Visualization of exhaled breath metabolites reveals distinct diagnostic signatures for acute cardiorespiratory breathlessness

Acute cardiorespiratory breathlessness accounts for one in eight of all emergency hospitalizations. Early, non-invasive diagnostic testing is a clinical priority that allows rapid triage and treatment. Here, we sought to find and replicate diagnostic breath volatile organic compound (VOC) biomarkers of acute cardiorespiratory disease and understand breath metabolite network enrichment in acute disease, with a view to gaining mechanistic insight of breath biochemical derangements. We collected and analyzed exhaled breath samples from 277 par-ticipants presenting acute cardiorespiratory exacerbations and aged-matched healthy volunteers. Topological data analysis phenotypes differentiated acute disease from health and acute cardiorespiratory exacerbation subtypes (acute heart failure, acute asthma, acute chronic obstructive pulmonary disease, and community -ac-quired pneumonia). A multibiomarker score (101 breath biomarkers) demonstrated good diagnostic sensitivity and specificity (>= 80%) in both discovery and replication sets and was associated with all-cause mortality at 2 years. In addition, VOC biomarker scores differentiated metabolic subgroups of cardiorespiratory exacerbation. Louvain clustering of VOCs coupled with metabolite enrichment and similarity assessment revealed highly spe-cific enrichment patterns in all acute disease subgroups, for example, selective enrichment of correlated C5-7 hydrocarbons and C3-5 carbonyls in heart failure and selective depletion of correlated aldehydes in acute asthma. This study identified breath VOCs that differentiate acute cardiorespiratory exacerbations and associ-ated subtypes and metabolic clusters of disease-associated VOCs.

Automated summary

Acute cardiorespiratory breathlessness is a significant cause of emergency hospitalizations. This study identified breath volatile organic compound biomarkers that can diagnose acute cardiorespiratory disease and investigated the metabolic enrichment patterns in acute disease. The findings demonstrate that the multibiomarker score can effectively differentiate acute disease from health and different subtypes of acute cardiorespiratory exacerbation. Furthermore, the study revealed specific enrichment patterns in different subgroups of acute disease.