Advances in Proton Transfer Reaction Mass Spectrometry–Assisted Breath Analysis for Disease Diagnosis

Proton Transfer Reaction Mass Spectrometry (PTR-MS) has emerged as a transformative tool in breath analysis, enabling the real-time, high-sensitivity profiling of volatile organic compounds (VOCs) down to the pptv level without sample preparation. This review critically examines the technological evolution of PTR-MS, from fundamental ion-molecule kinetics to advanced configurations, including Time-of-Flight (TOF) analyzers and Switchable Reagent Ion (SRI) technologies. We systematically evaluate the clinical potential of PTR-MS in identifying volatile signatures associated with pulmonary malignancies, infectious diseases (e.g., COVID-19), and systemic metabolic disorders. Even with such technological leaps, the transition from discovery to routine clinical practice remains stalled. We identify the lack of metrological traceability as a primary bottleneck, specifically criticizing the widespread reliance on theoretical quantification and the challenges in isomer discrimination. To bridge this "trust gap," this review proposes a rigorous validation framework. We advocate for the implementation of matrix-matched reference materials for absolute quantification and the development of standardized spectral atlases anchored by GC retention times. This metrological approach is essential to solidify the role of PTR-MS in precision medicine.