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Ebola virus disease
"Ebola" redirects here. For other uses, see Ebola (disambiguation).
Ebola virus disease
Classification and external resources

A 1976 photograph of two nurses standing in front of Mayinga N., a person with Ebola virus disease; she died only a few days later due to severe internal hemorrhaging.
ICD-10 A98.4
ICD-9 065.8
DiseasesDB 18043
MedlinePlus 001339
eMedicine med/626
MeSH D019142
Ebola virus disease (EVD), Ebola hemorrhagic fever (EHF) or simply Ebola is a disease of humans and other mammals caused by an ebolavirus. Symptoms start two days to three weeks after contracting the virus, with a fever, sore throat, muscle pain and headaches. Typically, vomiting, diarrhea and rash follow, along with decreased function of the liver and kidneys. Around this time, affected people may begin to bleed both within the body and externally.[1]

The virus may be acquired upon contact with blood or other bodily fluids of an infected human or other animal.[1] Spreading through the air has not been documented in the natural environment.[2] Fruit bats are believed to be the normal carrier in nature, able to spread the virus without being affected. Humans become infected by contact with the bats or living or dead animals that have been infected by bats. Once human infection occurs, the disease may spread between people as well. Male survivors may be able to transmit the disease via semen for nearly two months. To diagnose EVD, other diseases with similar symptoms such as malaria, cholera and other viral hemorrhagic fevers are first excluded. Blood samples are tested for viral antibodies, viral RNA, or the virus itself to confirm the diagnosis.[1]

Outbreak control requires a coordinated series of medical services, along with a certain level of community engagement. The necessary medical services required include rapid detection and contact tracing, quick access to appropriate laboratory services, proper management of those who are infected, and proper disposal of the dead through cremation or burial.[1][3] Prevention includes decreasing the spread of disease from infected animals to humans.[1] This may be done by only handling potentially infected bush meat while wearing proper protective clothing and by thoroughly cooking it before consumption.[1] It also includes wearing proper protective clothing and washing hands when around a person with the disease.[1] Samples of bodily fluids and tissues from people with the disease should be handled with special caution.[1]

No specific treatment for the disease is yet available.[1] Efforts to help those who are infected are supportive and include giving either oral rehydration therapy (slightly sweet and salty water to drink) or intravenous fluids.[1] This supportive care improves outcomes.[1] The disease has a high risk of death, killing between 25% and 90% of those infected with the virus (average is 50%).[1] EVD was first identified in an area of Sudan that is now part of South Sudan, as well as in Zaire (now the Democratic Republic of the Congo). The disease typically occurs in outbreaks in tropical regions of sub-Saharan Africa.[1] From 1976 (when it was first identified) through 2013, the World Health Organization reported a total of 1,716 cases.[1][4] The largest outbreak to date is the ongoing 2014 West African Ebola outbreak, which is currently affecting Guinea, Sierra Leone, Liberia, and Nigeria.[5][6] As of 10 October 2014, 8,376 suspected cases resulting in the deaths of 4,024 have been reported.[7] Efforts are under way to develop a vaccine; however, none yet exists.[1]

Signs and symptoms


Signs and symptoms of Ebola.[8]
Signs and symptoms of Ebola virus disease (EVD) usually begin suddenly with an influenza-like stage characterized by fatigue, fever, headaches, and pain in the joints, muscles, and abdomen.[9][10] Vomiting, diarrhea, and loss of appetite are also common.[10] Less common symptoms include the following: sore throat, chest pain, hiccups, shortness of breath, and trouble swallowing.[10] The average time between contracting the infection and the start of symptoms (incubation period) is 8 to 10 days, but it can vary between 2 and 21 days.[10][11] In about 5-50% of cases, skin manifestations may include a maculopapular rash (a flat, area on the skin that can be red in white skinned people covered with small joined bumps).[12] [13]Early symptoms of EVD may be similar to those of malaria, dengue fever, or other tropical fevers, before the disease progresses to the bleeding phase.[9]

In 40–50% of cases, bleeding from puncture sites and mucous membranes (e.g., gastrointestinal tract, nose, vagina, and gums) has been reported.[14] In the bleeding phase, which typically begins five to seven days after first symptoms,[15] internal and subcutaneous bleeding may present itself in the form of reddened eyes and bloody vomit.[9] Bleeding into the skin may create petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites).[16] Sufferers may cough up blood, vomit it, or excrete it in their stool.[17][18]

Heavy bleeding is rare and is usually confined to the gastrointestinal tract.[12][19] In general, the development of bleeding symptoms often indicates a worse prognosis and this blood loss can result in death.[9] All people infected show some signs of circulatory system involvement, including impaired blood clotting.[12] If the infected person does not recover, death due to multiple organ dysfunction syndrome occurs within 7 to 16 days (usually between days 8 and 9) after first symptoms.[15]

Cause

Main articles: Ebolavirus (taxonomic group) and Ebola virus (specific virus)
Ebola virus is caused by four of five viruses classified in the genus Ebolavirus, family Filoviridae, order Mononegavirales. The four disease-causing viruses are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV), and one called, simply, Ebola virus (EBOV, formerly Zaire Ebola virus).[18] Ebola virus is the only member of the Zaire ebolavirus species and the most dangerous of the known EVD-causing viruses, as well as being responsible for the largest number of outbreaks.[20] The fifth virus, Reston virus (RESTV), is not thought to be disease-causing in humans.[18] These five viruses are closely related to marburgviruses.[18]

Transmission

Life cycles of the Ebolavirus
Human-to-human transmission occurs only via direct contact with blood or body fluid from an infected person (including embalming of an infected dead body), or by contact with objects contaminated by the virus, particularly needles and syringes.[21][22] Other body fluids that may transmit ebolaviruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine, and semen. Entry points include the nose, mouth, eyes, or open wounds, cuts and abrasions.[23] Transmission from other animals to humans occurs only via contact with, or consumption of, an infected mammal, such as a fruit bat, or ape. The potential for widespread EVD infections in countries with medical systems capable of observing the correct medical isolation procedures where needed is considered low as the disease is only spread by direct contact with the secretions from someone who is showing signs of infection.[22]

The symptoms limit a person's ability to spread the disease as they are often too sick to travel during the infectious stages of the progression of the disease. As transmission via air is generally ruled out, the possibility of transmission between non-seat-mate airline passengers is also generally ruled out.[24] Because dead bodies are still infectious, traditional burial rituals may spread the disease. Nearly two thirds of the cases of Ebola infections in Guinea during the 2014 outbreak are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals.[25][26] Semen may be infectious in survivors for up to 7 weeks.[1] It is not entirely clear how an outbreak is initially started.[27] The initial infection is believed to occur after an ebolavirus is transmitted to a human by contact with an infected animal's body fluids.

One of the primary reasons for spread is that the health systems in the part of Africa where the disease occurs function poorly.[28] Medical workers who do not wear appropriate protective clothing may contract the disease.[29] Hospital-acquired transmission has occurred in African countries due to the reuse of needles and lack of universal precautions.[30][31] Some healthcare centers caring for people with the disease do not have running water.[32]

Airborne transmission has not been documented during EVD outbreaks.[2] They are, however, infectious as breathable 0.8–1.2 μm laboratory-generated droplets.[33]

Reservoir

Bushmeat being prepared for cooking in Ghana, 2013. Human consumption of equatorial animals in Africa in the form of bushmeat has been linked to the transmission of diseases to people, including Ebola.[34]
Bats are considered the most likely natural reservoir of EBOV. Plants, arthropods, and birds were also considered.[1][35] In the wild, transmission may occur when infected fruit bats drop partially eaten fruits or fruit pulp, then land mammals such as gorillas and duikers may feed on these fallen fruits. This chain of events forms a possible indirect means of transmission from the natural host species to other animal species, which has led to research towards viral shedding in the saliva of fruit bats. Fruit production, animal behavior, and other factors vary at different times and places that may trigger outbreaks among animal populations.[36]

Bats were known to reside in the cotton factory in which the first cases for the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980.[37] Of 24 plant species and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected.[38] The absence of clinical signs in these bats is characteristic of a reservoir species. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo, 13 fruit bats were found to contain EBOV RNA fragments.[39] As of 2005, three types of fruit bats (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.[40][41] Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh, thus identifying potential virus hosts and signs of the filoviruses in Asia.[42] Fruit bats are also eaten by people in parts of West Africa where they are smoked, grilled or made into a spicy soup.[41][43]

Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from outbreak regions, no Ebola virus 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.[37][44] Traces of EBOV were detected in the carcasses of gorillas 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.[37] Transmission between natural reservoir and humans is rare, and outbreaks are usually traceable to a single case where an individual has handled the carcass of gorilla, chimpanzee or duiker.[45]

Virology
Main articles: Ebolavirus (taxonomic group) and Ebola virus (specific virus)

Phylogenetic tree comparing the Ebolavirus and Marburgvirus. Numbers indicate percent confidence of branches.
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 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, D.C., to change the "-like viruses" to "-virus" resulting in today's Ebolavirus and Marburgvirus.[46]

Rates of genetic change are 100 times slower than influenza A in humans, but on the same magnitude as those of hepatitis B. Extrapolating backwards using these rates indicates that ebolaviruses and marburgviruses diverged several thousand years ago.[47] However, paleoviruses (genomic fossils) of filoviruses (Filoviridae) found in mammals indicate that the family itself is at least tens of millions of years old.[48] Fossilized viruses that are closely related to ebolaviruses have been found in the genome of the Chinese hamster.[49]

Genome

Electron micrograph of an Ebola virus virion
Like all mononegaviruses, ebolavirions contain linear nonsegmented, single-strand, non-infectious RNA genomes of negative polarity that possesses inverse-complementary 3' and 5' termini, do not possess a 5' cap, are not polyadenylated, and are not covalently linked to a protein.[50] Ebolavirus genomes are approximately 19 kilobase pairs long and contain seven genes in the order 3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR.[51] The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV, and TAFV) differ in sequence and the number and location of gene overlaps.

Structure
Like all 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.[51] In general, ebolavirions are 80 nm in width, but vary somewhat in length. In general, the median particle length of ebolaviruses ranges from 974 to 1,086 nm (in contrast to marburgvirions, whose median particle length was measured at 795–828 nm), but particles as long as 14,000 nm have been detected in tissue culture.[52]

Replication
The ebolavirus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol. The viral RNA polymerase, encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs, which are then translated into structural and nonstructural proteins. Ebolavirus RNA polymerase (L) binds to a single 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-strand antigenomes that are, in turn, transcribed into negative-strand virus progeny genome copy. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions 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. The Ebola virus genetics are difficult to study due to its virulent nature.[53]

Pathophysiology


Pathogenesis schematic
Cells lining the inside of blood vessels (endothelial cells), macrophages, monocytes, and liver cells are the main targets of infection. After infection, a secreted glycoprotein, known as small soluble glycoprotein (sGP) or as the Ebola virus glycoprotein (GP), is synthesized. Ebolavirus replication overwhelms protein synthesis of infected cells and host immune defenses. The GP forms a trimeric complex, which binds the virus to the endothelial cells. The sGP forms a dimeric protein that 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.[54] Filoviral infection is known to interfere with proper function of the innate immune system.[55] Ebolavirus has demonstrated the ability to blunt the human immune system's response to viral infections by inhibiting the production of the interferon-beta protein.[56]

The presence of viral particles and cell damage resulting from budding causes the release of chemical signals (TNF-α, IL-6, IL-8, etc.), which are the signaling molecules for fever and inflammation. The damage to human cells, caused by infection of the endothelial cells, results in a loss of blood vessel 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 improper clotting.[57]

Diagnosis

The travel and work history along with exposure to wildlife are important to consider when the diagnosis of EVD is suspected. The diagnosis is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture, detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) works best early and in those who have died from the disease. Detecting antibodies against the virus works best late in the disease and in those who recover.[58]

During an outbreak, virus isolation is often not feasible. The most common diagnostic methods are therefore real-time PCR and ELISA detection of proteins, which can be performed in field or mobile hospitals.[59] Filovirions can be seen and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot tell the difference between the various filoviruses despite there being some length differences.[52]

Differential diagnosis
The symptoms of EVD are similar to those of Marburg virus disease.[60] It can also easily be confused with many other diseases common in Equatorial Africa such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative septicemia, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that should be included in the differential diagnosis include the following: leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis.[61] Non-infectious diseases that can be confused with EVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin poisoning.[62][63][64][65]

Prevention


A researcher working with the Ebola virus while wearing a BSL-4 positive pressure suit to avoid infection
Infection control
The Ebola virus is only transmitted via direct contact with the bodily fluids of an infected mammal.[21] Transmitability does not end with a person's death, and thus it is recommended that the bodies of people who have died from Ebola be buried or cremated only with proper care.[66]

The risk of transmission is increased amongst Ebola caregivers. Recommended measures when caring for people infected with Ebola include barrier-isolation, sterilizing equipment and surfaces, and wearing protective clothing including masks, gloves, gowns, and goggles.[27] If a person with Ebola dies, direct contact with the body of the deceased patient should be avoided.[27] The care of those individuals who have become infected with Ebola must be administered while carefully observing a very high-level of barrier-separation from the person infected, along with various certain cleaning and disinfection techniques.[67] Education of those who provide care in these techniques, and the provision of the such barrier-separation supplies has been a priority of the Doctors Without Borders organization.[68] Successfully addressing one of the "biggest danger(s) of infection" faced by medical staff requires their learning how to properly suit-up with personal protective equipment and to remove it afterwards. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days.[69]

One step recommended by the World Health Organization is the education of the general public of the risk factors for Ebola infection and of the protective measures individuals can take.[70] These include avoiding direct contact with infected people and regular hand washing using soap and water.[71] Bush meat, an important source of protein in the diet of some Africans, should be handled with appropriate protective clothing and thoroughly cooked before consumption.[1] Some research suggests that an outbreak in the wild animals used for consumption, bushmeat, may result in a corresponding human outbreak. Since 2003, such outbreaks have been monitored through surveillance of animal populations with the aim of predicting and preventing Ebola outbreaks in humans.[72]

Older burial rituals, which might have included making any kind of direct contact with a corpse, require reformulation such that they consistently maintain a proper protective barrier between the corpse and the living.[73][74] Social anthropologists may help find alternatives to traditional rules for burials.[75] Airline crews are instructed to follow a certain isolation procedure should anyone exhibit symptoms resembling the Ebola virus disease.[76]

Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for 5 minutes). On surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants at appropriate concentrations can be used as disinfectants.[77][78]

In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required, since ebolaviruses are World Health Organization Risk Group 4 pathogens. Laboratory researchers must be properly trained in BSL-4 practices and wear proper personal protective equipment.

Quarantine
Quarantine, also known as enforced isolation, is usually effective in decreasing spread.[79][80] Governments often quarantine areas where the disease is occurring or individuals who may be infected.[81] In the United States, the law allows quarantine of those infected with ebolaviruses.[82] During the 2014 outbreak, Liberia closed schools.[83]

Contact tracing
Contact tracing is regarded as important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and watching for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested, and treated. Then repeat the process by tracing the contacts' contacts.[84][85]

Treatment

Standard support

A hospital isolation ward in Gulu, Uganda, during the October 2000 outbreak
No ebolavirus-specific treatment is currently approved.[86] However, survival is improved by early supportive care with rehydration and symptomatic treatment.[1] Treatment is primarily supportive in nature.[87] These measures may include management of pain, nausea, fever and anxiety, as well as rehydration via the oral or by intravenous route.[87] Blood products such as packed red blood cells, platelets or fresh frozen plasma may also be used.[87] Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding.[87] Antimalarial medications and antibiotics are often used before the diagnosis is confirmed,[87] though there is no evidence to suggest such treatment is in any way helpful.

Intensive care
Intensive care is often used in the developed world.[16] This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop.[16] Dialysis may be needed for kidney failure while extracorporeal membrane oxygenation may be used for lung dysfunction.[16]

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.[88] 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.[89]

Prognosis

The disease has a high mortality rate which varies between 25 percent and 90 percent of those infected.[1][90] As of September 2014, information from WHO puts the average mortality among those infected at 50%.[1] The 90% rate was just reported in a single outbreak.[91] There are indications based on variations in death rate between countries that early and effective treatment of symptoms (e.g., supportive care to prevent dehydration) may reduce the fatality rate significantly.[92]

If an infected person survives, recovery may be quick and 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. Eye symptoms, such as light sensitivity, excess tearing, iritis, iridocyclitis, choroiditis, and blindness have also been described. EBOV and SUDV may be able to persist in the semen of some survivors for up to seven weeks, which could give rise to infections and disease via sexual intercourse.[1]

Epidemiology


Cases of ebola fever in Africa from 1979 to 2008.
For more about specific outbreaks and their descriptions, see List of Ebola outbreaks.

CDC worker incinerates medical waste from Ebola patients in Zaire in 1976
The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa.[1] From 1976 (when it was first identified) through 2013, the World Health Organization reported 1,716 confirmed cases.[1][4] The largest outbreak to date is the ongoing 2014 West Africa Ebola virus outbreak, which is affecting Guinea, Sierra Leone, Liberia and Nigeria.[5][6] As of 10 October, 8,376 suspected cases have been identified, with 4,024 deaths.[7]

1976
The first known outbreak of Ebola virus disease (EVD), was identified only after the fact, occurring between June and November 1976 in Nzara, South Sudan,[18] (then part of Sudan) and was caused by Sudan virus (SUDV), one of the ebolaviruses. The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara, who was hospitalized on 30 June and died on 6 July.[93][94] While the WHO medical staff involved in the Sudan outbreak were aware that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in the Democratic Republic of the Congo.[93]

On 26 August 1976, a second outbreak of EVD caused by Ebola virus (formerly called Zaire ebolavirus) began in Yambuku, a small rural village in Mongala District in northern Democratic Republic of the Congo (then known as Zaire).[95][96] The first person infected with the disease was village school headmaster Mabalo Lokela, who had toured an area near the Central African Republic border along the Ebola River between 12–22 August. On 8 September he died of what would become known as the Ebola virus (EBOV) member of the ebolaviruses.[97]

Soon after his death, others who had been in contact with him also died, and people in the village of Yambuku began to panic. This led the country's Minister of Health along with Zaire President Mobutu Sese Seko to declare the entire region, including Yambuku and the country's capital, Kinshasa, a quarantine zone. No one was permitted to enter or leave the area, with roads, waterways, and airfields placed under martial law. Schools, businesses and social organizations were closed.[98] Researchers from the CDC, including Peter Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic."[99] The outbreak lasted 26 days, with the quarantine lasting two weeks. Among the reasons that researchers speculated caused the disease to disappear, were the precautions taken by locals, the quarantine of the area, and possibly most important, the discontinuance of reusing needles by local nurses.[98]

The virus responsible for the initial outbreak, first thought to be Marburg virus, was later identified as a new type of virus related to Marburg. Virus strain samples isolated from both outbreaks were named as the "Ebola virus" after the Ebola River, located near the originally identified viral outbreak site in Zaire.[100] Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team[101] or Belgian researchers.[102] Subsequently a number of other cases were reported, almost all centered on the Yambuku mission hospital or having close contact with another case.[97] 318 cases and 280 deaths (a 88% fatality rate) occurred in the DRC.[103] Although it was assumed that the two outbreaks were connected, scientists later realized that they were caused by distinct species of filoviruses, Sudan virus and Ebola virus.[96] The Zaire outbreak was contained with the help of the World Health Organization and transport from the Congolese air force, by quarantining villagers, sterilizing medical equipment, and providing protective clothing.

1995 to 2013
The second major outbreak occurred in 1995 in the Democratic Republic of Congo, affecting 315 and killing 254. The next major outbreak occurred in Uganda in 2000, affecting 425 and killing 224; in this case the Sudan virus was found to be the ebolavirus species responsible for the outbreak.[104] In 2003 there was an outbreak in the Republic of Congo that affected 143 and killed 128, a death rate of 90%, the highest to date.[105]

In 2004 a Russian scientist died from Ebola after sticking herself with an infected needle.[106]

In August 2007, 103 people 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.[104][107][108] The 2007 outbreak eventually affected 264 individuals and resulted in the deaths of 187.[1]

On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. 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 was tentatively named Bundibugyo.[109] The WHO reported 149 cases of this new strain and 37 of those led to deaths.[1]

The WHO confirmed two small outbreaks in Uganda in 2012. The first outbreak affected 7 people and resulted in the death of 4 and the second affected 24, resulting in the death of 17. The Sudan variant was responsible for both outbreaks.[1]

On 17 August 2012, the Ministry of Health of the Democratic Republic of the Congo reported an outbreak of the Ebola-Bundibugyo variant[110] in the eastern region.[111][112] Other than its discovery in 2007, this was the only time that this variant has been identified as the ebolavirus responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and claimed 29 lives. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana.[1][113]

2014 outbreak
Main article: 2014 West Africa Ebola virus outbreak

Increase over time in the cases and deaths during the 2014 outbreak
In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea, a western African nation.[114] Researchers traced the outbreak to a two-year old child who died on 28 December 2013.[115][116] The disease then rapidly spread to the neighboring countries of Liberia and Sierra Leone. It is the largest Ebola outbreak ever documented, and the first recorded in the region.[114]

On 8 August 2014, the WHO declared the epidemic to be an international public health emergency. Urging the world to offer aid to the affected regions, the Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible."[117] By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital Monrovia as "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city’s health system, leaving many people without treatment for other conditions.[118] By late August 2014, the disease had spread to Nigeria, and one case was reported in Senegal.[119][120] [121][122] On 30 September 2014, the first confirmed case of Ebola in the United States was diagnosed.[123] The patient died eight days later.[124]

Aside from the human cost, the outbreak has severely eroded the economies of the affected countries. A Financial Times report suggested the economic impact of the outbreak could kill more people than the virus itself. As of 23 September, in the three hardest hit countries, Liberia, Sierra Leone, and Guinea, there were only 893 treatment beds available while the current need was 2122. In a 26 September statement, the WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long."[125]

By 10 October, 8,376 suspected cases and 4,024 deaths had been reported;[7] however, the World Health Organization has said that these numbers may be vastly underestimated.[126] The WHO reports that more than 216 healthcare workers are among the dead, partly due to the lack of equipment and long hours.[127][128]

On 12 October 2014, the CDC confirmed that a health care worker in Texas was found to be positive for the Ebola virus, the first known case of the disease to be contracted in the United States.[129]

Society and culture

Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponized for use in biological warfare,[130][131] and was investigated by the Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air.[132]

Literature
Richard Preston's 1995 best-selling book, The Hot Zone, dramatized the Ebola outbreak in Reston, Virginia.[133]

William Close's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire.[134]

Tom Clancy's 1996 novel, Executive Orders, involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka).[135]

Other animals

Wild animals
Ebola has a high mortality among primates.[136] Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas.[137] Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in 420 square kilometer Lossi Sanctuary between 2002 and 2003.[138] Transmission among chimpanzees through meat consumption constitutes a significant risk factor, while contact between the animals, such as touching dead bodies and grooming, is not.[139]

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.[138]

Domesticated animals
For more about the outbreak in Virginia, US, see Reston virus.
In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia, suffered a mysterious outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as Simian hemorrhagic fever virus (SHFV), and occured amongst a shipment of crab-eating macaque monkeys imported from the Philippines.

Hazelton's veterinary pathologist sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland, where a laboratory test known as an ELISA assay showed antibodies to Ebola virus.[140] An electron microscopist from USAMRIID discovered filoviruses similar in appearance to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit.[141]

Shortly afterward, a US Army team headquartered at USAMRIID went into action to euthanize the monkeys which had not yet died, bringing those monkeys and those which had already died of the disease to Ft. Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions.[140]

Blood samples were taken from 178 animal handlers during the incident.[142] Of those, six animal handlers eventually seroconverted, including one who had cut himself with a bloody scalpel.[54][143] Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans.[143][144]

The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident.[140]

Reston virus (RESTV) can be transmitted to pigs.[145]

Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy.[81] where the virus had infected pigs.[146]

In 2012 it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates.[145][147] According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or other detergents should be effective in inactivating the Reston ebolavirus. If an outbreak is suspected, the area must be immediately quarantined.[148]

While pigs that have been infected with RESTV tend to show symptoms of the disease, it has been shown that dogs may become infected with EBOV and remain asymptomatic. Dogs in some parts of Africa scavenge for their food and it is known that they sometimes eat infected animals and the corpses of humans. Although they remain asymptomatic, a 2005 survey of dogs during an EBOV outbreak found that over 31.8% showed a seroprevalence for EBOV closest to an outbreak versus 9% a farther distance away.[149]

Research

A number of experimental treatments are being studied.[150] In the United States, the Food and Drug Administration (FDA)'s animal efficacy rule is being used to demonstrate reasonable safety to obtain permission to treat people who are infected with Ebola. It is being used because the normal path for testing drugs is not possible for diseases caused by dangerous pathogens or toxins. Experimental drugs are made available for use with the approval of regulatory agencies under named patient programs, known in the US as "expanded access".[151] On 12 August 2014 the WHO released a statement that the use of not yet proven treatments is ethical in certain situations in an effort to treat or prevent the disease.[152]

Medications

Researchers looking at slides of cultures of cells that make monoclonal antibodies. These are grown in a lab and the researchers are analyzing the products to select the most promising of them.
Antivirals
A number of antiviral medications are being studied.

Favipiravir, an anti-viral drug approved in Japan for stockpiling against influenza pandemics, appears to be useful in a mouse model of Ebola.[9][153] On 4 October 2014, it was reported that a French nun who contracted Ebola while volunteering in Liberia was cured with Favipiravir treatment.[154]
BCX4430 is a broad-spectrum small molecule antiviral drug developed by BioCryst Pharmaceuticals and undergoing animal testing as a potential human treatment for Ebola by USAMRIID.[155] The drug has been approved to progress to Phase 1 trials, expected late in 2014.[156]
Brincidofovir, another broad-spectrum antiviral drug, has been granted an emergency FDA approval as an investigational new drug for the treatment of Ebola, after in vitro tests found it to be effective against Ebola virus.[157] It has subsequently been used to treat the first patient diagnosed with Ebola in the USA, after he had recently returned from Liberia.[158][159]
Lamivudine, an antiviral drug which is usually used to treat HIV / AIDS, was reported in September 2014 to have been used successfully to treat 13 out of 15 Ebola-infected patients by a doctor in Liberia, as part of a combination therapy also involving intravenous fluids and antibiotics to combat opportunistic bacterial infection of Ebola-compromised internal organs.[160] Western virologists have however expressed caution about the results, due to the small number of patients treated and confounding factors present. Researchers at the NIH stated that lamivudine had so far failed to demonstrate anti-Ebola activity in preliminary in vitro tests, but that they would continue to test it under different conditions and would progress it to trials if even slight evidence for efficacy is found.[161]
Lack of available treatment options has spurred research into a number of other possible antivirals targeted against Ebola, including natural products such as scytovirin and griffithsin,[162][163] as well as synthetic drugs including FGI-103, FGI-104, FGI-106, dUY11 and LJ-001,[164] and other newer agents.[165][166][167]
Antisense technology
Other promising treatments rely on antisense technology. Both small interfering RNAs (siRNAs) and phosphorodiamidate morpholino oligomers (PMOs) targeting Ebola virus (EBOV) RNA polymerase L protein could prevent disease in nonhuman primates.[168][169] TKM-Ebola is a small interfering RNA compound, currently being tested in a Phase I clinical trial in humans.[170][171] Sarepta Therapeutics has completed a Phase I clinical trial with its Morpholino oligo targeting Ebola virus.[172]

Other
Two selective estrogen receptor modulators used to treat infertility and breast cancer (clomiphene and toremifene) have been found to inhibit the progress of Ebola virus in vitro as well as in infected mice. Ninety percent of the mice treated with clomiphene and fifty percent of those treated with toremifene survived the tests. [173] The study authors conclude that given their oral availability and history of human use, these drugs would be candidates for treating Ebola virus infection in remote geographical locations, either on their own or together with other antiviral drugs.

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 virus into cells in vitro.[174]

Melatonin has also been suggested as a potential treatment for Ebola based on promising in vitro results.[175]

ZMapp is a monoclonal antibody vaccine. The limited supply of the drug has been used to treat a small number of individuals infected with the Ebola virus. Although some individuals have recovered, the outcome is not considered statistically significant.[176] ZMapp has proved effective in a trial involving Rhesus macaque monkeys.[170][177]

Blood products
The WHO has stated that transfusion of whole blood or purified serum from Ebola survivors is the therapy with the greatest potential to be implemented immediately, although there is little information as to its efficacy.[178] September 2014, WHO issued an interim guideline for this therapy.[179] The blood serum from those who have survived an infection is currently being studied to see if it is an effective treatment.[180] During a meeting arranged by WHO this research was deemed to be a top priority.[180] Seven of eight people with Ebola survived after receiving a transfusion of blood donated by individuals who had previously survived the infection in an 1999 outbreak in the Democratic Republic of the Congo.[87][181] This treatment, however, was started late in the disease meaning they may have already been recovering on their own and the rest of their care was better than usual.[87] Thus this potential treatment remains controversial.[16] Intravenous antibodies appear to be protective in non-human primates who have been exposed to large doses of Ebola.[182] The World Health Organisation has approved the use of convalescent serum and whole blood products to treat people with Ebola.[183]

Vaccine
As of September 2014, no vaccine was approved by the United States Food and Drug Administration (FDA) for clinical use in humans.[180][184] It was hoped that one would be initially available by November 2014.[180] The most promising candidates are DNA vaccines[185] or vaccines derived from adenoviruses,[186] vesicular stomatitis Indiana virus (VSIV)[187][188][189] or filovirus-like particles (VLPs)[190] because these candidates could protect nonhuman primates from ebolavirus-induced disease. DNA vaccines, adenovirus-based vaccines, and VSIV-based vaccines have entered clinical trials.[191][192][193][194]

Vaccines have protected nonhuman primates. Immunization takes six months, which impedes the counter-epidemic use of the vaccines. Searching for a quicker onset of effectiveness, in 2003, a vaccine using an adenoviral (ADV) vector carrying the Ebola spike protein was tested on crab-eating macaques. Twenty-eight days later, they were challenged with the virus and remained resistant.[186] A vaccine based on attenuated recombinant vesicular stomatitis virus (VSV) vector carrying either the Ebola glycoprotein or the Marburg glycoprotein in 2005 protected nonhuman primates,[195] opening clinical trials in humans.[191] Over a three month human trial, three vaccinations safely induced an immune response. Individuals for a year were followed, and, in 2006, a study testing a faster-acting, single-shot vaccine began; this new study was completed in 2008.[192] Trying the vaccine on a strain of Ebola that more resembles one that infects humans is the next step.[196]

On 6 December 2011, the development of a successful vaccine against Ebola for mice was reported. Unlike the predecessors, it can be freeze-dried and thus stored for long periods in wait for an outbreak.[197] An experimental vaccine made by researchers at Canada's national laboratory in Winnipeg was used, in 2009, to pre-emptively treat a German scientist who might have been infected during a lab accident.[198] However, actual EBOV infection was never demonstrated beyond doubt.[199] Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of EBOV or SUDV (e.g. VSV-EBOV), has been used successfully in nonhuman primate models as post-exposure prophylaxis.[200][201] The CDC's recommendations are currently under review.[citation needed]

Simultaneous phase 1 trials of an experimental vaccine known as the NIAID/GSK vaccine commenced in September 2014.[202] GlaxoSmithKline and the NIH jointly developed the vaccine,[202] based on a modified chimpanzee adenovirus, and contains parts of the Zaire and Sudan ebola strains.[202] If this phase is completed successfully, the vaccine will be fast tracked for use in West Africa. In preparation for this, GSK is preparing a stockpile of 10,000 doses.[203][204]

See also

List of human disease case fatality rates
References

Notes

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Ryabchikova, Elena I.; Price, Barbara B. (2004). Ebola and Marburg Viruses: A View of Infection Using Electron Microscopy. Columbus, Ohio: Battelle Press. ISBN 978-1-57477-131-2.
External links

Ebola virus disease at DMOZ
CDC: Ebola hemorrhagic fever – Centers for Disease Control and Prevention, Special Pathogens Branch
WHO: Ebola haemorrhagic fever – World Health Organization, Global Alert and Response
Google Map of Ebola Outbreaks
WHO recommended infection control measures
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