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Epidemiology and pathogenesis of Ebola virus disease

Epidemiology and pathogenesis of Ebola virus disease
Authors:
Mike Bray, MD, MPH
Daniel S Chertow, MD, MPH
Section Editor:
Martin S Hirsch, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Dec 22, 2022.

INTRODUCTION — The family Filoviridae consists of three genera: Ebolavirus and Marburgvirus (which are among the most virulent pathogens of humans) [1-3], and Cuevavirus, which has only been detected in bats in Spain [4]. The genus Ebolavirus consists of six species: Zaire, Sudan, Bundibugyo, Tai Forest, Reston, and Bombali [5]. Of these, only the first four have caused recognized disease in humans; all but the Reston virus are indigenous to Africa. The disease caused by Marburg virus is reviewed elsewhere. (See "Marburg virus".)

The Zaire species of Ebola virus was the first to be discovered [6]. From 1976 through 2013, it caused multiple outbreaks in the Democratic Republic of the Congo (DRC) and neighboring countries in Central Africa, with case fatality rates often approaching 90 percent. Those outbreaks usually involved fewer than 100 cases and were contained within a period of weeks to a few months. In 2014, the Zaire virus appeared in West Africa, producing an epidemic in Liberia, Guinea, and Sierra Leone that took more than two years to bring under control [7]. There were nearly 29,000 total cases (suspected, probable, or confirmed), of which more than 15,000 were laboratory confirmed, and the overall case fatality rate was approximately 40 percent. Since then, the Zaire species has been responsible for additional epidemics, including an outbreak in the Équateur Province of the DRC from May to July 2018, an epidemic in the North Kivu province in the eastern region of the DRC that was recognized in August 2018 and declared over on June 25, 2020, and another outbreak in Équateur Province recognized in early June 2020 and declared over on November 18, 2020 [8,9]. An outbreak caused by Zaire ebolavirus was recognized in the Équateur province of the DRC in April 2022, representing the third outbreak in this province and the sixth in the country since 2018.

The Sudan species of Ebola virus was also discovered in 1976 [10]. In four outbreaks in Uganda and Sudan, case fatality rates have averaged 50 percent. The Bundibugyo species has been responsible for small outbreaks in Uganda and the adjacent DRC [11], while the Ivory Coast virus has caused one nonfatal case [12]. The Reston virus, which has been found in pigs in the Philippines, and the Bombali virus, identified as viral RNA in African bats, are not known to cause disease in humans.

Epidemics typically begin when a human comes into contact with an infected animal or its body fluids [1,3]. However, the persistence of virus in persons who have recovered from Ebola virus disease may potentially be a source of infection for new outbreaks [13-15]. Person-to-person transmission is based upon direct physical contact with the body fluids of a living or deceased patient. Patients typically present with a nonspecific febrile syndrome that may include headache, muscle aches, and fatigue [1,3,16]. Vomiting and diarrhea frequently develop during the first few days of illness and may lead to significant volume losses. A maculopapular rash is sometimes observed. Despite the traditional name of "Ebola hemorrhagic fever," major bleeding is not found in most patients, and severe hemorrhage tends to be observed only in the late stages of disease. Some patients develop progressive hypotension and shock with multiorgan failure, which typically results in death during the second week of illness. By comparison, patients who survive infection commonly begin to show signs of clinical improvement during the second week of illness.

The experience of the 2014 to 2016 West African epidemic demonstrated that the mortality associated with Ebola virus disease may be reduced through adequate supportive care [7]. It also accelerated the investigation of therapies and vaccines for treatment and prevention of the Zaire species of Ebola virus [14,15]. As an example, since then, two different monoclonal antibody therapies were found to be beneficial in the “PALM” clinical trial conducted in the North Kivu epidemic in the DRC [16]. In addition, the rVSV-ZEBOV vaccine, first found to provide significant protection in West Africa, was given to more than 300,000 people during the course of the North Kivu epidemic and to more than 30,000 people during the 2020 outbreak in the Équateur Province [9].

The epidemiology and pathogenesis of Ebola virus disease will be presented here. The clinical manifestations, diagnosis, treatment, and prevention of Ebola virus disease are discussed elsewhere. (See "Clinical manifestations and diagnosis of Ebola virus disease" and "Treatment and prevention of Ebola virus disease".)

CLASSIFICATION — Ebola virus is a nonsegmented, negative-sense, single-stranded RNA virus that resembles rhabdoviruses (eg, rabies) and paramyxoviruses (eg, measles, mumps) in its genome organization and replication mechanisms. It is a member of the family Filoviridae, taken from the Latin "filum," meaning thread-like, based upon their filamentous structure.

In the past, Ebola and Marburg viruses were classified as "hemorrhagic fever viruses," based upon their clinical manifestations, which include coagulation defects, bleeding, and shock. However, the term "hemorrhagic fever" is no longer used to refer to Ebola virus disease because only a small percentage of Ebola patients actually develop significant hemorrhage, and it usually occurs in the terminal phase of fatal illness, when the individual is already in shock. (See "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Clinical manifestations'.)

The genus Ebolavirus is divided into six species (Zaire, Sudan, Tai Forest, Bundibugyo, Reston, and Bombali) [5,17]. The following four species cause disease in humans [18]:

The Zaire virus, since it was first recognized in 1976, has caused multiple large outbreaks in Central Africa, with mortality rates ranging from 55 to 88 percent [19-22]. The Zaire virus was the causative agent of the 2014 to 2016 West African epidemic, and it has caused multiple outbreaks in the Democratic Republic of the Congo (DRC) since 2018. An outbreak caused by Z. ebolavirus was recognized in the Équateur province of the DRC in April 2022, representing the third outbreak in this province and the sixth in the country since 2018 [23]. (See 'Democratic Republic of the Congo' below.)

The Sudan virus has been associated with a case fatality rate of approximately 50 percent in four epidemics: two in Sudan in the 1970s, one in Uganda in 2000, and another in Sudan in 2004 [10,24-27].

The Tai Forest virus has only been identified as the cause of illness in one person in the Ivory Coast, and that individual survived [28]. The exposure occurred when an ethologist performed a necropsy on a chimpanzee found dead in the Tai Forest, where marked reductions in the great ape population had been observed.

The Bundibugyo virus emerged in Uganda in 2007, causing an outbreak of Ebola virus disease with a lower case fatality rate (approximately 30 percent) than is typical for the Zaire and Sudan viruses [29]. Another epidemic with a case fatality rate of 22 percent among confirmed cases occurred in the northeastern DRC in 2012 [29,30]. Sequencing has shown that the agent is most closely related to the Tai Forest species [11].

The fifth Ebola species, the Reston virus, differs markedly from the others, because it is apparently maintained in an animal reservoir in the Philippines and has not been found in Africa [31,32] (see 'Viral reservoirs' below). The Ebola Reston virus was discovered when it caused an outbreak of lethal infection in macaques imported into the United States in 1989. This episode brought the filoviruses to worldwide attention through the publication of Richard Preston's book, The Hot Zone [33]. Three more outbreaks occurred among nonhuman primates in quarantine facilities in the United States and Europe before the Philippine animal supplier ceased operations. None of the animal caretakers who were exposed to sick animals without protective equipment became ill, but several showed evidence of seroconversion consistent with asymptomatic infection.

Nothing further was heard of the Reston virus until 2008, when the investigation of an outbreak of disease in pigs in the Philippines unexpectedly revealed that some of the sick animals were infected both by an arterivirus (porcine reproductive and respiratory disease virus) and by Ebola Reston virus [34]. Serologic studies have shown that a small percentage of Philippine pig farmers have IgG antibodies against the agent without ever developing severe symptoms, providing additional evidence that Ebola Reston virus is able to cause mild or asymptomatic infection in humans.

Similar to the Reston virus, the Bombali virus, which was identified as viral RNA in African bats, is not known to cause disease in humans [5].

EPIDEMIOLOGY

Overview — Filoviral disease of humans is a zoonosis, with bats in east, central, and west Africa as the apparent reservoir hosts. (See 'Viral reservoirs' below.)

Single infections or small clusters of cases may occur frequently within the enzootic region, but since human-to-human transmission requires direct physical contact with virus-containing body fluids of a sick person, these introductions may "burn out" without being diagnosed. Epidemics are typically recognized only after several generations of transmission have occurred, weeks after the initial infection, when a severely ill patient is treated in a medical facility. The initial case usually cannot be retrospectively identified. (See 'West Africa' below and 'Democratic Republic of the Congo' below and 'Uganda' below.)

The filoviruses were first recognized in 1967, when the inadvertent importation of infected monkeys from Uganda resulted in an explosive outbreak of severe illness among vaccine plant workers in Marburg, Germany who came into direct contact with the animals by killing them, removing their kidneys, or preparing primary cell cultures for polio vaccine production [35]. The causative agent, designated Marburg virus, has caused a number of outbreaks in Africa, including one in Uganda that was recognized in the beginning of October 2012 and was contained within a few weeks [36]. (See "Marburg virus".)

The other genus, Ebolavirus, has caused outbreaks in Central, Northeast, and West Africa:

Central Africa – Ebola virus was first recognized when two outbreaks occurred almost simultaneously in Zaire and in Sudan in 1976 [6,10]. An epidemic caused by the Zaire species subsequently caused several hundred cases in 1995 in Kikwit, Democratic Republic of the Congo (DRC) [21]. Additional outbreaks have subsequently occurred in the DRC, as described below. (See 'Democratic Republic of the Congo' below.)

Northeast Africa – The Sudan species of Ebolavirus caused an epidemic in the Sudan in 1976 and has been responsible for several outbreaks in East Africa since that time, including an epidemic of some 400 cases in Gulu, Uganda in 2000 [25,26]. The most recent outbreak was reported in 2022. (See 'Uganda' below.)

West Africa – The 2014 to 2016 Ebola epidemic, caused by the Zaire species of virus, was not only the first to occur in West Africa, but was far larger than all previous outbreaks combined [22]. (See 'West Africa' below.)

In addition to causing human infections, Ebola virus has also spread to wild nonhuman primates, apparently as a result of their contact with an unidentified reservoir host (possibly bats) [37-40]. This has contributed to a reduction in chimpanzee and gorilla populations in Central Africa, and has also triggered some human epidemics due to handling and/or consumption of sick or dead animals by local villagers [37,41]. (See 'Viral reservoirs' below and 'Transmission from animals' below and 'Democratic Republic of the Congo' below.)

West Africa — An Ebola epidemic due to the Zaire species began in the West African nation of Guinea in late 2013 and was confirmed by the World Health Organization (WHO) in March 2014 [22]. Prior to that, all previous Ebola outbreaks caused by the Zaire virus occurred in Central Africa. (See 'Democratic Republic of the Congo' below and 'Overview' above.)

The initial case was believed to have been a two-year-old child who developed fever, vomiting, and black stools, without other evidence of hemorrhage [22]. The epidemic subsequently spread to Liberia, Sierra Leone, Nigeria, Senegal, and Mali. Sequence analysis of viruses isolated from patients indicated that the epidemic resulted entirely from sustained person-to-person transmission, without additional introductions from animal reservoirs [42,43].

Nearly 29,000 probable, suspected, and laboratory-confirmed cases of Ebola virus disease were identified, with more than 11,000 deaths. These cases included 881 infected health care workers, of whom approximately 60 percent died. The magnitude of the epidemic, especially in Liberia and Sierra Leone, was probably underestimated, due in part to individuals with Ebola virus disease being cared for outside the hospital setting early in the epidemic.

In Guinea, Liberia, and Sierra Leone, there was widespread Ebola virus transmission, and the rate of new infections did not slow significantly until the spring of 2015. Extended periods of disease-free transmission were subsequently reported. In certain nearby countries (Senegal, Nigeria, Mali), introductions of Ebola virus resulted in short chains of person-to-person transmission, which were quickly terminated.

The end of the epidemic was officially recognized in early 2016. However, sporadic cases continued to be detected, which were attributed to sexual transmission from survivors with persistent virus [44]. (See 'Convalescent period' below.)

During the epidemic, cases of Ebola virus disease occurred in residents and health care workers who were exposed to the virus in West Africa and were then treated in hospitals in the United States and Europe [45-47]. As an example, on September 30, 2014, the first travel-associated case of Ebola was reported in the United States. An individual who was asymptomatic while traveling from Liberia to Dallas, Texas developed clinical findings consistent with Ebola virus disease approximately five days after arriving in the United States and subsequently died. Two nurses involved in his care developed Ebola virus disease but recovered.

Measures that appear to have contributed to the control of the epidemic include the introduction of infection control precautions in hospitals, instructions to the population regarding safe funeral practices, and the use of Ebola treatment units and community care centers to help isolate patients with suspected or confirmed infection [48-50]. (See "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

Democratic Republic of the Congo — Since 1976, there have been multiple recognized outbreaks of Ebola virus disease in the DRC. These have usually involved fewer than 100 cases and have been contained within a period of weeks to a few months. All but one were caused by the Zaire strain of the virus.

Several outbreaks due to the Zaire species have been reported since early 2018. These include:

An outbreak in the Équateur Province was detected in early May 2018, leading to an intensive response by the DRC Ministry of Health, the WHO, Médecins Sans Frontières, and other international organizations to rapidly establish treatment facilities, case finding, and contact tracing to prevent further transmission. The end of the outbreak was announced on July 24, 2018 [51]. Of the 38 confirmed and 16 probable cases, there were 33 deaths (a case fatality rate of 61 percent). Notably, ring vaccination with the vesicular stomatitis virus-Zaire Ebola virus (VSV-Ebola) vaccine was begun less than two weeks after the outbreak was confirmed; nearly 4000 health care workers, contacts of patients, and their contacts received the vaccine.

A subsequent outbreak was reported on August 1, 2018 in the North Kivu Province, which is located in the northeastern region of the country, bordering Rwanda and Uganda, where long-term armed conflicts have produced large numbers of refugees [8,52]. On June 11, 2019, the WHO reported that the outbreak spread to the Kasese District of Uganda, which borders the DRC; however, all of the cases were imported from the DRC, and there were no transmission or secondary cases in Uganda. During this outbreak, mobile field laboratories and Ebola treatment centers were rapidly established, and vaccination of health care workers and close contacts of patients using the VSV-Ebola vaccine (sold as Ervebo) was initiated. When the epidemic was declared over on June 25, 2020, there had been 3470 confirmed cases with 2287 deaths, a fatality rate of 66 percent [53]. Of those cases, approximately 57 percent were female, 29 percent were younger than 18 years of age, and 5 percent were health care workers. During the North Kivu epidemic, medical workers investigated some 250,000 case contacts, tested 220,000 blood samples, and vaccinated more than 300,000 people.

On June 1, 2020, an outbreak of Ebola virus disease was identified in Mbandaka, Équateur Province of the DRC, the same region in which an epidemic was reported in May 2018, as described above. In contrast to the earlier outbreak, cases were widely distributed within the province, occurring in 13 of the 18 health zones. By the time it was declared over on November 18, 2020, there had been 119 confirmed and 11 probable cases, with 55 deaths. More than 40,000 people at high risk of infection were given the VSV-Ebola vaccine.

On February 7, 2021, an outbreak of Ebola virus disease was identified in the North Kivu region. After the occurrence of 11 confirmed cases and six deaths, and the administration of 2000 doses of vaccine to persons at risk, the outbreak was declared over on May 3, 2021. Virus sequencing suggests that it had resulted from transmission of virus from a survivor of the 2014 to 2016 epidemic and not through the introduction from an animal reservoir [54]. In October 2021, a cluster of Ebola cases in the same area was recognized and quickly contained; these cases originated from persistent virus in a survivor of an earlier epidemic in North Kivu [23]. As discussed below, numerous instances of persist infectious virus in the semen of male survivors have been recognized. (See 'Convalescent period' below.)

On April 23, 2022, the Ministry of Health of the DRC declared an outbreak of Ebola virus disease in the northwestern Equateur province. Full genome sequencing of the virus performed at the INRB (Institut National de Recherche Biomédicale) in Kinshasa has shown that this outbreak is due to a new spillover event from an animal source and not from viral persistence in a survivor. This outbreak was declared over in July 2022.

Subsequent cases have continued to be reported [55]. Updated information on outbreaks of Ebola virus disease can be found on the WHO website. Discussions of vaccines and therapies are presented in a separate topic review. (See "Treatment and prevention of Ebola virus disease", section on 'Ebola vaccines' and "Treatment and prevention of Ebola virus disease", section on 'Ebola-specific therapies'.)

Uganda — The Sudan species of Ebolavirus has been responsible for several outbreaks in East Africa, including an epidemic of some 400 cases in Gulu, Uganda, in 2000 [25,26] and a subsequent outbreak in 2012.

On September 20, 2022, an outbreak of Ebola disease caused by Sudan virus was reported in Uganda [56]. As of November 7, 2022 there were 136 confirmed cases, with 53 confirmed deaths [57]. The first recognized patient became ill on the 11th of September, with high fever, vomiting, diarrhea, and other signs consistent with Ebola disease. A positive RT-PCR test for Sudan virus was obtained on September 19th, the day of his death. The patient was diagnosed in Mubende district, where similar cases appear to have been reported as early as the beginning of September.

The 2022 outbreak is of particular concern since it is likely that there were undetected chains of transmission over several weeks and the potential wide mobility of infected individuals who were asymptomatic, including men working in local gold mines. In addition, available countermeasures, such as vaccination, are more limited than those employed in recent Ebola epidemics in the Democratic Republic of the Congo. As an example, the single-dose recombinant vesicular stomatitis virus vaccine, which elicits a rapid immune response against the Zaire virus, is not expected to protect against the Sudan virus. Although a two-dose vaccine approved by the European Medicines Agency expresses the Sudan virus surface glycoprotein among other antigens, it requires a 56-day interval between doses and would thus offer little protection in a rapidly spreading outbreak.

Updated information on the Uganda outbreak can be found on the WHO website. A detailed discussion of available Ebola virus vaccines is presented in a separate topic review. (See "Treatment and prevention of Ebola virus disease", section on 'Ebola vaccines'.)

VIRAL RESERVOIRS — Perhaps the greatest mysteries regarding the filoviruses are the identity of their natural reservoir(s) and the mode of transmission to wild apes and humans [17,39]. While Marburg virus has been isolated directly from bats captured in Uganda [58], only Ebola virus RNA sequences, not infectious virus, have been detected in samples collected from bats in Central Africa, and none have been isolated in West Africa [59,60]. Nevertheless, data suggest that bats are at least one of the reservoir hosts of Ebola viruses in Africa [61]. The transmission pathway from bats to humans and the possible role of bats in the initiation of Ebola outbreaks have not been defined.

TRANSMISSION — Epidemics of Ebola virus disease are generally thought to begin when an individual becomes infected through contact with the tissues or body fluids of an infected animal. Once the patient becomes ill or dies, the virus then spreads to others who come into direct contact with the infected individual’s blood, skin, or other body fluids. Studies in laboratory primates have found that animals can be infected with Ebola virus through droplet inoculation of virus into the mouth or eyes [62,63], suggesting that human infection can result from the inadvertent transfer of virus to these sites from contaminated hands. Persistence of virus in semen can also transmit infection. (See 'Convalescent period' below.)

Prior to the epidemic in West Africa, outbreaks of Ebola virus disease were typically controlled within a period of a few weeks to a few months. This outcome was generally attributed to the fact that most outbreaks occurred in remote regions with low population density, where residents rarely traveled far from home. However, the West African epidemic showed that Ebola virus disease can spread rapidly and widely as a result of the extensive movement of infected individuals (including undetected travel across national borders), the spread of the disease to densely populated urban areas, the avoidance and/or lack of adequate personal protective equipment (PPE), and the absence of dedicated medical isolation centers. (See "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

Person-to-person — Person-to-person transmission is principally associated with direct contact with the body fluids of individuals, who are ill with Ebola virus disease or have died from the infection, in the absence of PPE [64,65]. Those who provide hands-on medical care or prepare a cadaver for burial are at greatest risk. As examples:

In a meta-analysis of Ebola virus transmission among household contacts that included nine studies, the secondary attack rates for those providing nursing care was 47.9 percent compared with 2.1 percent for those household members who had direct physical contact but did not provide nursing care [66].

The ritual washing of Ebola victims at funerals has played a significant role in the spread of infection in past outbreaks and contributed to the epidemic in West Africa. As an example, a single funeral ceremony in late 2014 in Guinea was linked to 85 subsequent cases of Ebola virus disease [67].

During the early phase of the West African epidemic, several hundred African doctors and nurses who performed patient care without appropriate personal protection acquired Ebola virus disease. (See 'West Africa' above and 'Nosocomial transmission' below.)

A retrospective study of intra-household transmission in the West African epidemic found that the spread of infection was more likely in larger households [68]. In addition, more transmissions resulted from older patients and those with severe disease. The estimated secondary attack rate was 18 percent.

Men who have recovered from Ebola virus infection can also be a source of virus transmission through semen. (See 'Convalescent period' below.)

Risk of transmission through different body fluids — The likelihood of infection depends, in part, upon the type of body fluid to which an individual is exposed and the amount of virus it contains. Transmission is most likely to occur through direct contact of broken skin or unprotected mucous membranes with virus-containing body fluids from a person who has developed signs and symptoms of illness.

Acute infection — According to the World Health Organization, the most infectious body fluids are blood, feces, and vomitus. Infectious virus has also been detected in urine, semen, saliva, aqueous humor, vaginal fluid, and breast milk [45,69-72]. Reverse-transcription polymerase chain reaction (RT-PCR) testing has also identified viral RNA in tears and sweat, suggesting that infectious virus may be present.

Ebola virus can also be spread through direct contact with the skin of a patient, but the risk of developing infection from this type of exposure is thought to be lower than from exposure to blood or body fluids. Virus present on the skin surface might result either from viral replication in dermal and epidermal structures, contamination with blood or other body fluids, or both.

The risk of Ebola transmission also depends upon the quantity of virus in the fluid. During the early phase of illness, the amount of virus in the blood may be quite low, but levels then increase rapidly and may exceed 108 RNA copies/mL of serum in severely ill and moribund patients [73]. Epidemiologic studies have found that family members were at greatest risk of infection if they had physical contact with sick relatives (or their body fluids) during the later stages of illness or helped to prepare a corpse for burial [64,68].

Discussions of how to prevent transmission of Ebola virus during acute infection are found elsewhere. (See "Treatment and prevention of Ebola virus disease", section on 'Infection control precautions during acute illness'.)

Convalescent period — Infectious virus or viral RNA can persist in some body fluids of patients recovering from Ebola virus disease even after it is no longer detected in blood. As examples:

Follow-up studies of approximately 40 survivors in the 1995 outbreak in Kikwit, Democratic Republic of the Congo found that viral RNA sequences could be detected by RT-PCR in the semen of male patients for up to three months, and infectious virus was recovered from the semen of one individual 82 days after disease onset [69].

A study of patient samples collected during the outbreak of Ebola Sudan virus disease in Gulu, Uganda in 2000 detected virus in the breast milk of a patient even after virus was no longer detectable in the bloodstream [70]. Two children who were breastfed by infected mothers died of the disease.

During the 2014 to 2016 outbreak in West Africa, infectious virus or viral RNA was detected in several sites. These include:

Semen – The persistence of Z. ebolavirus in the semen of survivors has been evaluated in several studies. In a sample of 93 men who were discharged from an Ebola treatment center, virus was detected in semen up to nine months after discharge; however, the percentage of patients with persistent virus and the level of virus detected in semen decreased over time [74]. In another study that evaluated a cohort of 267 male survivors, viral RNA was detected in the semen of 30 percent of survivors an average of 19 months following acute Ebola virus disease illness [75]. Many of these men (44 percent) had two negative tests followed by a positive test, and one man had viral RNA detected in semen 40 months after acute illness. In one report, the concentration of viral RNA in semen during early recovery was 4 logs higher than in blood during peak infection [76].

Aqueous humor – Ebola virus RNA was detected and infectious virus isolated from the aqueous humor of a patient with uveitis 14 weeks after the onset of Ebola symptoms and 9 weeks after viremia had resolved [71].

Cerebrospinal fluid – A patient who had recovered from Ebola virus disease developed meningitis approximately 10 months after her initial diagnosis, and infectious virus was recovered from the cerebrospinal fluid [77].

Urine – Ebola virus was cultured from a patient's urine 26 days after the onset of symptoms, which was nine days after the plasma RNA level became negative [45].

Transmission from persistent virus from semen has been shown to occur, but the risk is not well established. As one example, a patient in the 2014 to 2016 West African epidemic who had viral RNA in his semen at least 199 days after symptom onset transmitted Ebola virus to one, but not another, of his sexual contacts [78,79]. The transmission occurred approximately five months after his blood tested negative for Ebola virus.

Similarly, a retrospective study of the 2018-2020 outbreak in the North Kivu region of the Democratic Republic of the Congo (DRC) has supported the potential epidemiologic importance of persistent virus [13]. One man who developed Ebola virus disease despite prior vaccination, and who recovered following treatment with the monoclonal antibody mAb114, relapsed six months later and died from the disease. Sequence analysis showed that the same virus strain persisted in the patient throughout his illness, and during his convalescence, he was the source of a transmission chain that resulted in 91 additional cases.

The outbreak declared in Guinea on February 14, 2021 also appears to have been initiated by the persistence of virus in an individual who developed Ebola virus disease during the 2014 to 2016 epidemic. (See 'West Africa' above.)

Discussions of how to prevent transmission of Ebola virus during the convalescent period are found elsewhere. (See "Treatment and prevention of Ebola virus disease", section on 'Prevention'.)

Risk of transmission through contact with contaminated surfaces — Ebola virus may be transmitted though contact with contaminated surfaces and objects. The US Centers for Disease Control and Prevention (CDC) indicates that virus on surfaces may remain infectious from hours to days. There are no high-quality data to confirm transmission through exposure to contaminated surfaces, but it is clear that the potential risk can be greatly reduced or eliminated by proper environmental cleaning. (See "Treatment and prevention of Ebola virus disease", section on 'Environmental infection control'.)

Risk of airborne transmission — There are no reported cases of Ebola virus being spread from person to person by the respiratory route. However, laboratory experiments have shown that Ebola virus released as a small-particle aerosol is infectious for rodents and nonhuman primates [80,81]. Health care workers may therefore be at risk of Ebola virus disease if exposed to aerosols generated during medical procedures.

Nosocomial transmission — Transmission to health care workers may occur when appropriate PPE is not available or is not properly used, especially when caring for a severely ill patient who is not recognized as having Ebola virus disease.

During the epidemic in West Africa, a large number of doctors and nurses became infected with Ebola virus (see 'West Africa' above). In Sierra Leone, the incidence of confirmed cases over a seven-month period was approximately 100-fold higher in health care workers than in the general population [82]. Several factors accounted for these infections, including errors in triage and/or failure to recognize patients and corpses with Ebola virus disease, delayed laboratory diagnosis, limited availability of appropriate PPE and hand washing facilities, and inadequate training about safe management of contaminated waste and burial of corpses.

Medical procedures played a major role in some past Ebola epidemics by amplifying the spread of infection.

An example of an iatrogenic point-source outbreak occurred in 1976, when an individual infected with Ebola virus was among the patients treated in a small missionary hospital in Yambuku, Zaire [83]. At this hospital, the medical staff routinely injected all febrile patients with antimalarial medications, employing syringes that were rinsed in the same pan of water, then reused. Virus from the index case was transmitted simultaneously to nearly 100 people, all of whom developed Ebola virus disease and died [84]. Infection then spread to family caregivers, hospital staff, and those who prepared bodies for burial.

A different type of iatrogenic amplification occurred in 1995 in Kikwit, Democratic Republic of the Congo, when a patient was hospitalized with abdominal pain and underwent exploratory laparotomy [21]. The entire surgical team became infected, probably through unprotected respiratory exposure to aerosolized blood. Once those persons were hospitalized, the disease spread to hospital staff, patients, and family members through direct physical contact.

Despite these dramatic episodes of nosocomial transmission, other hospital-based experiences have demonstrated a much lower incidence of secondary spread. As an example, when a patient with unrecognized Ebola virus disease was treated in a South African hospital in 1998, only one person became infected among 300 potentially exposed health care workers [85,86]. A similar observation was made when a patient with an unrecognized infection with Marburg virus, a closely related filovirus, was treated in a South African hospital in 1975, resulting in the spread of infection to only two people with close physical contact [87].

Assistance from the international medical community has played an important role in controlling large epidemics in Africa. In the past, intervention strategies focused largely on helping local health care workers to identify Ebola patients, transfer them to isolation facilities, provide basic supportive care, monitor all persons who had been in direct contact with cases, and rigorously enforce infection control practices [88-90]. During the West African epidemic, the massive international response made it possible to supplement isolation procedures with more effective supportive care [91].

The subsequent outbreaks in the DRC have also benefited from a response from international aid organizations. In the epidemic in the North Kivu region, patient care included enrollment in a randomized trial of four potential therapies, of which two (REGN-EB3 and mAb114, both monoclonal antibody preparations) provided a significant survival benefit [92,93]. These agents have been approved by the US Food and Drug Administration (FDA) for the treatment of Z. ebolavirus infection. (See "Treatment and prevention of Ebola virus disease".)

Transmission from animals

Contact with infected animals — Human infection with Ebola virus can occur through contact with wild animals (eg, hunting, butchering, and preparing meat from infected animals). In Mayibou, Gabon in 1996, for example, a dead chimpanzee found in the forest was butchered and eaten by 19 people, all of whom became severely ill over a short interval [41]. Since that time, several similar episodes have resulted from human contact with infected gorillas or chimpanzees through hunting [94]. To help prevent infection, food products should be properly cooked, since the Ebola virus is inactivated through cooking. In addition, basic hygiene measures (eg, hand washing and changing clothes and boots after touching the animals) should be followed. Some public health messages in West Africa regarding the consumption of "bush meat" have contained incorrect information and may have been counterproductive [95].

Exposure to bats — Direct transmission of Ebola virus infection from bats to wild primates or humans has not been proven. However, Z. ebolavirus RNA sequences and antibodies to the virus have been detected in bats captured in Central Africa [59,60,96]. Bats have been identified as a direct source of human infection with Marburg virus. (See 'Viral reservoirs' above.)

Other routes — Other potential routes of transmission include the following:

Accidental infection of workers in any Biosafety-Level-4 (BSL-4) facility where filoviruses are being studied.

Use of filoviruses as biological weapons [97,98]. (See "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Bioterrorism'.)

There is no evidence that Ebola virus can be transferred from person to person by mosquitoes or other biting arthropods. Epidemics of Ebola virus disease would certainly be much larger and more difficult to control if the virus were transmitted by these mechanisms.

PATHOGENESIS — Because of the difficulty of performing clinical studies under outbreak conditions, most data on the pathogenesis of Ebola virus disease have been obtained from laboratory experiments employing mice, guinea pigs, and nonhuman primates. Case reports and large-scale observational studies of patients in the West African epidemic provided additional data on pathogenesis; observations of disease mechanisms from the epidemic were consistent with findings in animal studies [16,45,46,91,99].

Cell entry and tissue damage — After entering the body through mucous membranes, breaks in the skin, or parenterally, Ebola virus infects many different cell types. Macrophages and dendritic cells are probably the first to be infected; filoviruses replicate readily within these ubiquitous "sentinel" cells, causing their necrosis and releasing large numbers of new viral particles into extracellular fluid (figure 1).

Rapid systemic spread is aided by virus-induced suppression of type I interferon responses [100]. Dissemination to regional lymph nodes results in further rounds of replication, followed by spread through the bloodstream to dendritic cells and fixed and mobile macrophages in the liver, spleen, thymus, and other lymphoid tissues. Necropsies of infected animals have shown that many cell types may be infected, including endothelial cells, fibroblasts, hepatocytes, adrenal cortical cells, and epithelial cells; lymphocytes and neurons are the only major cell types that remain uninfected. Fatal disease is characterized by multifocal necrosis in tissues such as the liver and spleen.

Gastrointestinal dysfunction — Patients with Ebola virus disease commonly suffer from severe vomiting and diarrhea, which can result in acute volume depletion, hypotension, and shock [101]. It is not clear if such dysfunction in Ebola virus disease is the result of viral infection of the gastrointestinal tract, or if it is induced by circulating cytokines, or both. Discussions of the gastrointestinal manifestations of Ebola virus disease and their impact on treatment and prognosis are found elsewhere. (See "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Signs and symptoms' and "Treatment and prevention of Ebola virus disease", section on 'Supportive care' and "Treatment and prevention of Ebola virus disease", section on 'Prognostic factors'.)

Systemic inflammatory response — In addition to causing extensive tissue damage, Ebola virus also produces a systemic inflammatory syndrome by causing the release of cytokines, chemokines, and other proinflammatory mediators from macrophages and other cells [99].

Infected macrophages produce proinflammatory mediators such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, macrophage chemotactic protein (MCP)-1, as well as the vasoactive molecule nitric oxide (NO). These and other substances have also been identified in blood samples from Ebola-infected macaques and from acutely ill patients in Africa [26]. Breakdown products of necrotic cells also stimulate the release of these mediators.

This systemic inflammatory response may play a role in inducing gastrointestinal dysfunction, as well as the diffuse vascular leak and multiorgan failure that are seen later in the disease course. (See 'Gastrointestinal dysfunction' above and "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Clinical manifestations'.)

Coagulation defects — The coagulation defects seen in Ebola virus disease appear to be induced indirectly, through the host inflammatory response. Virus-infected macrophages synthesize cell-surface tissue factor (TF), triggering the extrinsic coagulation pathway; proinflammatory cytokines also induce macrophages to produce TF [99,102]. The simultaneous occurrence of these two stimuli helps to explain the rapid development and severity of the coagulopathy in Ebola virus infection.

Additional factors may also play a role in the coagulation defects that are seen with Ebola virus disease. As examples, blood samples from Ebola-infected monkeys contain D-dimers within 24 hours after virus challenge, and D-dimers are also present in the plasma of humans with Ebola virus disease [102,103]. In Ebola virus-infected macaques, activated protein C is decreased on day two, but the platelet count does not begin to fall until days three or four after virus challenge, suggesting that activated platelets are adhering to endothelial cells. As the disease progresses, hepatic injury may also cause a decline in plasma levels of certain coagulation factors. (See "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Laboratory findings'.)

Impairment of adaptive immunity — Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis helps to explain how filoviruses are able to cause a severe, frequently fatal illness [99]. Ebola virus acts both directly and indirectly to disable antigen-specific immune responses. Dendritic cells, which have primary responsibility for the initiation of adaptive immune responses, are a major site of filoviral replication. In vitro studies have shown that infected cells fail to undergo maturation and are unable to present antigens to naive lymphocytes, potentially explaining why patients dying from Ebola virus disease may not develop antibodies to the virus [26,104-106].

Adaptive immunity is also impaired by the loss of lymphocytes that accompanies lethal Ebola virus infection [104,107,108]. Although these cells appear to remain uninfected, they undergo "bystander" apoptosis, presumably induced by inflammatory mediators and/or the loss of support signals from dendritic cells. A similar phenomenon is observed in septic shock. However, one study has shown that, at least in Ebola-infected mice, virus-specific lymphocyte proliferation still occurs despite the surrounding massive apoptosis, but it arrives too late to prevent a fatal outcome [109]. Discovering ways to accelerate and strengthen such responses may prove to be a fruitful area of research.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ebola virus".)

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Basics topic (see "Patient education: Ebola (The Basics)")

SUMMARY AND RECOMMENDATIONS

Virology – The family Filoviridae contains three genera, Ebolavirus and Marburgvirus, which cause severe disease in humans, and Cuevavirus, which has only been detected as viral RNA in bats in Spain. (See 'Introduction' above.)

The genus Ebolavirus is divided into six species (Zaire, Sudan, Tai Forest, Bundibugyo, Reston, and Bombali). The Zaire species of Ebola virus is among the most virulent human pathogens known. The case-fatality rate in outbreaks has been reported to be as high as 80 to 90 percent. (See 'Classification' above.)

Epidemiology – Most outbreaks of Ebola virus disease have occurred in Central Africa or the Sudan. However, the largest filovirus outbreak on record occurred in West Africa between 2014 and 2016. During the West African epidemic, there was widespread transmission of the Zaire species in Guinea, Liberia, and Sierra Leone, with nearly 29,000 cases of Ebola virus disease identified and more than 11,000 deaths. (See 'West Africa' above.)

Since then, there have been several outbreaks of the Zaire species in the Democratic Republic of the Congo, and an outbreak of the Sudan species in Uganda. (See 'Democratic Republic of the Congo' above and 'Uganda' above.)

Viral reservoirs – The reservoir host of Ebola virus is not known. Evidence is accumulating that various bat species may serve as a source of infection for both humans and wild primates. (See 'Viral reservoirs' above.)

Transmission

Person to person – Person-to-person transmission is principally associated with direct contact with body fluids from patients with Ebola virus disease or from cadavers of deceased patients. Transmission to health care workers may occur when appropriate personal protective equipment (PPE) is not available or is not properly used, especially when caring for a severely ill patient. (See 'Person-to-person' above.)

Infectious virus and/or viral RNA can persist in certain bodily fluids of convalescent patients; such fluids include semen, urine, and breast milk. Several instances of sexual transmission of the virus from convalescent men have been identified, but the risk posed by persistent virus in semen has not been established. (See 'Convalescent period' above.)

Animal to human – Human infection with Ebola virus can also occur through contact with wild animals (eg, hunting, butchering, and preparing meat from infected animals). (See 'Transmission from animals' above.)

Pathogenesis – Almost all data on the pathogenesis of Ebola virus disease have been obtained from laboratory experiments employing mice, guinea pigs, and nonhuman primates. Case reports and large-scale observational studies of patients in the West African epidemic provided additional data on pathogenesis consistent with findings in laboratory animals. (See 'Pathogenesis' above.)

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References