Abstract:
Endothelial dysfunction leading to vascular leak is the hallmark of severe
dengue. Vascular leak typically becomes clinically evident 3–6 days after
the onset of illness, which is known as the critical phase. This critical phase
follows the period of peak viraemia, and lasts for 24–48 hr and usually
shows rapid and complete reversal, suggesting that it is likely to occur as a
result of inflammatory mediators, rather than infection of the endothelium.
Cytokines such as tumour necrosis factor-a, which are known to be elevated
in the critical phase of dengue, are likely to be contributing factors. Dengue
NS1, a soluble viral protein, has also been shown to disrupt the endothelial
glycocalyx and thus contribute to vascular leak, although there appears to
be a discordance between the timing of NS1 antigenaemia and occurrence
of vascular leak. In addition, many inflammatory lipid mediators are elevated
in acute dengue viral infection such as platelet activating factor (PAF)
and leukotrienes. Furthermore, many other inflammatory mediators such
as vascular endothelial growth factor and angiopoietin-2 have been shown
to be elevated in patients with dengue haemorrhagic fever, exerting their
action in part by inducing the activity of phospholipases, which have
diverse inflammatory effects including generation of PAF. Platelets have
also been shown to significantly contribute to endothelial dysfunction by
production of interleukin-1b through activation of the NLRP3 inflammasome
and also by inducing production of inflammatory cytokines by monocytes.
Drugs that block down-stream immunological mediator pathways
such as PAF may also be beneficial in the treatment of severe disease
