Background: Since no effective vaccine or specific treatment for dengue exists, the early prediction of progression to severe disease plays a keys role in patient triage and clinical management during the febrile phase. Without differentiating the time-course of the illness, previous systematic reviews and meta-analyses may have failed to identify early prognostic factors for progression to severe disease. This study aimed to identify the factors associated with progression to severe dengue disease, which are detectable specifically in the febrile phase.

Methods and materials: We conducted a systematic review and meta-analysis to identify prognostic factors associated with disease progression identifiable during the febrile phase. Eight medical databases including MEDLINE, EMBASE, and Web of Science were searched for studies published from January 1997 to February 2018. The relevant studies were selected and assessed by three reviewers independenly with discrepancies resolved by consensus. We performed meta-analysis for factors reported in at least four studies. Meta-analysis were performed using random-effects models; heterogeneity and publication bias were also assessed.

Results: In line with the 2009 WHO guidelines, we found that vomiting, abdominal pain and tenderness, spontaneous and mucosal bleeding, and clinical fluid accumulation were clinical features associated with severe disease. In addition, we found that the presence of specific pre-existing comorbidities (diabetes mellitus, hypertension and renal disease) were associated with progression to severe disease. We also found that individuals with a lower platelet count, lower serum albumin and higher aminotransferase levels (AST or ALT), detected during the first four days of the illness, were more prone to progress to severe disease. Dengue virus serotype 2 and secondary infections were also associated with progression to severe disease.

Conclusion: This study 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 or ALT during the febrile phase of illness would improve the early prediction of severe dengue. This improvement would have major implications for the management of patients, particularly on presentation, and health care resource allocation in endemic areas.