Title: Clinical manifestation and laboratory parameters associated with progression to severe dengue in children: a systematic review and meta-analysis

BackgroundThe ingenuity to predict the progression to severe dengue is crucial in managing dengue patients. The previous meta-analysis has been performed on adults, and none has been performed specifically on children. We conducted a systematic review and meta-analysis to determine the clinical manifestations and laboratory parameters associated with the progression to severe dengue according to WHO criteria. MethodsWe focused on searching six medical databases for studies published from Jan 1, 2000, to Dec 31, 2020. The meta-analysis used random-effects or fixed-effects models to estimate pooled effect sizes. We also assessed the heterogeneity and publication bias. This study was registered with PROSPERO, CRD42021224439. ResultsWe included 49 of papers in the systematic review, and we encased the final selected 39 papers comprising 23 potential predictors in the meta-analyses. Among 23 factors studied, seven clinical manifestations demonstrated association with disease progression in children, including neurological signs, gastrointestinal bleeding, clinical fluid accumulation, hepatomegaly, vomiting, abdominal pain, and petechiae. Six laboratory parameters are associated during the early days of illness, including elevated hematocrit, elevated aspartate aminotransferase [AST], elevated alanine aminotransferase [ALT], low platelet count, low albumin levels, and elevated activated partial thromboplastin time. Dengue virus serotype 2 (DENV-2) and secondary infections were also associated with severe disease progression. ConclusionThis finding supports the use of the warning signs described in the WHO 2009 guidelines. In addition, monitoring serum albumin, AST/ALT levels, identifying infecting dengue serotypes, and immunological status could improve the risk prediction of disease progression.