Perturbed pediatric circulating metabolome in mild and severe dengue disease

Four billion people are at risk of infection with dengue viruses (DENV), 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 but debilitating febrile illness (DF), and some infections progress to severe disease with hemorrhagic manifestations and shock (dengue hemorrhagic fever/dengue shock syndrome [DHF/DSS]). DENV infection drives the metabolic state of host cells for viral benefit and induces a host-immune response with metabolic implications that link to disease. Here, a dynamic metabolic response to DENV infection and disease was measured in 535 pediatric patients from Nicaragua using liquid chromatography-tandem mass spectrometry. Metabolomic analyses revealed profound disruptions of critical biochemical pathways and metabolites within the circulating metabolome, especially in those with more severe manifestations of dengue disease. A biomarker panel of 28 metabolites was utilized to classify DF versus DHF/DSS with high sensitivity and specificity, equating to a balanced accuracy of 96.88%. Identified metabolites belonged to biochemical pathways of omega-3 and omega-6 fatty acids, sphingolipids, dipeptides, purines, and tryptophan metabolism. Dipeptides emerged as the most critical molecules for severe disease classification. Additionally, a previously reported trend between serotonin and platelets in DHF patients was expanded upon here, revealing a major depletion of serotonin, but not platelets, in DSS patients. In this study, the perturbed metabolome was used for disease state classification and exploration of the biochemistry of severe dengue disease pathology.IMPORTANCEThe international burden of dengue is intensifying, as the number of reported cases in only the first 5 months of 2025 exceeded that of the previous annual high in 2023. The occurrence of deadly severe manifestations of dengue disease will escalate as the total cases rise, and pediatric patients are at greater risk of developing the rapidly progressing severe dengue diseases than adults. Suboptimal vaccines, lack of clinically approved therapeutics, and no methodologies for prognosis of severe disease exacerbate the difficulty of preventative and supportive care. Because human metabolism is rapidly altered due to infection, perturbations in patients' circulating metabolome can be attributed to dengue disease and correlated to severity. This study contributes metabolic biomarkers of dengue disease in pediatric patients from Nicaragua, indicating that metabolic biomarkers are conserved across patients of different ages and geographic and genetic backgrounds. With validation across many cohorts, there is potential to improve diagnostics.