Background

The combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor/tezacaftor/elexacaftor (ETI) restores CFTR activity in patients with a F508del mutation which translates into an improved respiratory status. Yet, full mechanism of action remains to be elucidated. Volatile organic compounds (VOCs) exhaled in breath are thought to reflect lung and systemic metabolism. We hypothesised that ETI induces in-depth metabolic modifications leading to significant changes in the composition of breath and may provide novel mechanistic insights.

Methods

Twelve children with CF naïve of CFTR modulators were enrolled in a prospective open-label study at the paediatric Necker hospital (Paris; EUDRACT n° 2016-A00309-42). Breath and clinical data were collected before, during the first week and after one month of treatment. Breath samples were analysed by gas chromatography-mass spectrometry (GC-MS). VOCs significantly modified were detected by univariate analysis using a linear mixed-model and tentatively identified using GC-MS libraries.

Results

Statistical analysis revealed distinctive breath profiles at each visit. 8070 features were detected and 47 were significantly modified throughout patients. These were primarily hydrocarbons, such as branched alkanes, terpenes and phenyl compounds.

Conclusions

The metabolic origin of these VOCs is being investigated and could unveil novel mechanisms of action of ETI. Modifications in breath were observed as soon as in the first days of treatment and may serve as a tool for drug monitoring in patients with normal lung function such as children.

Fundings

ABCF2 patient association, ECFS, CF Europe, Vaincre la Mucoviscidose, AP-HP (CRC2022)