Le lundi 31 août 2026, Thibault MASSENET présentera l'examen en vue de l’obtention du grade académique de Docteur en Sciences (Collège de doctorat en Chimie) sous la direction de Pierre-Hugues STEFANUTO.

Cette épreuve consistera en la défense publique d’une dissertation intitulée :

« Breathomics for Clinical Pulmonology: Advancing a TD-GC×GC-MS Platform Toward Direct Clinical Implementation ».

Le Jury sera composé de :

M. L. QUINTON (Président), Mmes et MM. J.-F. FOCANT (Secrétaire), F. SCHLEICH (CHU), P.-H. STEFANUTO (Promoteur), A. VANIYA (Sacramento), M. WILDE (University of Plymouth).

Abstract

Exhaled breath contains hundreds of volatile organic compounds (VOCs) that reflect ongoing metabolic and inflammatory processes, making breath analysis an attractive non-invasive approach in respiratory medicine. Despite three decades of research, no VOC-based test has entered routine clinical practice. This thesis addresses that gap by treating analytical performance and clinical feasibility as co-equal requirements rather than sequential concerns, following the translational pathway a breath biomarker must travel: how the sample is collected, what it adds to clinical assessment, whether it can inform a treatment decision before it is taken, and how it could eventually be measured in a clinical laboratory. All work was built upon an established thermal desorption comprehensive two-dimensional gas chromatography mass spectrometry (TD-GC×GC-MS) platform. The three offline sampling devices in widest use were first compared within the peppermint benchmarking protocol. No device proved universally optimal. Tedlar® bags showed the lowest overall variability (mean pooled RSD 54%) but sensitivity to exogenous contamination; ReCIVA® offered superior selectivity and reduced background at the cost of detecting fewer compounds, greater complexity and higher cost; BioVOC-2® provided operational simplicity but limited sensitivity. Focus groups with clinicians, researchers and participants established practical requirements for clinical deployment, yielding use-case-dependent guidance and extending the peppermint reference database. VOC profiling was then evaluated as a supplementary clinical parameter in two contrasting settings. In 79 patients with uncontrolled moderate-to-severe asthma randomised to a 12-week submaximal aerobic training programme, clear improvements in symptom control, quality of life and exercise tolerance occurred without detectable modulation of airway or systemic inflammation, including VOCs. In a bicentric cohort of 42 systemic sclerosis patients, a nine-compound signature discriminated those with interstitial lung disease with an AUC of 0.82, comparable to DLco (0.83). An eosinophil-derived 17-VOC signature measured immediately before the first anti-IL-5/Rα injection predicted clinical response with AUROCs of 0.95 and 0.98 in two independent cohorts analysed through entirely separate workflows, outperforming FeNO and blood eosinophil count. Comparable accuracy was retained by a five-compound subset of reactive aldehyde species. Finally, SICRIT coupled to high-resolution mass spectrometry was evaluated for the direct measurement of 16 clinically relevant aldehydes. Linearity was good for 13 compounds (R² ≥ 0.99), with limits of detection between 1.33 and 25.13 ppbv and low intra-day variability. Protonated species emerged as the preferred monitoring targets, ionisation competition from a Tedlar® contaminant was identified and mitigated, and cyclic ion mobility permitted tentative isomer separation at a prohibitive sensitivity cost. Taken together, this work shows that a single breath sample and a single workflow can address clinically diverse questions that conventional parameters answer only partially, and that the obstacles to implementation are identifiable and addressable. It does not deliver a ready-to-use test, but contributes comparative data for standardisation, a refined molecular target, and an analytical route toward measurement compatible with clinical timescales. 

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