Editing Dengue fever (section)

== Cause ==

=== Virology ===
{{Main|Dengue virus}}
[[File:Dengue.jpg|thumb|upright=1.3|alt=A transmission electron microscopy image showing dengue virus|A [[Transmission electron microscopy|TEM]] [[micrograph]] showing dengue virus [[virion]]s (the cluster of dark dots near the center)]]

Dengue virus (DENV) is an [[RNA virus]] of the family ''[[Flaviviridae]]''; genus ''[[Flavivirus]]''. Other members of the same genus include [[yellow fever|yellow fever virus]], [[West Nile virus]], and [[Zika|Zika virus]].
Dengue virus [[genome]] (genetic material) contains about 11,000 [[nucleotide base]]s, which [[Genetic code|code]] for the three [[structural protein]] molecules (C, prM and E) that form the [[Virion|virus particle]] and seven other protein molecules that are required for replication of the virus.<ref name=Life10>{{cite journal | vauthors = Rodenhuis-Zybert IA, Wilschut J, Smit JM | title = Dengue virus life cycle: viral and host factors modulating infectivity | journal = Cellular and Molecular Life Sciences | volume = 67 | issue = 16 | pages = 2773–2786 | date = August 2010 | pmid = 20372965 | pmc = 11115823 | doi = 10.1007/s00018-010-0357-z | url = https://link.springer.com/content/pdf/10.1007/s00018-010-0357-z.pdf | url-status = live | s2cid = 4232236 | archive-url = https://ghostarchive.org/archive/20221009/https://link.springer.com/content/pdf/10.1007/s00018-010-0357-z.pdf | archive-date = 2022-10-09 }}</ref><ref name=Guzman10>{{cite journal | vauthors = Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martínez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW | title = Dengue: a continuing global threat | journal = Nature Reviews. Microbiology | volume = 8 | issue = 12 Suppl | pages = S7-16 | date = December 2010 | pmid = 21079655 | pmc = 4333201 | doi = 10.1038/nrmicro2460 }}</ref> There are four confirmed strains of the virus, called [[serovar|serotype]]s, referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their [[antigenicity]].<ref>{{cite book| vauthors = Solomonides T|title=Healthgrid applications and core technologies : proceedings of HealthGrid 2010|year=2010|publisher=IOS Press|location=Amsterdam|isbn=978-1-60750-582-2|page=235|url=https://books.google.com/books?id=nf-Q0TYTS-0C&pg=PA235|edition=[Online-Ausg.]|url-status=live|archive-url=https://web.archive.org/web/20160501063614/https://books.google.com/books?id=nf-Q0TYTS-0C&pg=PA235|archive-date=1 May 2016}}</ref>

=== Transmission ===

[[File:Aedes aegypti feeding.jpg|upright=1.3|alt=Close-up photograph of an ''Aedes aegypti'' mosquito biting human skin|thumb|The mosquito ''Aedes aegypti'' feeding on a human host]]

Dengue virus is most frequently transmitted by the bite of mosquitos in the ''[[Aedes]]'' genus, particularly ''[[Aedes aegypti|A.&nbsp;aegypti]]''.<ref>{{Cite web |date=2017-06-09 |title=Aedes aegypti – Factsheet for experts |url=https://www.ecdc.europa.eu/en/disease-vectors/facts/mosquito-factsheets/aedes-aegypti |access-date=2024-02-25 |website=www.ecdc.europa.eu |language=en |archive-date=10 July 2017 |archive-url=https://web.archive.org/web/20170710145706/https://ecdc.europa.eu/en/healthtopics/vectors/mosquitoes/Pages/aedes-aegypti.aspx |url-status=live }}</ref> They prefer to feed at dusk and dawn,<ref name="WHO2012">{{cite book |url=http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf |title=Global Strategy For Dengue Prevention And Control |publisher=World Health Organization |year=2012 |isbn=978-92-4-150403-4 |pages=16–17 |archive-url=https://web.archive.org/web/20121030141619/http://apps.who.int/iris/bitstream/10665/75303/1/9789241504034_eng.pdf |archive-date=30 October 2012 |url-status=live}}</ref> but they may bite and thus spread infection at any time of day.<ref>{{cite web |url=http://wwwnc.cdc.gov/travel/content/outbreak-notice/dengue-tropical-sub-tropical.aspx |title=Travelers' Health Outbreak Notice |publisher=Centers for Disease Control and Prevention |date=2 June 2010 |access-date=27 August 2010 |archive-url=https://web.archive.org/web/20100826005756/http://wwwnc.cdc.gov/travel/content/outbreak-notice/dengue-tropical-sub-tropical.aspx |archive-date=26 August 2010 |url-status=dead }}</ref> Other ''Aedes'' species that may transmit the disease include ''[[Aedes albopictus|A.&nbsp;albopictus]]'', ''[[Aedes polynesiensis|A.&nbsp;polynesiensis]]'' and ''[[Aedes scutellaris|A.&nbsp;scutellaris]]''. Humans are the primary [[Host (biology)|host]] of the virus,<ref name="Gould">{{cite journal | vauthors = Gould EA, Solomon T | title = Pathogenic flaviviruses | journal = Lancet | volume = 371 | issue = 9611 | pages = 500–509 | date = February 2008 | pmid = 18262042 | doi = 10.1016/S0140-6736(08)60238-X | url = https://www.thelancet.com/action/showPdf?pii=S0140-6736%2808%2960238-X | access-date = 6 June 2020 | url-status = live | s2cid = 205949828 | doi-access = free | archive-url = https://web.archive.org/web/20210828054828/https://www.thelancet.com/action/showPdf?pii=S0140-6736%2808%2960238-X | archive-date = 28 August 2021 }}</ref> but it also circulates in nonhuman [[primate]]s, and can infect other mammals.<ref>{{cite journal | vauthors = Gwee SX, St John AL, Gray GC, Pang J | title = Animals as potential reservoirs for dengue transmission: A systematic review | journal = One Health | volume = 12 | pages = 100216 | date = June 2021 | pmid = 33598525 | pmc = 7868715 | doi = 10.1016/j.onehlt.2021.100216 }}</ref><ref>{{cite web|title=Vector-borne viral infections|url=https://www.who.int/vaccine_research/diseases/vector/en/index1.html|publisher=World Health Organization|access-date=17 January 2011|url-status=dead|archive-url=https://web.archive.org/web/20110203162048/http://www.who.int/vaccine_research/diseases/vector/en/index1.html|archive-date=3 February 2011}}</ref> An infection can be acquired via a single bite.<ref name=Yellow10>{{cite web|url=http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-5/dengue-fever-dengue-hemorrhagic-fever.aspx|title=Chapter 5 – dengue fever (DF) and dengue hemorrhagic fever (DHF)|work=2010 Yellow Book|author=Center for Disease Control and Prevention|access-date=23 December 2010|url-status=live|archive-url=https://web.archive.org/web/20101229212025/http://wwwnc.cdc.gov/travel/yellowbook/2010/chapter-5/dengue-fever-dengue-hemorrhagic-fever.aspx|archive-date=29 December 2010}}</ref>

For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the [[Viremia|viremic]] period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut.<ref>{{cite book| vauthors = St Georgiev V |title=National Institute of Allergy and Infectious Diseases, NIH.|year=2009|publisher=Humana|location=Totowa, N.J.|isbn=978-1-60327-297-1|page=268|url=https://books.google.com/books?id=pymSBkVU-FsC&pg=PA268|edition=1|url-status=live|archive-url=https://web.archive.org/web/20160501133441/https://books.google.com/books?id=pymSBkVU-FsC&pg=PA268|archive-date=1 May 2016}}</ref> Over the next few days, the virus spreads to other tissues including the mosquito's [[salivary gland]]s and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease.<ref>{{Cite web |title=Dengue Transmission {{!}} Learn Science at Scitable |url=https://www.nature.com/scitable/topicpage/dengue-transmission-22399758/ |access-date=2024-02-28 |website=© 2014 Nature Education |language=en |archive-date=28 February 2024 |archive-url=https://web.archive.org/web/20240228211633/https://www.nature.com/scitable/topicpage/dengue-transmission-22399758/ |url-status=live }}</ref> The virus seems to have no detrimental effect on the mosquito, which remains infected for life.<ref name="Gubler2010" />

Dengue can also be transmitted via infected [[blood products]] and through [[organ donation]].<ref name="WHO2023" /> [[Vertical transmission]] (from mother to child) during pregnancy or at birth has been reported.<ref name="pmid20130380">{{cite journal | vauthors = Wiwanitkit V | title = Unusual mode of transmission of dengue | journal = Journal of Infection in Developing Countries | volume = 4 | issue = 1 | pages = 51–54 | date = November 2009 | pmid = 20130380 | doi = 10.3855/jidc.145 | doi-access = free }}</ref>

=== Risk factors ===

The principal risk for infection with dengue is the bite of an infected mosquito.<ref name="Bisen-2013">{{Cite book | vauthors = Bisen PS, Raghuvanshi R |url=https://onlinelibrary.wiley.com/doi/book/10.1002/9781118393277 |title=Emerging Epidemics: Management and Control |date=2013-07-22 |publisher=Wiley |isbn=978-1-118-39323-9 |edition=1 |language=en |doi=10.1002/9781118393277.ch8 |access-date=23 February 2024 |archive-date=23 February 2024 |archive-url=https://web.archive.org/web/20240223222706/https://onlinelibrary.wiley.com/doi/book/10.1002/9781118393277 |url-status=live }}</ref> This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed.<ref name="Bisen-2013" /> It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using [[mosquito net]]ting while resting, and/or the application of [[insect repellent]] ([[DEET]] being the most effective).<ref name="Yellow10" />

Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease.<ref>{{Cite web |title=Host Response to the Dengue Virus {{!}} Learn Science at Scitable |url=https://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106/ |access-date=2024-02-23 |website=www.nature.com |language=en |archive-date=23 February 2024 |archive-url=https://web.archive.org/web/20240223222706/https://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106/ |url-status=live }}</ref> Other risk factors for severe disease include female sex and high [[body mass index]].<ref name="NEJM2012" /><ref name="Guzman10" /> Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three.<ref name="Chen" /> Subsequent re-infection with a different serotype increases the risk of severe complications due to a phenomenon known as [[antibody-dependent enhancement]] (ADE).<ref name="CDC-Yello-2024" /><ref name="pmid36996026">{{cite journal | vauthors = Teo A, Tan HD, Loy T, Chia PY, Chua CL | title = Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern? | journal = PLOS Pathogens | volume = 19 | issue = 3 | pages = e1011223 | date = March 2023 | pmid = 36996026 | pmc = 10062565 | doi = 10.1371/journal.ppat.1011223 | doi-access = free }}</ref>[[File:antibody dependent enhancement.svg|thumb|In antibody-dependent enhancement (ADE), antibodies bind to both viral particles and Fc gamma receptors expressed on immune cells, increasing the likelihood that the viruses will infect those cells.]]The exact mechanism of ADE is not fully understood.<ref>{{cite journal | vauthors = Teo A, Tan HD, Loy T, Chia PY, Chua CL | title = Understanding antibody-dependent enhancement in dengue: Are afucosylated IgG1s a concern? | journal = PLOS Pathogens | volume = 19 | issue = 3 | pages = e1011223 | date = March 2023 | pmid = 36996026 | pmc = 10062565 | doi = 10.1371/journal.ppat.1011223 | doi-access = free }}</ref> It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the [[Fc receptor|Fcγ]] receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself.<ref name="pmid36996026" /><ref>{{Cite web |date=2020-12-07 |title=Antibody-dependent Enhancement (ADE) and Vaccines |url=https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-safety/antibody-dependent-enhancement-and-vaccines |access-date=2024-02-29 |website=The Children's Hospital of Philadelphia |archive-date=29 February 2024 |archive-url=https://web.archive.org/web/20240229214549/https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-safety/antibody-dependent-enhancement-and-vaccines |url-status=live }}</ref>

=== Mechanism of infection ===
When a dengue virus carrying mosquito bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called [[keratinocyte]]s, as well as specialized immune cells located in the skin, called [[Langerhans cell]]s.<ref>{{Cite web |title=Host Response to the Dengue Virus {{!}} Learn Science at Scitable |url=https://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106/ |access-date=2024-02-28 |website=© 2014 Nature Education |language=en |archive-date=23 February 2024 |archive-url=https://web.archive.org/web/20240223222706/https://www.nature.com/scitable/topicpage/host-response-to-the-dengue-virus-22402106/ |url-status=live }}</ref> The Langerhans cells migrate to the [[lymph node]]s, where the infection spreads to [[white blood cell]]s, and reproduces inside the cells while they move throughout the body.<ref name="Martina09" />

The white blood cells respond by producing several signaling proteins, such as [[cytokines]] and [[interferons]], which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the [[liver]] and the [[bone marrow]]) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased [[capillary permeability]]. As a result, [[blood volume]] decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever.<ref name="Martina09">{{cite journal | vauthors = Martina BE, Koraka P, Osterhaus AD | title = Dengue virus pathogenesis: an integrated view | journal = Clinical Microbiology Reviews | volume = 22 | issue = 4 | pages = 564–581 | date = October 2009 | pmid = 19822889 | pmc = 2772360 | doi = 10.1128/CMR.00035-09 }}</ref>