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Observational Study
. 2023 Aug 3;62(2):2202153.
doi: 10.1183/13993003.02153-2022. Print 2023 Aug.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis

Laura Schaupp  1   2   3 , Annalisa Addante  1   2   3 , Mirjam Völler  1   2   3 , Kerstin Fentker  4   5   3 , Aditi Kuppe  1   2 , Markus Bardua  1   2 , Julia Duerr  1   2 , Linus Piehler  1   2 , Jobst Röhmel  1   2   6 , Stephanie Thee  1   2   6 , Marieluise Kirchner  4   6 , Matthias Ziehm  4   6 , Daniel Lauster  5   7 , Rainer Haag  5 , Michael Gradzielski  7 , Mirjam Stahl  1   2   6 , Philipp Mertins  4   6   8 , Sébastien Boutin  9   10   11   8 , Simon Y Graeber  1   2   6   8 , Marcus A Mall  12   2   6   8
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Free article
Observational Study

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis

Laura Schaupp et al. Eur Respir J. .
Free article

Abstract

Background: Recent studies demonstrated that the triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in cystic fibrosis (CF) patients with at least one F508del allele. However, effects of ETI on downstream consequences of CFTR dysfunction, i.e. abnormal viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was to determine the longitudinal effects of ETI on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged ≥12 years throughout the first 12 months of therapy.

Methods: In this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ETI.

Results: In total, 79 patients with CF and at least one F508del allele and 10 healthy controls were enrolled in this study. ETI improved the elastic modulus and viscous modulus of CF sputum at 3 and 12 months after initiation (all p<0.01). Furthermore, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all time points. In addition, ETI reduced interleukin-8 at 3 months (p<0.05) and free neutrophil elastase activity at all time points (all p<0.001), and shifted the CF sputum proteome towards healthy.

Conclusions: Our data demonstrate that restoration of CFTR function by ETI improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele over the first 12 months of therapy; however, levels close to healthy were not reached.

Trial registration: ClinicalTrials.gov NCT04732910.

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Conflict of interest statement

Conflict of interest: J. Röhmel reports payment for presentations at educational events from Vertex Pharmaceuticals, outside the submitted work. D. Lauster has received funding from Deutsche Forschungsgemeinschaft for work related to this manuscript. M. Stahl reports funding from Deutsche Forschungsgemeinschaft related to this manuscript, and grants from Vertex Pharmaceuticals and Mukoviszidose e.V. (German CF Foundation) outside the submitted work, payment for work on an advisory board from Vertex Pharmaceuticals, and is elected, unpaid secretary of the group on paediatric CF of Assembly 7 of the ERS. P. Mertins received funding from Deutsche Forschungsgemeinschaft and the German Federal Ministry of Education and Research related to this work. S.Y. Graeber reports grant support from Mukoviszidose e.V. (German CF Foundation) and Vertex Pharmaceuticals Incorporated outside the submitted work, with payments made to the author's institution. Chiesi GmbH and Vertex Pharmaceuticals Incorporated have provided personal fees for presentations and advisory boards. M.A. Mall declares that he has received funding from Deutsche Forschungsgemeinschaft and German Ministry for Education and Research for work related to this manuscript. In the past 36 months, he has received grants from Vertex Pharmaceuticals, personal fees for consultancy from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio and Abbvie, lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals and Vertex Pharmaceuticals, travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals, and personal fees for participation in advisory boards from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Abbvie and Pari. Additionally, he served as a member of the Board and Vice-President of the European Cystic Fibrosis Society from 2014 to 2020. All other authors have nothing to disclose.

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