Risk factors and biomarkers of severe dengue Abhay PS Rathore 1 , Farouk S Farouk 2 and Ashley L St. John 1 ,3 ,4 ,5 Dengue virus infects several million people each year. Although usually a self-limiting disease, some patients can develop life- threatening severe complications, characterized by plasma leakage, hemorrhaging, and shock. The signs and symptoms of severe disease usually arise late in the disease course when patients are recovering and fever has subsided, making it difficult to predict. Efforts are underway to identify risk factors and biomarkers that can accurately predict disease severity in the acute febrile phase of the disease, facilitating early intervention and treatment strategies for those at greatest risk. In this review we discuss recent advancements in identifying risk factors and biomarkers for the prognosis of severe dengue. Addresses 1 Department of Pathology, Duke University Medical Center, Durham, NC, United States 2 Graduate Program in Global Health, Duke University, Durham, NC, United States 3 Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore 4 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 SingHealth Duke-NUS Global Health Institute, Singapore Corresponding authors: Rathore, Abhay PS (abhay.rathore@duke.edu), St. John, Ashley L (ashley.st.john@duke-nus.edu.sg) Current Opinion in Virology 2020, 43:xx–yy This review comes from a themed issue on Special section: defeat dengue Edited by John Hiscott and Annelies Wilder-Smith https://doi.org/10.1016/j.coviro.2020.06.008 1879-6257/ã 2020 Elsevier B.V. All rights reserved. Introduction to dengue Dengue virus (DENV), belonging to the family of Flaviviridae, is a human pathogen that is spread by mosquitoes. DENV has four antigenically distinct sero- types, DENV 1–4. Specific immunity against each of the serotypes is long-lasting; however, a patient can be infected with viruses from different serotypes multiple times [1]. DENV infects nearly 390 million people world- wide every year [2] and billions of people around the world are at risk of contracting the disease [3]. Travel related DENV infections are also on the rise and are a leading cause of febrile illness among travelers [4–6]. In its primary form, the disease is known as dengue fever (DF) and is usually a self-limiting febrile illness. How- ever, some patients can progress to severe illness, usually towards the end of the disease course, possibly resulting in death. Severe dengue is characterized by hemorrhaging and shock and is also known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) [7]. The DENV incubation period is 4–7 days on average before disease symptoms appear. DF symptoms include fever, headache, retro-orbital pain, muscle and joint pain, nausea, and rash, which can last for up to five days [8,9]. Throm- bocytopenia, or a reduction in platelets, is one of the hallmarks of DENV disease and frequently observed in both mild and severe cases, although thrombocytopenia is usually worse in patients currently experiencing severe disease [7,10]. The symptoms of DHF arise late in the disease when a patient is recovering and viremia has begun to subside. These include bleeding, worsened or prolonged thrombocytopenia, and plasma or vascular leakage. Patients experiencing DHF can also progress to develop DSS. DSS is the most critical stage of illness and its clinical signs include circulatory failure, low blood pressure, and shock with persistent abdominal pain and vomiting, restlessness/ lethargy, and a swift change from fever to hypothermia with sweating [8]. Once these signs are present in a patient, it is imperative that they receive immediate medical care. Case fatality rates spike from 0.2% among patients with DHF to as high as 44% for DSS patients [8]. Unlike closely related Zika virus, sexual transmission of DENV is extremely rare [11]. However, severe DENV illness in pregnant mothers could result in pregnancy complications [12]. The World Health Organization guidelines for dengue management highlight the importance of monitoring patients for warning signs, which include persistent vomit- ing, abdominal pain, lethargy or restlessness, irritability, giddiness, and oliguria [7]. Since these clinical warning signs appear late in the disease, even within only a few hours of needing life-saving interventions [7,13], it is extremely difficult to predict severe dengue outcomes. Therefore it is of high value to identify risk factors and biomarkers that can serve as prognostic indicators of severe disease so urgent care and intervention can be provided to prevent life threatening complications or death. Disease intervention Conventional treatment for DF generally involves hos- pitalization and fluid replacement [7,14]. However, there Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Virology 2020, 43:1–8