Ebola virus disease (EVD), formerly known as Ebola hemorrhagic fever, is a viral infection with high mortality caused by four viruses in the genus Ebolavirus, which belongs to the Filoviridae family. The four ebolaviruses that cause disease in humans are Bundibugyo ebolavirus (BDBV); Sudan ebolavirus (SUDV); Tai Forest ebolavirus (TAFV); and Ebola virus (EBOV), formerly called Zaire ebolavirus. All ebolaviruses are classified as viral hemorrhagic fevers or VHFs.
EBOV is the most dangerous of the four species that infect humans and is responsible for most of the known outbreaks as of 2018. A fifth ebolavirus, Reston ebolavirus (RESTV), causes infections in monkeys and other primates but is not known to cause symptomatic disease in humans. EVD takes its name from the Ebola River in the Democratic Republic of the Congo near the village where the first outbreak of EBOV occurred in 1976.
The origin of EVD was not completely understood as of 2018. The natural reservoir of EBOV is thought to be three species of African fruit bats of the Pteropodidae family. Bats were found roosting in the cotton factory where the initial 1976 outbreak began, and fruit bats have been found to carry EBOV without becoming sick themselves. Some epidemiologists think that African birds and insects may also be reservoirs of Ebola viruses. It is thought that other animal species known to become infected with EBOV, such as several monkey species, chimpanzees, gorillas, baboons, and duikers (African antelopes), acquire the virus from eating fruit partially consumed by infected bats.
Humans are believed to contract the virus from contact with either infected bats or infected primates, often through eating bushmeat. Once the virus has spilled over into humans, it then spreads rapidly from person to person through direct contact with the body fluids of infected people. In most cases the virus is spread through vomit, blood, and feces, but people have also contracted the virus through contact with the sweat, tears, urine, mucus, saliva, semen, and breast milk of a symptomatic patient. In addition, the virus can spread from severely infected patients in hospitals through droplet infection or through contaminated needles or syringes. While Ebola viruses survive for only a few hours after drying on countertops or other hard surfaces, they can survive in body fluids outside the body for several days and in semen for as long as three months after the patient recovers.
People at greatest risk of Ebola virus disease include:
Although most cases of EVD as of 2018 had occurred among blacks due to the geographic location of most outbreaks in sub-Saharan Africa, there was no evidence as of 2018 that black people were more susceptible to infection than members of other races.
EVD was first identified in 1976 in two local outbreaks, one caused by SUDV in Sudan and the other by EBOV in Zaire (later the Democratic Republic of the Congo). From 1976 through 2013, according to the World Health Organization (WHO), there were a total of 1,716 confirmed cases of EVD, all in various countries of sub-Saharan Africa. In addition, there were small outbreaks of asymptomatic RESTV infection among laboratory workers in the Philippines, United States, and Italy between 1989 and 1992. An additional outbreak of RESTV infection in the Philippines in 2008 proved that pigs can be infected by Ebola viruses, but as with other RESTV outbreaks, no humans became sick.
With the West African outbreak of 2013–2016, however, EVD became a worldwide public health emergency. The epidemic was the largest to date, with 28,616 confirmed cases and 11,310 deaths; 10% of the dead were healthcare workers; and 17 cases involved persons traveling to or returning to other countries (Spain, the United Kingdom, and the United States). The outbreak also led to appeals for help to the international community; worldwide revision of quarantine and travel restriction policies; intensified vaccine research; and updated standards of infection control in hospitals and clinics.
As far as is known, men and women are equally susceptible to EVD, as are members of all races and ethnic groups. The major demographic difference in the African countries where EVD is endemic is age group: children below the age of 16 are less likely to become infected than adults. It is thought, however, that this difference is related to adults' greater exposure to infection due to their occupational responsibilities rather than an age-related difference in susceptibility.
The cause of Ebola virus disease is any of four Ebola viruses known to cause disease in humans. Humans, however, are not the natural reservoir of EVD. It is thought that humans acquire the virus through contact with the blood or body fluids of infected bats or by eating bushmeat, and that the virus gains entrance to the body through the mucous membranes of the nose and mouth, eyes, open wounds, cuts, abrasions, or needle sticks from contaminated hypodermic needles. The incubation period ranges from 2 to 21 days, with an average of 8 to 10 days. Once the index patients have been infected, they can spread the virus to other persons through vomit, fecal matter, or blood, but such other body fluids as sweat, tears, breast milk, and semen can also convey the virus to others.
As of 2018, researchers did not fully understand how Ebola viruses gain entrance to human cells, which they must do in order to replicate and survive. In better-known viruses, a virus attaches itself to a specific protein (receptor) on the surface of a cell, but the receptor of the Ebola virus has not yet been conclusively identified. There are two candidate receptors of the Ebola virus: a cholesterol transporter protein called NPC1; and TIM-1, a protein involved in the regulation of immune cell activity.
Ebola viruses infect a wide number of different types of cells in the human body, including several different types of white blood cells; dendritic cells in the immune system; fibroblasts (cells in connective tissue), liver cells, and cells in the adrenal glands. Once the white blood cells are infected, the virus is carried to lymph nodes, where it continues to replicate and enters the lymphatic system and the bloodstream. In the bloodstream, the virus infects the tissue lining the walls of the blood vessels as well as the liver, leading to abnormal blood clotting, tissue necrosis, and the widespread bleeding seen in patients with EVD. The virus also suppresses the responses of the immune system, leading to the death of large numbers of white cells and eventual organ failure.
The early symptoms of EVD usually appear between 2 and 20 days after exposure as a flu-like syndrome, with fever at or above 38.3°C (101°F), sore throat, headache, cough, chest pain, and conjunctival injection. The patient's eyes may be abnormally sensitive to light (photophobia). Nausea, vomiting, and diarrhea may also occur. There may be a skin rash with reddish spots or bumps (papules), which may be difficult to detect in darker-skinned patients. If the virus affects the central nervous system during the early phase of illness, the patient may become delirious or comatose.
Hemorrhagic symptoms begin within 5–7 days after symptom onset; these include pinpoint hemorrhages (petechiae) in the skin or areas of bleeding beneath the skin (ecchymosis); bleeding from the mucous membranes or injection sites; vomiting blood; or passing blood in the stool. Severe bleeding is uncommon but is most likely to occur in the digestive tract. Death occurs between 6 and 16 days after the first symptoms and usually results from multiple organ failure and shock resulting from fluid loss. The patient often falls into a coma toward the end.
Patients who survive generally show signs of recovery during the second week of illness, when the fever begins to drop. Recovery is slow in most cases, with patients suffering from partial loss of hearing, loss of appetite, visual disturbances, muscle pains and weakness, fatigue, and difficulty regaining their pre-illness weight. Pregnant women usually miscarry.
Prompt diagnosis of EVD depends to a considerable degree on the physician's index of suspicion. One of the reasons why the 2013–2016 outbreak was not stopped quickly is that the index case, a two-year-old boy, occurred in Guinea, a country that had not had previous outbreaks of Ebola. Second, the initial symptoms of EVD resemble those of typhoid, cholera, and malaria, three diseases that are much more common than EVD in the area where the outbreak occurred. In Canada and the United States, EVD would likely be suspected in any patient who had recently visited Africa, was running a fever, had bleeding tendencies, and other symptoms consistent with an ebolavirus infection.
If EVD is suspected, the patient is placed at once in isolation in a single hospital room with a private bathroom, and healthcare workers must follow standard, contact, and droplet precautions as well as wear personal protective equipment. The treating physician must notify state and city public health authorities immediately that the patient may have EVD, and consult with them as to whether further testing of body fluids and tracing the patient's contacts are needed.
Basic blood tests may be done to look for the low levels of platelets and white blood cells that are characteristic of the early phase of EVD, but these tests are not definitive of an ebolavirus infection.
Definitive diagnosis of EVD requires culturing the virus in tissue samples; however, this procedure is dangerous to laboratory personnel and is done in only a few high-containment laboratories in the world.
In 2014, 2015, and 2016, the Food and Drug Administration (FDA) issued a set of emergency use authorizations for rapid tests to detect EBOV or its antigens in blood samples. Six of the rapid tests are real-time PCR assays, and five are rapid tests to detect antigens to the virus in fingerstick or venipuncture blood samples. One of the tests can also be performed on urine samples. The tests yield results in about an hour and can be performed on site at any hospital with the equipment specified by the tests' manufacturers.
There were no medications approved to treat Ebola as of mid-2017, although patients may be given analgesic medications for symptom relief. NSAIDs, however, should not be given as they can affect blood clotting. Treatment is primarily supportive, with fluid replacement, correction of electrolyte imbalances, and replacement of blood coagulation factors considered essential to recovery. Invasive procedures are kept to a minimum. Patient are kept in strict barrier isolation, and all equipment or other objects that have come in contact with the patient's body fluids must be disinfected with sodium hypochlorite.
If patients die, they must be buried promptly and with as little contact with others as possible.
Research toward medications that are safe as well as effective is ongoing; an article published in the New England Journal of Medicine in the spring of 2018 suggested the use of monoclonal antibodies in treating EVD. The authors noted that since 2015, “investigators have isolated multiple Ebola antibodies that could serve as essential tools for Ebola treatment in future outbreaks.”
Ebola virus disease is a notifiable disease in the United States. The outbreak that began in West Africa in December 2014, however, was the first that affected the United States in terms of direct patient care. The Reston ebolavirus (RESTV) had been discovered in tissue samples taken from a macaque (a genus of Asian monkeys) in 1989 at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) in Maryland but was found to be nonpathogenic in humans and so did not cause any local cases of illness. Richard Preston's bestselling book about the discovery of RESTV called The Hot Zone (1995), however, made many readers fearful of Ebola and has been criticized by scientists for sensationalizing the physical effects of EVD. Although the book did elicit a major response from WHO regarding the 1976 EBOV outbreak in Zaire, it also contributed to heightened public anxiety when patients who had contracted EVD in West Africa in 2014 came (or returned) to the United States for treatment. The Texas hospital that treated the first patient who arrived in the United States reported a significant surge in visits to the hospital's emergency department within hours of the patient's admission. The total number of people affected was 11: nine who had contracted the disease outside the country, and two who contracted EVD in the United States while caring for a diagnosed patient. Two of the 11 infected persons died, but no one both contracted and died of EVD while in the United States.
Although the number of EVD patients was small, the 11 cases required the tracing of hundreds of contacts, from family members and health care workers to airplane passengers, taxi drivers, and baggage handlers. While the U.S. Army sent 4,000 troops to West Africa to set up modular hospitals for local health care workers, the CDC was also forced to revise its previous standards for infection control measures to contain EVD. The Texas hospital that treated one of the 2014 patients noted that the CDC's guidelines for personal protective equipment and other disinfection precautions were completely inadequate. One of the positive results that came out of the 2014 experience, however, was the establishment of the National Ebola Training and Education Center (NETEC), a consortium of university-based medical centers in Nebraska, Georgia, and New York that offers on-site and online training to prepare health care professionals for the next outbreak of EVD or another dangerous pathogen.
Other responses to the 2014 cases in the United States included stepped-up research into vaccines against EVD and experimental treatments for the disease. In addition, four specialized biocontainment units for inpatient treatment were built within hospitals in Omaha, Nebraska; Bethesda, Maryland; Atlanta, Georgia; and Missoula, Montana.
International efforts to contain the 2013–2014 outbreak built on measures that go back to the nineteenth century, when an international conference was held in Paris in 1851 to deal with cholera epidemics in Europe. After WHO was established in 1948, a more comprehensive set of principles was formulated, known as the International Health Regulations or IHR. The most recent IHR, drawn up in 2005, is in its third edition as of 2018. According to WHO, the purpose of the IHR is “to prevent, protect against, control and provide a public health response to the international spread of disease in ways that are commensurate with and restricted to public health risks, and which avoid unnecessary interference with international traffic and trade.” The 2005 IHR empowers the WHO Director-General to declare a Public Health Emergency of International Concern, or PHEIC, when circumstances warrant. A PHEIC is defined by WHO as “an extraordinary event which is determined to constitute a public health risk to other States through the international spread of disease and to potentially require a coordinated international response.” The 2014 outbreak of EVD prompted the third PHEIC issued by WHO since 2007.
Other international efforts include research into vaccines against Ebola. The Public Health Agency of Canada (PHAC) has funded an experimental vaccine called VSV-EBOV, which is based on an animal virus called the vesicular stomatitis virus or VSV. The vaccine combines the virus with a portion of the protein covering of the Ebola virus; it does not contain live EBOV. Phase 1 studies of the vaccine were completed in 2015. Other investigational vaccines include cAd3-EBO, cAd3-EBOZ, MVA-EbolaZ, and MVA-BN Filo; these vaccines are undergoing field tests in Mali, Kenya, the United Kingdom, Germany, Switzerland, China, Guinea, Liberia, Uganda, Senegal, Sierra Leone, the Russian Federation, Australia, and the United States. There are 60 clinical trials either completed or under way of these vaccines as of mid-2018.
Ebola viruses are also of concern at the international level because of their potential as agents of bioterrorism. On the one hand, these viruses are spread primarily by direct contact with contaminated body fluids rather than airborne particles or insect vectors. This characteristic would make them difficult to weaponize without exposing the terrorists to very high levels of risk. On the other hand, viruses mutate, and it is not impossible that Ebola viruses could mutate into forms that are either more virulent or transmissible through the air—in which case they could be exploited by terrorists.
The prognosis for most patients with EVD is poor, particularly if they are infected with EBOV; however, those who survive for two weeks after symptom onset usually make a slow recovery. Recovery depends partly on the quantity of virus in the patient's initial exposure, partly on how quickly treatment can be started, and partly on the patient's age and immune response. In general, younger patients have a better prognosis than older ones.
The mortality rate of Ebola viruses varies, however; RESTV does not cause symptomatic illness in humans as far as is known. The sole human case of TAFV infection to date fell ill but recovered completely. The outbreaks of SUDV that occurred between 1976 and 2012 had mortality rates that ranged from 41% to 71%. The two known outbreaks of BDBV, in 2007 and 2012, had mortality rates of 25% and 47% respectively. EBOV outbreaks usually have the highest fatality rates; the lowest mortality rate to date with this ebolavirus was 45% (Democratic Republic of the Congo, 2008) and the highest, 90% (Republic of the Congo, 2002). The major outbreak of EBOV that began in 2013 and continued into 2016 had an overall case fatality rate of 71%.
Ebola virus disease is marked by considerable morbidity among survivors. Survivors may experience a range of symptoms during recovery that include pain in the joints and muscles; severe headaches; hearing loss or tinnitus (ringing or buzzing in the ears); extreme fatigue; inflammation of the testicles in men (orchitis) and cessation of menstrual periods (amenorrhea) in women; and inflammation of the salivary glands (parotitis). Long-term complications include uveitis (inflammation of the vascular inner layer of the eye), recurrent hepatitis, persistent muscle pain, and recurrent orchitis.
Other than avoiding travel to areas where EVD outbreaks are known to have occurred, preventive measures against Ebola virus disease are largely limited to infection prevention and control (IPC), as elimination of the animal reservoirs of EBOV and other Ebola viruses is not feasible as of 2018. IPC includes the following measures:
WHO issued interim guidance on IPC during the 2014 Ebola outbreak; the 27-page manual includes detailed instructions for hand hygiene, preparation of disinfectant solutions, and safe use and removal of personal protective equipment. The manual can be downloaded in PDF format at http://apps.who.int/iris/bitstream/10665/130596/1/WHO_HIS_SDS_2014.4_eng.pdf .
See also Globalization and emerging diseases ; Hemorrhagic fevers ; Viruses ; World Health Organization .
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Rebecca J. Frey, PhD