Ebola Virus Disease

Ebola virus disease

“Ebola” redirects here. For other uses, see Ebola body fluids and tissues from people with the disease (disambiguation). should be handled with special caution.[1] No specific treatment or vaccine for the virus is commer- Ebola virus disease (EVD; also Ebola hemorrhagic cially available, although a number of potential treatments fever, or EHF), or simply Ebola, is a disease of hu- are being studied. Efforts to help those who are infected mans and other primates caused by ebolaviruses. Signs are supportive; they include either oral rehydration ther- and symptoms typically start between two days and three apy (drinking slightly sweetened and salty water) or giv- weeks after contracting the virus as a fever, sore throat, ing intravenous fluids as well as treating symptoms. This muscle pain, and headaches. Then, vomiting, diarrhea supportive care improves outcomes. EVD was first iden- and rash usually follow, along with decreased function of tified in 1976 in an area of Sudan (now part of South the liver and kidneys. At this time some people begin to Sudan), and in Zaire (now the Democratic Republic of bleed both internally and externally.[1] The disease has a the Congo). The disease typically occurs in outbreaks in high risk of death, killing between 25 percent and 90 per- tropical regions of sub-Saharan Africa.[1] Through 2013, cent of those infected with the virus, averaging out at 50 the World Health Organization reported a total of 1,716 percent.[1] This is often due to low blood pressure from cases in 24 outbreaks.[1][6] The largest outbreak to date fluid loss, and typically follows six to sixteen days after is the ongoing epidemic in West Africa, which is cen- symptoms appear.[2] tered in Guinea, Sierra Leone and Liberia.[7][8][9] As of 23 November 2014, this outbreak has 15,963 reported The virus spreads by direct contact with blood or other [10][11][12] body fluids of an infected human or other animal.[1] In- cases resulting in 6,003 deaths. fection with the virus may also occur by direct contact with a recently contaminated item or surface.[1] Spread of the disease through the air between primates, includ- 1 Signs and symptoms ing humans, has not been documented in either laboratory or natural conditions.[3] The virus may be spread by semen or breast milk for several weeks to months after recovery.[1][4] Fruit bats are believed to be the normal carrier in nature, able to spread the virus without being affected by it. Humans become infected by contact with the bats or with a living or dead animal that has been infected by bats. After human infection occurs, the disease may also spread between people. Other diseases such as malaria, cholera, typhoid fever, meningitis and other viral hemorrhagic fevers may resemble EVD. Blood samples are tested for viral RNA, viral antibodies or for the virus itself to confirm the diagnosis.[1] Control of outbreaks requires coordinated medical services, along with a certain level of community engage- ment. The medical services include: rapid detection of cases of disease, contact tracing of those who have come into contact with infected individuals, quick access to laboratory services, proper care and management of those who are infected and proper disposal of the dead through [1][5] cremation or burial. Prevention includes limiting the Signs and symptoms of Ebola[13] spread of disease from infected animals to humans.[1] This may be done by handling potentially infected bush The length of time between exposure to the virus and meat only while wearing protective clothing and by thor- the development of symptoms (incubation period) is be- [1] oughly cooking it before consumption. It also includes tween 2 to 21 days.[1][13] Most often this is between 4 to wearing proper protective clothing and washing hands 10 days.[14] However, recent estimates based on mathe- [1] when around a person with the disease. Samples of matical models predict that around 5% of cases may take

1 2 2 CAUSE

greater than 21 days to develop.[15] 2.1 Transmission Symptoms usually begin with a sudden influenza-like stage characterized by feeling tired, fever, weakness, decreased appetite, muscle pain, joint pain, headache, and sore throat.[1][14][16][17] The fever is usually higher than 38.3 °C (100.9 °F).[18] This is often followed by vomiting, diarrhea and abdominal pain.[17] Next, shortness of breath and chest pain may occur, along with swelling, headaches and confusion.[17] In about half of the cases, the skin may develop a maculopapular rash (a flat red area covered with small bumps), which may be seen 5 to 7 days after symptoms begin.[14][18] In some cases, internal and external bleeding may occur.[1] This typically begins five to seven days after the first symptoms.[19] All infected people show some decreased blood clotting.[18] Bleeding from mucous Life cycles of the Ebolavirus membranes or from sites of needle punctures has been reported in 40–50 percent of cases.[20] This may result Between people, Ebola disease spreads only by direct in the vomiting of blood, coughing up of blood or blood contact with the blood or body fluids of a person who in stool.[21] Bleeding into the skin may create petechiae, has developed symptoms of the disease.[29][30][31] Body purpura, ecchymoses or hematomas (especially around fluids that may contain ebola viruses include saliva, mu- needle injection sites).[22] Bleeding into the whites of the cus, vomit, feces, sweat, tears, breast milk, urine and eyes may also occur. Heavy bleeding is uncommon, and semen.[24] The WHO states that only people who are very if it occurs, it is usually located within the gastrointestinal sick are able to spread Ebola disease in saliva, and whole tract.[18][23] virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces Recovery may begin between 7 and 14 days after the start [32] [17] and vomit. Entry points for the virus include the nose, of symptoms. Death, if it occurs, follows typically 6 to [24] 16 days from the start of symptoms and is often due to mouth, eyes, open wounds, cuts and abrasions. Ebola low blood pressure from fluid loss.[2] In general, bleeding may be spread through large droplets; however, this is believed to occur only when a person is very sick.[33] This often indicates a worse outcome, and this blood loss may [33] result in death.[16] People are often in a coma near the end can happen if a person is splashed with droplets. Con- of life.[17] Those who survive often have ongoing muscle tact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the and joint pain, liver inflammation, and decreased hear- [34][35] ing among other difficulties.[17] Additionally they develop infection. The virus is able to survive on objects for a few hours in a dried state and can survive for a few antibodies against Ebola that last at least 10 years but it is [24] unclear if they are immune to repeated infections.[24] If days within body fluids. someone survives Ebola, they can no longer transmit the The Ebola virus may be able to persist for up to 8 weeks in disease.[24] the semen of survivors after they recovered, which could lead to infections via sexual intercourse.[1] Ebola may also occur in the breast milk of women after recovery, and it [4] 2 Cause is not known when it is safe to breastfeed again. Other- wise, people who have recovered are not infectious.[34]

Main articles: Ebolavirus (taxonomic group) and Ebola The potential for widespread infections in countries with virus (specific virus) medical systems capable of observing correct medical isolation procedures is considered low.[36] Usually when someone has symptoms of the disease, they are unable to EVD in humans is caused by four of five viruses of travel without assistance.[37] the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) Dead bodies remain infectious; thus, people handling hu- and one simply called Ebola virus (EBOV, formerly Zaire man remains in practices such as traditional burial ritu- [25] als or more modern processes such as embalming are at Ebola virus). EBOV, species Zaire ebolavirus, is the [36] most dangerous of the known EVD-causing viruses, and risk. 69% of the cases of Ebola infections in Guinea is responsible for the largest number of outbreaks.[26] during the 2014 outbreak are believed to have been con- The fifth virus, Reston virus (RESTV), is not thought tracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial to cause disease in humans, but has caused disease in [38][39] other primates.[27][28] All five viruses are closely related rituals. to marburgviruses.[25] Health-care workers treating those who are infected are 2.3 Reservoir 3

at greatest risk of getting infected themselves.[34] The risk increases when these workers do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly.[34] This risk is particularly common in parts of Africa where health systems function poorly and where the disease mostly occurs.[40] Hospital-acquired transmission has also occurred in some African countries resulting from the reuse of needles.[41][42] Some health-care centers caring for people with the disease do not have running water.[43] In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures.[44] Bushmeat being prepared for cooking in Ghana. In Africa, wild animals including fruit bats are hunted for food and are referred 2.1.1 Airborne transmission to as bushmeat.[48][49] In equatorial Africa, human consumption of bushmeat has been linked to animal-to-human transmission Human to human transmission of EBOV through the air of diseases, including Ebola.[50] has not been reported to occur during EVD outbreaks[3] and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from tion, animal behavior and other factors may trigger out- [52] pigs to primates but not from primates to primates.[29][35] breaks among animal populations. Spread of EBOV by water or food, other than bush- Evidence indicates that both domestic dogs and pigs can meat, has also not been observed.[34][35] No spread by also be infected with EBOV.[53] Dogs do not appear to mosquitos or other insects has been reported.[34] develop symptoms when they carry the virus, and pigs The apparent lack of airborne transmission among hu- appear to be able to transmit the virus to at least some [53] mans is believed to be due to low levels of the virus in primates. Although some dogs in an area in which a the lungs and other parts of the respiratory system of pri- human outbreak occurred had antibodies to EBOV, it is mates, that are insufficient to cause new infections.[45] unclear whether they played a role in spreading the dis- [53] A number of studies examining airborne transmission ease to people. broadly concluded that transmission from pigs to primates could happen without direct contact, because un- like humans and primates, pigs with EVD get very high 2.3 Reservoir ebolavirus concentrations in their lungs, and not their bloodstream.[46] Therefore pigs with EVD can spread the The natural reservoir for Ebola has yet to be confirmed; disease through droplets in the air or on the ground when however, bats are considered to be the most likely candi- they sneeze or cough.[47] By contrast, humans and other date species.[35] Three types of fruit bats (Hypsignathus primates accumulate the virus throughout their body and monstrosus, Epomops franqueti and Myonycteris torquata) specifically in their blood, but not very much in their were found to possibly carry the virus without getting lungs.[47] It is believed that this is the reason researchers sick.[54] As of 2013, whether other animals are involved have observed pig to primate transmission without phys- in its spread is not known.[53] Plants, arthropods and birds ical contact, but no evidence has been found of primates have also been considered possible viral reservoirs.[1] being infected without actual contact, even in experi- Bats were known to roost in the cotton factory in which ments where infected and uninfected primates shared the the first cases of the 1976 and 1979 outbreaks were [46][47] same air. observed, and they have also been implicated in Mar- burg virus infections in 1975 and 1980.[55] Of 24 plant and 19 vertebrate species experimentally inoculated with 2.2 Initial case EBOV, only bats became infected.[56] The bats displayed no clinical signs of disease, which is considered evidence Although it is not entirely clear how Ebola initially that these bats are a reservoir species of EBOV. In a spreads from animals to humans, the spread is believed to 2002–2003 survey of 1,030 animals including 679 bats involve direct contact with an infected wild animal or fruit [34] from Gabon and the Republic of the Congo, 13 fruit bat. Besides bats, other wild animals sometimes in- bats were found to contain EBOV RNA.[57] Antibodies fected with EBOV include several monkey species, chim- [51] against Zaire and Reston viruses have been found in fruit panzees, gorillas, baboons and duikers. bats in Bangladesh, suggesting that these bats are also Animals may become infected when they eat fruit par- potential hosts of the virus and that the filoviruses are tially eaten by bats carrying the virus.[52] Fruit produc- present in Asia.[58] 4 3 PATHOPHYSIOLOGY

Between 1976 and 1998, in 30,000 mammals, birds, which are then translated into structural and nonstruc- reptiles, amphibians and arthropods sampled from re- tural proteins. The most abundant protein produced is gions of EBOV outbreaks, no Ebola virus was detected the nucleoprotein, whose concentration in the host cell apart from some genetic traces found in six rodents (be- determines when L switches from gene transcription to longing to the species Mus setulosus and Praomys) and genome replication. Replication of the viral genome re- one shrew (Sylvisorex ollula) collected from the Central sults in full-length, positive-strand antigenomes that are, African Republic.[55][59] However, further research ef- in turn, transcribed into genome copies of negative-strand forts have not confirmed rodents as a reservoir.[60] Traces virus progeny.[67] Newly synthesized structural proteins of EBOV were detected in the carcasses of gorillas and and genomes self-assemble and accumulate near the in- chimpanzees during outbreaks in 2001 and 2003, which side of the cell membrane. Virions bud off from the cell, later became the source of human infections. However, gaining their envelopes from the cellular membrane from the high rates of death in these species resulting from which they bud from. The mature progeny particles then EBOV infection make it unlikely that these species rep- infect other cells to repeat the cycle. The genetics of the resent a natural reservoir for the virus.[55] Ebola virus are difficult to study because of EBOV’s vir- ulent characteristics.[68]

2.4 Virology 3 Pathophysiology Main articles: Ebolavirus (taxonomic group) and Ebola virus (speciﬁc virus) Ebolaviruses contain single-stranded, non-infectious

Electron micrograph of an Ebola virus virion

RNA genomes.[61] Ebolavirus genomes contain seven genes including 3'-UTR-NP-VP35-VP40-GP-VP30- VP24-L-5'-UTR.[22][62] The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As all filoviruses, ebolavirions are filamentous particles that may appear in the shape of a shepherd’s crook, of a “U” or of a “6,” and they may be coiled, toroid or branched.[62][63] In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm.[64] Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins, DC-SIGN, or integrins, which is followed by fusion of the viral envelope with cellular membranes.[65] The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved.[65] This processing appears to allow the virus Pathogenesis schematic to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid.[65] Similar to other filoviridae, EBOV replicates very effi- The Ebolavirus structural glycoprotein (known as GP1,2) ciently in many cells, producing large amounts of virus is responsible for the virus’ ability to bind to and in- in monocytes, macrophages, dendritic cells and other fect targeted cells.[66] The viral RNA polymerase, en- cells including liver cells, fibroblasts, and adrenal gland coded by the L gene, partially uncoats the nucleocapsid cells.[69] Replication of the virus in monocytes triggers and transcribes the genes into positive-strand mRNAs, the release of high levels of inflammatory chemical sig- 5 nals.[70] interferon-beta, and interferon gamma.[66][72] EBOV is thought to infect humans through contact with The VP24 and VP35 structural proteins of EBOV play a mucous membranes or through skin breaks.[29] Once in- key role in this interference. When a cell is infected with fected, endothelial cells (cells lining the inside of blood EBOV, receptors located in the cell’s cytosol (such as vessels), liver cells, and several types of immune cells RIG-I and MDA5) or outside of the cytosol (such as Toll- such as macrophages, monocytes, and dendritic cells like receptor 3 (TLR3), TLR7, TLR8 and TLR9), rec- are the main targets of infection.[29] Following infec- ognize infectious molecules associated with the virus.[66] tion with the virus, the immune cells carry the virus to On TLR activation, proteins including interferon regula- nearby lymph nodes where further reproduction of the tory factor 3 and interferon regulatory factor 7 trigger a virus takes place.[29] From there, the virus can enter the signaling cascade that leads to the expression of type 1 in- bloodstream and lymphatic system and spread through- terferons.[66] The type 1 interferons are then released and out the body.[29] Macrophages are the first cells infected bind to the IFNAR1 and IFNAR2 receptors expressed on with the virus, and this infection results in programmed the surface of a neighboring cell.[66] Once interferon has cell death.[64] Other types of white blood cells, such as bound to its receptors on the neighboring cell, the signal- lymphocytes, also undergo programmed cell death leading proteins STAT1 and STAT2 are activated and move ing to an abnormally low concentration of lymphocytes in to the cell’s nucleus.[66] This triggers the expression of the blood.[29] This contributes to the weakened immune interferon-stimulated genes, which code for proteins with response seen in those infected with EBOV.[29] antiviral properties.[66] EBOV’s V24 protein blocks the Endothelial cells may be infected within 3 days after ex- production of these antiviral proteins by preventing the posure to the virus.[64] The breakdown of endothelial cells STAT1 signaling protein in the neighboring cell from en- tering the nucleus.[66] The VP35 protein directly inhibits leading to vascular injury can be attributed to EBOV [72] glycoproteins. The widespread hemorrhage that occurs in the production of interferon-beta. By inhibiting these [70] immune responses, EBOV may quickly spread through- affected people causes edema and hypovolemic shock. [64] The damage to human cells, caused by infection of the out the body. endothelial cells, decreases the integrity of blood vessels. This loss of vascular integrity increases with the synthesis of GP, which reduces the availability of specific integrins 4 Diagnosis responsible for cell adhesion to the intercellular structure and causes damage to the liver, leading to improper clot- When EVD is suspected in a person, his or her travel and ting. The dysfunction in bleeding and clotting commonly work history, along with an exposure to wildlife, are im- seen in EVD has been attributed to increased activation portant factors to consider for possible further medical of the extrinsic pathway of the coagulation cascade due examination. to excessive production of tissue factor by macrophages and monocytes.[14] 4.1 Nonspecific laboratory testing After infection, a secreted glycoprotein, small soluble glycoprotein (sGP) (or Ebola virus glycoprotein [GP]), is Possible laboratory indicators of EVD include a low synthesized. EBOV replication overwhelms protein syn- platelet count; an initially decreased white blood cell thesis of infected cells and the host immune defenses. count followed by an increased white blood cell count; The GP forms a trimeric complex, which tethers the virus elevated levels of the liver enzymes alanine aminotrans- to the endothelial cells. The sGP forms a dimeric pro- ferase (ALT) and aspartate aminotransferase (AST); and tein that interferes with the signaling of neutrophils, an- abnormalities in blood clotting often consistent with other type of white blood cell, which enables the virus disseminated intravascular coagulation (DIC) such as to evade the immune system by inhibiting early steps of a prolonged prothrombin time, partial thromboplastin neutrophil activation. The presence of viral particles and time, and bleeding time.[73] the cell damage resulting from viruses budding out of the cell causes the release of chemical signals (such as TNF- α, IL-6 and IL-8), which are molecular signals for fever 4.2 Specific laboratory testing and inflammation. The diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies 3.1 Immune system evasion against the virus in a person’s blood. Isolating the virus by cell culture, detecting the viral RNA by polymerase chain Filoviral infection also interferes with proper function- reaction (PCR)[14] and detecting proteins by enzyme- ing of the innate immune system.[67][71] EBOV proteins linked immunosorbent assay (ELISA) are methods best blunt the human immune system’s response to viral infec- used in the early stages of the disease and also for de- tions by interfering with the cells’ ability to produce and tecting the virus in human remains. Detecting antibod- respond to interferon proteins such as interferon-alpha, ies against the virus is most reliable in the later stages of 6 5 PREVENTION the disease and in those who recover.[74] IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected 6 to 18 days after symptom onset.[14] During an outbreak, isolation of the virus via cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA.[75] In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission.[76] Filovirions, such as EBOV, may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy, but this method cannot distinguish the various filoviruses.[77]

4.3 Diﬀerential diagnosis

Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever.[16] The symptoms are also similar to those of Marburg virus disease and other viral hemorrhagic fevers.[78] The complete differential diagnosis is extensive and requires consideration of many other infectious dis- VHF isolation precautions poster eases such as typhoid fever, shigellosis, rickettsial diseases, cholera, sepsis, borreliosis, EHEC enteritis, leptospirosis, scrub typhus, plague, Q fever, candidiasis, tective equipment (PPE); in addition, a designated per- histoplasmosis, trypanosomiasis, visceral leishmaniasis, [79] son, appropriately trained in biosafety, should be watch- measles and viral hepatitis among others. ing each step of these procedures to ensure they are done Non-infectious diseases that may result in symptoms correctly.[84] In Sierra Leone, the typical training period similar to those of EVD include acute promyelocytic for the use of such safety equipment lasts approximately leukemia, hemolytic uremic syndrome, snake enven- 12 days.[86] omation, clotting factor deficiencies/platelet disorders, The infected person should be in barrier-isolation from thrombotic thrombocytopenic purpura, hereditary hem- other people.[83] All equipment, medical waste, patient orrhagic telangiectasia, Kawasaki disease and warfarin [75][80][81][82] waste and surfaces that may have come into contact with poisoning. body fluids need to be disinfected.[85] During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which include protective 5 Prevention clothing as well as chlorine powder and other cleaning supplies.[87] Education of those who provide care in these Main article: Prevention of viral hemorrhagic fever techniques, and the provision of such barrier-separation supplies has been a priority of Doctors Without Bor- ders.[88] Ebolaviruses can be eliminated with heat (heating for 5.1 Infection control 30 to 60 minutes at 60 °C or boiling for 5 minutes). To disinfect surfaces, some lipid solvents such as some People who care for those infected with Ebola should alcohol-based products, detergents, sodium hypochlo- wear protective clothing including masks, gloves, gowns rite (bleach) or calcium hypochlorite (bleaching powder), and goggles.[83] The US Centers for Disease Control and other suitable disinfectants may be used at appropri- (CDC) recommend that the protective gear leaves no skin ate concentrations.[51][89] Education of the general pub- exposed.[84] These measures are also recommended for lic about the risk factors for Ebola infection and of the those who may handle objects contaminated by an in- protective measures individuals may take to prevent infected person’s body fluids.[85] In 2014, the CDC be- fection is recommended by the World Health Organiza- gan recommending that medical personnel receive train- tion.[1] These measures include avoiding direct contact ing on the proper suit-up and removal of personal pro- with infected people and regular hand washing using soap 5.2 Putting on protective equipment 7 and water.[90] 5.2 Putting on protective equipment Bushmeat, an important source of protein in the diet of • Play media some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption.[1] Some research suggests that an out- Introduction break of Ebola disease in the wild animals used for con- • sumption may result in a corresponding human outbreak. Play media Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans.[91] Trained observer

If a person with Ebola disease dies, direct contact with • Play media the body should be avoided.[83] Certain burial rituals, which may have included making various direct contacts with a dead body, require reformulation such that they Removing own clothing consistently maintain a proper protective barrier between • Play media the dead body and the living.[92][93][94] Social anthropologists may help find alternatives to traditional rules for burials.[95] Examining equipment Transportation crews are instructed to follow a certain • Play media isolation procedure should anyone exhibit symptoms re- sembling EVD.[96] As of August 2014, the WHO does Hand cleaning not consider travel bans to be useful in decreasing spread of the disease.[37] In October 2014, the CDC defined four • Play media risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities.[97] Boot covers In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are • Play media not required for the following defined risk levels:[97] Inner gloves • having been in a country with widespread Ebola dis- • ease transmission and having no known exposure Play media (low risk); or having been in that country more than 21 days ago (no risk) Coverall • • encounter with a person showing symptoms; but not Play media within 3 feet of the person with Ebola without wearing PPE; and no direct contact of body fluids N95 respirator • • having had brief skin contact with a person showing Play media symptoms of Ebola disease when the person was believed to be not very contagious (low risk) Surgical hood

• Play media • in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) Outer apron • Play media • contact with a person with Ebola disease before the person was showing symptoms (no risk). Outer gloves

The CDC recommends monitoring for the symptoms of • Play media Ebola disease for those both at “low risk” and at higher [97] risk. Face shield In laboratories where diagnostic testing is carried out, • biosafety level 4-equivalent containment is required.[98] Play media Laboratory researchers must be properly trained in BSL- 4 practices and wear proper PPE.[98] Veriﬁcation 8 7 PROGNOSIS

5.3 Isolation these medications.[109] Blood products such as packed red blood cells, platelets or fresh frozen plasma may Isolation refers to separating those who are sick from also be used.[108] Other regulators of coagulation have those who are not. Quarantine refers to separating those also been tried including heparin in an effort to pre- who may have been exposed to a disease until they ei- vent disseminated intravascular coagulation and clotting ther show signs of the disease or are no longer at risk.[99] factors to decrease bleeding.[108] Antimalarial medica- Quarantine, also known as enforced isolation, is usually tions and antibiotics are often used before the diagnosis effective in decreasing spread.[100][101] Governments of- is confirmed,[108] though there is no evidence to suggest ten quarantine areas where the disease is occurring or in- such treatment is in any way helpful. Interferon thera- dividuals who may transmit the disease outside of an ini- pies have been tried as a form of treatment for EVD, but tial area.[102] were found to be ineffective.[64] Ribavirin is also known In the United States, the law allows quarantine of those in- to be ineffective against ebolaviruses despite its effective- [103] ness against other viral hemorrhagic fevers such as Lassa fected with ebolaviruses. During the 2014 Ebola dis- [14] ease outbreak, Liberia closed schools.[104] fever. If professional care is not possible, guidelines by WHO for care at home have been relatively successful. In such 5.4 Contact tracing situations, recommendations include using towels soaked in bleach solutions when moving infected people or bod- Contact tracing is considered important to contain an ies and applying bleach on stains. It is also recommended outbreak. It involves finding everyone who had close that the caregivers wash hands with bleach solutions and contact with infected individuals and watching for signs cover their mouth and nose with a cloth.[110] of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated by tracing the con- 6.2 Intensive care tacts’ contacts.[105][106] Intensive care is often used in the developed world.[22] This may include maintaining blood volume and elec- 6 Treatment trolytes (salts) balance as well as treating any bacterial infections that may develop.[22] Dialysis may be needed for kidney failure, and extracorporeal membrane oxygena- 6.1 Standard support tion may be used for lung dysfunction.[22]

6.3 Alternative medicine

The Food and Drug Administration (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products.[111] The FDA has already sent out at least one letter of warning to a seller of colloidal silver who made unverified claims of Ebola related benefits, supposedly derived from the use of their products.[112]

7 Prognosis

A hospital isolation ward in Gulu, Uganda, during the October EVD has a high risk of death in those infected which 2000 outbreak varies between 25 percent and 90 percent of those infected.[1][113] As of September 2014, the average risk No speciﬁc treatment is currently approved.[107] How- of death among those infected is 50 percent.[1] The ever, survival is improved by early supportive care highest risk of death was 90 percent in the 2002–2003 with rehydration and symptomatic treatment.[1] Treat- Republic of the Congo outbreak.[114] ment is primarily supportive in nature.[108] These measures may include management of pain, nausea, fever Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pres- and anxiety, as well as rehydration via the oral or by [2] [108] sure from ﬂuid loss. Early supportive care to prevent intravenous route. The World Health Organization [115] recommends avoiding the use of aspirin or ibuprofen dehydration may reduce the risk of death. for pain due to the bleeding risk associated with use of If an infected person survives, recovery may be quick and 8.1 1976 9

complete. Prolonged cases are often complicated by the occurrence of long-term problems, such as inﬂammation of the testicles, joint pains, muscle pains, skin peeling, or hair loss.[14] Eye symptoms, such as light sensitiv- ity, excess tearing, iritis, iridocyclitis, choroiditis, and blindness have also been described.

8 Epidemiology

Cases of Ebola fever in Africa from 1979 to 2008 CDC worker incinerates medical waste from Ebola patients in Zaire in 1976. For more about specific outbreaks and their descriptions, see List of Ebola outbreaks. 8.1.2 Zaire outbreak The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa.[1] From 1976 (when See also: Yambuku § Ebola outbreak it was first identified) through 2013, the World Health Organization reported 1,716 confirmed cases.[1][6] The largest outbreak to date is the ongoing 2014 West Africa On 26 August 1976, a second outbreak of EVD began Ebola virus outbreak, which is affecting Guinea, Sierra in Yambuku, a small rural village in Mongala District in Leone, Liberia, Mali, and Nigeria.[8][9] As of 23 Novem- northern Zaire (now known as the Democratic Repub- ber 2014, 15,963 suspected cases and 6,003 deaths had lic of the Congo).[120][121] This outbreak was caused by been reported.[116][117] EBOV, formerly designated Zaire ebolavirus, which is a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the 8.1 1976 disease was village school headmaster Mabalo Lokela, who began displaying symptoms on 26 August 1976.[122] 8.1.1 Sudan outbreak Lokela had returned from a trip to Northern Zaire near the Central African Republic border, having visited the The first known outbreak of EVD was identified only af- Ebola River between 12 and 22 August. He was originally ter the fact, occurring between June and November 1976 believed to have malaria and was given quinine. However, in Nzara, South Sudan,[25][118] (then part of Sudan) and his symptoms continued to worsen, and he was admitted was caused by Sudan virus (SUDV). The Sudan outbreak to Yambuku Mission Hospital on 5 September. Lokela died on 8 September, 14 days after he began displaying infected 284 people and killed 151. The first identifiable [123][124][125] case in Sudan occurred on 27 June in a storekeeper in symptoms. a cotton factory in Nzara, who was hospitalized on 30 Soon after Lokela’s death, others who had been in con- June and died on 6 July.[22][119] While the WHO medical tact with him also died, and people in the village of staff involved in the Sudan outbreak were aware that they Yambuku began to panic. This led the country’s Min- were dealing with a heretofore unknown disease, the ac- ister of Health along with Zaire President Mobutu Sese tual “positive identification” process and the naming of Seko to declare the entire region, including Yambuku the virus did not occur until some months later in the and the country’s capital, Kinshasa, a quarantine zone. Democratic Republic of the Congo.[119] No one was permitted to enter or leave the area, with 10 8 EPIDEMIOLOGY

roads, waterways, and airfields placed under martial Between April and August 2007, a fever epidemic[136] in law. Schools, businesses and social organizations were a four-village region[137] of the Democratic Republic of closed.[126] Researchers from the CDC, including Peter the Congo was confirmed in September to have cases of Piot, co-discoverer of Ebola, later arrived to assess the Ebola.[138] Many people who attended the recent funeral effects of the outbreak, observing that “the whole region of a local village chief died.[137] The 2007 outbreak even- was in panic.”[127][128][129] Piot concluded that the Belgian tually affected 264 individuals and resulted in the deaths nuns had inadvertently started the epidemic by giving un- of 187.[1] necessary vitamin injections to pregnant women, without On 30 November 2007, the Uganda Ministry of Health sterilizing the syringes and needles. The outbreak lasted confirmed an outbreak of Ebola in the Bundibugyo Dis- 26 days, with the quarantine lasting 2 weeks. Among the trict in Western Uganda. After confirmation of samples reasons that researchers speculated caused the disease to tested by the United States National Reference Labora- disappear, were the precautions taken by locals, the quar- tories and the Centers for Disease Control, the World antine of the area, and discontinuing the injections.[126] Health Organization confirmed the presence of a new During this outbreak, Dr. Ngoy Mushola recorded the species of genus Ebolavirus, which was tentatively named first clinical description of EVD in Yambuku, where he Bundibugyo.[139] The WHO reported 149 cases of this wrote the following in his daily log: “The illness is char- new strain and 37 of those led to deaths.[1] acterized with a high temperature of about 39 °C (102 The WHO confirmed two small outbreaks in Uganda in °F), hematemesis, diarrhea with blood, retrosternal ab- 2012. The first outbreak affected 7 people and resulted in dominal pain, prostration with “heavy” articulations, and [130] the death of 4 and the second affected 24, resulting in the rapid evolution death after a mean of 3 days.” death of 17. The Sudan variant was responsible for both The virus responsible for the initial outbreak, first thought outbreaks.[1] to be Marburg virus, was later identified as a new type On 17 August 2012, the Ministry of Health of the of virus related to marburgviruses. Virus strain sam- Democratic Republic of the Congo reported an out- ples isolated from both outbreaks were named as the break of the Ebola-Bundibugyo variant[140] in the eastern “Ebola virus” after the Ebola River, located near the region.[141][142] Other than its discovery in 2007, this was originally identified viral outbreak site in Zaire.[22] Re- the only time that this variant has been identified as reports conflict about who initially coined the name: ei- sponsible for an outbreak. The WHO revealed that the ther Karl Johnson of the American CDC team[131] or [132] virus had sickened 57 people and claimed 29 lives. The Belgian researchers. Subsequently a number of other probable cause of the outbreak was tainted bush meat cases were reported, almost all centered on the Yambuku hunted by local villagers around the towns of Isiro and mission hospital or having close contact with another Viadana.[1][143] case.[122] 318 cases and 280 deaths (a 88 percent fatality rate) occurred in Zaire.[133] Although it was assumed that the two outbreaks were connected, scientists later re- 8.3 2013 to 2014 West African outbreak alized that they were caused by two distinct ebolaviruses, [121] SUDV and EBOV. The Zaire outbreak was contained Main article: Ebola virus epidemic in West Africa with the help of the World Health Organization and trans- In March 2014, the World Health Organization (WHO) port from the Congolese air force, by quarantining villagers, sterilizing medical equipment, and providing protective clothing.

8.2 1995 to 2012

The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo) in 1995, affecting 315 and killing 254.[1] In 2000, Uganda had an outbreak affecting 425 and killing 224; in this case the Sudan virus was found to be the Ebola species responsible for the outbreak.[1] In 2003 there was an outbreak in the Republic of the Increase over time in the cases and deaths during the 2013–2014 Congo that affected 143 and killed 128, a death rate of outbreak 90 percent, the highest death rate of a genus Ebolavirus [134] reported a major Ebola outbreak in Guinea, a western outbreak to date. African nation.[144] Researchers traced the outbreak to In 2004 a Russian scientist died from Ebola after sticking a two-year old child who died December 2013.[145][146] herself with an infected needle.[135] The disease then rapidly spread to the neighboring coun- 8.5 2014 spread outside of Africa 11 tries of Liberia and Sierra Leone. It is the largest Ebola 8.5 2014 spread outside of Africa outbreak ever documented, and the first recorded in the region.[144] Main articles: Ebola virus disease in the United States On 8 August 2014, the WHO declared the epidemic and Ebola virus disease in Spain to be an international public health emergency. Urg- ing the world to offer aid to the affected regions, the As of 15 October 2014, there have been 17 cases of Ebola Director-General said, “Countries affected to date sim- treated outside of Africa, four of whom have died.[165] ply do not have the capacity to manage an outbreak of In early October, Teresa Romero, a 44-year-old Span- this size and complexity on their own. I urge the inter- ish nurse, contracted Ebola after caring for a priest who national community to provide this support on the most had been repatriated from West Africa. This was the first urgent basis possible.”[147] By mid-August 2014, Doc- transmission of the virus to occur outside of Africa.[166] tors Without Borders reported the situation in Liberia’s On 20 October, it was announced that Teresa Romero capital Monrovia as “catastrophic” and “deteriorating had tested negative for the Ebola virus, suggesting that daily”. They reported that fears of Ebola among staff she may have recovered from Ebola infection.[167] On 19 members and patients had shut down much of the city’s September, Eric Duncan flew from his native Liberia to health system, leaving many people without treatment Texas; 5 days later he began showing symptoms and vis- for other conditions.[148] By late August 2014, the dis- ited a hospital, but was sent home. His condition wors- ease had spread to Nigeria, and one case was reported ened and he returned to the hospital on 28 September, in Senegal.[149][150] [151][152] On 30 September 2014, the where he died on 8 October.[168] Health officials con- first confirmed case of Ebola in the United States was firmed a diagnosis of Ebola on 30 September—the first diagnosed.[153] The patient died 8 days later.[154] case in the United States.[44] On 12 October, the CDC Aside from the human cost, the outbreak has severely confirmed that a nurse in Texas who had treated Dun- eroded the economies of the affected countries. A can was found to be positive for the Ebola virus, the first known case of the disease to be contracted in the Financial Times report suggested the economic impact [169] of the outbreak could kill more people than the virus United States. On 15 October, a second Texas health- itself. As of 23 September, in the three hardest hit care worker who had treated Duncan was confirmed to have the virus.[170] Both of these people have since countries, Liberia, Sierra Leone and Guinea, only 893 [171] treatment beds were available even though the current recovered. On 23 October, a doctor in New York need was 2122 beds. In a 26 September statement, the City, who returned to the United States from Guinea after working with Doctors Without Borders, tested positive WHO said, “The Ebola epidemic ravaging parts of West [172] Africa is the most severe acute public health emergency for Ebola. His case is unrelated to the Texas cases. The person has recovered and was discharged from Belle- seen in modern times. Never before in recorded his- [171] tory has a biosafety level four pathogen infected so many vue Hospital Center on November 11. people so quickly, over such a broad geographical area, for so long.”[155] The WHO reported that by 25 August more than 216 health-care workers were among the dead, 9 Society and culture partly due to the lack of equipment and long hours.[156] On 23 October, the Malian government confirmed its first 9.1 Weaponization case.[157] In response, UNMEER, in cooperation with the Logistics Cluster, air-lifted 1,050 kg of personal protec- Ebolavirus is classified as a biosafety level 4 agent, as well tive equipment (PPE) and body bags from Monrovia to [158] as a Category A bioterrorism agent by the Centers for Dis- Mali. As of 23 November 2014, 15,963 suspected [69][173] [10][11][12][117] ease Control and Prevention. It has the potential to cases and 6,003 deaths had been reported; be weaponized for use in biological warfare,[174][175] and however, the WHO has said that these numbers may be [158][159][160] was investigated by Biopreparat for such use, but might vastly underestimated. be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air.[176] Fake emails pretending to be Ebola information from the WHO or the Mexican Government have in 2014 been misused to spread computer malware.[177] 8.4 2014 DRC Congo outbreak

An outbreak in Boende District in Equatorial Province 9.2 Literature was stopped eﬀectively with ﬂexible organization and [161] Richard Preston's 1995 best-selling book, The Hot Zone, funding, as well as social mobilization led by [178] UNICEF advising action people could use.[162][163] The dramatized the Ebola outbreak in Reston, Virginia. DRC outbreak was from a local Ebola strain and not the William Close's 1995 Ebola: A Documentary Novel of one from West Africa (WHO).[164] Its First Explosion and 2002 Ebola: Through the Eyes of 12 11 RESEARCH

the People focused on individuals’ reactions to the 1976 that there were “potential implications for preventing and Ebola outbreak in Zaire.[179] controlling human outbreaks.” Tom Clancy's 1996 novel, Executive Orders, involves a Middle Eastern terrorist attack on the United States using 10.3 Reston virus an airborne form of a deadly Ebola virus strain named [180] “Ebola Mayinga” (see Mayinga N'Seka). For more about the outbreak in Virginia, US, see Reston As the Ebola virus epidemic in West Africa developed virus. in 2014, a number of popular self-published and well- reviewed books containing sensational and misleading in- In late 1989, Hazelton Research Products’ Reston Quar- formation about the disease appeared in electronic and antine Unit in Reston, Virginia, suffered an outbreak of printed formats. The authors of some such books ad- fatal illness amongst certain lab monkeys. This lab out- mitted that they lacked medical credentials and were not break was initially diagnosed as simian hemorrhagic fever technically qualified to give medical advice. The World virus (SHFV), and occurred amongst a shipment of crab- Health Organization and the United Nations stated that eating macaque monkeys imported from the Philippines. such misinformation had contributed to the spread of the [181] Hazelton’s veterinary pathologist sent tissue samples from disease. dead animals to the United States Army Medical Re- search Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland, where an ELISA test indicated 10 Other animals the antibodies present in the tissue were a response to Ebola virus and not SHFV.[187] An electron microscopist 10.1 Wild animals from USAMRIID discovered filoviruses similar in ap- pearance to Ebola in the tissue samples sent from Hazel- ton Research Products’ Reston Quarantine Unit.[188] Ebola has a high mortality among primates.[107] Frequent outbreaks of Ebola may have resulted in the deaths of A US Army team headquartered at USAMRIID 5,000 gorillas.[182] Outbreaks of Ebola may have been re- euthanized the surviving monkeys, and brought all sponsible for an 88 percent decline in tracking indices of the monkeys to Ft. Detrick for study by the Army’s observed chimpanzee populations in 420 square kilome- veterinary pathologists and virologists, and eventual ter Lossi Sanctuary between 2002 and 2003.[183] Trans- disposal under safe conditions.[187] Blood samples were mission among chimpanzees through meat consumption taken from 178 animal handlers during the incident.[189] constitutes a significant risk factor, whereas contact be- Of those, six animal handlers eventually seroconverted, tween the animals, such as touching dead bodies and including one who had cut himself with a bloody grooming, is not.[184] scalpel.[70][190] Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the Recovered carcasses from gorillas contain multiple Ebola handlers did not become ill, the CDC concluded that the virus strains, which suggest multiple introductions of virus had a very low pathogenicity to humans.[190][191] the virus. Bodies decompose quickly and carcasses are not infectious after 3 to 4 days. Contact between The Philippines and the United States had no previous gorilla groups is rare, suggesting transmission among cases of Ebola infection, and upon further isolation, re- gorilla groups is unlikely, and that outbreaks result searchers concluded it was another strain of Ebola, or a from transmission between viral reservoir and animal new filovirus of Asian origin, which they named Reston populations.[183] ebolavirus (RESTV) after the location of the incident.[187] Reston virus (RESTV) can be transmitted to pigs.[53] Since the initial outbreak it has since been found in non- 10.2 Domestic animals human primates in Pennsylvania, Texas, and Italy,[192] where the virus had infected pigs.[193] According to In 2012 it was demonstrated that the virus can travel with- the WHO, routine cleaning and disinfection of pig (or out contact from pigs to nonhuman primates, although the monkey) farms with sodium hypochlorite or detergents same study failed to achieve transmission in that manner should be effective in inactivating the Reston ebolavirus. between primates.[53][185] Pigs that have been infected with RESTV tend to show symptoms of the disease. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs 11 Research during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to A number of experimental treatments are being an outbreak showed a seroprevalence for EBOV versus 9 studied.[194] In the United States, the Food and Drug Ad- percent of those farther away.[186] The authors concluded ministration (FDA)'s animal efficacy rule is being used 11.1 Medications 13 to demonstrate reasonable safety to obtain permission to cessfully to treat 13 out of 15 Ebola-infected pa- treat people who are infected with Ebola. It is being used tients by a doctor in Liberia, as part of a com- because the normal path for testing drugs is not possible bination therapy also involving intravenous fluids for diseases caused by dangerous pathogens or toxins. and antibiotics to combat opportunistic bacterial in- Experimental drugs are made available for use with the fection of Ebola-compromised internal organs.[204] approval of regulatory agencies under named patient Western virologists have however expressed caution programs, known in the US as “expanded access”.[195] about the results, due to the small number of pa- On 12 August 2014 the WHO released a statement that tients treated and confounding factors present. Re- the use of not yet proven treatments is ethical in certain searchers at the NIH stated that lamivudine had situations in an effort to treat or prevent the disease.[196] so far failed to demonstrate anti-Ebola activity in preliminary in vitro tests, but that they would con- tinue to test it under different conditions and would 11.1 Medications progress it to trials if even slight evidence for efficacy is found.[205]

• JK-05 is developed by the Chinese company Sihuan Pharmaceutical along with the Chinese Academy of Military Medical Sciences. It is reportedly being fast tracked through human trials for Ebola treatment after successful tests in mice.[206][207]

• Lack of available treatment options has spurred research into a number of other possible antivirals targeted against Ebola,[208][209] including natural products such as scytovirin and griﬃthsin,[210][211] as well as synthetic drugs including DZNep,[212] FGI-103, FGI-104, FGI-106, dUY11 and LJ-001,[213] and [214][215][216][217][218][219][220] Researchers looking at slides of cultures of cells that make mon- other newer agents. oclonal antibodies. These are grown in a lab and the researchers are analyzing the products to select the most promising. 11.1.2 Antisense technology

Other promising treatments rely on antisense technol- 11.1.1 Antivirals ogy. Both small interfering RNAs (siRNAs) and phosphorodiamidate morpholino oligomers (PMOs) tar- A number of antiviral medications are being studied. geting EBOV RNA polymerase L protein may prevent disease in nonhuman primates.[221][222] TKM-Ebola is a • Favipiravir, approved in Japan for stockpiling small interfering RNA compound, currently being tested against influenza pandemics, appears to be useful in in a Phase I clinical trial in humans.[223][224] Sarepta Ther- [16][197] a mouse model of Ebola. On 4 October 2014, apeutics has completed a Phase I clinical trial with its it was reported that a French nun who contracted PMO protecting up to 80-100 percent of the nonhuman Ebola while volunteering in Liberia was cured with primates tested.[225] Favipiravir treatment.[198] • BCX4430 is a broad-spectrum small molecule an- 11.1.3 Antibodies tiviral drug developed by BioCryst Pharmaceuticals and undergoing animal testing as a potential human [199] ZMapp is a monoclonal antibody vaccine. The limited treatment for Ebola by USAMRIID. The drug supply of the drug has been used to treat a small num- has been approved to progress to Phase 1 trials, ex- [200] ber of individuals infected with the Ebola virus. Al- pected late in 2014. though some individuals have recovered, the outcome [226] • Brincidofovir is a broad-spectrum antiviral drug. Its is not considered statistically significant. ZMapp has maker has been granted FDA approval to proceed proved effective in a trial involving rhesus macaque [223][227][228] with a trial to test its safety and efficacy in Ebola monkeys. The Bill & Melinda Gates Foun- patients.[201] It has been used to treat the first pa- dation has donated $150,000 to help Amgen increase tient diagnosed with Ebola in the USA, after he had its production, and the U.S. Department of Health and recently returned from Liberia.[202][203] Human Services has asked a number of centers to also increase production.[229] There was no confirmation or • Lamivudine, usually used to treat HIV/AIDS, was proof that the ZMapp drug was a factor in the recov- reported in September 2014 to have been used suc- ery of two American Ebola patients, however;[230] a 14 13 REFERENCES

Spanish priest with Ebola had taken ZMapp but died 11.3 Vaccine afterward.[231] Main article: Ebola vaccine Researchers in Thailand claim to have developed an antibody-based treatment for Ebola using synthesized fragments of the virus. It has not been tested against Many Ebola vaccine candidates had been developed Ebola itself. Scientists from the WHO and NIH have of- in the decade prior to 2014,[241] but as of October fered to test the treatment against live Ebola virus, but 2014, none had yet been approved by the United States there is still a great deal of development needed before Food and Drug Administration (FDA) for clinical use human trials.[232] in humans.[237][242][243] Several promising vaccine candidates have been shown to protect nonhuman primates (usually macaques) against lethal infection.[25][244] These include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and 11.1.4 Other human parainfluenza (HPIV-3) vectors, and virus-like particle preparations. Conventional trials to study effi- Two selective estrogen receptor modulators usually used cacy by exposure of humans to the pathogen after immu- to treat infertility and breast cancer (clomiphene and nization are obviously not feasible in this case. For such toremifene) have been found to inhibit the progress of situations, the FDA has established the “animal rule” al- Ebola virus in vitro as well as in infected mice. Ninety lowing licensure to be approved on the basis of animal percent of the mice treated with clomiphene and 50 model studies that replicate human disease, combined percent of those treated with toremifene survived the with evidence of safety and a potentially potent immune [233] tests. The study authors conclude that given their oral response (antibodies in the blood) from humans given the availability and history of human use, these drugs would vaccine. Phase I clinical trials involve the administration be candidates for treating Ebola virus infection in remote of the vaccine to healthy human subjects to evaluate the geographical locations, either on their own or together immune response, identify any side effects and determine with other antiviral drugs. the appropriate dosage. A 2014 study found that three ion channel blockers used in the treatment of heart arrhythmias, amiodarone, dronedarone and verapamil, block the entry of Ebola 12 See also virus into cells in vitro.[234] • List of human disease case fatality rates

11.2 Blood products 13 References

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15.1 Text

• Ebola virus disease Source: http://en.wikipedia.org/wiki/Ebola%20virus%20disease?oldid=635886368 Contributors: AxelBoldt, Magnus Manske, LC, Mav, The Anome, Higbvuyb, Andre Engels, Eclecticology, Josh Grosse, Danny, William Avery, SimonP, Azhyd, Rsabbatini, Mintguy, Olivier, Edward, Michael Hardy, Kwertii, Liftarn, Ixfd64, Delirium, Minesweeper, Ams80, Ahoerstemeier, William M. 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VandalBot, Yonatan, Luna Santin, Widefox, Seaphoto, Jraytram, Fru1tbat, Tsu Dho Nimh, Quintote, CPMartin, Quixote9, Vanjagenije, Farosdaughter, Malcolm, Spencer, Yellowdesk, Nancy Vandal, Fireice, Elaragirl, Res2216firestar, Sluzzelin, JAnDbot, Dogru144, Hu- sond, Barek, MER-C, Sperber, Giler, Wizardboy777, Andonic, Kirrages, Rothorpe, Alastair Haines, LittleOldMe, ThePrznKonection, Acroterion, DIETER, Wildhartlivie, FaerieInGrey, Magioladitis, A12n, WolfmanSF, Secret Squïrrel, ParadiseMissouri, Freedomlinux, ZPM, Bongwarrior, VoABot II, Hb2019, Dekimasu, Nyq, Wikidudeman, JNW, Zatham, Trentono, Ed!, Nyttend, Kevinmon, Prestonmc- conkie, Brusegadi, Day and Nite, Sub40Hz, Catgut, Cgingold, BatteryIncluded, Torchiest, Adrian J. Hunter, 28421u2232nfenfcenc, Mkdw, Allstarecho, Tins128, Cpl Syx, Sabedon, Glen, DerHexer, Valerius Tygart, Sanjay12, Djsquintz, Oren0, Read-write-services, Hdt83, Mar- tinBot, STBot, Gandydancer, Scheuerm, NReitzel, Juansidious, Milov, Glrx, Kingofrock, Fastman99, Mschel, R'n'B, AlexiusHoratius, Nono64, Lilac Soul, RockMFR, AlphaEta, Cold534, J.delanoy, Captain panda, Pharaoh of the Wizards, Lithui, CFCF, AAA!, Bogey97, Nbauman, Boghog, Uncle Dick, Xris0, Colincbn, Ginsengbomb, Dr.Ballsack Phd, WarthogDemon, Milo03, Acalamari, Mathglot, Kata- laveno, Cannonmc, Buhadram, Ghidorah221, McSly, Xizes, Chicken666, Trumpet marietta 45750, Mikael Häggström, AntiSpamBot, Muffinman100010, (jarbarf), 97198, Floaterfluss, M-le-mot-dit, Veganaxos, Bobianite, EconomistBR, 83d40m, Mcintosh3102, Heero Ki- rashami, Kingcampo, Wa3pxx, Thioxane, KylieTastic, Cometstyles, STBotD, Bioform 1234, EarthRise33, Tototo7, Jaimeastorga2000, 15.1 Text 25

Inter16, Mikeeeman, Ja 62, Martial75, MikeLeeds, Spellcast, Azuriteking, PetsTheCatfish, My Core Competency is Competency, Jru- gordon, Deor, Puffmush, Shiggity, Cireshoe, CWii, DrMicro, Jeff G., Jennavecia, JohnBlackburne, Moman5, Orthologist, Rubyuser, Naysie, Soliloquial, Prelate Zeratul, Sodapopkid, CART fan, Barneca, QuackGuru, Philip Trueman, HiraV, Oshwah, Crevox, Mxtbcca, Dwaynebailey, Malljaja, Nikolaivich, Z.E.R.O., Anonymous Dissident, Aymatth2, Qxz, Imasleepviking, Clarince63, Leafyplant, Don4of4, Millebe, LeaveSleaves, ^demonBot2, Raymondwinn, PDFbot, Optigan13, Sovietpride, Luuva, Maxim, Saturn star, Quindraco, Kaiketsu, Bogus987654321, Dmickan, Petero9, Lebron15594, Hedington, Itsmeiam, Rituido, Insanity Incarnate, Otterthay, Mr. Sandy, Doc James, Billytrousers, Steven Weston, SylviaStanley, Karthik Sarma, Unused000702, Pvanheus, Gaelen S., BP-baller, BPP-baller, Lionfan1991, SieBot, Sonicology, Milnivri, Favouritesky, Jturner3, Graham Beards, Hertz1888, VVVBot, Da Joe, Dawn Bard, Ybidiotic, RJaguar3, Wienandwienand, M.thoriyan, LeadSongDog, GlassCobra, Francish7, Keilana, Flyer22, Tiptoety, Captain Yankee, Oda Mari, Grimey109, Taejin, Hiddenfromview, Stylesjx, Madam Sillyface, Mimihitam, Lanzarotemaps, Oxymoron83, Antonio Lopez, Faradayplank, Nuttyco- conut, Bagatelle, Thirdeyeopen33, Lightmouse, Techman224, Johndheathcote, PbBot, Afernand74, Pediainsight, Adragon111, Cheese- fondue, Crazycasta, Dabomb87, Nn123645, Dolphin51, Hordaland, Denisarona, Pgokey, Vanyo, Jamesdreherjr, TheCatalyst31, Zurp- pies, ClueBot, CiudadanoGlobal, Foxj, Colorado Dave, The Thing That Should Not Be, Sematimba, Jan1nad, Nnemo, Ohcrapitsdevvii, R000t, Chessy999, Arakunem, O Goncho88, Ezzex, Mild Bill Hiccup, WDM27, DigitalNinja, CounterVandalismBot, Robertpedley, Wa- terpolo379, Blanchardb, Dylan620, Fattman123, Auntof6, Lyonspen, Boneyard90, Loadbang, LeoFrank, Tomtomlily, Mkativerata, Ex- cirial, HetmanSydor, Jusdafax, Nathan Laing, Eeekster, Leonard^Bloom, Lartoven, Ykhwong, Sun Creator, NuclearWarfare, Aurora2698, Gralgrathor, Psinu, Bcrossiter, Falco11 2011, Iohannes Animosus, Bidimensional, Indians99, CowboySpartan, Morel, Razorflame, Gciri- ani, Dekisugi, MedicRoo, Ottawa4ever, Kakofonous, Light show, Thingg, Aitias, Tuberculosishivaids, Jdiplacidi, Versus22, Rabid bee, IJA, Tezero, SoxBot III, Wnt, Vanished User 1004, DumZiBoT, XLinkBot, ViperNerd, Spitfire, Jytdog, Licourtrix, ChyranandChloe, Stickee, Marco369, Rror, Corker1, Ericloewe, Revancher, WikiDao, Jinxed4ever, Ikihi123, Jpboia, Dsulkar, Jinnatun, Yameogo, Addbot, Proof- reader77, Jianrong95, Some jerk on the Internet, Imeriki al-Shimoni, Causecausecause, DOI bot, Blechnic, AliasMe, Ocdnctx, Wda, Elisha- bet, Ronhjones, Hockeyspeed, Hondamx267, MartinezMD, Dela01241, Szico VII, CanadianLinuxUser, Fluffernutter, Mentisock, Chamal N, CarsracBot, Awanta, Glane23, Lihaas, Stuttermullet1, AnnaFrance, Keepcalmandcarryon, Danman999, Pantherfreak12, 5 albert square, -Ettrig, Maya ,55דוד ,Megamike345, Ehend661, 84user, JennieMacGuire, Matthias of redwall, Tide rolls, Lightbot, OlEnglish, Pietrow mussa, LuK3, Ben Ben, Legobot, Luckas-bot, Vedran12, Yobot, GRLant1, 2D, Kartano, Mcdennis13, Tohd8BohaithuGh1, Tmwerty, Legobot II, Welshdragon0586, II MusLiM HyBRiD II, Jason Recliner, Esq., Yngvadottir, Andreiwest, ArchonMagnus, THEN WHO WAS PHONE?, Coachuponnow, RotogenRay, Telekineticturtle, R500Mom, Tempodivalse, Anonymous from the 21th century, Bbarney, Diver- Dave, AnomieBOT, LordShonus, KDS4444, Popezilla, Archon 2488, SwiftlyTilt, Williamsu95, IsabelleHubert, Jim1138, IRP, Dwayne, Neptune5000, Blokeice, Biosafety 4 Exert, Kingpin13, Tommoxyz, Materialscientist, The High Fin Sperm Whale, Citation bot, Rick- -Char ,יונה בנדלאק ,james20000, Futur3g4ry, GB fan, Quebec99, LilHelpa, Najarro, Sluchy523, Bryantwilson91, Obersachsebot, Zad68 acter.assassin, The sock that should not be, Capricorn42, Gigemag76, Renaissancee, Ktwalker01, Locos epraix, Kalieroxs567, RadManCF, NOrbeck, DrShane, Laurel.jensen, Gatorgirl7563, Anonymous from the 21st century, Ruy Pugliesi, A dullard, INick3, Omnipaedista, Frankie0607, Queen Rhana, Doulos Christos, Taylornate, Moxy, GNRY09, Shortelz, Miyagawa, Nciszdabest, SchnitzelMannGreek, Mishka.medvezhonok, SD5, Snurg, Spongefrog, FrescoBot, Surv1v4l1st, Tobby72, Charlie1volley, Mu Mind, StaticVision, RoyGoldsmith, Alxeedo, Saxifrage853, Bullgarbage, Goldentolken, BenzolBot, CanadianNine, Citation bot 2, Raikirisenpai, Cannolis, Citation bot 1, Cita- tion bot 4, Pizik, Amplitude101, DrilBot, DKMell, RubiksMaster110, Cubs197, JKDw, Pinethicket, Abductive, Ericbourland, Jonesey95, Lolaxoxo, Geogene, Dhomya, Jschnur, Francescad, VenomousConcept, Salvidrim!, Shanmugamp7, SW3 5DL, Ce-boHemFe, Salsaman22, Kgrad, Andrewmwolfe, Ryckpage, Nickpost05, Evert:Meulie, Dinamik-bot, Sangjinhwa, Vrenator, Zvn, Mannaro85, Clarkcj12, MrX, Mt- mulch, Raidon Kane, Ink Falls, Reaper Eternal, Kitfoxxe, Weedwhacker128, Colton.eastman, Reach Out to the Truth, RobertMfromLI, DARTH SIDIOUS 2, Sojoho09, Lozion, RjwilmsiBot, 7mike5000, Protenpinner, Thedues, Agent Smith (The Matrix), Power t, Shaktal, DASHBot, Karin127, Helwr, Mukogodo, EmausBot, Bobjoejrthethird, Francophile124, Insorak, Echokilocharlie, Heracles31, Kather- ine, Dewritech, Racerx11, Tinss, RA0808, JohnValeron, Borovi4ok, NotAnonymous0, Willjones98, Slightsmile, Wikipelli, K6ka, Lucas Thoms, CrimsonBlue (Rollback), Mz7, Ronk01, John Cline, Bongoramsey, Ncboy2010, Jonpatterns, Ὁ οἶστρος, Redav, Medeis, Iseecow- boys, Marcofontes, Manwhatsup, Ewa5050, G-FINN22, Wingman4l7, Sbmeirow, Scotware, Brandmeister, Lorem Ip, Danmuz, Donner60, DeCausa, Fanyavizuri, CSMasick, Waugh Bacon, Olivia Francois, Guitarguy949, Hubertus.j, Bpickett, Llightex, Sven Manguard, DASH- BotAV, Spicemix, FeatherPluma, Sp4cetiger, Teaktl17, GoGeo, Mixer98, ClueBot NG, Gareth Griffith-Jones, Jack Greenmaven, Torsten- Mandal, This lousy T-shirt, 4Jmaster, Pizza1016, Clarkdn, Viveleroux, Wimpus, Armouredduck, Snotbot, Delusion23, O.Koslowski, Saint- fevrier, Hwiseley, Widr, Warm Worm, FiesTyPanDA, Pbmaise, GuyHimGuy, Pragmaticstatistic, Helpful Pixie Bot, WEWEE, Jamie Tubers, Tholme, Tarikupu, Wbm1058, Bibcode Bot, Jamesthecat, BG19bot, Rodakarth, GruntUltra567, EvilResident, Kimchi1333, Mr- johncummings, Kaltenmeyer, Wzrd1, Patrug, CatPath, Huhshyeh, Kendall-K1, Badon, Mark Arsten, Moocow119, Bigdogbigdog52, Float- ing Boat, Jeancey, Swampdonkeyxx, Sodaant, The Almightey Drill, Smbrizendine, Sparkie82, MrBill3, AnselaJonla, Sdesalas, Zedshort, Joshua4157, Zorecchi, Duxwing, Kalkeeli, Barrett at central college, Daviscentralcollege, Void900, BattyBot, Factsearch, Biosthmors, Metsfreak2121, Tutelary, Happy1892, Pete.clat, W.D., The Illusive Man, Ravikantc, Vincent Le Ho, Sermadison, Foxtrot620, Layzeeboi, Tietomanni, Khazar2, TylerDurden8823, Siuenti, Thecudder15, IjonTichyIjonTichy, Thundermoose18, Dexbot, , Cheeseface101, Wolfblade0, Webclient101, Mogism, OscarK878, Inayity, Ptrw08, Cornelius90, Lugia2453, Vanished user fijerij2o2, Frosty, Electronsare- green, Tiffanyshi, Jmoney90, Wywin, ZX95, Coachlover1000, Epicgenius, Rwhite2366, Pdecalculus, Lokmac, Biomedicinal, American In Brazil, Jmisasi, Jodosma, VoiceOfTheCommons, Everymorning, War&passion, Jake stranzl, Randomer679, EvergreenFir, Nodove, Froglich, Nijoakim, Kintamanimatt, Adiecoly, Prokaryotes, YiFeiBot, GvacWP, 3AlarmLampscooter, Wolfscopez, Tshuva, Kind Tennis Fan, Glenburne, Anrnusna, Vigo1100, Jeremyb-phone, Jonnywidefoot, Lexanglopaddy, Impsswoon, AH999, Drkvncnt, Drsoumyadeepb, Biggem001, Craigrottman, Slenderdan, Lagoset, Monkbot, LeoLi1234, Kingrain1, Ddluv09, Vieque, AntiqueReader, NewEnglandDr, Ydanay, Coffeedrinker115, TheQ Editor, BernieGordon, Dwade64, Amw2017, Lgkkitkat, Qwertyxp2000, Nowzer, Georsche, Badnaam, Elchap, Biblioworm, 59Ballons, Plantduets, Itztony, Kirby777, Anguskhan01, Trololololololol321, Amortias, Wontsilence, NQ, Signedzzz, ClaudioUEC, Wikicology, Malerisch, Joneys Joes, Artsipan, Lemos the Mad scientist, MissKatie89, Wikipedian 2, Homomnius, Ryubyss, Emily1015, Pigi5, Davidjconnolly, Dragonmagicediter, ExoSuho, Bhavinderrao9, Omodeletobi, 93notes, Eftonia, Harrismark, Doc Ayo- mide, Ebola guy, Wrsa, Chizzy92, Inemudom, Chibike94, RealPyro, Fakecolepoland, Crlaozwyn, Dylang010, 2manyJimmiesRustled, Bri- anGroen, EoRdE6, FriarTuck1981, Starstr, Xqxf, Wikipedianorthernireland, Kieran P. Clark, Bkcunningham, Yellow Dingo, 21 bruh, As- racing120, Jsoik, Iwalrusfriend, Theebola, Daqueenonmypeen, Pizzaguy232roundhouse, Clinton227, EpicistLamaEver, Jamesrowland008 and Anonymous: 1959 26 15 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

15.2 Images

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15.3 Content license

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