Abstract
Background Recent studies demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) improves lung function and reduces pulmonary exacerbations in 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, therefore, 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 and older 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). Further, ETI decreased the relative abundance of Pseudomonas aeruginosa in CF sputum at 3 months and increased the microbiome α-diversity at all timepoints. ETI also reduced IL-8 at 3 months (p<0.05) and free NE activity at all timepoints (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, without reaching levels close to healthy.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Mirjam Völler reports support for the present manuscript from German Federal Ministry of Education and Research (82DZL009B1), German Research Foundation – Project ID 431232613 – SFB 1449 (projects A01, B03, C03, C04, Z01, Z02), BIH-Charité Clinician Scientist Program (SYG and MS).
Conflict of interest: Kerstin Fentker reports support for the present manuscript in the form of a PhD stipend paid via the MDC (SFB1449).
Conflict of interest: Jobst Röhmel reports payment for presentations among educational events from Vertex Pharmaceuticals, outside the submitted work.
Conflict of interest: Daniel Lauster reports grants from CRC1449, outside the submitted work.
Conflict of interest: Mirjam Stahl reports support for the present manuscript from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) and German Ministry for Education and Research (BMBF) - SFB 1449 – Z02 (431232613) and Grant #82DZL009B1 respectively, payments were made to institution. Outside the submitted work, Mirjam Stahl reports grants from Vertex Pharmaceuticals and Mukoviszidose e.V. (German CF Foundation); Vertex Pharmaceuticals - Payment for work in an advisory board; Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Elected unpaid Secretary of Group Pediatric CF of Assembly 7 of the ERS.
Conflict of interest: Philipp Mertins discloses that the research presented in this manuscript was supported by the German Research Foundation (DFG) Collaborative Research Center (CRC; SFB1449) “Dynamic Hydrogels” without time limit, and by the German Federal Ministry of Education and Research (BMBF) through the MSTARS research core on implementation of mass spectrometry for the clinic within the past 36 months.
Conflict of interest: Simon Y. Graeber report support for the present manuscript from The German Ministry for Education and Research (BMBF) (Grant #82DZL009B1) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (SFB 1449 – Z02 (431232613)). Outside the submitted work, Mukoviszidose e.V. (German CF Foundation) and Vertex Pharmaceuticals Incorporated have also provided grants with payments made to Dr Graeber's institution. Chiesi GmbH and Vertex Pharmaceuticals Incorporated have provided personal fees for presentations and advisory boards.
Conflict of interest: Marcus 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 personal fees for consultancy from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio, and Abbvie. He has also received lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals and Vertex Pharmaceuticals. He has also received 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 2012 to 2020.
Conflict of interest: All other authors have nothing to disclose.
- Received November 9, 2022.
- Accepted May 21, 2023.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org
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