Serum biomarkers and anti-flavivirus antibodies at presentation as indicators of severe dengue

BackgroundDengue is the most common vector-borne viral disease worldwide. Most cases are mild, but some evolve into severe dengue (SD), with high lethality. Therefore, it is important to identify biomarkers of severe disease to improve outcomes and judiciously utilize resources. Methods/Principal findingsOne hundred forty-five confirmed dengue cases (median age, 42; range <1-91 years), enrolled from February 2018 to March 2020, were selected from an ongoing study of suspected arboviral infections in metropolitan Asuncion, Paraguay. Cases included dengue virus types 1, 2, and 4, and severity was categorized according to the 2009 World Health Organization guidelines. Testing for anti-dengue virus IgM and IgG and serum biomarkers (lipopolysaccharide binding protein and chymase) was performed on acute-phase sera in plate-based ELISAs; in addition, a multiplex ELISA platform was used to measure anti-dengue virus and anti-Zika virus IgM and IgG. Complete blood counts and chemistries were performed at the discretion of the care team. Age, gender, and pre-existing comorbidities were associated with SD vs. dengue with/without warning signs in logistic regression with odds ratios (ORs) of 1.07 (per year; 95% confidence interval, 1.03, 1.11), 0.20 (female; 0.05,0.77), and 2.09 (presence; 1.26, 3.48) respectively. In binary logistic regression, for every unit increase in anti-DENV IgG in the multiplex platform, odds of SD increased by 2.54 (1.19-5.42). Platelet count, lymphocyte percent, and elevated chymase were associated with SD in a combined logistic regression model with ORs of 0.99 (1,000/mu L; 0.98,0.999), 0.92 (%; 0.86,0.98), and 1.17 (mg/mL; 1.03,1.33) respectively. ConclusionsMultiple, readily available factors were associated with SD in this population. These findings will aid in the early detection of potentially severe dengue cases and inform the development of new prognostics for use in acute-phase and serial samples from dengue cases. Author summaryDengue fever is an acute disease caused by dengue virus and transmitted to humans through the bite of infected Aedes mosquitoes. Dengue is the most common vector-borne viral disease worldwide affecting an estimated 50-100 million people and with 10,000 dengue-related deaths each year. Currently, there is no specific treatment, and safe and effective vaccines have not been fully implemented. Most dengue cases present with nonspecific mild symptoms, but some will evolve into severe dengue, which can be fatal. Early detection and subsequent timely treatment have been shown to decrease mortality among severe cases. Therefore, it is very important to identify biomarkers for the early identification of cases at risk for progression to severe disease. In this study we analyze demographic factors, clinical laboratory data, lipopolysaccharide binding protein and chymase to evaluate associations with disease severity. This study was carried out in Paraguay, which is a hyperendemic country for dengue where the disease has been understudied. A number of factors were found to be associated with severe disease in this population, including patient age, male gender, presence of comorbid illnesses, low platelet count, low lymphocyte percentage, and elevated chymase level.