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Predictors of plasma leakage among dengue patients in Thailand: A plasma-leak score analysis.

ABSTRACT: Delayed plasma leakage recognition could lead to improper fluid administration resulting in dengue shock syndrome, subsequently, multi-organ failure, and death. This prospective observational study was conducted in Bangkok, Thailand, between March 2018 and February 2020 to determine predictors of plasma leakage and develop a plasma leakage predictive score among dengue patients aged ≥15 years. Of 667 confirmed dengue patients, 318 (47.7%) developed plasma leakage, and 349 (52.3%) had no plasma leakage. Multivariate analysis showed three independent factors associated with plasma leakage, including body mass index ≥25.0 kg/m2 (odds ratio [OR] = 1.784; 95% confidence interval [CI] = 1.040-3.057; P = 0.035), platelet count <100,000/mm3 on fever days 3 to 4 (OR = 2.151; 95% CI = 1.269-3.647; P = 0.004), and aspartate aminotransferase or alanine aminotransferase ≥100 U/l on fever days 3 to 4 (OR = 2.189; 95% CI = 1.231-3.891; P = 0.008). Because these three parameters had evidence of equality, each independent factor was weighted to give a score of 1 with a total plasma-leak score of 3. Higher scores were associated with increased plasma leakage occurrence, with ORs of 2.017 (95% CI = 1.052-3.869; P = 0.035) for score 1, 6.158 (95% CI = 2.914-13.015; P <0.001) for score 2, and 6.300 (95% CI = 2.419-16.407; P <0.001) for score 3. The area under the receiver operating characteristics curves for predicting plasma leakage was good (0.677 [95% CI = 0.616-0.739]). Patients with a plasma-leak score ≥1 had high sensitivity (88.8%), and those with a plasma-leak score of 3 had high specificity (93.4%) for plasma leakage occurrence. This simple and easily accessible clinical score might help physicians provide early and timely appropriate clinical dengue management in endemic areas.

SUBMITTER: Talukdar S

PROVIDER: S-EPMC8321125 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundEndothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection.MethodsHeparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo.ResultsHeparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets.ConclusionTaken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase.

Project description:Background: Dengue is the most common arboviral infection globally; a minority of patients develop shock due to profound plasma leak through a disrupted endothelial barrier. Understanding of the pathophysiology underlying plasma leak is incomplete, but emerging evidence indicates a key role for degradation of the endothelial glycocalyx. Methods: We conducted an observational study in Vietnam to evaluate the sublingual microcirculation using sidestream darkfield imaging in (1) outpatients with confirmed dengue (2) patients hospitalized with dengue and (3) outpatients with other febrile illness (OFI). We estimated the glycocalyx degradation by measuring the perfused boundary region (PBR hf) and an overall microvascular health score (MVHS) with the software application GlycoCheckTM at enrolment, 48 h later and hospital discharge/defervescence. We measured plasma syndecan1 and endocan at the same time-points. We compared PBR hf, MVHS, syndecan1 and endocan, between (1) outpatients with confirmed dengue vs. OFI and (2) patients with dengue subdivided by clinical severity of plasma leak. Results: We included 75 patients with dengue (41 outpatients, 15 inpatients, 19 in intensive care) and 12 outpatients with OFI. Images from 45 patients were analyzed using GlycoCheckTM. There was no significant difference in PBR hf or MVHS between outpatients with dengue and OFI. Median plasma syndecan1 was not significantly different in outpatients with dengue vs. OFI, while median plasma endocan was significantly lower among patients with dengue vs. OFI during the critical phase. In patients with dengue, PBR hf was higher in patients with Grade 2 vs. Grade 0 plasma leakage during the critical phase (PBR hf 1.96 vs. 1.36 μm for Grade 2 vs. Grade 0 plasma leakage on days 4-6, respectively, p < 0.001). Median levels of plasma syndecan1 and endocan were higher in Grade 2 vs. Grade 0 plasma leakage, especially during the critical phase (Syndecan1 2,613.8 vs. 125.9 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4-6, respectively, p < 0.001, and endocan 3.21 vs. 0.16 ng/ml for Grade 2 vs. Grade 0 plasma leakage on days 4-6, respectively). Conclusions: We present the first human in vivo evidence of glycocalyx disruption in dengue, with worse visual glycocalyx damage and higher plasma degradation products associated with more severe plasma leak.