Real-time breath metabolomics to assess early response to CFTR modulators in adults with cystic fibrosis: an open-label proof-of-concept study

Abstract

BackgroundThe combination of CFTR modulators ivacaftor/tezacaftor/elexacaftor (ETI) achieves unprecedented improvements in clinical symptoms and respiratory function of people with cystic fibrosis. Yet, evaluation is difficult in people with high baseline lung function and the sweat test may vary depending on the type of CFTR mutation. Exhaled breath is a non-invasive sample, rich in personalised metabolic information and breathomics has emerged as a promising tool to monitor and assess therapeutic response. We hypothesised that ETI induces alterations in the breath composition and that these changes may correlate with clinical readouts.MethodsTen adults initiating ETI were enrolled in a prospective open-label study. Exhaled breath was analysed before, after one week and one month of treatment by real-time, proton transfer reaction-mass spectrometry. Clinical symptoms, lung function and sweat test results were recorded.ResultsA total of 29 breath samples were analysed; 108 volatile organic compounds (VOCs) were consistently detected. In responders (8/10), 21 VOCs were significantly modified, mostly hydrocarbons or small carbonyl compounds. At baseline, these VOCs exhibited significantly different concentrations compared to healthy young adults; throughout the first month of treatment, their level in CF breath evolved towards that of healthy volunteers. Eight of these also correlated with variations in lung function.ConclusionReal-time breath analysis identified alterations in the breath at the early stages of treatment that tended to normalise after one month. These changes exhibited correlations with clinical indicators, suggesting that breath VOCs may serve as early biomarkers useful for treatment monitoring.Trial registrationNCT05295524Key messagesWhat is already known on this topicAs efficient new generations of treatments are emerging for patients with CF, we are lacking early, non-invasive, personalised biomarkers associated with response to therapies. The previous generation of CFTR modulators modified the composition of breath within 3 months, yet nothing was known about the early impact of the newer combinations.What this study addsThe triple combination of CFTR modulators modifies the composition of breath in people with CF as soon as within one week of treatment and tends to normalise basal alterations in CF breath. These changes in breath composition may be captured with real-time mass spectrometry and correlate with clinical outcomes.How this study might affect research, practice or policyReal-time breath analysis may become useful in monitoring companion biomarkers associated with therapeutic response in patients with CF. Identification of related biological pathways could also help to elucidate the mode of action of these drugs.