LAUSR

Without an effective vaccine or specific treatment for dengue, the ability to accurately predict early progression to severe disease relies on patient triage and clinical management. Previous systematic reviews and meta-analyses have found significant heterogeneity in predictors associated with severe disease, due to large variations of these factors during the time-course of the illness. Our study aimed to identify the factors associated with progression to severe dengue disease, which are detectable specifically in the febrile phase. We conducted a systematic review and meta-analysis to identify predictors associated with disease progression identifiable during the febrile phase. Eight medical databases were searched for studies published from January 1997 to February 2018. Relevant studies were selected and assessed by three reviewers with discrepancies resolved by consensus. Meta-analyses were performed using random-effects models to estimate pooled effect sizes. Heterogeneity and publication bias were also assessed. Of 5,293 studies identified, 98 were included in the meta-analyses. The presence of pre-existing comorbidities (diabetes mellitus, hypertension and renal disease) were associated with severe dengue. Vomiting, abdominal pain and tenderness, spontaneous and mucosal bleeding, and clinical fluid accumulation were clinical features associated with progression to severe disease. During the first four days of illness, platelet count, and serum albumin were lower among individuals who progressed to severe disease whilst aminotransferase levels were higher. Dengue virus serotype 2 and secondary infection were also associated with severe disease. This analysis supports the monitoring of the warning signs described in the 2009 WHO guidelines. In addition, testing for infecting serotype and monitoring platelet count, serum albumin, AST and ALT during the febrile phase of illness would improve the early prediction of severe dengue. Funding Statement: The authors state: "There was no funding source for this study." SS acknowledges funding from the Collaborative Project to Increase Production of Rural Doctor and Royal Thai Government Scholarship. ID ackowledges research funding from an Imperial College Junior Research Fellowship, a Wellcome Trust Sir Henry Dale Fellowship, Janssen Pharmaceutica and joint Centre funding from the UK Medical Research Council and Department for International Development. AH is a National Institute for Health Research (NIHR) Senior Investigator. She also acknowledges the support of the NIHR Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Imperial College London in partnership with Public Health England (PHE), in collaboration with The Sanger Institute, the University of Cambridge Veterinary School and Imperial College Health Partners Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: We followed the protocol described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Protocols (PRISMA-P) guidelines and the steps discussed in the guide to systematic review and meta-analysis of prognostic factor studies by Riley et al . Our protocol was registered with PROSPERO (CRD42018093363).