Microvascular and endothelial dysfunction in the pathophysiology of disease progression in dengue: an observational study in Vietnam

Abstract

Dengue infection can present with a broad spectrum of clinical phenotypes. The hallmark of severe disease is increased vascular permeability, sometimes leading to hypovolaemic shock. Microvascular/ endothelial dysfunction may underlie this, but have not been assessed clinically. I performed a prospective observational study in two hospitals in Vietnam recruiting 300 children (> 3 years) and adults presenting to a) outpatient department with fever for <72 hours and suspected dengue, b) patients hospitalized with warning signs or severe disease. Clinical and laboratory assessments were performed daily for 5 days, and 2 weeks later. Microvascular imaging using Sidestream dark field Imaging (SDF), and endothelial function testing using peripheral artery tonometry (EndoPAT) were performed at enrolment, defervescence/hospital discharge and follow-up. Plasma endothelial biomarkers were performed at the same time-points. Echocardiogram derived parameter of intravascular volume and cardiac function were also assessed at the same time-points and daily in patients admitted to ICU. We demonstrated firstly, that moderate microcirculatory alterations occur in dengue and are most prominent in the critical phase and worst in patients with plasma leakage. In the outpatient arm, these microcirculatory alterations were similar in other febrile illnesses. The flow alterations correlated with VCAM-1 and Angiopoietin-2 in dengue patients. Significantly elevated levels of syndecan-1 were shown in dengue patients during the critical phase, associated with the degree of plasma leakage, suggesting there is widespread endothelial glycocalyx degradation. In addition, we have shown patients with dengue have endothelial dysfunction with impaired endothelium-dependent vasodilation, worst in patients with severe plasma leakage, which is apparent early in the febrile phase. Endothelial dysfunction correlated with high levels of arginase-1 and low L-arginine levels. In severe dengue, myocardial impairment was associated with respiratory distress but not recurrent shock. High lactate levels at admission to intensive care and lower stroke volumes were associated with recurrent shock. Overall, this work has shown microvascular and endothelial dysfunction are associated with disease progression and severe outcomes in dengue, and may provide useful future biomarkers and therapeutic targets.