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

Acute cardiorespiratory breathlessness accounts for 1 in 8 of all emergency hospitalisations. Early, non-invasive diagnostic testing is a clinical priority that allows rapid triage and treatment. Here, we sought to discover 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 analysed exhaled breath samples from 277 participants presenting with acute cardiorespiratory exacerbations and aged matched healthy volunteers. Topological data analysis (TDA) phenotypes differentiated acute disease from health and acute cardiorespiratory exacerbation subtypes [acute heart failure, acute asthma, acute Chronic Obstructive Pulmonary Disease (COPD) and community-acquired pneumonia]. A multi-biomarker 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 specific enrichment patterns in all acute disease subgroups, for example selective enrichment of correlated C(5-7) hydrocarbons and C(3-5) carbonyls in heart failure and selective depletion of correlated aldehydes in acute asthma. This study identified breath VOCs that differentiate acute cardiorespiratory exacerbations and associated subtypes and metabolic clusters of disease-associated VOCs.