Ebola virus disease

Ebola nurse Pauline Cafferkey now ‘critically ill’

Read full story on BBC News: Ebola nurse Pauline Cafferkey now ‘critically ill’

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5 Terrifying Facts About Ebola

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Ebola virus disease (EVD; also Ebola hemorrhagic fever, or EHF), or simply Ebola, is a disease of humans and other primates caused by ebolaviruses. Signs and symptoms typically start between two days and three weeks after contracting the virus with a fever, sore throat, muscular pain, and headaches. Then, vomiting, diarrhea and rash usually follow, along with decreased function of the liver and kidneys. At this time some people begin to bleed both internally and externally.^[1] The disease has a high risk of death, killing between 25 and 90 percent of those infected, with an average of about 50 percent.^[1] This is often due to low blood pressure from fluid loss, and typically follows six to sixteen days after symptoms appear.^[2]

The virus spreads by direct contact with body fluids, such as blood, of an infected human or other animals.^[1] This may also occur through contact with an item recently contaminated with bodily fluids.^[1] Spread of the disease through the air between primates, including humans, has not been documented in either laboratory or natural conditions.^[3] Semen or breast milk of a person after recovery from EVD may still carry the virus for several weeks to months.^[1][4] Fruit bats are believed to be the normal carrier in nature, able to spread the virus without being affected by it. 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]

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Ebola Virus Outbreak 2014: Dying at the Hospital Door

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Control of outbreaks requires coordinated medical services, alongside a certain level of community engagement. 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 healthcare for those who are infected, and proper disposal of the dead through cremation or burial.^[1][5] Samples of body fluids and tissues from people with the disease should be handled with special caution. Prevention includes limiting the spread of disease from infected animals to humans. This may be done by handling potentially infected bush meat only while wearing protective clothing and by thoroughly cooking it before eating it. It also includes wearing proper protective clothing and washing hands when around a person with the disease.^[1] No specific treatment or vaccine for the virus is available, although a number of potential treatments are being studied. Supportive efforts, however, improve outcomes. This includes either oral rehydration therapy (drinking slightly sweetened and salty water) or giving intravenous fluids as well as treating symptoms.^[1]

The disease was first identified in 1976 in two simultaneous outbreaks, one in Nzara, and the other in Yambuku, a village near the Ebola River from which the disease takes its name.^[6] EVD outbreaks occur intermittently in tropical regions of sub-Saharan Africa.^[1] Between 1976 and 2013, the World Health Organization reports a total of 24 outbreaks involving 1,716 cases.^[1][7] The largest outbreak is the ongoing epidemic in West Africa, still affecting Guinea and Sierra Leone.^[8][9][10] As of 27 September 2015^[update], this outbreak has 28,424 reported cases resulting in 11,311 deaths.^[11]

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EBOLA | Inside the Deadly Outbreak

[FULL DOCUMENTARY]

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Signs and symptoms

Signs and symptoms of Ebola^[12]

Onset

The length of time between exposure to the virus and the development of symptoms (incubation period) is between 2 to 21 days,^[1][12] and usually between 4 to 10 days.^[13] However, recent estimates based on mathematical models predict that around 5% of cases may take greater than 21 days to develop.^[14]

Symptoms usually begin with a sudden influenza-like stage characterized by feeling tired, fever, weakness, decreased appetite, muscular pain, joint pain, headache, and sore throat.^{[1][13][15][16]} The fever is usually higher than 38.3 °C (101 °F).^[17] This is often followed by vomiting, diarrhea and abdominal pain.^[16] Next, shortness of breath and chest pain may occur, along with swelling, headaches and confusion.^[16] In about half of the cases, the skin may develop a maculopapular rash, a flat red area covered with small bumps, 5 to 7 days after symptoms begin.^[13][17]

Bleeding

In some cases, internal and external bleeding may occur.^[1] This typically begins five to seven days after the first symptoms.^[18] All infected people show some decreased blood clotting.^[17] Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50 percent of cases.^[19] This may cause vomiting blood, coughing up of blood, or blood in stool.^[20] Bleeding into the skin may create petechiae, purpura, ecchymoses or hematomas (especially around needle injection sites).^[21] Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually located within the gastrointestinal tract.^[17][22]

Recovery and death

Recovery may begin between 7 and 14 days after first symptoms.^[16] Death, if it occurs, follows typically 6 to 16 days from first symptoms and is often due to low blood pressure from fluid loss.^[2] In general, bleeding often indicates a worse outcome, and blood loss may result in death.^[15] People are often in a coma near the end of life.^[16]

Those who survive often have ongoing muscular and joint pain, liver inflammation, decreased hearing, and may have continued feelings of tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight.^[16][23] Problems with vision may develop.^[24]

Additionally they develop antibodies against Ebola that last at least 10 years, but it is unclear if they are immune to repeated infections.^[25] If someone recovers from Ebola, they can no longer transmit the disease.^[25]

Cause

EVD in humans is caused by four of five viruses of the genus Ebolavirus. The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus).^[26] EBOV, species Zaire ebolavirus, is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks.^[27] The fifth virus, Reston virus (RESTV), is not thought to cause disease in humans, but has caused disease in other primates.^[28][29] All five viruses are closely related to marburgviruses.^[26]

Virology

Electron micrograph of an Ebola virus virion

Ebolaviruses contain single-stranded, non-infectious RNA genomes.^[30] Ebolavirus genomes contain seven genes including 3′-UTR–NP–VP35–VP40–GP–VP30–VP24–L–5′-UTR.^[21][31] 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 with all filoviruses, ebolavirus virions 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.^[31][32] In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm.^[33]

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.^[34] The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved.^[34] This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid.^[34] The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus’ ability to bind to and infect targeted cells.^[35] 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. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny.^[36] 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 from which they bud from. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV’s virulent characteristics.^[37]

Transmission

Life cycles of the Ebolavirus

It is believed that between people, Ebola disease spreads only by direct contact with the blood or body fluids of a person who has developed symptoms of the disease.^[38][39][40] Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen.^[25] The WHO states that only people who are very sick are able to spread Ebola disease in saliva, and whole virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit.^[41] Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions.^[25] Ebola may be spread through large droplets; however, this is believed to occur only when a person is very sick.^[42] This contamination can happen if a person is splashed with droplets.^[42] Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection.^[43][44] The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person.^[25][45]

The Ebola virus may be able to persist for more than 3 months in the semen after recovery, which could lead to infections via sexual intercourse.^[46][47] Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again.^[4] The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood.^[48] Otherwise, people who have recovered are not infectious.^[43]

The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low.^[49] Usually when someone has symptoms of the disease, they are unable to travel without assistance.^[50]

Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk.^[49] 69% 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.^[51][52]

Health-care workers treating people with Ebola are at greatest risk of infection.^[43] The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly.^[43] This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly.^[53] There has been transmission in hospitals in some African countries that reuse hypodermic needles.^[54][55] Some health-care centers caring for people with the disease do not have running water.^[56] In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures.^[57]

Human-to-human transmission of EBOV through the air 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 pigs to primates, but not from primates to primates.^[38][44] Spread of EBOV by water, or food other than bushmeat, has not been observed.^[43][44] No spread by mosquitos or other insects has been reported.^[43] Other possible methods of transmission are being studied.^[45]

The apparent lack of airborne transmission among humans is believed to be due to low levels of the virus in the lungs and other parts of the respiratory system of primates, insufficient to cause new infections.^[58] A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream.^[59] Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough.^[60] By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs.^[60] It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air.^[59][60]

Initial case

Bushmeat being prepared for cooking in Ghana. In Africa, wild animals including fruit bats are hunted for food and are referred to as bushmeat.^[61][62] In equatorial Africa, human consumption of bushmeat has been linked to animal-to-human transmission of diseases, including Ebola.^[63]

Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat.^[43] Besides bats, other wild animals sometimes infected with EBOV include several monkey species, chimpanzees, gorillas, baboons and duikers.^[64]

Animals may become infected when they eat fruit partially eaten by bats carrying the virus.^[65] Fruit production, animal behavior and other factors may trigger outbreaks among animal populations.^[65]

Evidence indicates that both domestic dogs and pigs can also be infected with EBOV.^[66] Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates.^[66] Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people.^[66]

Reservoir

The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate species.^[44] Three types of fruit bats (Hypsignathus monstrosus, Epomops franqueti and Myonycteris torquata) were found to possibly carry the virus without getting sick.^[67] As of 2013, whether other animals are involved in its spread is not known.^[66] Plants, arthropods and birds have also been considered possible viral reservoirs.^[1]

Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980.^[68] Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected.^[69] The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. 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.^[70] Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh, suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia.^[71]

Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys) and one shrew (Sylvisorex ollula) collected from the Central African Republic.^[68][72] However, further research efforts have not confirmed rodents as a reservoir.^[73] 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 rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus.^[68]

Pathophysiology

Pathogenesis schematic

Similar to other filoviruses, EBOV replicates very efficiently in many cells, producing large amounts of virus in monocytes, macrophages, dendritic cells and other cells including liver cells, fibroblasts, and adrenal gland cells.^[74] Viral replication triggers the release of high levels of inflammatory chemical signals and leads to a septic state.^[23]

EBOV is thought to infect humans through contact with mucous membranes or through skin breaks.^[38] Once infected, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes, and dendritic cells are the main targets of infection.^[38] Following infection with the virus, the immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place.^[38] From there, the virus can enter the bloodstream and lymphatic system and spread throughout the body.^[38] Macrophages are the first cells infected with the virus, and this infection results in programmed cell death.^[33] Other types of white blood cells, such as lymphocytes, also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood.^[38] This contributes to the weakened immune response seen in those infected with EBOV.^[38]

Endothelial cells may be infected within 3 days after exposure to the virus.^[33] The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins. This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting. The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume.^[75] The dysfunction in bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes.^[13]

After infection, a secreted glycoprotein, small soluble glycoprotein (sGP or GP) is synthesized. EBOV replication overwhelms protein synthesis of infected cells and the host immune defenses. The GP forms a trimeric complex, which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signaling of neutrophils, another type of white blood cell, which enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. The presence of viral particles and 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 and inflammation.

Immune system evasion

Filoviral infection also interferes with proper functioning of the innate immune system.^[34][36] EBOV proteins blunt the human immune system’s response to viral infections by interfering with the cells’ ability to produce and respond to interferon proteins such as interferon-alpha, interferon-beta, and interferon gamma.^[35][76]

The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell’s cytosol (such as RIG-I and MDA5) or outside of the cytosol (such as Toll-like receptor 3 (TLR3), TLR7, TLR8 and TLR9), recognize infectious molecules associated with the virus.^[35] On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signaling cascade that leads to the expression of type 1 interferons.^[35] The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighboring cell.^[35] Once interferon has bound to its receptors on the neighboring cell, the signaling proteins STAT1 and STAT2 are activated and move to the cell’s nucleus.^[35] This triggers the expression of interferon-stimulated genes, which code for proteins with antiviral properties.^[35] EBOV’s V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signaling protein in the neighboring cell from entering the nucleus.^[35] The VP35 protein directly inhibits the production of interferon-beta.^[76] By inhibiting these immune responses, EBOV may quickly spread throughout the body.^[33]

Diagnosis

When EVD is suspected in a person, his or her travel and work history, along with an exposure to wildlife, are important factors to consider with respect to further diagnostic efforts.

Laboratory testing

Possible non-specific laboratory indicators of EVD include a low platelet count; an initially decreased white blood cell count followed by an increased white blood cell count; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time, partial thromboplastin time, and bleeding time.^[77] 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.^[78]

The specific diagnosis of EVD 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)^[13] and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover.^[79] IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected 6 to 18 days after symptom onset.^[13] 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.^[80] In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission.^[81] In 2015 a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected.^[82]

Differential diagnosis

Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever.^[15] The symptoms are also similar to those of Marburg virus disease and other viral hemorrhagic fevers.^[83]

The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever, shigellosis, rickettsial diseases, cholera, sepsis, borreliosis, EHEC enteritis, leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, measles, and viral hepatitis among others.^[84]

Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and warfarin poisoning.^{[80][85][86][87]}

Prevention

VHF isolation precautions poster

Infection control

British woman wearing protective gear

People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles.^[88] The US Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed.^[89] These measures are also recommended for those who may handle objects contaminated by an infected person’s body fluids.^[90] In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly.^[89] In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days.^[91]

The infected person should be in barrier-isolation from other people.^[88] All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected.^[90] During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which include protective clothing as well as chlorine powder and other cleaning supplies.^[92] Education of those who provide care in these techniques, and the provision of such barrier-separation supplies has been a priority of Doctors Without Borders.^[93]

Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for 5 minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations.^[64][94] Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization.^[1] These measures include avoiding direct contact with infected people and regular hand washing using soap and water.^[95]

Bushmeat, an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption.^[1] Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans.^[96]

If a person with Ebola disease dies, direct contact with the body should be avoided.^[88] Certain burial rituals, which may have included making various direct contacts with a dead body, require reformulation such that they consistently maintain a proper protective barrier between the dead body and the living.^[97][98][99] Social anthropologists may help find alternatives to traditional rules for burials.^[100]

Transportation crews are instructed to follow a certain isolation procedure should anyone exhibit symptoms resembling EVD.^[101] As of August 2014, the WHO does not consider travel bans to be useful in decreasing spread of the disease.^[50] In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities.^[102] In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels:^[102]

• having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk)
• encounter with a person showing symptoms; but not within 3 feet of the person with Ebola without wearing PPE; and no direct contact of body fluids
• having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk)
• in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk)
• contact with a person with Ebola disease before the person was showing symptoms (no risk).

The CDC recommends monitoring for the symptoms of Ebola disease for those both at “low risk” and at higher risk.^[102]

In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required.^[103] Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE

Isolation

Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk.^[104] Quarantine, also known as enforced isolation, is usually effective in decreasing spread.^[105][106] Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area.^[107] In the United States, the law allows quarantine of those infected with ebolaviruses.^[108]

Contact tracing

Contact tracing is considered 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 the process is repeated by tracing the contacts’ contacts.^[109][110]

Management

No specific treatment is currently approved.^[111] 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.^[112][113]

Standard support

A hospital isolation ward in Gulu, Uganda, during the October 2000 outbreak

Treatment is primarily supportive in nature.^[114] Early supportive care with rehydration and symptomatic treatment improves survival.^[1] Rehydration may be via the oral or by intravenous route.^[114] These measures may include management of pain, nausea, fever and anxiety.^[114] The World Health Organization recommends avoiding the use of aspirin or ibuprofen for pain due to the bleeding risk associated with use of these medications.^[115]

Blood products such as packed red blood cells, platelets or fresh frozen plasma may also be used.^[114] Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding.^[114] Antimalarial medications and antibiotics are often used before the diagnosis is confirmed,^[114] though there is no evidence to suggest such treatment helps. A number of experimental treatments are being studied.

If hospital care is not possible, the World Health Organization has guidelines for care at home that have been relatively successful. In such situations, recommendations include using towels soaked in bleach solutions when moving infected people or bodies and applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth.^[116]

Intensive care

Intensive care is often used in the developed world.^[21] This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop.^[21] Dialysis may be needed for kidney failure, and extracorporeal membrane oxygenation may be used for lung dysfunction.^[21]

Prognosis

EVD has a high risk of death in those infected which varies between 25 percent and 90 percent of those infected.^[1][117] As of September 2014^[update], the average risk of death among those infected is 50 percent.^[1] The highest risk of death was 90 percent in the 2002–2003 Republic of the Congo outbreak.^[118]

Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pressure from fluid loss.^[2] Early supportive care to prevent dehydration may reduce the risk of death.^[119]

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, muscular pain, skin peeling, or hair loss.^[13] Eye symptoms, such as light sensitivity, excess tearing, and vision loss have been described.^[120]

Ebola can stay in some body parts like the eyes,^[121] breasts, and testicles after infection.^[122][123] Sexual transmission after recovery has been suggested.^[124][125]

Epidemiology

Cases of Ebola fever in Africa from 1979 to 2008

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][7] The largest outbreak to date is the ongoing 2014 West Africa Ebola virus outbreak, which has caused a large number of deaths in Guinea, Sierra Leone, and Liberia.^[9][10]

2014 to 2015 West African outbreak

Increase over time in the cases and deaths during the 2013–2015 outbreak

In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea, a western African nation.^[126] Researchers traced the outbreak to a one-year-old child who died December 2013.^[127][128] 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.^[126] 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.”^[129] 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.^[130] 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.”^[131]

Intense contact tracing and strict isolation techniques largely prevented further spread of the disease in the countries that had imported cases, but in the most severely affected countries, Guinea, Liberia, and Sierra Leone, this disease is ongoing. As of 27 September 2015^[update], 28,424 suspected cases and 11,311 deaths have been reported;^[11][132] however, the WHO has said that these numbers may be underestimated.^[133] Because they work closely with the body fluids of infected patients, healthcare workers have been especially vulnerable to catching the disease; in August 2014, the WHO reported that ten percent of the dead have been healthcare workers.^[134]

In September 2014, it was estimated that the countries’ capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was resulting in serious shortfalls in some areas.^[135] On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic.^[136] On 8 April 2015, the WHO reported a total of only 30 confirmed cases, the lowest weekly total since the third week of May 2014.^[137]

2014 Ebola spread outside West Africa

As of 15 October 2014, there have been 17 cases of Ebola treated outside Africa, four of whom have died.^[138]

In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa.^[139] On 20 October, it was announced that Teresa Romero had tested negative for the Ebola virus, suggesting that she may have recovered from Ebola infection.^[140]

On 19 September, Eric Duncan flew from his native Liberia to Texas; 5 days later he began showing symptoms and visited a hospital, but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October.^[141] Health officials confirmed a diagnosis of Ebola on 30 September—the first case in the United States.^[57] On 12 October, the CDC confirmed that a nurse in Texas who had treated Duncan was found to be positive for the Ebola virus, the first known case of the disease to be contracted in the United States.^[142] On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus.^[143] Both of these people have since recovered.^[144]

On 23 October, a doctor in New York City, who returned to the United States from Guinea after working with Doctors Without Borders, tested positive for Ebola. His case is unrelated to the Texas cases.^[145] The person has recovered and was discharged from Bellevue Hospital Center on November 11.^[144] On 24 December 2014, a laboratory in Atlanta, Georgia reported that a technician had been exposed to Ebola.^[146]

On 29 December 2014, Pauline Cafferkey, a British nurse who had just returned to Glasgow from Sierra Leone was diagnosed with Ebola at Glasgow’s Gartnavel General Hospital.^[147] After initial treatment in Glasgow, she was transferred by air to RAF Northolt, then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment.^[148]

1995 to 2014

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 Congo that affected 143 and killed 128, a death rate of 90 percent, the highest death rate of a genus Ebolavirus outbreak to date.^[149]

In 2004 a Russian scientist died from Ebola after sticking herself with an infected needle.^[150]

Between April and August 2007, a fever epidemic^[151] in a four-village region^[152] of the Democratic Republic of the Congo was confirmed in September to have cases of Ebola.^[153] Many people who attended the recent funeral of a local village chief died.^[152] 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 genus Ebolavirus, which was tentatively named Bundibugyo.^[154] 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^[155] in the eastern region.^[156][157] Other than its discovery in 2007, this was the only time that this variant has been identified as 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][158]

In 2014, an outbreak of Ebola virus disease occurred in the Democratic Republic of the Congo (DRC). Genome-sequencing has shown that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak, but was of the same EBOV species, the Zaire species.^[159] It began in August 2014 and was declared over in November of that year with a total of 66 cases and 49 deaths.^[160] This is the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire.^[161]

1976

CDC worker incinerates medical waste from Ebola patients in Zaire in 1976.

Sudan outbreak

The first known outbreak of EVD was identified only after the fact, occurring between June and November 1976 in Nzara, South Sudan,^[26][162] (then part of Sudan) and was caused by Sudan virus (SUDV). 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.^[21][163] Although 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.^[163]

Zaire outbreak

On 26 August 1976, a second outbreak of EVD began in Yambuku, a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo).^[164][165] This outbreak was caused by 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 disease was village school headmaster Mabalo Lokela, who began displaying symptoms on 26 August 1976.^[166] Lokela had returned from a trip to Northern Zaire near the Central African Republic border, having visited the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine. However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September, 14 days after he began displaying symptoms.^{[167][168][169]}

Soon after Lokela’s 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.^[170] 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.”^{[171][172][173]} Piot concluded that the Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women, without sterilizing the syringes and needles. The outbreak lasted 26 days, with the quarantine lasting 2 weeks. Among the reasons that researchers speculated caused the disease to disappear, were the precautions taken by locals, the quarantine of the area, and discontinuing the injections.^[170]

During this outbreak, Dr. Ngoy Mushola recorded the first clinical description of EVD in Yambuku, where he wrote the following in his daily log: “The illness is characterized with a high temperature of about 39 °C (102 °F), hematemesis, diarrhea with blood, retrosternal abdominal pain, prostration with “heavy” articulations, and rapid evolution death after a mean of 3 days.”^[174]

The virus responsible for the initial outbreak, first thought to be Marburg virus, was later identified as a new type of virus related to marburgviruses. 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.^[21] Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team^[175] or Belgian researchers.^[176] Subsequently a number of other cases were reported, almost all centered on the Yambuku mission hospital or having close contact with another case.^[166] 318 cases and 280 deaths (an 88 percent fatality rate) occurred in Zaire.^[177] Although it was assumed that the two outbreaks were connected, scientists later realized that they were caused by two distinct ebolaviruses, SUDV and EBOV.^[165] 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.

Society and culture

Weaponization

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.^[74][178] It has the potential to be weaponized for use in biological warfare,^[179][180] and was investigated by 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.^[181] Fake emails pretending to be Ebola information from the WHO or the Mexican Government have in 2014 been misused to spread computer malware.^[182] The BBC reported in 2015 that, “North Korean state media has suggested the disease was created by the US military as a biological weapon.”^[183]

Literature

Richard Preston‘s 1995 best-selling book, The Hot Zone, dramatized the Ebola outbreak in Reston, Virginia.^[184]

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.^[185]

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).^[186]

As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease.^[187]

Other animals

Wild animals

Ebola has a high mortality among primates.^[111] Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas.^[188] Outbreaks of Ebola may have been responsible for an 88 percent decline in tracking indices of observed chimpanzee populations in 420 square kilometer Lossi Sanctuary between 2002 and 2003.^[189] Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not.^[190]

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 3 to 4 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.^[189]

Domestic animals

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.^[66][191]

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 during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus 9 percent of those farther away.^[192] The authors concluded that there were “potential implications for preventing and controlling human outbreaks.”

Reston virus

In late 1989, Hazelton Research Products’ Reston Quarantine Unit in Reston, Virginia, suffered an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian hemorrhagic fever virus (SHFV), and occurred 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 an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV.^[193] An electron microscopist from USAMRIID discovered filoviruses similar in appearance to Ebola in the tissue samples sent from Hazelton Research Products’ Reston Quarantine Unit.^[194]

A US Army team headquartered at USAMRIID euthanized the surviving monkeys, and brought all the monkeys to Ft. Detrick for study by the Army’s veterinary pathologists and virologists, and eventual disposal under safe conditions.^[193] Blood samples were taken from 178 animal handlers during the incident.^[195] Of those, six animal handlers eventually seroconverted, including one who had cut himself with a bloody scalpel.^[75][196] 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.^[196][197]

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.^[193] Reston virus (RESTV) can be transmitted to pigs.^[66] Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy,^[198] where the virus had infected pigs.^[199] According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus. Pigs that have been infected with RESTV tend to show symptoms of the disease.

Research

Treatments

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.

As of July 2015, there is no medication which has been proven to be safe and effective in treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014 and early 2015, but some were abandoned due to lack of efficacy or lack of people to study.

Vaccines

Many Ebola vaccine candidates had been developed in the decade prior to 2014,^[200] but as of November 2014, none had yet been approved by the United States Food and Drug Administration (FDA) for clinical use in humans.^{[201][202][203]}

Several promising vaccine candidates have been shown to protect nonhuman primates (usually macaques) against lethal infection.^{[26][162][204]} These include replication-deficient adenovirus vectors, replication-competent vesicular stomatitis (VSV) and human parainfluenza (HPIV-3) vectors, and virus-like particle preparations. Conventional trials to study efficacy by exposure of humans to the pathogen after immunization are obviously not feasible in this case. For such situations, the FDA has established the “animal rule” allowing licensure to be approved on the basis of animal model studies that replicate human disease, combined with evidence of safety and a potentially potent immune response (antibodies in the blood) from humans given the vaccine. Phase I clinical trials involve the administration of the vaccine to healthy human subjects to evaluate the immune response, identify any side effects and determine the appropriate dosage.

In September 2014, an Ebola vaccine was used after exposure to Ebola and the person appears to have developed immunity without getting sick.^[205]

In July 2015 early results from a trial of the vaccine VSV-EBOV showed effectiveness.^[206]

Diagnostic tests

One issue which hinders control of Ebola is that diagnostic tests which are currently available require specialized equipment and highly trained personnel. Since there are few suitable testing centers in West Africa, this leads to delay in diagnosis. In December, a conference in Geneva will aim to work out which diagnostic tools could be to identify Ebola reliably and more quickly. The meeting, convened by the WHO and the non-profit Foundation for Innovative New Diagnostics, seeks to identify tests that can be used by untrained staff, do not require electricity or can run on batteries or solar power and use reagents that can withstand temperatures of 40 °C.^[207]

On 29 November, a new 15-minute Ebola test was reported that if successful, “not only gives patients a better chance of survival, but it prevents transmission of the virus to other people.” The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. The equipment is currently being tested in Guinea.^[208]

On December 29, the FDA approved LightMix (R) Ebola Zaire rRT-PCR Test on patients with symptoms of Ebola. The report indicates it could help health care authorities around the world