Effects of Elexacaftor/Tezacaftor/Ivacaftor on Sputum Viscoelastic Properties, Airway Infection and Inflammation in Patients with Cystic Fibrosis

Abstract

AbstractBackgroundWe recently demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves lung ventilation and airway mucus plugging determined by multiple-breath washout and magnetic resonance imaging in CF patients with at least oneF508delallele. However, effects of ELX/TEZ/IVA on viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. The aim of this study was, therefore, to determine the effects of ELX/TEZ/IVA on airway mucus rheology, microbiome and inflammation in CF patients with one or twoF508delalleles aged 12 years and older.MethodsIn this prospective observational study, we assessed sputum rheology, the microbiome, inflammation markers and proteome before and 8 to 16 weeks after initiation of ELX/TEZ/IVA.ResultsIn total, 59 patients with CF and at least oneF508delallele and 10 healthy controls were enrolled in this study. ELX/TEZ/IVA improved the elastic modulus (G’; -6.3 Pa; IQR, -17.9 to 1.2;P<0.01) and viscous modulus (G’’; -1.6 Pa; IQR, -3.6 to 0.5;P<0.05) of CF sputum. Further, ELX/TEZ/IVA improved the microbiome α-diversity (0.6; IQR, 0.0 to 1.2;P<0.001) and decreased the relative abundance ofPseudomonas aeruginosain CF sputum. ELX/TEZ/IVA also reduced IL-8 (−11.7 ng/ml, IQR, -36.5 to 11.2;P<0.05) and free NE activity (−27.5 µg/ml, IQR, - 64.5 to -3.5;P<0.001), and shifted the CF sputum proteome towards healthy.ConclusionsOur data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least oneF508delallele, however, without reaching levels close to healthy.Clinical trial registered withwww.clinicaltrials.gov(NCT04732910)