Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers

Abstract

The exhaled breath represents an ideal matrix for noninvasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review, we specifically address volatile organic compounds in the breath, with a view toward fulfilling the promise of these as actionable biomarkers, in particular, for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.

Keywords: biomarker; breath tests; precision medicine; technology readiness level; volatile organic compounds.

Figure 1.

Timeline depicting key advances toward clinical application of breath volatiles. ERS = European Respiratory Society; FDA = Food and Drug Administration; GC = gas chromatography; MS = mass spectrometry; PTR = proton-transfer reaction; SIFT = selected-ion flow tube; VOCs = volatile organic compounds. Created with BioRender.com.

Figure 2.

Concept map of breath-specific confounders influencing the composition of volatile organic compounds.

Figure 3.

Current status of breath sampling and analytical technologies using the technology readiness level (TRL) assessment method (adapted from https://www.gov.uk/government/news/guidance-on-technology-readiness-levels). Clinically validated biomarkers are presented as comparative models for airway disease stratification. Online versus offline methods are color coded as orange versus red, respectively. Fe_NO = fractional exhaled nitric oxide; GC = gas chromatography; IMS = ion mobility spectrometry; MS = mass spectrometry; PTR = proton-transfer reaction; SESI = secondary electrospray ionization; SICRIT = soft ionization by chemical reaction in transfer; SIFT = selected-ion flow tube; TD = thermal desorption; TOF = time of flight.