title: Serum Metabolomics Reveals Serotonin as a Predictor of Severe Dengue in the Early Phase of Dengue Fever.
abstract: Effective triage of dengue patients early in the disease course for in- or out-patient management would be useful for optimal healthcare resource utilization while minimizing poor clinical outcome due to delayed intervention. Yet, early prognosis of severe dengue is hampered by the heterogeneity in clinical presentation and routine hematological and biochemical measurements in dengue patients that collectively correlates poorly with eventual clinical outcome. Herein, untargeted liquid-chromatography mass spectrometry metabolomics of serum from patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) in the febrile phase (<96 h) was used to globally probe the serum metabolome to uncover early prognostic biomarkers of DHF. We identified 20 metabolites that are differentially enriched (p<0.05, fold change >1.5) in the serum, among which are two products of tryptophan metabolism-serotonin and kynurenine. Serotonin, involved in platelet aggregation and activation decreased significantly, whereas kynurenine, an immunomodulator, increased significantly in patients with DHF, consistent with thrombocytopenia and immunopathology in severe dengue. To sensitively and accurately evaluate serotonin levels as prognostic biomarkers, we implemented stable-isotope dilution mass spectrometry and used convalescence samples as their own controls. DHF serotonin was significantly 1.98 fold lower in febrile compared to convalescence phase, and significantly 1.76 fold lower compared to DF in the febrile phase of illness. Thus, serotonin alone provided good prognostic utility (Area Under Curve, AUC of serotonin = 0.8). Additionally, immune mediators associated with DHF may further increase the predictive ability than just serotonin alone. Nine cytokines, including IFN-γ, IL-1β, IL-4, IL-8, G-CSF, MIP-1β, FGF basic, TNFα and RANTES were significantly different between DF and DHF, among which IFN-γ ranked top by multivariate statistics. Combining serotonin and IFN-γ improved the prognosis performance (AUC = 0.92, sensitivity = 77.8%, specificity = 95.8%), suggesting this duplex panel as accurate metrics for the early prognosis of DHF.
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Cui
authors.affiliation: KK Research Centre, KK Women's and Children's Hospital, Singapore.
authors.forename: Yie Hou
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Communicable Disease Center, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
authors.forename: Tun Linn
authors.initials: TL
authors.lastname: Thein
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors.forename: Jinling
authors.initials: J
authors.lastname: Fang
authors.affiliation: Communicable Disease Center, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors.forename: Junxiong
authors.initials: J
authors.lastname: Pang
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore.|Emerging Infectious Diseases Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.affiliation: Communicable Disease Center, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
authors.forename: Yee Sin
authors.initials: YS
authors.lastname: Leo
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|NUS Environment Research Institute, National University of Singapore, Singapore.
authors.forename: Choon Nam
authors.initials: CN
authors.lastname: Ong
authors.affiliation: Infectious Diseases Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology (SMART), Singapore.|Departments of Biological Engineering and Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Tannenbaum
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002853:Chromatography, Liquid; D016207:Cytokines / Q000097:blood; D006801:Humans; D007737:Kynurenine / Q000097:blood; D013058:Mass Spectrometry; D055442:Metabolome; D011379:Prognosis; D012701:Serotonin / Q000097:blood*; D044967:Serum / Q000737:chemistry*; D019595:Severe Dengue / Q000175:diagnosis* / Q000473:pathology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D012701:Serotonin; D007737:Kynurenine