Effects of Lumacaftor-Ivacaftor on Lung Clearance Index, Magnetic Resonance Imaging and Airway Microbiome in Phe508del Homozygous Patients with Cystic Fibrosis.

Abstract

RATIONALE\nPrevious studies showed that lumacaftor-ivacaftor therapy results in partial rescue of cystic fibrosis transmembrane conductance regulator (CFTR) activity and moderate improvement of spirometry in Phe508del homozygous patients with cystic fibrosis (CF). However, the effects of lumacaftor-ivacaftor on lung clearance index (LCI), lung morphology and perfusion detected by chest magnetic resonance imaging (MRI), and effects on the airway microbiome and inflammation remain unknown.\n\n\nOBJECTIVES\nTo investigate the effects of lumacaftor-ivacaftor on LCI, lung MRI scores, and airway microbiome and inflammation.\n\n\nMETHODS\nIn this prospective observational study we assessed clinical outcomes including spirometry and body mass index, LCI, lung MRI scores, sputum microbiome and pro-inflammatory cytokines in 30 Phe508del homozygous patients with CF 12 years and older before and 8-16 weeks after initiation of lumacaftor-ivacaftor therapy.\n\n\nMEASUREMENTS AND MAIN RESULTS\nLumacaftor-ivacaftor had no effects on FEV1 % predicted (1.7%, 95% confidence interval (CI) -1.0 to 4.3%; P = 0.211), but improved LCI (-1.6, 95% CI -2.6 to -0.5; P < 0.01) and MRI morphology (-1.3, 95% CI -2.3 to -0.3; P < 0.05) and perfusion score (-1.2, 95% CI -2.3 to -0.2; P < 0.05) in our study cohort. Further, lumacaftor-ivacaftor decreased the total bacterial load (-1.8, 95% CI -3.3 to -0.34; P < 0.05) and increased the Shannon diversity of the airway microbiome (0.4, 95% CI 0.1 to 0.8; P < 0.05), and reduced IL-1β levels (median change -324.2 pg/ml, 95% CI -938.7 to 290.4 pg/ml; P < 0.05) in sputum of Phe508del homozygous patients.\n\n\nCONCLUSIONS\nThis study shows that lumacaftor-ivacaftor has beneficial effects on lung ventilation, morphology and perfusion, as well as on the airway microbiome and inflammation in Phe508del homozygous patients. Our results suggest that LCI and MRI may be more sensitive than FEV1 % predicted to detect response to CFTR modulator therapy in patients with chronic CF lung disease. Clinical trial registered with ClinicalTrials.gov (NCT02807415).