Breathing new life into clinical testing and diagnostics: perspectives on volatile biomarkers from breath.

Human breath offers several benefits for diagnostic applications, including simple, noninvasive collection. Breath is a rich source of clinically-relevant biological information; this includes a volatile fraction, where greater than 1,000 volatile organic compounds (VOCs) have been described so far, and breath aerosols that carry nucleic acids, proteins, signaling molecules, and pathogens. Many of these factors, especially VOCs, are delivered to the lung by the systemic circulation, and diffusion of candidate biomarkers from blood into breath allows systematic profiling of organismal health. Biomarkers on breath offer the capability to advance early detection and precision medicine in areas of global clinical need. Breath tests are noninvasive and can be performed at home or in a primary care setting, which makes them well-suited for the kind of public screening program that could dramatically improve the early detection of conditions such as lung cancer. Since measurements of VOCs on breath largely report on metabolic changes, this too aids in the early detection of a broader range of illnesses and can be used to detect metabolic shifts that could be targeted through precision medicine. Furthermore, the ability to perform frequent sampling has envisioned applications in monitoring treatment responses. Breath has been investigated in respiratory, liver, gut, and neurological diseases and in contexts as diverse as infectious diseases and cancer. Preclinical research studies using breath have been ongoing for some time, yet only a few breath-based diagnostics tests are currently available and in widespread clinical use. Most recently, tests assessing the gut microbiome using hydrogen and methane on breath, in addition to tests using urea to detect Helicobacter pylori infections have been released, yet there are many more applications of breath tests still to be realized. Here, we discuss the strengths of breath as a clinical sampling matrix and the technical challenges to be addressed in developing it for clinical use. Historically, a lack of standardized methodologies has delayed the discovery and validation of biomarker candidates, resulting in a proliferation of early-stage pilot studies. We will explore how advancements in breath collection and analysis are in the process of driving renewed progress in the field, particularly in the context of gastrointestinal and chronic liver disease. Finally, we will provide a forward-looking outlook for developing the next generation of clinically relevant breath tests and how they may emerge into clinical practice.

Performance and Interpretation of Hydrogen and Methane Breath Testing Impact of North American Consensus Guidelines.

BACKGROUND: Hydrogen and methane breath tests (HMBT) are widely used clinical investigations but lack standardization. To address this, the North American Consensus (NAC) group published evidence-based recommendations for HMBT. AIMS: To evaluate results obtained using NAC recommendations for HMBT, compared to retrospective data that utilized guidelines previously recommended. METHODS: HMBT data from 725 patients referred for small intestinal bacterial overgrowth (SIBO) and/or carbohydrate malabsorption (CM) testing were analyzed. Data were compared regarding dose of substrate for SIBO testing (16 vs. 10 g lactulose, and 50 vs. 75 g glucose) and the effect of post-ingestion sampling period for malabsorption testing. The effect of different recommended cut-off values for SIBO were examined. RESULTS: Substrate dose did not affect methane production. 10 g lactulose significantly reduced positive SIBO results compared to 16 g lactulose (42 vs. 53%, p = 0.04). 75 g glucose significantly increased positive results compared to 50 g glucose (36 vs. 22%, p = 0.04). Provoked symptoms were significantly more prevalent in patients testing positive by both North American Consensus and Ledochowski cut-off values. 34.5% of patients tested positive for CM at 180-min compared to 28% at 120-min (not significant, p = 0.19). CONCLUSIONS AND INFERENCES: 10 g lactulose substrate produces fewer positive SIBO results than 16 g lactulose, while 75 g glucose dose produces more positive SIBO results than 50 g. Performing CM breath tests for 180 min increases number of positive results when compared to 120 min. SIBO cut-off timings require further investigation, but our findings broadly support the NAC recommendations for SIBO and CM testing.