Immune Response and Exhaled Breath Profile Changes after Initiation of CFTR Modulator Therapy in Children with CF

Abstract

Background: In recent years, cystic fibrosis transmembrane regulator (CFTR) modulating therapy has made it possible to treat the underlying pathophysiological defect in children with cystic fibrosis (CF). Response to therapy varies among patients. We investigated the immune responses and exhaled breath profile changes after the initiation of CFTR modulator therapy to explore their potential as markers of therapy response. Methods: We performed a prospective, longitudinal proof-of-principle study, investigating immune responses and exhaled breath volatile organic component (VOC) profiles prior to and during the initiation of therapy with Lumacaftor/Ivacaftor in a cohort of 17 patients with CF aged 2 to 6 years old. Response to therapy was assessed based on clinical markers and the decrease in sweat chloride. Whole blood stimulation assays were performed at t = 0, 6 and 18 weeks, while VOC analysis was performed at t = 0 and 18 weeks. Results: A pattern of immune reconstitution was found in the first 4 months of therapy. The same pattern was found in responders and non-responders. Exhaled breath VOC profiles were significantly affected by therapy. A trend toward a significant difference was found between responders and non-responders. Conclusions: Pediatric CF patients show a pattern of immune reconstitution after the initiation of CFTR modulating therapy. We hypothesize that this could be explained by the need for a pro-inflammatory profile for a more effective clearance of latent airway pathogens in the initial phase. The exhaled breath profile also clearly changes after the initiation of therapy, indicating the therapy’s influence on airway inflammation and oxidative stress; thus, it might predict the response to therapy.

Keywords

• pediatric
• cystic fibrosis
• exhaled breath
• volatile organic components
• gas chromatography time-of-flight mass spectrometry
• immune response