Direct sampling of the peripheral lung identifies lung-derived volatile organic compounds detectable in exhaled breath: a feasibility study

Exhaled breath testing holds potential for non-invasive screening and early detection of lung cancer. Development of such a test requires knowledge of volatile organic compounds (VOCs) originating in the lung microenvironment, rather than exogenous sources or non-lung endogenous sources such as the GI tract and oral cavity. Direct evidence linking peripheral lung-derived VOCs to exhaled breath is lacking. The peripheral lung air (≥ 4th generation airways) of thirty-five participants (9 lung cancers; 26 controls) was sampled during bronchoscopy using micro-thermal desorption-gas chromatography-ion mobility spectrometry (µTD-GC-IMS) for direct on-site analysis and was compared to exhaled breath obtained immediately prior. Data processing included signal-normalized background subtraction to evaluate which VOCs originate in the peripheral lung and comparison to exhaled breath. Forty-three IMS clusters (features) were determined to originate from the lung microenvironment. All forty-three lung-originating features were detected in exhaled breath. Twenty-four out of forty-three features had higher median signal in either the exhaled breath or peripheral lung air compared to the environmental background. Some features had higher signal in exhaled breath compared to peripheral lung air, while others showed the reverse trend. Direct analysis of peripheral lung air, proximal to the tumour, using µTD-GC-IMS was clinically feasible. These findings help address a key translational barrier in breath-based respiratory biomarker development and support the feasibility of non-invasive approaches for lung cancer screening grounded in lung-specific VOC biology, and will inform larger clinical trials directed at breath biomarker discovery.