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Vascular leak typically becomes clinically evident 3\u20136 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\u201348 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\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    , which are known to be elevated in the critical phase of dengue, are likely to be contributing factors. Dengue\n                    <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\n                    1, 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\n                    <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\n                    1 antigenaemia and occurrence of vascular leak. In addition, many inflammatory lipid mediators are elevated in acute dengue viral infection such as platelet activating factor (\n                    <jats:styled-content style=\"fixed-case\">PAF<\/jats:styled-content>\n                    ) and leukotrienes. Furthermore, many other inflammatory mediators such as vascular endothelial growth factor and angiopoietin\u20102 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\n                    <jats:styled-content style=\"fixed-case\">PAF<\/jats:styled-content>\n                    . Platelets have also been shown to significantly contribute to endothelial dysfunction by production of interleukin\u20101\n                    <jats:italic>\u03b2<\/jats:italic>\n                    through activation of the\n                    <jats:styled-content style=\"fixed-case\">NLRP<\/jats:styled-content>\n                    3 inflammasome and also by inducing production of inflammatory cytokines by monocytes. Drugs that block down\u2010stream immunological mediator pathways such as\n                    <jats:styled-content style=\"fixed-case\">PAF<\/jats:styled-content>\n                    may also be beneficial in the treatment of severe disease.\n                  <\/jats:p>","DOI":"10.1111\/imm.12748","type":"journal-article","created":{"date-parts":[[2017,4,24]],"date-time":"2017-04-24T11:51:21Z","timestamp":1493034681000},"page":"261-269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":271,"title":["Pathogenesis of vascular leak in dengue virus infection"],"prefix":"10.1111","volume":"151","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-0449","authenticated-orcid":false,"given":"Gathsaurie Neelika","family":"Malavige","sequence":"first","affiliation":[{"name":"Centre for Dengue Research University of Sri Jayewardenepura Nugegoda Sri Lanka"},{"name":"MRC Human Immunology Unit Radcliffe Department of Medicine Weatherall 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