Short-term modification of breathprint by Elexacaftor/Tezacaftor/Ivacaftor in a paediatric cohort.

Background: The triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) translates into major respiratory improvements in adults; yet current clinical endpoints may prove insufficiently sensitive in young children. We hypothesised that ETI rapidly modifies the lungs' metabolism, resulting in changes in breath composition.

Methods: Eleven children with CF were enrolled in a longitudinal pilot study at the paediatric Necker hospital. Breath was collected on sorbent tubes using a ReCIVA® device before, after one week and one month of ETI. Samples were analysed by 2D-gas chromatography-mass spectrometry (2D-GC-MS). A linear mixed-effect model, corrected for clinical confounding factors, identified exhaled metabolites differentially expressed throughout the visits. Correlations were calculated between these and clinical indicators.

Results: Breath collection was successful in all children from six years old. They presented a decreased sweat chloride and improved lung function as early as within one week of ETI. Breath composition gradually evolved over the visits. ETI induced significant modifications in the level of 12 breath metabolites. Amongst those, dimethyl sulphide and tetradecene changes correlated with improvements in forced expiratory volume in one second (FEV) and forced expiratory flow (FEF), whilst 3-methyldecane and 3-(chloromethyl)-heptane were predictive of changes in lung clearance index (LCI).

Conclusions: ETI impacts the breath profile from the first week of treatment. Not only could "breathomics" bring mechanistic insights into the metabolic impact of ETI, but it may also offer novel non-invasive options to monitor CF disease and predict therapeutic response.