Introduction: Dengue is one of the fastest-growing RNA virus infections globally with a higher disease burden in low- and middle-income countries. Without an early warning system to triage patients at risk of adverse outcomes (dengue haemorrhagic fever, severe dengue, plasma leakage), indiscriminate admissions result in hospital overcrowding and suboptimal care.
Methods: In this nested case-control comparison of patients with and without plasma leakage, plasma collected in early infection (within the first 96 hours of fever) was tested for differential expression of biomarkers. Each group was further stratified as those with primary or secondary dengue in a subgroup analysis. Thirty-four biomarkers were tested, guided by a systematic review of literature, on a Luminex MAGPIX bead-based assay.
Results: A total of 228 patient samples (114 had plasma leakage) were tested. Elevated Vascular cell adhesion molecule -1 (OR:3.289, 95% CI: 1.090-9.926, p<0.05), and Interleukin 33 receptor levels (OR: 2.677, 95% CI: 1.244-5.856, p<0.05) were associated with an increased risk of plasma leakage while C-C motif chemokine 11 was associated with a decreased risk (OR: 0.166, 95% CI: 0.057-0.483, p<0.05). When adjusted for prior dengue exposure, a few other biomarkers (CXCL11, serum amyloid A) were also associated with plasma leakage.
Conclusion: Plasma leakage, unlike severe dengue or dengue haemorrhagic fever (DHF) is an adverse dengue outcome that can be more objectively demonstrated. Hence associating early differential expression of biomarkers to plasma leakage has less inter-observer bias. This study fills an important knowledge gap on early biomarkers predictive of plasma leakage in dengue.