Abstract
Plasma leakage is a major pathogenic mechanism of severe dengue, but the etiology remains unclear. The association between endothelial glycocalyx integrity and vascular permeability in older adults with dengue has not been evaluated. A prospective cohort study of adults with undifferentiated fever screened for dengue by RT-PCR or NS1 antigen testing was performed. Patients were assessed daily while symptomatic and at convalescence. Serum hyaluronic acid (HA), heparan sulfate (HS) and selected cytokines (TNF-α, IL-6, IL-10) were measured on enrollment and convalescence. Patients were diagnosed as dengue fever (DF, n = 30), dengue hemorrhagic fever (DHF, n = 20) and non-dengue (ND) febrile illness (n = 11). Acute HA and HS levels were significantly higher in all dengue patients compared to ND (p = 0.0033 and p = 0.0441 respectively), but not different between DF and DHF (p = 0.3426 and p = 0.9180 respectively). Enrolment HA inversely correlated with serum albumin, protein and platelets in all dengue and DHF (p < 0.05). HA and HS in all dengue patients decreased significantly at convalescence. Serum IL-10 was significantly associated with HA in all dengue patients (p = 0.002). Serum HA and HS levels were increased in adult dengue and HA was associated with markers of disease severity. Endothelial glycocalyx damage may have a role in vascular leakage in dengue.
Highlights
Dengue is a systemic febrile illness caused by 4 serotypes of the dengue virus (DENV-1-4) under the genus Flavivirus[1,2]
DENV real-time polymerase chain reaction (RT-PCR) or nonstructural protein 1 (NS1) was positive in all dengue patients with serotype 2 (DEN-2) being the predominant strain
There was no significant difference in RT-PCR crossing point (Cp) values between dengue fever (DF) and dengue hemorrhagic fever (DHF) groups (p = 0.348) and between primary infection and secondary infection (p = 0.0734)
Summary
Dengue is a systemic febrile illness caused by 4 serotypes of the dengue virus (DENV-1-4) under the genus Flavivirus[1,2]. The 1997 and 2009 World Health Organization (WHO) guidelines classified dengue into several subgroups according to severity; those without complications are diagnosed with dengue fever (DF), while those with more severe disease are classified as dengue hemorrhagic fever (DHF) or severe dengue (SD)[4,5] In both the 1997 and 2009 classifications, plasma leakage is a major criteria in the definition of DHF and SD4,5. In vitro studies of dengue have shown viral replication or increased pro-inflammatory cytokines result in endothelial cell damage with increased vascular permeability[8,9,10]. The glycocalyx is a carbohydrate-rich layer covering the vascular luminal endothelium consisting of a network of interlinked molecules including proteoglycans, glycoproteins, glycosaminoglycans (GAGs) and plasma proteins[13,14] It functions as a semipermeable barrier regulating flow between plasma and interstitial fluid[13]. None of these studies assessed the levels of glycocalyx constituents in older adults with dengue of varying severity or compared this to non-dengue febrile illness
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