Predictive Markers for the Early Prognosis of Dengue Severity: A Systematic Review and Meta-Analysis

Abstract

Background: Predictive markers for severe dengue stand out as a solution for the proactive management of dengue. Despite the low mortality rate resulting from severe cases, dengue requires vigilant examination and round-the-clock nursing care due to an abrupt and unpredictable progression of complications, posing a burden on clinical triage and material resources. Accordingly, identifying markers that allow for predicting disease prognosis from the initial stage of diagnosis is needed. Given the betterment of laboratory techniques and pathogenesis understanding, myriad candidates have been proposed to be associated with severe dengue progression. Therefore, we aim to provide a systematic overview of the relationship between putative biomarkers and severe dengue. Methods: We performed a systematic review and meta-analysis to compare the differences in host data collected within 72 hours of fever onset amongst the different severity levels. We searched nine bibliographic databases without restrictive criteria of language or publication date. We assessed risk of bias and graded robustness of evidence using NHLBI quality assessment tools, Q-genie tool (for genetic association studies), and GRADE, respectively. We synthesized the body of evidence by narrative review and frequentist meta-analysis, which estimated the effects of the markers in either absolute or relative measures. Findings: Of 4000 records found, 40 studies were eligible for qualitative synthesis, 19 for meta-analysis. We identified 108 host markers collected within 72 hours of fever onset from 6160 laboratory-confirmed dengue, including hematopoietic parameters, biochemical substances, clinical symptoms, immune mediators, viral particles, and genes. There was substantial heterogeneity in most findings, and the analyses lacked statistical power due to a small number of participants. As an exception, there was robust evidence of a significant decrease in platelet counts (MD -40.75, 95% CI -58.61 to -22.88) as well as the increase in AST levels (SMD 0.87, 95% CI 0.36 to 1.38) in severe dengue during this timeframe. Interpretation: Dengue infected patients presenting with either low blood platelet count or high serum AST level—in the first 72 hours of fever onset—are more likely to develop severe dengue. Registration Details: This study protocol is registered in PROSPERO (CRD42018104495). Funding Information: None. Declaration of Interests: We declare no competing interests.