Examine individual changes

'{{redirect|Ebola}} {{infobox disease | Name = Ebola virus disease | Image = 7042 lores-Ebola-Zaire-CDC Photo.jpg | Caption = 1976 photograph of two nurses standing in front of Mayinga N., a patient with Ebola virus disease; she died only a few days later due to severe internal bleeding and hemorrhaging. | DiseasesDB = 18043 | ICD10 = {{ICD10|A|98|4|a|90}} | ICD9 = {{ICD9|065.8}} | MedlinePlus = 001339 | eMedicineSubj = med | eMedicineTopic = 626 | MeshID = D019142 }} '''Ebola virus disease''' ('''EVD''') or '''Ebola hemorrhagic fever''' ('''EHF''') is the human disease which may be caused by any of four of the five known [[ebola virus]]es. These four viruses are: [[Bundibugyo virus]] (BDBV), [[Ebola virus]] (EBOV), [[Sudan virus]] (SUDV), and [[Ta&iuml; Forest virus]] (TAFV, formerly and more commonly Côte d'Ivoire Ebola virus (Ivory Coast Ebolavirus, CIEBOV)). EVD is a [[viral hemorrhagic fever]] (VHF), and is clinically nearly indistinguishable from [[Marburg virus disease|Marburg virus disease (MVD)]]. The name comes from the [[Ebola River]] in the [[Democratic Republic of the Congo]], where it was first found. {{TOC limit|3}} ==Classification== The genera ''Ebolavirus'' and ''[[Marburgvirus]]'' were originally classified as the species of the now-obsolete ''Filovirus'' genus. In March 1998, the Vertebrate Virus Subcommittee proposed in the [[International Committee on Taxonomy of Viruses]] (ICTV) to change the ''Filovirus'' genus to the ''Filoviridae''oro0gjogi3jewwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww family with two specific genera: ''Ebola-like viruses'' and ''Marburg-like viruses''. This proposal was implemented in Washington, DC on April 2001 and in Paris on July 2002. In 2000, another proposal was made in Washington, DC, to change the "-like viruses" to "-virus" resulting in today's ''Ebolavirus'' and ''Marburgvirus''.<ref>{{Cite web|url=http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/01.025.0.02.htm|title=ICTVdB Virus Description – 01.025.0.02. Ebolavirus|accessdate=2009-06-02|last=Büchen-Osmond|first=Cornelia|date=2006-04-25|publisher=International Committee on Taxonomy of Viruses}}</ref> [[File:Filovirus phylogenetic tree.svg|238px|thumb|[[Phylogenetic tree]] comparing the Ebolavirus and Marburgvirus. Numbers indicate percent confidence of branches.]] Rates of genetic change are 100 times slower than [[influenza A]] in humans, but on the same magnitude as those of [[hepatitis B]]. [[Molecular clock|Extrapolating backwards]] using these rates indicates that Ebolavirus and Marburgvirus diverged several thousand years ago.<ref>{{Cite pmid|9254917}}</ref> However, [[paleovirus]]es (genomic fossils) of [[filovirus]]es (Filoviridae) found in mammals indicate that the family itself is at least tens of millions of years old.<ref name="Cite pmid| 20569424">{{Cite pmid| 20569424}}</ref> Viral fossils that are closely related to ebolaviruses have been found in the genome of the [[Chinese hamster]].<ref>{{cite journal|last=Taylor|first=D. J.|coauthors=K. Dittmar, M.J. Ballinger, & J. A. Bruenn|title=Evolutionary maintenance of filovirus-like genes in bat genomes|journal=BMC Evolutionary Biology|year=2011|volume=11|doi=10.1186/1471-2148-11-336}}</ref> The five characterised Ebola species are: ; Zaire ebolavirus (ZEBOV) : Also known simply as the ''Zaire virus'', ZEBOV has the highest [[case-fatality rate]] of the ebolaviruses, up to 90% in some epidemics, with an average case fatality rate of approximately 83% over 27 years. There have been more outbreaks of ''Zaire ebolavirus'' than of any other species. The first outbreak occurred on 26 August 1976 in [[Yambuku]].<ref>{{Cite journal|author=Isaacson, M; Sureau, P; Courteille, G; Pattyn, SR;|title=Clinical Aspects of Ebola Virus Disease at the Ngaliema Hospital, Kinshasa, Zaire, 1976|url=http://www.itg.be/ebola/ebola-12.htm|accessdate=2009-07-08|ref=harv}}</ref> The first recorded case was Mabalo Lokela, a 44‑year-old schoolteacher. The symptoms resembled [[malaria]], and subsequent patients received [[quinine]]. Transmission has been attributed to reuse of unsterilized needles and close personal contact. ; Sudan ebolavirus (SEBOV) : Like the ''Zaire virus'', SEBOV emerged in 1976; it was at first assumed to be identical with the Zaire species.<ref name=Lancet2011>{{Cite pmid|21084112}}</ref> SEBOV is believed to have broken out first among cotton factory workers in Nzara, [[Sudan]], with the first case reported as a worker exposed to a potential natural reservoir. The virus was not found in any of the local animals and insects that were tested in response. The carrier is still unknown. The lack of [[Universal precautions#Additional precautions|barrier nursing]] (or "bedside isolation") facilitated the spread of the disease. The most recent outbreak occurred in May, 2004. Twenty confirmed cases were reported in Yambio County, Sudan, with five deaths resulting. The average fatality rates for SEBOV were 54% in 1976, 68% in 1979, and 53% in 2000 and 2001. ; Reston ebolavirus (REBOV) : Discovered during an outbreak of [[simian hemorrhagic fever virus]] (SHFV) in [[Crab-eating Macaque|crab-eating macaques]] from [[Covance|Hazleton Laboratories]] (now Covance) in 1989. Since the fagaggagagaasgfgafsjgksafjgajkshfeoiheaoighiogheiekghaighioaehoigeahogeiaheagoihaegoihegokaegnojieagbaegungeauigaeuiaegiugeabuiaegbgeaiuinitial outbreak in [[Reston, Virginia]], it has since been found in non-human primates in Pennsylvania, Texas and [[Siena]], [[Italy]]. In each case, the affected animals had been imported from a facility in the Philippines,<ref name="KnownCasesCDC">{{Cite web|url=http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola/ebolatable.htm|title=Known Cases and Outbreaks of Ebola Hemorrhagic Fever|accessdate=2008-08-02|author=Special Pathogens Branch CDC|date=2008-01-14|publisher=Center for Disease Control and Prevention}}</ref> where the virus has also infected pigs.<ref>{{cite news|url=http://www.nytimes.com/2009/01/24/health/24ebola.html|title=Pig-to-Human Ebola Case Suspected in Philippines|accessdate=2009-01-26|date=2009-01-24|publisher=New York Times | first=Donald G. | last=McNeil Jr}}</ref> Despite its status as a [[Biosafety level#Biosafety level 4|Level‑4]] organism and its apparent [[pathogen]]icity in monkeys, REBOV did not cause disease in exposed human laboratory workers.<ref>{{harvnb|McCormick|Fisher-Hoch|1999|p=300}}</ref> ; Côte d'Ivoire ebolavirus (CIEBOV): Also referred to as ''Taï Forest ebolavirus'' and by the English place name, "Ivory Coast", it was first discovered among [[chimpanzee]]s from the [[Taï National Park|Taï Forest]] in [[Côte d'Ivoire]], Africa, in 1994. [[Necropsies]] showed blood within the heart to be brown; no obvious marks were seen on the organs; and one necropsy showed lungs filled with blood. Studies of tissues taken from the chimpanzees showed results similar to human cases during the 1976 Ebola outbreaks in Zaire and Sudan. As more dead chimpanzees were discovered, many tested positive for Ebola using molecular techniques. The source of the virus was believed to be the meat of infected [[Western Red Colobus]] monkeys, upon which the chimpanzees preyed. One of the scientists performing the necropsies on the infected chimpanzees contracted Ebola. She developed symptoms similar to those of [[dengue fever]] approximately a week after the necropsy, and was transported to Switzerland for treatment. She was discharged from the hospital after two weeks and had fully recovered six weeks after the infection.<ref>{{Cite book|last=Waterman|first=Tara|title=Ebola Cote D'Ivoire Outbreaks|url=http://virus.stanford.edu/filo/eboci.html|accessdate=2009-05-30|year=1999|publisher=Stanford University}}</ref> ; Bundibugyo ebolavirus (BEBOV): On 24 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebolavirus in the [[Bundibugyo District]]. After confirmation of samples tested by the United States National Reference Laboratories and the [[Centers for Disease Control and Prevention|CDC]], the [[World Health Organization]] confirmed the presence of the new species. On 20 February 2008, the Uganda Ministry officially announced the end of the epidemic in Bundibugyo, with the last infected person discharged on 8 January 2008.<ref>{{Cite press release|title=End of Ebola outbreak in Uganda|publisher=World Health Organization|date=2008-02-20|url=http://www.who.int/csr/don/2007_02_20b/en/index.html}}</ref> An epidemiological study conducted by WHO and Uganda Ministry of Health scientists determined there were 116 confirmed and probable cases of the new Ebola species, and that the outbreak had a mortality rate of 34% (39 deaths). In 2012, there was an outbreak of Bundibugyo ebolavirus in a northeastern province of the Democratic Republic of the Congo. There were 15 confirmed cases and 10 fatalities.<ref>{{Cite journal|author=Wamala, J; Lukwago, L; Malimbo, M; Nguku, P; Yoti, Z; Musenero, M; Amone, J; Mbabazi, W; Nanyunja, M; Zaramba, S; Opio, A; Lutwama, J; Talisuna, A; Okware, I;|title=Ebola Hemorrhagic Fever Associated with Novel Virus Strain, Uganda, 2007–2008 | year = 2010 | journal = Emerging Infectious Disease | volume = 16 | issue = 7 | url = http://www.cdc.gov/eid/content/16/7/1087.htm | accessdate = 2010-06-24|ref=harv }}</ref> ==Signs and symptoms== {{Cleanup|reason=references need tidying|date=September 2012}} Ebola Virus Disease begins with a sudden onset of an [[influenza]]-like stage characterized by general [[malaise]], fever with chills, [[arthralgia]] and [[myalgia]], and chest pain. Nausea is accompanied by abdominal pain, [[anorexia (symptom)|anorexia]], diarrhea, and vomiting. [[Respiratory tract]] involvement is characterized by [[pharyngitis]] with sore throat, cough, [[dyspnea]], and hiccups. The [[central nervous system]] is affected as judged by the development of severe headaches, [[Psychomotor agitation|agitation]], confusion, [[fatigue (medical)|fatigue]], [[major depressive disorder|depression]], [[seizures]], and sometimes [[coma]]. Cutaneous presentation may include: [[Cutaneous conditions|maculopapular]] rash, [[petechia]]e, [[purpura]], [[Ecchymosis|ecchymoses]], and [[hematoma]]s (especially around needle injection sites). Development of hemorrhagic symptoms is generally indicative of a negative prognosis. However, contrary to popular belief, hemorrhage does not lead to [[hypovolemia]] and is not the cause of [[death]] (total blood loss is low except during [[Childbirth|labor]]). Instead, death occurs due to [[multiple organ dysfunction syndrome|multiple organ dysfunction syndrome (MODS)]] due to fluid redistribution, [[hypotension]], [[disseminated intravascular coagulation]], and focal [[tissue (biology)|tissue]] [[necrosis|necroses]]. The mean [[incubation period]], best calculated currently for EVD outbreaks due to EBOV infection, is 12.7 days ([[standard deviation]] = 4.3 days), but can be as long as 25 days.<ref name=Eichner2011>{{cite journal|last1 = Eichner|first1 = Martin|last2 = Dowell|first2 = Scott F.|last3 = Firese|first3 = Nina|year = 2011|title = Incubation Period of Ebola Hemorrhagic Virus Subtype Zaire OH AND BRETT|journal = Osong Public Health and Research Perspectives|volume = 2|issue = 1|pages = 3–7|doi = 10.1016/j.phrp.2011.04.001}}</ref> === Hemorrhage === All patients show some extent of [[coagulopathy]] and impaired circulatory system symptomology.<ref name=Hoenen2006 /> Bleeding from mucous membranes and puncture sites is reported in 40–50% of cases,<ref>{{cite web|title=Medscape: Ebola Virus, Clinical Presentation|url=http://emedicine.medscape.com/article/216288-clinical#a0217|accessdate=2012-07-30}}</ref> while maculopapular rashes are evident in approximately 50% of cases.<ref name=Hoenen2006 /> Sources of bleeds include [[hematemesis]], [[hemoptysis]], [[melena]], and aforementioned bleeding from [[mucous membranes]] ([[human gastrointestinal tract|gastroinestinal tract]], [[nose]], [[vagina]] and [[gingiva]]). Diffuse bleeding, however, is rare, and is usually exclusive to the gastrointestinal tract.<ref name=Hoenen2006>{{cite journal|last=Hoenen|first=Thomas|coauthors=Allison Groseth, Darryl Falzaran, Heinz Feldmann|title=Ebola virus: unravelling pathogenesis to combat a deadly disease|journal=Trends in Molecular Medicine|year=2006|month=May|volume=12|issue=5|pages=206–215}}</ref><ref>{{cite journal|last=Fisher-Hoch|first=S.P.|coauthors=et al|title=Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola)|journal=J. Infect. Dis.|year=1985|volume=152|pages=887–894}}</ref> ==Causes== {{Main| Ebolavirus}} EVD is caused by four of five viruses classified in the genus ''[[Ebolavirus]]'', family ''[[Filoviridae]]'', order ''[[Mononegavirales]]'': [[Bundibugyo virus]] (BDBV), [[Ebola virus]] (EBOV), [[Sudan virus]] (SUDV), and [[Ta&iuml; Forest virus]] (TAFV). The fifth virus, [[Reston virus]] (RESTV), is thought to be apathogenic for humans and therefore not discussed here. {| class="wikitable" style = "float: right; margin-left:15px; text-align:center" |+ Genus ''Ebolavirus'': species and their EVD-causing viruses |- ![[International Committee on Taxonomy of Viruses|Species name]]||[[International Committee on Taxonomy of Viruses|Virus name (Abbreviation)]] |- valign="TOP" | ''[[Bundibugyo ebolavirus]]'' (accepted)<ref name=KuhnArch>{{cite journal |last1=Kuhn |first1=Jens H. |last2=Becker |first2=Stephan |last3=Ebihara |first3=Hideki |last4=Geisbert |first4=Thomas W. |last5=Johnson |first5=Karl M. |last6=Kawaoka |first6=Yoshihiro |last7=Lipkin |first7=W. Ian |last8=Negredo |first8=Ana I |last9=Netesov |first9=Sergey V. |year = 2010 |title = Proposal for a revised taxonomy of the family Filoviridae: Classification, names of taxa and viruses, and virus abbreviations |journal = Archives of Virology |volume = 155 |issue = 12 |pages = 2083–103 |doi = 10.1007/s00705-010-0814-x |pmid = 21046175 |pmc=3074192 }}</ref> | [[Bundibugyo virus]] (BDBV; previously BEBOV) |- valign="TOP" | ''[[Sudan ebolavirus]]'' | [[Sudan virus]] (SUDV; previously SEBOV) |- valign="TOP" | ''[[Ta&iuml; Forest ebolavirus]]'' | [[Ta&iuml; Forest virus]] (TAFV; previously CIEBOV) |- valign="TOP" | ''[[Zaire ebolavirus]]''* | [[Ebola virus]] (EBOV; previously ZEBOV) |- valign="TOP" |} Table legend: "*" denotes the type species and "accepted" refers to a taxon that has been accepted by the Executive Committee of the ICTV but that has yet to be ratified. ===Risk factors=== Between 1976 and 1998, from 30,000 mammals, birds, reptiles, amphibians, and [[arthropod]]s sampled from outbreak regions, no ''ebolavirus'' was detected apart from some genetic traces found in six rodents (''[[Mus setulosus]]'' and ''[[Praomys]]'') and one [[shrew]] (''[[Sylvisorex ollula]]'') collected from the [[Central African Republic]].<ref name="Pourrut2005">{{Cite doi|10.1016/j.micinf.2005.04.006}}</ref><ref name="Morvan1999">{{Cite doi|10.1016/S1286-4579(99)00242-7}}</ref> Traces of EBOV were detected in the carcasses of [[gorilla]]s and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high lethality from infection in these species makes them unlikely as a natural reservoir.<ref name="Pourrut2005" /> [[Plant]]s, [[arthropods]], and birds have also been considered as possible reservoirs; however, [[bat]]s are considered the most likely candidate.<ref>{{Cite news|title=Fruit bats may carry Ebola virus |url=http://news.bbc.co.uk/2/hi/health/4484494.stm|work=BBC News|date=2005-12-11|accessdate=2008-02-25}}</ref> Bats were known to reside in the cotton factory in which the [[index case]]s for the 1976 and 1979 outbreaks were employed, and they have also been implicated in Marburg virus infections in 1975 and 1980.<ref name="Pourrut2005" /> Of 24 plant species and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected.<ref>{{Cite pmid|8969248}}</ref> The absence of clinical signs in these bats is characteristic of a reservoir species. In a 2002–2003 survey of 1,030 animals which included 679 bats from [[Gabon]] and the [[Republic of the Congo]], 13 fruit bats were found to contain EBOV RNA fragments.<ref>{{Cite doi|10.1038/438575a}}</ref> As of 2005, three types of [[fruit bat]]s (''[[Hypsignathus monstrosus]]'', ''[[Epomops franqueti]]'', and ''[[Myonycteris torquata]]'') have been identified as being in contact with EBOV. They are now suspected to represent the EBOV reservoir hosts.<ref>{{Cite pmid|17940947}}</ref> The existence of integrated genes of filoviruses in some genomes of small rodents, insectivorous bats, shrews, tenrecs, and marsupials indicates a history of infection with filoviruses in these groups as well.<ref name="Cite pmid| 20569424"/> However, it has to be stressed that infectious ebolaviruses have not yet been isolated from any nonhuman animal. Bats drop partially eaten fruits and pulp, then terrestrial mammals such as gorillas and [[duiker]]s feed on these fallen fruits. This chain of events forms a possible indirect means of transmission from the natural host to animal populations, which have led to research towards viral shedding in the saliva of bats. Fruit production, animal behavior, and other factors vary at different times and places which may trigger outbreaks among animal populations.<ref>{{Cite pmid|17848072}}</ref> Transmission between natural reservoirs and humans are rare, and outbreaks are usually traceable to a single index case where an individual has handled the carcass of gorilla, chimpanzee, or duiker.<ref>{{Cite pmid|15078595}}</ref> The virus then spreads person-to-person, especially within families, hospitals, and during some [[mortuary]] rituals where contact among individuals becomes more likely.<ref>{{Cite book|title=Questions and Answers about Ebola Hemorrhagic Fever|url=http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola/qa.htm|accessdate=2009-05-31|date=2009-03-25|publisher=Centers for Disease Control and Prevention}}</ref> The virus has been confirmed to be transmitted through [[body fluid]]s. Transmission through oral exposure and through [[conjunctiva]] exposure is likely<ref>{{Cite pmid|8551825}}</ref> and has been confirmed in non-human primates.<ref>{{Cite pmid|8712894}}</ref> Filoviruses are not naturally transmitted by aerosol. They are, however, highly infectious as breathable 0.8–1.2 micrometre droplets in laboratory conditions;<ref>{{Cite pmid|7547435}}</ref> because of this potential route of infection, these viruses have been classified as Category A biological weapons.<ref>{{Cite pmid|15588056}}</ref> All epidemics of Ebola have occurred in sub-optimal hospital conditions, where practices of basic hygiene and sanitation are often either luxuries or unknown to caretakers and where disposable needles and [[autoclave]]s are unavailable or too expensive. In modern hospitals with disposable needles and knowledge of basic hygiene and barrier nursing techniques, Ebola has never spread on a large scale. In isolated settings such as a quarantined hospital or a remote village, most victims are infected shortly after the first case of infection is present. The quick onset of symptoms from the time the disease becomes contagious in an individual makes it easy to identify sick individuals and limits an individual's ability to spread the disease by traveling. Because bodies of the deceased are still infectious, some doctors had to take measures to properly dispose of dead bodies in a safe manner despite local traditional burial rituals.<ref name="nyt">{{Cite news|first=Blaine|last=Harden|title=Dr. Matthew's Passion|url=http://www.nytimes.com/library/magazine/home/20010218mag%2debola.html|work=[[New York Times]] Magazine|date=2001-02-18|accessdate=2008-02-25}}</ref> ===Virology=== {{Main| Ebola virus}} ====Genome==== [[File:Ebola virus virion.jpg|thumb|right|Electron [[micrograph]] of an Ebola virus [[virion]]]] Like all [[Mononegavirales|mononegaviruses]], ebolavirions contain linear nonsegmented, single-stranded, non-infectious [[RNA]] [[genome]]s of negative polarity that possesses inverse-complementary 3' and 5' termini, do not possess a [[5' cap]], are not [[Polyadenylation|polyadenylated]], and are not [[Covalent bond|covalently]] linked to a [[protein]].<ref name=Fauquet2005>{{Citation |last1=Pringle |first1=C. R. |chapter=Order Mononegavirales |year=2005 |editor-last=Fauquet |editor-first=C. M. |editor2-last=Mayo |editor2-first=M. A. |editor3-last=Maniloff |editor3-first=J. |editor4-last=Desselberger |editor4-first=U. |editor5-last=Ball |editor5-first=L. A. |title=Virus Taxonomy—Eighth Report of the International Committee on Taxonomy of Viruses |pages=609–614 |publisher=Elsevier/Academic Press |location=San Diego, USA |isbn=0-12-370200-3 }}</ref> Ebolavirus genomes are approximately 19 kilobase pairs long and contain seven [[gene]]s in the order [[Three prime untranslated region|3'-UTR]]-''NP''-''VP35''-''VP40''-''GP''-''VP30''-''VP24''-''L''-[[Five prime untranslated region|5'-UTR]].<ref name = Kiley1982>{{Cite pmid|7118520}}</ref> The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV, and TAFV) differ in [[nucleic acid sequence|sequence]] and the number and location of gene overlaps. ====Structure==== Like all [[Filoviridae|filoviruses]], ebolavirions are filamentous particles that may appear in the shape of a shepherd's crook or in the shape of a "U" or a "6", and they may be coiled, toroid, or branched.<ref name = Kiley1982/> Ebolavirions are generally 80&nbsp;nm in [[width]], but vary somewhat in length. In general, the median particle length of ebolaviruses ranges from 974–1,086&nbsp;nm (in contrast to marburgvirions, whose median particle length was measured to be 795–828&nbsp;nm), but particles as long as 14,000&nbsp;nm have been detected in tissue culture.<ref name = Geisbert1995>{{Cite pmid|8837880}}</ref> Ebolavirions consist of seven structural proteins. At the center is the [[helical]] [[ribonucleoprotein|ribonucleocapsid]], which consists of the genomic RNA wrapped around a [[polymer]] of [[nucleoprotein]]s (NP). Associated with the ribonucleoprotein is the [[RNA-dependent RNA polymerase]] (L) with the polymerase cofactor (VP35) and a transcription activator (VP30). The ribonucleoprotein is embedded in a matrix, formed by the major (VP40) and minor (VP24) matrix proteins. These particles are surrounded by a [[lipid bilayer|lipid membrane]] derived from the host cell membrane. The membrane anchors a glycoprotein (GP_1,2) that projects 7 to 10&nbsp;nm spikes away from its surface. While nearly identical to marburgvirions in structure, ebolavirions are [[antigen]]ically distinct. ====Entry==== Niemann–Pick C1 ([[NPC1]]) appears to be essential for Ebola infection. Two independent studies reported in the same issue of [[Nature (journal)]] showed that Ebola virus cell entry and replication requires the cholesterol transporter protein NPC1.<ref name="pmid21866103">{{cite journal | author = Carette JE, Raaben M, Wong AC, Herbert AS, Obernosterer G, Mulherkar N, Kuehne AI, Kranzusch PJ, Griffin AM, Ruthel G, Dal Cin P, Dye JM, Whelan SP, Chandran K, Brummelkamp TR | title = Ebola virus entry requires the cholesterol transporter Niemann-Pick C1 | journal = Nature | volume = 477 | issue = 7364 | pages = 340–3 | year = 2011 | month = September | pmid = 21866103 | pmc = 3175325 | doi = 10.1038/nature10348 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref><ref name="pmid21866101">{{cite journal | author = Côté M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Li Q, Ory D, Chandran K, Cunningham J | title = Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection | journal = Nature | volume = 477 | issue = 7364 | pages = 344–8 | year = 2011 | month = September | pmid = 21866101 | pmc = 3230319 | doi = 10.1038/nature10380 | laysummary = http://www.nytimes.com/2012/01/17/health/npc1-protein-may-give-ebola-its-opening.html | laysource = New York Times }}</ref> When cells from [[Niemann-Pick disease, type C|Niemann Pick Type C]]1 patients were exposed to Ebola virus in the laboratory, the cells survived and appeared immune to the [[virus]], further indicating that Ebola relies on NPC1 to enter cells. This might imply that genetic mutations in the NPC1 gene in humans could make some people resistant to one of the deadliest known viruses affecting humans. The same studies described similar results with Ebola's cousin in the [[filovirus]] group, [[Marburg virus]], showing that it too needs NPC1 to enter cells.<ref name="pmid21866103"/><ref name="pmid21866101"/> Furthemore, NPC1 was shown to be critical to [[filovirus]] entry because it mediates infection by binding directly to the [[viral envelope]] glycoprotein.<ref name="pmid21866101"/> A later study confirmed the findings that NPC1 is a critical [[filovirus]] receptor that mediates infection by binding directly to the [[viral envelope]] glycoprotein and that the second lysosomal domain of NPC1 mediates this binding.<ref name="pmid22395071">{{cite journal | author = Miller EH, Obernosterer G, Raaben M, Herbert AS, Deffieu MS, Krishnan A, Ndungo E, Sandesara RG, Carette JE, Kuehne AI, Ruthel G, Pfeffer SR, Dye JM, Whelan SP, Brummelkamp TR, Chandran K | title = Ebola virus entry requires the host-programmed recognition of an intracellular receptor | journal = EMBO Journal | volume = 31 | issue = 8 | pages = 1947–60 | year = 2012 | month = March | pmid = 22395071 | pmc = 3343336 | doi = 10.1038/emboj.2012.53 }}</ref> In one of the original studies, a [[small molecule]] was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1.<ref name="pmid21866101"/><ref name="pmid21959282">{{cite journal | author = Flemming A | title = Achilles heel of Ebola viral entry | journal = Nat Rev Drug Discov | volume = 10 | issue = 10 | pages = 731 | year = 2011 | month = October | pmid = 21959282 | doi = 10.1038/nrd3568 }}</ref> In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus.<ref name="pmid21866103"/> Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug. ====Replication==== The ebolavirus [[Biological life cycle|life cycle]] begins with virion attachment to specific cell-surface [[Receptor (biochemistry)|receptors]], followed by [[Lipid bilayer fusion|fusion]] of the virion envelope with cellular membranes and the concomitant release of the virus [[nucleocapsid]] into the [[cytosol]]. The viral [[RNA-dependent RNA polymerase|RNA polymerase]], encoded by the L gene, partially uncoats the nucleocapsid and [[Transcription (genetics)|transcribes]] the [[genes]] into positive-stranded [[mRNA]]s, which are then [[translation (biology)|translated]] into structural and nonstructural [[proteins]]. Ebolavirus RNA polymerase (L) binds to a single [[Promoter (biology)|promoter]] located at the 3' end of the genome. Transcription either terminates after a gene or continues to the next gene downstream. This means that genes close to the 3' end of the genome are transcribed in the greatest abundance, whereas those toward the 5' end are least likely to be transcribed. The gene order is therefore a simple but effective form of transcriptional regulation. The most abundant protein produced is the [[nucleoprotein]], whose [[concentration]] in the cell determines when L switches from gene transcription to genome replication. Replication results in full-length, positive-stranded antigenomes that are, in turn, transcribed into negative-stranded virus progeny genome copy. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the [[cell membrane]]. Virions [[Budding|bud]] off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle.<ref name=Feldmann2005>{{Citation |last1=Feldmann |first1=H. |last2=Geisbert |first2=T. W. |last3=Jahrling |first3=P. B. |last4=Klenk |first4=H.-D. |last5=Netesov |first5=S. V. |last6=Peters |first6=C. J. |last7=Sanchez |first7=A. |last8=Swanepoel |first8=R. |last9=Volchkov |first9=V. E. |chapter=Family Filoviridae |year=2005 |editor-last=Fauquet |editor-first=C. M. |editor2-last=Mayo |editor2-first=M. A. |editor3-last=Maniloff |editor3-first=J. |editor4-last=Desselberger |editor4-first=U. |editor5-last=Ball |editor5-first=L. A. |title=Virus Taxonomy—Eighth Report of the International Committee on Taxonomy of Viruses |pages=645–653 |publisher=Elsevier/Academic Press |location=San Diego, USA |isbn=0-12-370200-3 }}</ref> ====Pathophysiology==== [[File:Ebola Pathenogensis path.svg|thumb|Pathogenesis schematic]] Endothelial cells, mononuclear [[phagocytes]], and [[hepatocytes]] are the main targets of infection. After infection, in a secreted glycoprotein (sGP) the Ebola virus glycoprotein (GP) is synthesized. Ebola replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a [[Trimer (biochemistry)|trimeric complex]], which binds the virus to the endothelial cells lining the interior surface of blood vessels. The sGP forms a [[protein dimer|dimeric protein]] which interferes with the signaling of [[neutrophils]], a type of [[white blood cell]], which allows the virus to evade the immune system by inhibiting early steps of neutrophil activation. These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen.<ref name="isbn0-7910-8505-8">{{cite book |author=Smith, Tara |title=Ebola (Deadly Diseases and Epidemics) |publisher=Chelsea House Publications |location= |year=2005 |pages= |isbn=0-7910-8505-8 |oclc= |doi= |accessdate=}}</ref> The presence of viral particles and cell damage resulting from budding causes the release of [[cytokines]] (specifically [[Tumor necrosis factor-alpha|TNF-α]], [[Interleukin 6|IL-6]], [[Interleukin 8|IL-8]], etc.), which are the signaling molecules for fever and inflammation. The [[cytopathic effect]], from infection in the endothelial cells, results in a loss of vascular integrity. This loss in vascular integrity is furthered with synthesis of GP, which reduces specific integrins responsible for cell adhesion to the inter-cellular structure, and damage to the liver, which leads to coagulopathy.<ref name="doi10.1128/JVI.77.18.9733-9737.2003">{{Cite doi|10.1128/JVI.77.18.9733-9737.2003}}</ref> ==Diagnosis== EVD is clinically indistinguishable from [[Marburg virus disease|Marburg virus disease (MVD)]], and it can also easily be confused with many other diseases prevalent in [[Equatorial Africa]], such as other [[viral hemorrhagic fever]]s, [[malaria|falciparum malaria]], [[typhoid fever]], [[shigellosis]], [[rickettsia|rickettsial diseases]] such as [[typhus]], [[cholera]], [[Gram-negative bacteria|gram-negative]] [[sepsis|septicemia]], [[borreliosis]] such as [[relapsing fever]] or [[Verotoxin-producing Escherichia coli|EHEC enteritis]]. Other infectious diseases that ought to be included in the [[differential diagnosis]] include [[leptospirosis]], [[scrub typhus]], [[plague (disease)|plague]], [[Q fever]], [[candidiasis]], [[histoplasmosis]], [[trypanosomiasis]], [[visceral]] [[leishmaniasis]], hemorrhagic [[smallpox]], [[measles]], and fulminant [[viral hepatitis]]. Non-infectious diseases that can be confused with EVD are [[acute promyelocytic leukemia]], [[hemolytic uremic syndrome]], [[snake]] [[envenomation]], [[coagulation|clotting factor]] deficiencies/platelet disorders, [[thrombotic thrombocytopenic purpura]], [[hereditary hemorrhagic telangiectasia]], [[Kawasaki disease]], and even [[warfarin]] intoxication.<ref name=Gear1989>{{Cite pmid|2665013}}</ref><ref name=Gear1978>{{Cite pmid|565951}}</ref><ref name=Grolla2005>{{Cite pmid|16267962}}</ref><ref name=Bogomolov1998>{{Cite pmid|9612907}}</ref> The most important indicator that may lead to the suspicion of EVD at clinical examination is the [[medical history]] of the patient, in particular the travel and occupational history (which countries were visited?) and the patient's exposure to wildlife (exposure to bats, bat excrement, nonhuman primates?). EVD can be confirmed by isolation of ebolaviruses from or by detection of ebolavirus antigen or genomic or subgenomic RNAs in patient [[blood]] or [[Blood serum|serum]] samples during the acute phase of EVD. Ebolavirus isolation is usually performed by [[inoculation]] of [[grivet]] kidney epithelial [[Vero cell|Vero E6]] or MA-104 [[cell culture]]s or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic [[cytopathic effect]]s.<ref>{{cite journal | last = Ksiazek | first = Thomas G. | year = 1991 | title = Laboratory diagnosis of filovirus infections in nonhuman primates | journal = Lab Animal | volume = 20 | issue = 7 | pages = 34–6}}</ref><ref name="van der Groen1978">{{Citation |last1 = van der Groen |first1 = G. |last2 = Webb |first2 = P. |last3 = Johnson |first3 = K. |last4 = Lange |first4 = J. |last5 = Lindsay |first5 = H. |last6 = Eliot |first6 = L. |year = 1978 |chapter = Growth of Lassa and Ebola viruses in different cell lines |editor-last=Pattyn |editor-first=S. R. |title=Ebola Virus Haemorrhagic Fever |pages=255–260 |publisher=Elsevier/North-Holland Biomedical Press |location=Amsterdam, Netherlands |isbn=0-444-80060-3 }}</ref> Filovirions can easily be visualized and identified in cell culture by [[electron microscopy]] due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences.<ref name=Geisbert1995>{{Cite pmid|8837880}}</ref> [[Immunofluorescence|Immunofluorescence assays]] are used to confirm ebolavirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore [[Reverse transcription polymerase chain reaction|RT-PCR]]<ref name=Sanchez1999>{{Cite pmid|9988180}}</ref><ref name=Leroy2000>{{Cite pmid|10686031}}</ref><ref name=Drosten2001>{{Cite pmid|12089242}}</ref><ref name=Gibb2001>{{Cite pmid|11682540}}</ref><ref name=Towner2004>{{Cite pmid|15047846}}</ref><ref name=Weidmann2004>{{Cite pmid|15072761}}</ref><ref name=Zhai2007>{{Cite pmid|17079496}}</ref> in conjunction with [[ELISA|antigen-capture ELISA]]<ref name=Ksiazek1992>{{Cite pmid|1572982}}</ref><ref name=Niikura2001>{{Cite pmid|11526161}}</ref><ref name=Lucht2003>{{Cite pmid|12821193}}</ref><ref name=Lucht2004>{{Cite pmid|14593476}}</ref><ref name=Yu2006>{{Cite pmid|16857271}}</ref> which can be performed in field or mobile hospitals and laboratories. [[Immunofluorescence|Indirect immunofluorescence assays (IFAs)]] are not used for diagnosis of EVD in the field anymore. ==Prevention== [[File:Biosafety level 4 hazmat suit.jpg|thumb|A researcher working with the Ebola virus while wearing a [[positive pressure personnel suit|BSL-4 positive pressure suit]] to avoid infection]] Ebola viruses are highly [[infection|infectious]] as well as [[Contagious disease|contagious]]. As an outbreak of ebola progresses, bodily fluids from diarrhea, vomiting, and bleeding represent a hazard. Due to lack of proper equipment and hygienic practices, large-scale epidemics occur mostly in poor, isolated areas without modern hospitals or well-educated medical staff. Many areas where the infectious reservoir exists have just these characteristics. In such environments, all that can be done is to immediately cease all needle-sharing or use without adequate [[Sterilization (microbiology)|sterilization]] procedures, isolate patients, and observe strict barrier nursing procedures with the use of a medical-rated disposable face mask, gloves, goggles, and a gown at all times, strictly enforced for all medical personnel and visitors.<ref name="Centers for Disease Control and Prevention and World Health Organization 1998">{{Cite book|last=Centers for Disease Control and Prevention and World Health Organization|title=Infection Control for Viral Haemorrhagic Fevers in the African Health Care Setting|url=http://www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual.htm|format=PDF|accessdate=2013-02-08|year=1998|publisher=Centers for Disease Control and Prevention|location=Atlanta, Georgia, USA|ref=CITEREFCDCWHO1998}}</ref> The aim of all of these techniques is to avoid any person’s contact with the blood or secretions of any patient, including those who are deceased.<ref>{{cite book|last=Center for Disease Control, Special Pathogens Branch|title=Questions and Answers about Ebola Hemorrhagic Fever|url=http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Fact_Sheets/Ebola_Fact_Booklet.pdf|publisher=Center for Disease Control|location=Atlanta, Georgia, USA}}</ref> Vaccines have successfully protected nonhuman primates; however, the six months needed to complete immunization made it impractical in an epidemic. To resolve this, in 2003, a vaccine using an [[Adenoviridae|adenoviral]] (ADV) vector carrying the Ebola spike protein was tested on crab-eating macaques. The monkeys were challenged with the virus 28 days later, and remained resistant.<ref name="Sullivan2003">{{Cite doi|10.1038/nature01876}}</ref> In 2005, a vaccine based on attenuated recombinant [[vesicular stomatitis virus]] (VSV) vector carrying either the Ebola glycoprotein or Marburg glycoprotein successfully protected nonhuman primates,<ref name="Jones2005">{{Cite doi|10.1038/nm1258}}</ref> opening clinical trials in humans.<ref name="Oplinger">{{Cite book|last=Oplinger|first=Anne A.|date=2003-11-18|title=NIAID Ebola vaccine enters human trial|url=http://news.bio-medicine.org/medicine-news-2/NIAID-Ebola-vaccine-enters-human-trial-4881-1/|publisher=Bio-Medicine}}</ref> By October, the study completed the first human trial; giving three vaccinations over three months showing capability of safely inducing an immune response. Individuals were followed for a year, and, in 2006, a study testing a faster-acting, single-shot vaccine began. This study was completed in 2008.<ref name="NIAIDVaccineDevelopment">{{Cite press release|title=Ebola/Marburg Vaccine Development|publisher=National Institute of Allergy and Infectious Diseases|date=2008-09-15|url=http://www3.niaid.nih.gov/topics/ebolaMarburg/default.htm}}</ref> The next step is to try the vaccine on a strain of Ebola that is closer to the one that infects humans.{{citation needed|date=June 2012}} There are currently no [[Food and Drug Administration]]-approved [[vaccine]]s for the prevention of EVD. Many candidate vaccines have been developed and tested in various animal models.<ref name=Mikhailov1994>{{Cite pmid|8017061}}</ref><ref name=Lupton1980>{{Cite pmid|6108462}}</ref><ref name=Geisbert2002>{{Cite pmid|11996686}}</ref> Of those, the most promising ones are [[DNA vaccination|DNA vaccines]]<ref name=Xu1998>{{Cite pmid|9427604}}</ref> or are based on [[Adenoviridae|adenoviruses]],<ref name=Sullivan2003/> [[vesicular stomatitis virus|vesicular stomatitis Indiana virus (VSIV)]]<ref name=Geisbert1-2008>{{Cite pmid|18930776}}</ref><ref name=Geisbert2-2008>{{Cite pmid|19043556}}</ref><ref name=Geisbert2009>{{Cite pmid|19386702}}</ref> or [[virus-like particle|filovirus-like particles (VLPs)]]<ref name=Warfield2007>{{Cite pmid|17940980}}</ref> as all of these candidates could protect nonhuman primates from ebolavirus-induced disease. DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccines have entered clinical trials.<ref name="Oplinger"/><ref name="NIAIDVaccineDevelopment"/><ref name=Martin2006>{{Cite pmid|16988008}}</ref><ref>{{Citation|last=Bush|first=L.|year=2005|title=Crucell and NIH sign Ebola vaccine manufacturing contract|journal=Pharmaceutical Technology|volume=29|pages=28}}</ref> Contrary to popular belief, ebolaviruses are not transmitted by [[aerosol]] during natural EVD outbreaks. Due to the absence of an approved vaccine, prevention of EVD therefore relies predominantly on behavior modification, proper [[personal protective equipment]], and [[sterilization (microbiology)|sterilization]]/[[disinfection]]. On 6 December 2011, the development of a successful [[vaccine]] against Ebola for mice was reported. Unlike the predecessors, it can be [[Freeze-drying|freeze-dried]] and thus stored for long periods in wait for an outbreak. The research will be presented in ''Proceedings of National Academy of Sciences''.<ref>{{Cite journal | last1 = Phoolcharoen | first1 = W. | last2 = Dye | first2 = J. M. | last3 = Kilbourne | first3 = J. | last4 = Piensook | first4 = K. | last5 = Pratt | first5 = W. D. | last6 = Arntzen | first6 = C. J. | last7 = Chen | first7 = Q. | last8 = Mason | first8 = H. S. | last9 = Herbst-Kralovetz | first9 = M. M. | doi = 10.1073/pnas.1117715108 | title = A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge | journal = Proceedings of the National Academy of Sciences | volume = 108 | issue = 51 | pages = 20695–20700 | year = 2011 |bibcode = 2011PNAS..10820695P }}<br/> '''Related news article:''' *{{Cite news |url=http://www.bbc.co.uk/news/science-environment-16011748 |title=Vaccine developed against Ebola |date=6 December 2011 |author=Jennifer Carpenter |work=BBC News}}</ref> ===In endemic zones=== The natural maintenance hosts of ebolaviruses remain to be identified. This means that primary infection cannot necessarily be prevented in nature. The avoidance of EVD risk factors, such as contact with nonhuman [[primates]] or [[bat]]s, is highly recommended, but may not be possible for inhabitants of tropical forests or people dependent on nonhuman primates as a [[Bush meat|food source]]. ===During outbreaks=== Since ebola viruses do not spread via aerosol, the most straightforward prevention method during EVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their [[excretion]]s and [[body fluids]], or possibly [[contamination|contaminated]] materials and utensils. Patients should be isolated and medical staff should be trained and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional [[burial]] rituals, especially those requiring [[embalming]] of bodies, should be discouraged or modified, ideally with the help of local [[traditional healer]]s.<ref name="Centers for Disease Control and Prevention and World Health Organization 1998"/> <!--Ebola can be spread via aerosol. Check out the Ebola Reston case. It was found that the Ebola had spread to the monkeys in various rooms throughout the building. These animals had had NO CONTACT with each other at all. The only thing the animals had in common, was Ebola. Sorry to contradict.--> ===In the laboratory=== Ebolaviruses are [[World Health Organization]] Risk Group 4 Pathogens, requiring [[Biosafety level|Biosafety Level 4-equivalent containment]]. Laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment. ==Treatment== [[File:Ebola outbreak in Gulu Municipal Hospital.jpg|thumb|A hospital isolation ward in [[Gulu]], [[Uganda]], during the October 2000 outbreak]] There is currently no [[Food and Drug Administration|FDA]]-approved ebolavirus-specific [[therapy]] for EVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and [[electrolyte]]s to counter [[dehydration]], administration of [[anticoagulants]] early in infection to prevent or control [[disseminated intravascular coagulation]], administration of [[coagulation|procoagulants]] late in infection to control [[bleeding|hemorrhaging]], maintaining [[oxygen]] levels, [[pain management]], and administration of [[antibacterial|antibiotics]] or [[antifungal medication|antimycotics]] to treat secondary infections.<ref>{{Cite pmid|17940941}}</ref><ref>{{Cite pmid|16483416}}</ref><ref>{{Cite pmid|15460155}}</ref> [[Hyperimmune globulin|Hyperimmune equine immunoglobulin]] raised against EBOV has been used in Russia to treat a laboratory worker who accidentally infected herself with EBOV—but the patient died anyway.<ref name=Akinfeeva>{{cite journal|last1=Akinfeeva|first1=L. A.|last2=Aksyonova|first2=O. I.|last3=Vasilevich|first3=I. V.|last4=Ginko|first4=Z. I.|last5=Zarkov|first5=K. A.|last6=Zubavichene|first6=L. R.|last7=Kuzovlev|first7=O. P.|last8=Kuzubov|first8=V. I.|last9=Lokteva|first9=L. I.|last9=Ryabchikova|first9=Ye. I.|year = 2005|title = A case of Ebola hemorrhagic fever|journal = Infektsionnye Bolezni|issue = 3|pages = 85–88}}</ref> Experimentally, recombinant [[Vesicular stomatitis virus|vesicular stomatitis Indiana virus]] (VSIV) expressing the glycoprotein of EBOV or SUDV has been used successfully in nonhuman primate models as post-exposure prophylaxis.<ref>{{Cite pmid|17238284}}</ref><ref>{{Cite pmid|18385248}}</ref> Such a recombinant post-exposure vaccine was also used to treat a German researcher who accidentally pricked herself with a possibly EBOV-contaminated needle. Treatment might have been successful as she survived. However, actual EBOV infection could never be demonstrated without a doubt.<ref>{{Cite pmid|19307268}}</ref> Novel, very promising, experimental therapeutic regimens rely on [[antisense therapy|antisense technology]]. Both [[small interfering RNA]]s (siRNAs) and [[Morpholino|phosphorodiamidate morpholino oligomers]] (PMOs) targeting the EBOV genome could prevent disease in nonhuman primates.<ref>{{Cite pmid|20511019}}</ref><ref>{{Cite pmid|20729866}}</ref> ==Prognosis== Prognosis is generally poor (average [[case-fatality rate]] of all EVD outbreaks to date = 68%). If a patient survives, recovery may be prompt and complete, or protracted with [[sequela]]e, such as [[orchitis]], [[arthralgia]], [[myalgia]], [[desquamation]] or [[alopecia]]. Ocular manifestations, such as [[photophobia]], [[hyperlacrimation]], [[iritis]], [[iridocyclitis]], [[choroiditis]] and [[blindness]] have also been described. Importantly, EBOV and SUDV are known to be able to persist in the [[sperm]] of some survivors, which could give rise to secondary infections and disease via [[sexual intercourse]].<ref name=BowenLloyd1978>{{Citation |last1 = Bowen |first1 = E. T. W. |last2 = Lloyd |first2 = G. |last3 = Platt |first3 = G. |last4 = McArdell |first4 = L. B. |last5 = Webb |first5 = P. A. |last6 = Simpson |first6 = D. I. H. |year = 1978 |chapter = Vitrological Studies on a Case of Ebola Virus Infection in Man and Monkeys |editor-last=Pattyn |editor-first=S. R. |title=Ebola Virus Haemorrhagic Fever |pages=95–102 |publisher=Elsevier/North-Holland Biomedical Press |location=Amsterdam, Netherlands |isbn=0-444-80060-3 }}</ref><ref name=Kibadi1999>{{Cite pmid|9988158}}</ref><ref name=Kalongi1999>{{Cite pmid|9988159}}</ref><ref name=Rodrigues1999>{{Cite pmid|9988181}}</ref><ref name=Rowe1999>{{Cite pmid|9988162}}</ref> ==Epidemiology== {{Multiple image|direction=vertical|align=right|image1=Ecologic and Geographic Distribution of Filovirus Disease in Africa.jpg|image2=Ecologic and Geographic Distribution of Filovirus Disease in Asia and the Philippines.jpg|width=180|caption2=Distribution of Ebola and [[Marburg virus]] in Africa (note that integrated genes from filoviruses have been detected in mammals from the New World as well<ref name="Cite pmid| 20569424"/>). (A) Known points of filovirus disease. Projected distribution of ecological niche of: (B) all filoviruses, (C) ebolaviruses, (D) marburgviruses.|Distribution of ecological niche of Reston virus in southeastern Asia and the Philippines. (A) Areas of research determining whether similar ecological conditions exist. (B) Projected distribution. Insert, detailed view of [[Mindanao]], Philippines}} {{For|more about specific outbreaks and their descriptions|List of Ebola outbreaks}} Outbreaks of EVD have mainly been restricted to Africa. The virus often consumes the population. Governments and individuals quickly respond to quarantine the area while the lack of roads and transportation helps to contain the outbreak.<ref name="KnownCasesCDC"/> EVD was first described after almost simultaneous viral hemorrhagic fever outbreaks occurred in Zaire and Sudan in 1976.<ref>{{Cite pmid|307455}}</ref><ref>{{Cite pmid|307456}}</ref> EVD is believed to occur after an ebolavirus is transmitted to a human index case via contact with an infected animal [[Host (biology)|host]]. Human-to-human transmission occurs via direct contact with blood or bodily fluids from an infected person (including embalming of a deceased victim) or by contact with contaminated medical equipment such as needles. In the past, explosive [[nosocomial]] transmission has occurred in underequipped African hospitals due to the reuse of needles and/or absence of proper barrier nursing. Aerosol transmission has not been observed during natural EVD outbreaks. The potential for widespread EVD [[epidemic]]s is considered low due to the high case-fatality rate, the rapidity of demise of patients, and the often remote areas where infections occur. {| class="sortable wikitable" |+ Ebola virus disease (EVD) outbreaks |- | '''Year''' | '''Virus''' | '''Geographic location''' | '''Human cases/deaths (case-fatality rate)''' |- valign="TOP" | 1976 | SEBOV | [[Juba]], [[Maridi]], Nzara, and Tembura, [[Sudan]] | 284/151 (53%) |- valign="TOP" | 1976 | EBOV | [[Yambuku]], [[Zaire]] | 318/280 (88%) |- valign="TOP" | 1977 | EBOV | Bonduni, [[Zaire]] | 1/1 (100%) |- valign="TOP" | 1979 | SUDV | Nzara, [[Sudan]] | 34/22 (65%) |- valign="TOP" | 1988 | EBOV | [[Porton Down]], [[United Kingdom]] | 1/0 (0%) [laboratory accident] |- valign="TOP" | 1994 | TAFV | [[Taï National Park]], [[Côte d'Ivoire]] | 1/0 (0%) |- valign="TOP" | 1994–1995 | EBOV | [[Woleu-Ntem Province|Woleu-Ntem]] and [[Ogooué-Ivindo Province]]s, [[Gabon]] | 52/32 (62%) |- valign="TOP" | 1995 | EBOV | [[Kikwit]], [[Zaire]] | 317/245 (77%) |- valign="TOP" | 1996 | EBOV | Mayibout 2, [[Gabon]] | 31/21 (68%) |- valign="TOP" | 1996 | EBOV | [[Sergiyev Posad]], [[Russia]] | 1/1 (100%) [laboratory accident] |- valign="TOP" | 1996–1997 | EBOV | [[Ogooué-Ivindo Province]], [[Gabon]]; [[Cuvette-Ouest Department]], [[Republic of the Congo]] | 62/46 (74%) |- valign="TOP" | 2000–2001 | SUDV | [[Gulu District|Gulu]], [[Gulu District|Mbarara]], and [[Masindi District]]s, [[Uganda]] | 425/224 (53%) |- valign="TOP" | 2001–2002 | EBOV | [[Ogooué-Ivindo Province]], [[Gabon]]; [[Cuvette-Ouest Department]], [[Republic of the Congo]] | 124/97 (78%) |- valign="TOP" | 2002 | EBOV | [[Ogooué-Ivindo Province]], [[Gabon]]; [[Cuvette-Ouest Department]], [[Republic of the Congo]] | 11/10 (91%) |- valign="TOP" | 2002–2003 | EBOV | [[Cuvette-Ouest Department]], [[Republic of the Congo]]; [[Ogooué-Ivindo Province]], [[Gabon]] | 143/128 (90%) |- valign="TOP" | 2003–2004 | EBOV | [[Cuvette-Ouest Department]], [[Republic of the Congo]] | 35/29 (83%) |- valign="TOP" | 2004 | EBOV | [[Koltsovo, Novosibirsk Oblast|Koltsovo]], [[Russia]] | 1/1 (100%) [laboratory accident] |- valign="TOP" | 2004 | SUDV | Yambio County, [[Sudan]] | 17/7 (41%) |- valign="TOP" | 2005 | EBOV | [[Cuvette-Ouest Department]], [[Republic of the Congo]] | 11/9 (82%) |- valign="TOP" | 2007 | EBOV | [[Kasai Occidental]] Province, [[Democratic Republic of the Congo]] | 264/186 (71%) |- valign="TOP" | 2007–2008 | BDBV | [[Bundibugyo District]], [[Uganda]] | 116/39 (34%) |- valign="TOP" | 2008–2009 | EBOV | [[Kasai Occidental]] Province, [[Democratic Republic of the Congo]] | 32/15 (47%) |- valign="TOP" | 2011 | SUDV | [[Luweero District]], [[Uganda]] | 1/1 (100%) |- valign="TOP" | 2012 | SUDV | [[Kibaale District]], Western [[Uganda]] | 24/17 (71%) |- valign="TOP" | 2012 | BDBV | [[Orientale Province]], [[Democratic Republic of the Congo]] | 72/32 (44%) |} While investigating an outbreak of [[Simian hemorrhagic fever virus]] (SHFV) in November 1989, an electron microscopist from [[USAMRIID]] discovered filoviruses similar in appearance to Ebola in tissue samples taken from Crab-eating Macaque imported from the Philippines to Hazleton Laboratories Reston, Virginia.<ref name="McCormick 1999 277–279">{{harvnb|McCormick|Fisher-Hoch|1999|pp=277–279}}</ref> Blood samples were taken from 178 animal handlers during the incident.<ref name="Waterman 1999">{{Cite book|last=Waterman|first=Tara|url=http://www.stanford.edu/group/virus/filo/ebor.html|title=Ebola Reston Outbreaks|accessdate=2008-08-02|year=1999|publisher=Stanford University}}</ref> Of those, six animal handlers eventually [[seroconverted]]. When the handlers failed to become ill, the CDC concluded that the virus had a very low pathogenicity to humans.<ref name="McCormick 1999 298–299">{{harvnb|McCormick|Fisher-Hoch|1999|pp=298–299}}</ref> Because of the virus's high mortality, it is a potential agent for biological warfare.<ref>{{Cite pmid|15207310}}</ref> Given the lethal nature of Ebola, and since no approved [[vaccine]] or treatment is available, it is classified as a [[Biosafety level#Levels|biosafety level 4]] agent, as well as a [[Bioterrorism#Category A agents|Category A bioterrorism]] agent by the Centers for Disease Control and Prevention. It has the potential to be weaponized for use in [[biological warfare]].<ref>{{Cite doi|10.1001/jama.287.18.2391}}</ref> The BBC reports in a study that frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas.<ref>{{Cite book|title=Ebola 'kills over 5,000 gorillas'|url=http://news.bbc.co.uk/2/hi/science/nature/6220122.stm|accessdate=2009-05-31|date=2006-12-08|publisher=BBC}}</ref> ===Recent cases=== As of 30 August 2007, 103 people (100 adults and three children) were infected by a suspected hemorrhagic fever outbreak in the village of [[Kampungu]], Democratic Republic of the Congo. The outbreak started after the funerals of two village chiefs, and 217 people in four villages fell ill. The World Health Organization sent a team to take blood samples for analysis and confirmed that many of the cases are the result of ''Ebolavirus''.<ref>{{Cite news|title=Ebola Outbreak Confirmed in Congo|url=http://www.newscientist.com/article/dn12624-ebola-outbreak-confirmed-in-congo.html|work=NewScientist.com|date=2007-09-11|accessdate=2008-02-25}}</ref><ref>{{Cite book|title=Ebola outbreak in Congo|url=http://www.cbc.ca/health/story/2007/09/12/ebola-outbreak.html|accessdate=2009-05-31|date=2007-09-12|publisher=CDC news}}</ref> The Congo's last major Ebola epidemic killed 245 people in 1995 in [[Kikwit]], about {{convert|200|mi|km}} from the source of the August 2007 outbreak.<ref>{{Cite news|title=Mystery DR Congo fever kills 100|url=http://news.bbc.co.uk/2/hi/africa/6973013.stm|work=BBC News|date=2007-08-31|accessdate=2008-02-25}}</ref> On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District. After confirmation of samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization confirmed the presence of a new species of ''Ebolavirus'' which is now tentatively named Bundibugyo.<ref>{{Cite news|title=Uganda: Deadly Ebola Outbreak Confirmed – UN|url=http://allafrica.com/stories/200711301070.html|work=UN News Service|date=2007-11-30|accessdate=2008-02-25}}</ref> The epidemic came to an official end on 20 February 2008. While it lasted, 149 cases of this new strain were reported, and 37 of those led to deaths. An International Symposium to explore the environment and filovirus, cell system and filovirus interaction, and filovirus treatment and prevention was held at Centre Culturel Français, [[Libreville]], Gabon, during March 2008.<ref>{{Cite book|title=The IV International Symposium on Filoviruses|url=http://www.ird.fr/filomeeting2008/venue.php|accessdate=2009-0-31|publisher=l'Institut de recherche pour le développement (IRD)}}</ref> The virus appeared in southern [[Kasai Occidental]] on 27 November 2008,<ref>{{Cite book|last=World Health Organization|title=RD Congo: Fièvre hémorragique à virus Ebola au Kasaï Occidental, Rapport de situation No 1 des 26 & 27 décembre 2008|url=http://www.reliefweb.int/rw/rwb.nsf/db900sid/ASAZ-7MSCBQ?OpenDocument|accessdate=2009-06-02|date=2008-12-27|publisher=Relief Web|language=French}}</ref> and blood and stool samples were sent to laboratories in Gabon and South Africa for identification. On 25 December 2008, a mysterious disease that had killed 11 and infected 21 people in southern Democratic Republic of Congo was identified as the Ebola virus.<ref>{{Cite book|title=Ebola epidemic kills nine in central DR Congo: report|url=http://www.google.com/hostednews/afp/article/ALeqM5hGhlK2pjCd0SJVrJKYNFTAP5I6Fg|accessdate=2009-05-30|date=2008-12-25|publisher=Agence France-Presse}}</ref> Doctors Without Borders reported 11 deaths as of 29 December 2008 in the Western Kasai province of the Democratic Republic of Congo, stating that a further 24 cases were being treated. In January 2009, Angola closed down part of its border with DRC to prevent the spread of the outbreak.<ref>{{Cite book|title=Ebola alert shuts Angolan border|url=http://news.bbc.co.uk/2/hi/africa/7812868.stm|accessdate=2009-05-31|date=2009-01-06|publisher=BBC}}</ref> On 12 March 2009, an unidentified 45-year-old scientist from Germany accidentally pricked her finger with a needle used to inject Ebola into lab mice. She was given an experimental vaccine never before used on humans. Since the peak period for an outbreak during the 21-day Ebola incubation period has passed as of 2 April 2009, she has been declared healthy and safe. It remains unclear whether or not she was ever actually infected with the virus.<ref>{{Cite news|last=Eddyn|first=Melissan|title=Scientist Injects Self With Ebola|url=http://www.gouverneurtimes.com/index.php?option=com_content&view=article&id=2202:scientist-injects-self-with-ebola&catid=54:worldnational-news&Itemid=153|accessdate=2009-05-02|date=2009-03-27|publisher=Associated Press}}</ref> In May 2011, a 12-year-old girl in Uganda died from Ebola (Sudan subspecies). No further cases were recorded.<ref>{{Cite news|last=Malone|first=Barry|title=Uganda says Ebola outbreak is over|url=http://www.reuters.com/article/2011/06/17/us-uganda-ebola-idUSTRE75G24E20110617|accessdate=2011-07-06|date=2011-06-17|publisher=Reuters}}</ref> In December 2011, an unidentified woman presented at a Nairobi hospital with "Ebola-like symptoms" and subsequently died. The pathogen has yet to be identified.<ref>{{Cite news |url=http://www.capitalfm.co.ke/news/2011/12/panic-as-woman-dies-of-ebola-like-symptoms-at-knh/ |title=Panic as woman dies of Ebola-like symptoms at KNH |author=Bernard Momanyi and Catherina Karongo |date=December 22, 2011 |work=Capital FM News |location=Kenya}}</ref> ===2012 outbreaks=== In July 2012, the Ugandan Health Ministry confirmed 13 deaths due to an outbreak of the Ebola-Sudan variant<ref>http://www.afrika.no/Detailed/22121.html</ref> in the [[Kibaale]] District.<ref>{{Cite news |url=http://www.bbc.co.uk/news/world-africa-19031860 |title=Outbreak of Ebola in Uganda kills 13 |work=BBC News |date=July 28, 2012 }}</ref> As of 28 July 2012, 14 out of 20 (70% mortality rate) had died in Kibaale.<ref>http://www.msnbc.msn.com/id/48372851/ns/health/</ref> On July 30, [[Stephen Byaruhanga]], a health official in Kibaale District, said the Ebola outbreak has spread from one remote village to several villages.<ref>{{cite news|title=Ebola Outbreak Spreads|accessdate=2012-07-31|newspaper=Associated Press – The Express|date=July 31, 2012}}</ref> The [[World Health Organization]]'s global and alert response network reported on August 3 that the suspected case count had risen to 53, including 16 deaths. Of these cases, five were confirmed by [[UVRI]] as Ebola cases. There have been no confirmed cases outside of [[Kibaale]] District except for a patient who was medically evacuated to [[Kampala]] District and has since died. [[WHO]] and [[Centers for Disease Control and Prevention|CDC]] support is on the ground in Uganda supporting the government response. There have been no confirmed cases outside of [[Uganda]].<ref>http://www.who.int/csr/don/2012_08_03/en/index.html</ref> Included among the populations confirmed to be affected are prisoners in Kabbale prison. One of the inmates suspected of infection escaped from medical isolation on the same day.<ref>http://www.cnn.com/2012/08/03/health/uganda-ebola-virus/index.html</ref> Dr. Joaquim Saweka, the [[WHO]] representative to Uganda, also reported that the outbreak was then under control and that everyone known to have had contact with a known Ebola patient is now in isolation.<ref>http://www.medicaldaily.com/news/20120803/11282/un-world-health-organization-ebola-uganda.htm</ref> On 8 August 2012, the Ugandan Ministry of Health has recorded 23 probable and confirmed cases, including 16 deaths. Ten cases were confirmed by the [[UVRI|Uganda Virus Research Institute]] as Ebola. 185 people who came into contact with probable and confirmed Ebola cases are being followed up during the incubation period of 21 days.<ref>{{cite web | url=http://www.who.int/csr/don/2012_08_10/en/index.html | title = Ebola in Uganda – update | publisher = WHO | accessdate = 2012-08-10}}</ref> On 17 August 2012, the Ministry of Health of the [[Democratic Republic of the Congo]] reported an outbreak of the Ebola-Bundibugyo variant<ref>http://www.voanews.com/content/Ebola-drc-outbreak/1492233.html</ref> in the eastern region.<ref>http://www.who.int/csr/don/2012_08_18/en/index.html</ref> By August 21, the [[WHO]] reported a total of 15 cases and 10 fatalities.<ref>http://www.who.int/csr/don/2012_08_21/en/index.html</ref> There is no evidence to date that this outbreak is connected to the Ugandan outbreak.<ref>http://www.disasternews.net/news/article.php?articleid=5009</ref> By 13 September 2012, the World Health Organisation revealed that the virus had claimed 32 lives and that the probable cause of the outbreak was tainted bush-meat hunted by local villagers around the towns of [[Isiro]] and Viadana.<ref>{{Citation | url = http://www.cbsnews.com/8301-504763_162-57512216-10391704/ebola-virus-claims-31-lives-in-democratic-republic-of-the-congo/ | title = Ebola virus claims 31 lives in Democratic Republic of the Congo | year = 2012 | publisher = [[CBS News]] | publication-place = [[United States]] | accessdate = 14 September 2012 }}</ref> ==History== {{For|more about the outbreak in Virginia|Reston virus}} [[File:EbolaSubmit2.png|thumb|Cases of ebola fever in Africa from 1979–2008.]] Ebolavirus first emerged in 1976 in outbreaks of Ebola hemorrhagic fever in Zaire and Sudan.<ref>{{Cite pmid|7787519}}</ref> The strain of Ebola that broke out in Zaire has one of the highest [[case fatality rate]]s of any human pathogenic virus, roughly 90%.<ref name="emedicine.com">{{Cite web|url=http://www.emedicine.com/MED/topic626.htm|accessdate=2008-10-06|author=King, John W|title=Ebola Virus|date=April 2, 2008|work=eMedicine|publisher=WebMd}}</ref> The Philippines and the United States had no previous cases of infection, and upon further isolation it was concluded to be another strain of Ebola or a new filovirus of Asian origin, and named ''Reston ebolavirus'' (REBOV) after the location of the incident. ==In other animals== Outbreaks of EVD among human populations generally result from handling infected wild animal carcasses. Declines in animal populations generally precede outbreaks among human populations. Since 2003, such declines have been monitored through surveillance of animal populations with the aim of predicting and preventing EVD outbreaks in humans.<ref name="Cite pmid|15752448">{{Cite pmid|15752448}}</ref> Recovered carcasses from gorillas contain multiple Ebola virus strains, which suggest multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoir and animal populations.<ref name="doi10.1126/science.1092528">{{Cite doi|10.1126/science.1092528}}</ref> Outbreaks of EVD may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in 420 square kilometer Lossi Sanctuary between 2002–2003.<ref name="doi10.1126/science.1092528" /> Transmission among chimpanzees through meat consumption constitutes a significant 5.2 (1.3–21.1 with 95% [[Confidence interval|confidence]]) [[relative risk]] factor, while contact between individuals, such as touching dead bodies and grooming, do not.<ref>{{Cite pmid|9988175}}</ref> ==Recent Research== In late 2012, Canadian scientists discovered that the deadliest form of the virus could be transmitted by air between species.<ref name=BBC>{{Citation | url = http://www.bbc.co.uk/news/science-environment-20341423 | title= Growing concerns over 'in the air' transmission of Ebola | year = 2012 | publisher = [[BBC News]] | publication-place = [[United Kingdom]] | accessdate = 16 November 2012 }}</ref> They managed to prove that the virus was transmitted from pigs to monkeys without any direct contact between them, leading to fears that airborne transmission could be contributing to the wider spread of the disease in parts of Africa. Evidence was also found that could put pigs as one of the natural hosts for the virus; the fruit bat has long been considered as the natural host of the virus.<ref name=BBC /> ==References== {{Reflist|colwidth=30em}} ;Bibliography {{Refbegin}} * {{Cite book|last=Klenk|first=Hans-Dieter|title=Marburg and Ebola Viruses (Current Topics in Microbiology and Immunology)|year=1999|month=January|publisher=Springer-Verlag Telos|location=Berlin, Germany|isbn=978-3-540-64729-4|ref=CITEREFKlenk1999}} * {{Cite book|first1=Hans-Dieter|last1=Klenk|first2=Heinz|last2=Feldmann|title=Ebola and Marburg viruses: molecular and cellular biology|url=http://books.google.com/?id=EV_mFgnyPoMC&printsec=frontcover|format=Limited preview|year=2004|publisher=Horizon Bioscience|location=Wymondham, Norfolk, UK|isbn=978-0-9545232-3-7|ref=CITEREFKlenkFeldmann2004}} * {{Cite book|last=Kuhn|first=Jens H.|title=Filoviruses – A Compendium of 40 Years of Epidemiological, Clinical, and Laboratory Studies. Archives of Virology Supplement, vol. 20|url=http://books.google.com/?id=LaOue0F9Ns4C&printsec=frontcover|format=Limited preview|year=2008|publisher=SpringerWienNewYork|location=Vienna, Austria|isbn=978-3-211-20670-6|ref=CITEREFKuhn2008}} * {{Cite book|last1=McCormick|first1=Joseph|last2=Fisher-Hoch|first2=Susan|others=Horvitz, Leslie Alan|title=Level 4: Virus Hunters of the CDC|url=http://books.google.com/?id=QEvR3aJX2m0C&printsec=frontcover|format=Limited preview|origyear=1996|edition="Updated edition" 3rd|year=1999|publisher=Barnes & Noble|isbn=978-0-7607-1208-5|ref=CITEREFMcCormickFisher-Hoch1999|month=June}} * {{Cite book|last=Pattyn|first=S. R.|title=Ebola Virus Haemorrhagic Fever|year=1978|url=http://www.itg.be/ebola/|format=Full free text|edition=1st|publisher=Elsevier/North-Holland Biomedical Press|location=Amsterdam, Netherlands|isbn=0-444-80060-3|ref=CITEREFPattyn1978}} * {{Cite book|last1=Ryabchikova|first1=Elena I.|last2=Price|first2=Barbara B.|title=Ebola and Marburg Viruses – A View of Infection Using Electron Microscopy|year=2004|publisher=Battelle Press|location=Columbus, Ohio, USA |isbn=978-1-57477-131-2|ref=CITEREFRyabchikovaPrice2004}} {{Refend}} ==External links== {{Sister project links|Ebola}} {{Refbegin}} * [http://www.expasy.org/viralzone/all_by_species/207.html '''ViralZone''': Ebola-like viruses]—Virological repository from the Swiss Institute of Bioinformatics * [http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Ebola.htm '''CDC''': Ebola Hemorrhagic Fever]—Centers for Disease Control and Prevention, Special Pathogens Branch * [http://www.who.int/csr/disease/ebola/en/index.html '''WHO''': Ebola haemorrhagic fever]—World Health Organization, Global Alert and Response * [http://www.viprbrc.org/brc/home.do?decorator=filo Virus Pathogen Database and Analysis Resource (ViPR): Filoviridae] *[http://www.pdbe.org/emsearch/ebola 3D macromolecular structures of the Ebola virus archived in the EM Data Bank(EMDB)] {{Refend}} {{Zoonotic viral diseases}} [[Category:Ebola]] [[Category:Arthropod-borne viral fevers and viral haemorrhagic fevers]] [[Category:Hemorrhagic fevers]] [[Category:Mononegavirales]] [[Category:Zoonoses]] [[Category:Tropical diseases]]'