Pathogenesis of vascular leak in dengue virus infection
Summary 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...
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description | Summary
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‐α, 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‐1β 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.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention. |
doi_str_mv | 10.1111/imm.12748 |
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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‐α, 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‐1β 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.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention.</description><identifier>ISSN: 0019-2805</identifier><identifier>EISSN: 1365-2567</identifier><identifier>DOI: 10.1111/imm.12748</identifier><identifier>PMID: 28437586</identifier><language>eng</language><publisher>England: Wiley Subscription Services, Inc</publisher><subject>Activation ; Angiopoietin ; Angiopoietins - metabolism ; Animals ; Blood Platelets - metabolism ; Blood Platelets - virology ; Capillary Permeability ; Cytokines ; Cytokines - metabolism ; dengue ; Dengue - metabolism ; Dengue - physiopathology ; Dengue - virology ; Dengue hemorrhagic fever ; Dengue Virus - metabolism ; Dengue Virus - pathogenicity ; Discordance ; Drugs ; Endothelium ; Endothelium, Vascular - metabolism ; Endothelium, Vascular - physiopathology ; Endothelium, Vascular - virology ; Fever ; Humans ; Immunology ; Infections ; Inflammasomes ; Inflammation ; Inflammation Mediators - metabolism ; Interleukin 1 ; Leukotrienes ; Leukotrienes - metabolism ; lipid mediators ; Mast Cells - metabolism ; Mast Cells - virology ; Monocytes ; NS1 antigen ; Pathogenesis ; Patients ; Platelet Activating Factor - metabolism ; Platelet-activating factor ; Platelets ; Review ; Signal Transduction ; Time measurement ; Tumor necrosis factor ; Tumors ; Vascular endothelial growth factor ; vascular leak ; Vector-borne diseases ; Viral diseases ; Viral infections ; Viral Nonstructural Proteins - metabolism ; Viremia ; Viruses</subject><ispartof>Immunology, 2017-07, Vol.151 (3), p.261-269</ispartof><rights>2017 John Wiley & Sons Ltd</rights><rights>2017 John Wiley & Sons Ltd.</rights><rights>Copyright © 2017 John Wiley & Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4438-63b89c7d7894f66347ced46bf958c3615d9cf58a600861959b1672529efc77673</citedby><cites>FETCH-LOGICAL-c4438-63b89c7d7894f66347ced46bf958c3615d9cf58a600861959b1672529efc77673</cites><orcidid>0000-0001-9201-0449</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461104/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461104/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28437586$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Malavige, Gathsaurie Neelika</creatorcontrib><creatorcontrib>Ogg, Graham S.</creatorcontrib><title>Pathogenesis of vascular leak in dengue virus infection</title><title>Immunology</title><addtitle>Immunology</addtitle><description>Summary
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‐α, 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‐1β 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.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention.</description><subject>Activation</subject><subject>Angiopoietin</subject><subject>Angiopoietins - metabolism</subject><subject>Animals</subject><subject>Blood Platelets - metabolism</subject><subject>Blood Platelets - virology</subject><subject>Capillary Permeability</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>dengue</subject><subject>Dengue - metabolism</subject><subject>Dengue - physiopathology</subject><subject>Dengue - virology</subject><subject>Dengue hemorrhagic fever</subject><subject>Dengue Virus - metabolism</subject><subject>Dengue Virus - pathogenicity</subject><subject>Discordance</subject><subject>Drugs</subject><subject>Endothelium</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - physiopathology</subject><subject>Endothelium, Vascular - virology</subject><subject>Fever</subject><subject>Humans</subject><subject>Immunology</subject><subject>Infections</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interleukin 1</subject><subject>Leukotrienes</subject><subject>Leukotrienes - metabolism</subject><subject>lipid mediators</subject><subject>Mast Cells - metabolism</subject><subject>Mast Cells - virology</subject><subject>Monocytes</subject><subject>NS1 antigen</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Platelet Activating Factor - metabolism</subject><subject>Platelet-activating factor</subject><subject>Platelets</subject><subject>Review</subject><subject>Signal Transduction</subject><subject>Time measurement</subject><subject>Tumor necrosis factor</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>vascular leak</subject><subject>Vector-borne diseases</subject><subject>Viral diseases</subject><subject>Viral infections</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>Viremia</subject><subject>Viruses</subject><issn>0019-2805</issn><issn>1365-2567</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1LxDAQhoMouq4e_ANS8KKHukmaz4sgix8Lih70HNI0XaNto8l2xX9vtLqo4FyGIQ8PM3kB2EPwGKWauLY9RpgTsQZGqGA0x5TxdTCCEMkcC0i3wHaMj2ksIKWbYAsLUnAq2AjwW7148HPb2ehi5utsqaPpGx2yxuqnzHVZZbt5b7OlC31Mc23NwvluB2zUuol296uPwf352d30Mr-6uZhNT69yQ0ghclaUQhpecSFJzVhBuLEVYWUtqTAFQ7SSpqZCMwgFQ5LKEjGOKZa2NpwzXozByeB97svWVsZ2i6Ab9Rxcq8Ob8tqp3y-de1Bzv1SUMIQgSYLDL0HwL72NC9W6aGzT6M76PiokJBKCY04TevAHffR96NJ5CknIMJIM40QdDZQJPsZg69UyCKqPOFSKQ33Gkdj9n9uvyO__T8BkAF5dY9_-N6nZ9fWgfAcIWJL7</recordid><startdate>201707</startdate><enddate>201707</enddate><creator>Malavige, Gathsaurie Neelika</creator><creator>Ogg, Graham S.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QR</scope><scope>7T5</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9201-0449</orcidid></search><sort><creationdate>201707</creationdate><title>Pathogenesis of vascular leak in dengue virus infection</title><author>Malavige, Gathsaurie Neelika ; Ogg, Graham S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4438-63b89c7d7894f66347ced46bf958c3615d9cf58a600861959b1672529efc77673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Activation</topic><topic>Angiopoietin</topic><topic>Angiopoietins - metabolism</topic><topic>Animals</topic><topic>Blood Platelets - metabolism</topic><topic>Blood Platelets - virology</topic><topic>Capillary Permeability</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>dengue</topic><topic>Dengue - metabolism</topic><topic>Dengue - physiopathology</topic><topic>Dengue - virology</topic><topic>Dengue hemorrhagic fever</topic><topic>Dengue Virus - metabolism</topic><topic>Dengue Virus - pathogenicity</topic><topic>Discordance</topic><topic>Drugs</topic><topic>Endothelium</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - physiopathology</topic><topic>Endothelium, Vascular - virology</topic><topic>Fever</topic><topic>Humans</topic><topic>Immunology</topic><topic>Infections</topic><topic>Inflammasomes</topic><topic>Inflammation</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interleukin 1</topic><topic>Leukotrienes</topic><topic>Leukotrienes - metabolism</topic><topic>lipid mediators</topic><topic>Mast Cells - metabolism</topic><topic>Mast Cells - virology</topic><topic>Monocytes</topic><topic>NS1 antigen</topic><topic>Pathogenesis</topic><topic>Patients</topic><topic>Platelet Activating Factor - metabolism</topic><topic>Platelet-activating factor</topic><topic>Platelets</topic><topic>Review</topic><topic>Signal Transduction</topic><topic>Time measurement</topic><topic>Tumor necrosis factor</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><topic>vascular leak</topic><topic>Vector-borne diseases</topic><topic>Viral diseases</topic><topic>Viral infections</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>Viremia</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Malavige, Gathsaurie Neelika</creatorcontrib><creatorcontrib>Ogg, Graham S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Malavige, Gathsaurie Neelika</au><au>Ogg, Graham S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathogenesis of vascular leak in dengue virus infection</atitle><jtitle>Immunology</jtitle><addtitle>Immunology</addtitle><date>2017-07</date><risdate>2017</risdate><volume>151</volume><issue>3</issue><spage>261</spage><epage>269</epage><pages>261-269</pages><issn>0019-2805</issn><eissn>1365-2567</eissn><abstract>Summary
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‐α, 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‐1β 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.
Endothelial dysfunction leading to increased vascular permeability is a hallmark of severe dengue, leading to leakage of fluid into pleural and peritoneal cavities and shock. Although cytokines such as tumour necrosis factor‐α, which are highly elevated in dengue, and are likely to result in increased vascular permeability, the roles of DENV‐NS1 antigen and lipid mediators such as PAF in causing vascular leak are emerging. It may be that in practice, there are several pathways that contribute to vascular leak, but by understanding key mechanisms there may be opportunities for intervention.</abstract><cop>England</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28437586</pmid><doi>10.1111/imm.12748</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-9201-0449</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Activation Angiopoietin Angiopoietins - metabolism Animals Blood Platelets - metabolism Blood Platelets - virology Capillary Permeability Cytokines Cytokines - metabolism dengue Dengue - metabolism Dengue - physiopathology Dengue - virology Dengue hemorrhagic fever Dengue Virus - metabolism Dengue Virus - pathogenicity Discordance Drugs Endothelium Endothelium, Vascular - metabolism Endothelium, Vascular - physiopathology Endothelium, Vascular - virology Fever Humans Immunology Infections Inflammasomes Inflammation Inflammation Mediators - metabolism Interleukin 1 Leukotrienes Leukotrienes - metabolism lipid mediators Mast Cells - metabolism Mast Cells - virology Monocytes NS1 antigen Pathogenesis Patients Platelet Activating Factor - metabolism Platelet-activating factor Platelets Review Signal Transduction Time measurement Tumor necrosis factor Tumors Vascular endothelial growth factor vascular leak Vector-borne diseases Viral diseases Viral infections Viral Nonstructural Proteins - metabolism Viremia Viruses |
title | Pathogenesis of vascular leak in dengue virus infection |
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