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

Background We 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 one F508del allele. 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 two F508del alleles aged 12 years and older.

Methods In 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.

Results In total, 59 patients with CF and at least one F508del allele 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 of Pseudomonas aeruginosa in 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.

Conclusions Our data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele, however, without reaching levels close to healthy.

Publication History

Article published online:
09 March 2023