Vespro; Maria Carmela Andrisani; Gianpaolo Carraffiello; Francesco Amati; Sonia Volpi; Stefano Aliberti; Marco Cipolli; Francesco Blasi

doi:10.1016/j.chest.2024.03.033

Relationship Between Lung Volumes and Heterogeneity in the Response to Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Lung Disease

Chest. 2024 Mar 21:S0012-3692(24)00404-5. doi: 10.1016/j.chest.2024.03.033. Online ahead of print.

Affiliations

¹ Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. Electronic address: andrea.gramegna@unimi.it.
² Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Department of Pediatrics, Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
³ Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
⁴ Cystic Fibrosis Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁵ Radiology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
⁶ Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Healthcare Professions Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁷ Radiology Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁸ Radiology Department, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Health Sciences, University of Milan, Milan, Italy.
⁹ Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Respiratory Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

PMID: 38521181
DOI: 10.1016/j.chest.2024.03.033

Abstract

Background: The effects of elexacaftor/tezacaftor/ivacaftor (ETI) on respiratory outcomes for people with cystic fibrosis (CF) were demonstrated by several clinical trials, mainly based on simple spirometry. However, gains in lung function may vary greatly between patients, and 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 people with CF 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 and 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 rank correlation coefficient (r) and median quantile regressions.

Results: After 12 months of ETI treatment, there was a significant increase in FEV₁ % predicted from a median value of 36.0 (25th-75th percentile, 33-39) to 52 (25th-75th percentile, 43-61) (P < .001). Inspiratory capacity/total lung capacity (TLC) ratio also increased from 32.0 (25th-75th percentile, 28.6-36.9) to 36.3 (25th-75th percentile, 33.4-41.3) (P < .001). Specific airway resistance decreased from 263 (25th-75th percentile, 182-405) to 207 (25th-75th percentile, 120-258) (P < .001). Functional residual capacity/TLC ratio decreased from 68.2 (25th-75th percentile, 63.3-71.9) to 63.9 (25th-75th percentile, 58.8-67.1) (P < .001), and residual volume (RV)/TLC ratio decreased from 53.1 (25th-75th percentile, 48.3-59.4) to 45.6 (25th-75th percentile, 39.4-49.8) (P < .001). Changes in FEV₁ % predicted negatively correlated with baseline functional residual capacity/TLC ratio (r = -0.38, P = .009) and RV/TLC ratio (r= -0.42, P = .004). After adjustment for age at treatment initiation and cystic fibrosis transmembrane conductance regulator 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 to -0.8).

Interpretation: ETI was associated with improvements in both static and dynamic volumes in people with CF and advanced lung disease. Heterogeneity in FEV₁ % predicted change after 12 months of treatment may be predicted by the severity of hyperinflation at baseline.

Keywords: cystic fibrosis; drug response; elexacaftor/tezacaftor/ivacaftor; heterogeneity of treatment; hyperinflation; plethysmography.