Perturbed pediatric serum metabolome in mild and severe dengue disease

Dengue viruses (DENVs) are the most prevalent arboviruses affecting humans. Four billion people are at risk of infection and this burden is rapidly increasing due to geographic expansion of the mosquito vector. Infection with any of the four serotypes of DENV can result in a self-limiting disease but debilitating febrile illness (DF), and some infections progress to severe disease with manifestations such as hemorrhage and shock. DENV infection drives the metabolic state of host cells for viral benefit and induces a host-immune response that has metabolic implications that link to disease. In this study, a dynamic metabolic response to DENV infection and disease was measured in 535 pediatric patient sera using liquid chromatography-mass spectrometry. The metabolome was interrogated to discover biochemical pathways and identify key metabolites perturbed in severe dengue disease. A biomarker panel of thirty-two perturbed metabolites was utilized to classify DF, and severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) with high sensitivity and specificity equating to a balanced accuracy of 96.9%. Some metabolites that were structurally confirmed here belong to important biochemical pathways of omega-3 and omega-6 fatty acids, sphingolipids, purines, and tryptophan metabolism. A previously reported trend between serotonin and platelets in DHF patients has been expanded upon here to reveal a major depletion of serotonin, but not platelets, in DSS patients. This study differentiated and classified DF and DHF/DSS using a serum metabolic biomarker panel based on perturbed biochemical pathways that have potential implications for severe dengue disease. One sentence summary: Metabolic biomarkers distinguish dengue hemorrhagic fever and dengue shock syndrome from dengue fever and lend insight to severe disease pathology