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

BACKGROUND: Highly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), produce rapid clinical improvements in people with cystic fibrosis. Yet early effects may be difficult to capture with spirometry or sweat test in patients with a mild disease or atypical mutations. Exhaled breath is rich in volatile organic compounds (VOCs) reflecting metabolic and inflammatory processes. We aimed to determine whether ETI induces early, measurable changes in breath composition and whether these relate to clinical outcomes. METHODS: Ten adults initiating ETI were enrolled in a prospective, open-label study with breath sampling at baseline, week one and month one. VOCs were measured using real-time proton-transfer-reaction - mass spectrometry (PTR-MS). Longitudinal changes were assessed using multilevel statistics, including univariate linear mixed-effects models, and multivariate repeated measures ANOVA-simultaneous component analysis plus (RM-ASCA+); repeated-measures correlations examined associations with lung function and sweat chloride concentration. Results were compared with a healthy cohort. RESULTS: Amongst the eight clinical responders, 11 features changed significantly after ETI initiation. Eight differed from healthy controls at baseline and shifted towards healthy levels over one month. RM-ASCA+ identified monotonous and non-monotonous patterns capturing various dynamics such as acute, progressive or delayed metabolic responses. A 11-feature PLS-DA model classified visits with high accuracy (AUC=0.84-0.96). Ten VOCs correlated with clinical readouts. Tentatively identified features pointed towards a shift in the microbiome and/or energy metabolism. CONCLUSIONS: ETI induces rapid alterations in exhaled VOCs, many trending towards healthy values and correlating with clinical improvement. Real-time breath analysis offers a promising non-invasive surrogate for early monitoring of therapeutic response.