Serum Metabolomics Reveals Serotonin as a Predictor of Severe Dengue in the Early Phase of Dengue Fever
| Autor: | Choon Nam Ong, Steven R. Tannenbaum, Eng Eong Ooi, Yie Hou Lee, Yee Sin Leo, Jinling Fang, Junxiong Pang, Liang Cui, Tun-Linn Thein |
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| Přispěvatelé: | Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Chemistry, Tannenbaum, Steven R |
| Rok vydání: | 2016 |
| Předmět: |
Serum
0301 basic medicine Viral Diseases Platelet Aggregation Physiology Fevers Pathology and Laboratory Medicine Biochemistry Mass Spectrometry Dengue Fever Dengue fever chemistry.chemical_compound 0302 clinical medicine Animal Cells Immunopathology Medicine and Health Sciences Metabolites Platelet Kynurenine media_common lcsh:Public aspects of medicine Convalescence Neurochemistry Neurotransmitters Hematology Prognosis Body Fluids Blood Infectious Diseases Metabolome Cytokines Tumor necrosis factor alpha Anatomy Cellular Types Research Article Neglected Tropical Diseases Platelets Serotonin Biogenic Amines lcsh:Arctic medicine. Tropical medicine lcsh:RC955-962 media_common.quotation_subject 030231 tropical medicine 03 medical and health sciences Signs and Symptoms Metabolomics Diagnostic Medicine medicine Humans Severe Dengue Blood Coagulation Blood Cells business.industry Public Health Environmental and Occupational Health Biology and Life Sciences lcsh:RA1-1270 Cell Biology Tropical Diseases medicine.disease Metabolism 030104 developmental biology chemistry Immunology business Biomarkers Chromatography Liquid Neuroscience |
| Zdroj: | PLoS Neglected Tropical Diseases Public Library of Science PLoS Neglected Tropical Diseases, Vol 10, Iss 4, p e0004607 (2016) |
| ISSN: | 1935-2735 |
| Popis: | 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 (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. Author Summary Dengue, an acute arboviral disease has emerged globally, inflicting debilitating symptoms in 96 million people. The early prediction of severe dengue (dengue hemorrhagic fever, DHF) is challenging due to varied and late-presenting symptoms, requiring frequent monitoring for signs of disease progression. An often used parameter to monitor disease progression is decrease in platelet count, or thrombocytopenia, which is a feature of DHF. However, whether platelet-derived compounds are useful as early biomarkers predictive of DHF has not been investigated. In this study, we investigated the utility of serum metabolites as predictive biomarkers. We developed quantitative and high-throughput tools and discovered circulating serotonin, conceivably platelet-derived, that showed a nearly two-fold decrease in DHF patients compared to mild dengue fever. Because immune mediators may increase the predictive ability, we measured them in blood and identified interferon-gamma as an important cytokine in DHF. When serotonin is used in combination with IFN-γ, this dual-panel predictive panel provides accurate prognosis of DHF within 96 h from fever onset. These findings may have important clinical implications not just in early dengue prognostication but also in the design of therapeutic strategies against dengue infections. |
| Databáze: | OpenAIRE |
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