Exhaled Biomarkers for Point-of-Care Diagnosis: Recent Advances and New Challenges in Breathomics

Abstract

Cancers, chronic diseases and respiratory infections are major causes of mortality and present diagnostic and therapeutic challenges for health care. There is an unmet medical need for non-invasive, easy-to-use biomarkers for the early diagnosis, phenotyping, predicting and monitoring of the therapeutic responses of these disorders. Exhaled breath sampling is an attractive choice that has gained attention in recent years. Exhaled nitric oxide measurement used as a predictive biomarker of the response to anti-eosinophil therapy in severe asthma has paved the way for other exhaled breath biomarkers. Advances in laser and nanosensor technologies and spectrometry together with widespread use of algorithms and artificial intelligence have facilitated research on volatile organic compounds and artificial olfaction systems to develop new exhaled biomarkers. We aim to provide an overview of the recent advances in and challenges of exhaled biomarker measurements with an emphasis on the applicability of their measurement as a non-invasive, point-of-care diagnostic and monitoring tool.

Keywords: COVID-19; artificial olfaction system; biosensors; breathomics; electronic nose; exhaled carbon monoxide; exhaled hydrogen sulfide; exhaled nitric oxide; volatile organic compounds.

Figure 1

One of the original chemiluminescence analyzers (Logan model LR2500, Logan Research; Rochester, Kent, UK) for online measurement of exhaled NO in the early nineties. The analyzer is sensitive to NO from 1 ppb (by volume) to 5000 ppb with a resolution of 0.3 ppb. It also measures CO₂ (resolution 0.1% CO₂; response time, 200 ms) in real time. The subject exhales slowly (5–6 L/min) from total lung capacity for 15–20 s against resistance to exclude nasal contamination. During expiration the pressure is kept constant (3 ± 0.4 mm Hg) by using a visual display of expiratory flow measured by pressure and volume sensors in the analyzer.

Figure 2

The recommended collection of breath samples. The subject inhales ambient air through a VOC filter, and exhales against a resistance at a controlled flow rate. The first fraction of exhaled air is collected in a separate bag to exclude dead space air from the sample. Sample is collected in a special collection bag and is analyzed with the electronic nose device.