Early circulating biomarker signatures of dengue-associated plasma leakage uncovered by proteomics

Plasma leakage, which is a defining feature of severe dengue, lacks early predictive biomarkers critical for timely clinical decision-making. We aimed to characterize early biomarkers of dengue-associated plasma leakage using two complementary high-throughput proteomics platforms. Plasma samples were collected from 222 patients with dengue during their early febrile phase (stratified by subsequent development of plasma leakage and prior dengue exposure), 50 non-dengue patients with febrile illnesses, and 6 healthy controls. Proteomic profiling of pooled plasma was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and SomaScan aptamer-based platforms. Differential protein expression, and pathway analyses were conducted to identify early biomarkers of plasma leakage. We identified 23 differentially expressed proteins detected across both platforms that distinguished patients who subsequently did or did not develop plasma leakage. Fourteen of these proteins are highly expressed in the liver, demonstrating a central role of early hepatic dysfunction in plasma leakage. Functional analysis of these biomarkers revealed convergent roles in endothelial dysfunction, immune dysregulation, extracellular matrix remodelling, and metabolic reprogramming. Proteomic screening using two powerful complementary methods applied to pooled plasma samples identified 23 biomarkers associated with subsequent plasma leakage. These biomarkers must be prioritized for validation in other cohorts to demonstrate generalisability.