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

Background and objectiveHighly effective CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI), produce rapid clinical improvements in people with cystic fibrosis. Yet early treatment effects may be difficult to capture with spirometry or a 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 changes relate to clinical outcomes. MethodsTen 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 RM-ASCA+; repeated-measures correlations examined associations with lung function and sweat chloride concentration. Results were compared with a healthy cohort. ResultsAmongst the eight responders, 11 VOC features changed significantly after ETI initiation. Eight differed from healthy controls at baseline and shifted towards healthy levels over one month. RM-ASCA+ identified linear and non-linear temporal patterns capturing acute and progressive metabolic responses. A 14-feature PLS-DA model classified visits with high accuracy (AUC=0.96-1.00). Ten VOCs correlated with clinical readouts. Features of interest were tentatively identified and pointed towards a shift in the microbiome and/or energy metabolism. ConclusionETI 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. SUMMARYReal-time PTR-MS breath analysis revealed rapid metabolic changes in adults with cystic fibrosis starting ETI therapy. Several VOCs shifted towards healthy levels within one month and correlated with lung function and sweat chloride. These findings support breathomics as a non-invasive surrogate for early monitoring of CFTR modulator response.