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

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Item Type:	Article
Title:	Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on sputum viscoelastic properties, airway infection and inflammation in patients with cystic fibrosis
Creators Name:	Schaupp, L., Addante, A., Völler, M., Fentker, K., Kuppe, A., Bardua, M., Duerr, J., Piehler, L., Röhmel, J., Thee, S., Kirchner, M., Ziehm, M., Lauster, D., Haag, R., Gradzielski, M., Stahl, M., Mertins, P., Boutin, S., Graeber, S.Y. and Mall, M.A.
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 a-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.
Keywords:	Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Mutation, Proteome, Sputum
Source:	European Respiratory Journal
ISSN:	0903-1936
Publisher:	European Respiratory Society
Volume:	62
Number:	2
Page Range:	2202153
Date:	1 August 2023
Official Publication:	https://doi.org/10.1183/13993003.02153-2022
PubMed:	View item in PubMed

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