ABSTRACT

Background The combination of CFTR modulators ivacaftor/tezacaftor/elexacaftor (ETI) achieves unprecedented improvements in clinical symptoms and respiratory function of people with cystic fibrosis. Yet, evaluation is difficult in people with high baseline lung function and the sweat test may vary depending on the type of CFTR mutation. Exhaled breath is a non-invasive sample, rich in personalised metabolic information and breathomics has emerged as a promising tool to monitor and assess therapeutic response. We hypothesised that ETI induces alterations in the breath composition and that these changes may correlate with clinical readouts.

Methods Ten adults initiating ETI were enrolled in a prospective open-label study. Exhaled breath was analysed before, after one week and one month of treatment by real-time, proton transfer reaction-mass spectrometry. Clinical symptoms, lung function and sweat test results were recorded.

Results A total of 29 breath samples were analysed; 108 volatile organic compounds (VOCs) were consistently detected. In responders (8/10), 21 VOCs were significantly modified, mostly hydrocarbons or small carbonyl compounds. At baseline, these VOCs exhibited significantly different concentrations compared to healthy young adults; throughout the first month of treatment, their level in CF breath evolved towards that of healthy volunteers. Eight of these also correlated with variations in lung function.

Conclusion Real-time breath analysis identified alterations in the breath at the early stages of treatment that tended to normalise after one month. These changes exhibited correlations with clinical indicators, suggesting that breath VOCs may serve as early biomarkers useful for treatment monitoring.

Trial registration NCT05295524

What is already known on this topic As efficient new generations of treatments are emerging for patients with CF, we are lacking early, non-invasive, personalised biomarkers associated with response to therapies. The previous generation of CFTR modulators modified the composition of breath within 3 months, yet nothing was known about the early impact of the newer combinations.

What this study adds The triple combination of CFTR modulators modifies the composition of breath in people with CF as soon as within one week of treatment and tends to normalise basal alterations in CF breath. These changes in breath composition may be captured with real-time mass spectrometry and correlate with clinical outcomes.

How this study might affect research, practice or policy Real-time breath analysis may become useful in monitoring companion biomarkers associated with therapeutic response in patients with CF. Identification of related biological pathways could also help to elucidate the mode of action of these drugs.

Competing Interest Statement

ISG reports a Vertex Innovation Award, consulting fees and travel support from Vertex therapeutics. The other authors declare that they have no competing interests.

Clinical Trial

NCT05295524

Funding Statement

This work was supported by Region Ile de France (VolatolHom, SESAME 2016 and MeLoMane, DIM 1HEALTH 2019), Fondation Foch, ECFS, CF Europe and Vaincre la Mucoviscidose (RC20220503003).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Patients were participating to the PHEAL-KAFTRIO study, which was approved by an ethics committee (Comite de protection des personnes Sud-Est I, 2021-A03119-32, NCT05295524). All patients provided written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

LIST OF ABBREVIATIONSCFcystic fibrosisCFTRcystic fibrosis transmembrane conductance regulatorCOPDchronic obstructive pulmonary diseaseCOVID-19coronavirus diseaseETIelexacaftor, tezacaftor, ivacaftor combinationFDAfood and drug administrationFEV1forced expiratory volume in one secondFRTfisher rat thyroidFVCforced vital capacityGC-MSgas chromatography – mass spectrometryIQRinterquartile rangem/zmass/charge ratioPLS-DApartial least square – discriminant analysispppercentage of predictive valuesPTR-MSproton-transfer reaction – mass spectrometryPTR-Qi-TOF MSproton-transfer reaction – quadrupole – time-of-flight mass spectrometerSCCsweat chloride concentrationTD-GCxGC-TOF-MSthermal desorption – two-dimensional gas chromatography – time-of-flight mass spectrometryVOC(s)volatile organic compound(s)