Background

The combination of cystic fibrosis transmembrane conductance regulator (CFTR) modulators ivacaftor/tezacaftor/elexacaftor restores CFTR activity in patients with a F508del mutation which may translate into an increase in respiratory function and quality of life. We hypothesised that the treatment induces in-depth metabolic modifications in the lungs leading to significant changes in the volatilomic profile of exhaled breath. Our primary objective was to assess the value of breath analysis to monitor short-term response to the triple combination.

Methods

Ten adults initiating the therapy were enrolled in a prospective open-label study at Foch hospital (ID-RCB n° 2021-A03119-32). Exhaled breath was analysed before, during the first week and after one month of treatment by real-time, proton transfer reaction mass spectrometry. The data was processed with the ptairMS package (Roquencourt, C. et al. Bioinformatics, 2022) employing machine learning tools. At each visit, clinical symptoms were reported, lung function was measured, and a sweat test was performed.

Results

A total of 168 volatilomic features were consistently detected amongst which six compounds were significantly decreased (p-value F-test mixed model < 0.05) in all patients from the first week of treatment.

Conclusions

CFTR modulators impact the composition of breath and modifications can be detected as soon as in the first days of treatment. Compounds? annotation and origin are currently being investigated as well as correlations with clinical outcomes to evaluate the potential of breath metabolomics as a tool for therapeutic drug monitoring in CF.

Acknowledgments

ECFS, CF Europe, Vaincre la Mucoviscidose.