Pathogens

Ebola and Marburg viruses are members of the Filoviridae family.

The Ebolavirus genus includes four human-pathogenic distinct species: Ebola virus, species Zaire ebolavirus (ZEBOV), Bundibugyo virus, species Bundibugyo ebolavirus (BDBV), Taï Forest virus, species Tai Forest ebolavirus (TAFV) and Sudan virus, species Sudan ebolavirus (SUDV). All four species are found in Africa and cause serious illness in humans. In addition, Reston virus, species Reston ebolavirus (RESTV) can cause epizootics reported in the Philippines and China, but Reston virus only causes asymptomatic infection in humans.

The Marburgvirus genus contains only one species, Marburg marburgvirus (MARV), which is responsible for several outbreaks of haemorrhagic fever in Africa.

The Cuevavirus genus of the Filoviridae family contains the Lloviu cuevavirus, another filovirus detected in European bats [2,3]. Recently, two new bat filovirus species were proposed within the Filoviridae family: the Bombali virus, species Bombali ebolavirus (BOMV) found in little free-tailed bats (Chaerephon pumilus) and in Angola free-tailed bats (Mops condylurus) in Bombali District, Sierra Leone [4] and the Měnglà virus, species Mengla dianlovirus (MLAV) identified in liver tissue of a bat (genus Rousettus) from Mengla County, Yunnan Province, China [5]. To date, these viruses are not known to be pathogenic for humans. Further genera of the Filoviridae family (Striavirus genus and Thamnovirus genus) contain filoviruses detected in fishes [6,7].

Ebola virus and Marburg virus are classified as biosafety level 4 (BSL-4) pathogens and require special containment and barrier protection measures for laboratory personnel, as well as for any persons taking care of potentially infected patients or dead bodies.

Clinical features and sequelae

Ebola virus disease

In most cases, an infected patient experiences a sudden onset of flu-like illness, with fever, general malaise and weakness, muscle and joint pains and headache, followed by progressive weakness, anorexia, diarrhoea (watery stools sometimes containing blood and mucus), nausea and vomiting. This first set of symptoms corresponds to the prodromal phase (duration up to 10 days). The next stage of the disease is characterised by symptoms and clinical manifestations from several organ systems. Symptoms can be gastrointestinal (vomiting, diarrhoea, anorexia and abdominal pain), neurological (headaches, confusion), vascular (conjunctival/pharyngeal injections), cutaneous (maculopapular rash) and respiratory (cough, chest pain, shortness of breath) and can include complete exhaustion (prostration). Haemorrhagic manifestations can appear (e.g. bloody diarrhoea, nosebleeds, haematemesis, petechiae, ecchymoses and prolonged bleeding from needle puncture sites). Certain patients develop profuse internal and external haemorrhages and disseminated intravascular coagulation. Patients in the final stage of disease die from a combination of multi-organ failure and hypovolemic shock due to severe fluid losses. Case fatality rates (CFR) vary according to the species of Ebola virus, with ZEBOV exhibiting higher fatality. Based on one literature review, the weighted CFR for Ebola virus disease was assessed to be 65.0% [95% CI (54.0–76.0%)] [8].

Marburg virus disease

Marburg virus disease has an incubation period ranging from 2–21 days (usually 5–10 days). The disease is characterized by a sudden onset of high fever, headache and general malaise. Gastrointestinal symptoms usually appear by the third day (nausea, vomiting, abdominal pain and watery diarrhoea). Approximately five to seven days after the onset of symptoms, patients may exhibit a maculopapular non-itchy rash mostly on their trunk. In severe cases, the central nervous system is involved with confusion, irritability or decreased level of consciousness. Severe haemorrhagic manifestations are observed in many patients. A weighted CFR of 53.8% [95% CI (26.0–80.0%)] has been estimated for Marburg virus disease, but with substantial heterogeneity across outbreaks [8].

Transmission

For both diseases, the spillover from animal to human is a rare event, but subsequent human-to-human transmission can sustain large outbreaks. The typical incubation period for both Ebola and Marburg viruses ranges from 2–21 days. The mean of the incubation period of Ebola virus disease has been estimated for past outbreaks at 6.3 days [13]. Short incubation periods are likely due to exposure to highly contaminated materials (e.g. occupational exposure through needle-stick injuries).

Transmission modes

Ebola and Marburg viruses are highly transmissible by direct contact (e.g. through mucous membranes or broken skin) with blood, other bodily fluids (e.g. saliva, urine, vomit) of living or dead infected persons or any surfaces and materials soiled by infectious fluids [14].

Transmission can also occur by contact with dead or living infected animals, including bushmeat (e.g. monkeys, chimpanzees, forest antelopes and bats) or by visiting caves or mines colonised by bats [15].

Nosocomial transmission can occur. Healthcare workers (HCW) can be infected through improperly protected contact with infected patients. Healthcare settings can play a substantial role in the amplification of the disease, particularly at the beginning of an outbreak before a definitive diagnosis is available and infection prevention and control (IPC) measures for Ebola/Marburg virus diseases are implemented [16]. The risk of infection can be strongly reduced through the appropriate use of infection control precautions and adequate barrier protection. This is especially important when performing invasive procedures.

Ebola and Marburg viruses can persist in immune-privileged sites of certain survivors such as testicles, central nervous system and aqueous humour from which new transmissions can potentially arise, notably through sexual transmission [15,17,18].

In the large West Africa outbreak (2014–2016), it was recognised that there is a spectrum of Ebola virus disease presentations that also include asymptomatic or paucisympotmatic patients, especially in the contacts of confirmed Ebola virus disease cases [8,19]. Asymptomatic infections are considered limited phenomenon for both diseases and likely do not contribute significantly to human-to-human transmission [17,18,20-23].

The presence of these viruses in blood and consequently organs and tissues of asymptomatic, infected or recovered individuals indicates that transmission of Ebola and Marburg viruses via transfusion and transplantation is possible. However, transmission of the viruses through substances of human origin (SoHO) has not been reported.

Filoviruses can survive in liquid or dried material for many days. They are inactivated by gamma irradiation, heating for 60 minutes at 60°C or boiling for five minutes, and are sensitive to lipid solvents, sodium hypochlorite and other disinfectants. Freezing or refrigeration do not inactivate filoviruses.

Reservoirs of Ebola and Marburg viruses

Several fruit bats of the Pteropodidae family in central and western Africa, particularly of the hammer-headed bat species (Hypsignathus monstrosus), Franquet's epauletted fruit bat (Epomops franqueti) and little collared fruit bat (Myonycteris torquata) are considered natural reservoirs [24]. In Africa, human Ebola virus infections have been linked to direct contact with wild gorillas, chimpanzees, monkeys, forest antelopes and porcupines found dead in the rainforest. Ebola viruses (Zaire ebolavirus and Tai Forest ebolavirus) have been detected in the wild in carcasses of chimpanzees in Côte d’Ivoire and the Republic of the Congo, gorillas in Gabon and the Republic of the Congo) and forest antelopes in the Republic of the Congo). Reston ebolavirus caused severe outbreaks in macaque monkeys in the Philippines and asymptomatic infections have been reported in pigs.

Scientific studies implicate African fruit bats, particularly the Egyptian fruit bat or Egyptian rousette (Rousettus aegypticus), as the reservoir of Marburgvirus [9,24]. Several outbreaks were linked to caves or mine locations colonised by bats. The geographic distribution of Marburg virus disease may accordingly correspond to the distribution of Rousettus bats.

Epidemiology

In 1967, isolated cases of VHF occurred among laboratory workers in Europe (Germany and the former Yugoslavia) handling tissues from green monkeys (Chlorocebus aethiops) from Uganda and in medical personnel who attended the laboratory workers. Among the 37 cases, nine died. Marburg virus was isolated and named after the city in Germany, Marburg, where it was first characterised [9]. In 1976, epidemics of severe haemorrhagic fever occurred simultaneously in southern Sudan and the northern part of the Democratic Republic of the Congo, where a new virus, Ebola virus (ZEBOV), was identified and named after a small river in Mongala Province. Later studies showed some differences between the virus isolated in the Democratic Republic of the Congo (ZEBOV) and the virus isolated in Sudan (Sudan virus, SUDV). These viruses were also serologically distinct from the Marburg virus. Multiple outbreaks of Ebola and Marburg virus diseases have been identified since their initial discovery [10].

From 1976–2012, 2 387 cases of Ebola virus disease and 1 590 deaths have been reported (CFR: 66.6%). In March 2014, an outbreak of ZEBOV was reported for the first time in eastern Guinea, then spread in neighbouring countries Sierra Leone and Liberia. According to WHO, 28 616 cases and 11 310 deaths were reported in three West African countries (Guinea, Liberia and Sierra Leone) from 2014–2016 [11]. Since 2014, four unrelated outbreaks were reported in the Democratic Republic of the Congo: two in Équateur Province (2014 and 2018), one in Bas-Uele Province (2017) and one large outbreak in North Kivu and Ituri Provinces (2018–2019).

From 1967–2012, 571 cases of Marburg virus disease including 470 deaths were reported. During this period, outbreaks were reported mainly in the Democratic Republic of the Congo, Democratic Republic of the Congo, Gabon, Sudan and Uganda [12]. Outbreaks of Marburg virus disease occurred in recent years in the Democratic Republic of the Congo, Kenya, Uganda and Angola (2005) and Uganda (2007, 2017).

Diagnosis

Laboratory tests on blood specimens detect viral material (viral genome or antigen) or specific antibodies. Ebola virus disease is diagnosed by the detection of Ebola virus ribonucleic acid (RNA) in whole blood, plasma, or serum during the acute phase of illness, using reverse transcription polymerase chain reaction (RT-PCR) [9]. Viral RNA can usually be detected up to a few days after the disappearance of symptoms. Viral RNA may also be detected in other bodily fluids, such as semen, saliva and urine [25,26]. Throat swabs are suitable for virus detection in deceased patients. Viral RNA has been detected in seminal fluid and in the breast milk of survivors months to years after acute illness, posing a risk for sexual or mother-to-child transmission. Identification of acute infections based on serology is uncommon.

Only a few tests are commercially available. Samples from infected patients should be handled under strict biological containment conditions in biosafety level 3 (e.g. RT-PCR and enzyme-linked immunosorbent assay on non-inactivated samples) or 4 laboratories (virus isolation). Any attempt for viral replication should be handled in biosafety level 4 laboratories [27,28]. For inactivated samples, RT-PCR and ELISA testing can be performed at a BSL2 laboratory facilities. Marburg and Ebola viruses are group 4 biological agents, according to Directive 2000/54/EC of the European Parliament and of the Council [29].

Case management and treatment

No curative treatment is presently available and validated for filovirus infections. Treatment is consequently mainly supportive (oral or intravenous rehydration with solutions containing electrolytes) and severe cases require intensive care. Symptomatic treatment and supportive care with rehydration (oral or intravenous fluids) improves survival.

Several potential treatments (e.g. convalescent serum collected from survivors, immune therapies based on monoclonal antibodies and antiviral drug therapies) and candidate vaccines against Ebola virus disease have been or are currently used as investigational therapeutics evaluated in clinical trials [30,31].

A vaccine based on replication-competent recombinant vesicular stomatitis virus (rVSV) expressing the ZEBOV glycoprotein appears to be a promising candidate for ZEBOV vaccine and potentially for post-exposure treatment. A Phase III efficacy vaccine trial of rVSV-ZEBOV in Guinea applying a ring vaccination strategy demonstrated that the vaccine is highly effective against Ebola virus disease [32]. This investigational vaccine has been recommended by the WHO Strategic Advisory Group of Experts on Immunization under ‘expanded access and compassionate use’ during Ebola virus disease outbreaks in the Democratic Republic of the Congo in 2018 and 2019 [33].

Public health control measures

The goal of Ebola and Marburg virus diseases outbreak control is to interrupt direct human-to-human transmission. Outbreak control activities are based on the early identification and systematic rapid isolation of cases under appropriate IPC measures, timely and comprehensive contact tracing, disinfection of infectious materials and the appropriate use of personal protective equipment. Isolation of infected patients with appropriate IPC measures has been shown to effectively stop the spread of disease in previous outbreaks.

Early and culturally appropriate community engagement and social mobilisation is essential to support outbreak response activities and to enhance the knowledge of affected populations on the risk factors of viral infection and individual protective measures, especially regarding practicing safe and dignified burials.

It is advisable to avoid habitats that may be populated by bats, such as caves or mines in areas/countries where Ebola and Marburg virus diseases are reported, as well as any form of close contact with wild animals, including monkeys, forest antelopes, rodents and bats, both alive and dead, and manipulation or consumption of any type of bushmeat.

Infection control, personal protection and prevention

Healthcare workers have been frequently infected while treating patients with suspected or confirmed Ebola or Marburg virus diseases. This occurred through close contact with patients when IPC measures were not strictly practiced or viral aetiology not yet recognised. The appropriate use of infection control precautions and strict barrier nursing procedures are critical to prevent nosocomial transmission. Implementation of appropriate infection control measures in healthcare settings, including use of personal protective equipment, is effective in minimising the risk for transmission of filoviruses.

Transmission by sexual contact has been documented and male survivors are recommended to practice safe sex for at least 12 months after clinical recovery according to WHO, unless their semen has tested negative on two different occasions [15,34,35]. Sexual transmission events from male survivors with documented ZEBOV RNA persistence in semen beyond 12 months have been reported [17,18], indicating the necessity for documenting the absence of the virus in semen through repeat testing after clinical recovery.

Individuals with evidence of EVD should be excluded from donating blood and other SoHO. Potentially exposed individuals (asymptomatic travellers or residents returning from an Ebola virus disease-affected area, monitored individuals) should be deferred from the donation of SoHO for eight weeks after return or from the beginning of the monitoring period. Due to the possibility of intermittent low-level viraemia after recovery from illness, permanent deferral from the donation of blood, cells and tissues is suggested for donors who have recovered from Ebola virus disease. Organ donation from deceased or live donors recovered from Ebola virus disease should be evaluated individually by assessing the urgency of recipient need, obtaining the donor laboratory test for the presence of filovirus, recipient informed consent, specific post-transplant monitoring and considering the risk for healthcare workers.

Further reading

Articles (in alphabetical order)

Brainard J, Pond K, Hooper L, Edmunds K, Hunter P. Presence and Persistence of Ebola or Marburg Virus in Patients and Survivors: A Rapid Systematic Review. PLoS Negl Trop Dis. 2016 Feb 29;10(2):e0004475.

Den Boon S, Marston BJ, Nyenswah TG, Jambai A, Barry M, Keita S, et al. Ebola Virus Infection Associated with Transmission from Survivors. Emerg Infect Dis. 2019 Feb;25(2):249-55.

Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet. 2011 Mar 5;377(9768):849-62.

Brainard J, Hooper L, Pond K, Edmunds K, Hunter PR. Risk factors for transmission of Ebola or Marburg virus disease: a systematic review and meta-analysis. Int J Epidemiol. 2016 Feb;45(1):102-16.

Fischer WA 2nd, Vetter P, Bausch DG, Burgess T, Davey RT Jr, Fowler R, Hayden FG, et al. Ebola virus disease: an update on post-exposure prophylaxis. Lancet Infect Dis. 2018 Jun;18(6):e183-e192.

Malvy D, McElroy AK, de Clerck H, Gunther S, van Griensven J. Ebola virus disease. Lancet.

2019 Mar 2;393(10174):936-48.

Reynolds P, Marzi A. Ebola and Marburg virus vaccines. Virus Genes. 2017 Aug;53(4):501-515.

Selvaraj SA, Lee KE, Harrell M, Ivanov I, Allegranzi B. Infection Rates and Risk Factors for Infection Among Health Workers During Ebola and Marburg Virus Outbreaks: A Systematic Review. J Infect Dis.

2018 Nov 22;218(suppl_5):S679-S689.

Schindell BG, Webb AL, Kindrachuk J. Persistence and Sexual Transmission of Filoviruses. Viruses. 2018 Dec 2;10(12).

Institutional resources (in alphabetical order)

European Centre for Disease Prevention and Control. Risk assessment guidelines for diseases transmitted on aircraft (RAGIDA) – PART 2: Operational guidelines. Second edition. Stockholm: ECDC; 2010. Available from: http://ecdc.europa.eu/publications-data/technical-guidance-risk-assessment-guidelines-diseases-transmitted-aircraft

European Centre for Disease Prevention and Control. Treatment and vaccines for Ebola virus disease [Internet]. Stockholm: ECDC; 2018 [cited 15 May 2019]. Available from: http://ecdc.europa.eu/ebola-and-marburg-fevers/prevention-and-control/treatment-vaccines

World Health Organization. Ebola virus disease [Internet]. Geneva: WHO; 2018 [cited 15 May 2019]. Available from: http://www.who.int/news-room/fact-sheets/detail/ebola-virus-disease

World Health Organization Regional Office for Africa. Marburg Haemorrhagic Fever [Internet]. Brazzaville: WHO Regional Office for Africa; 2017 [cited 15 May 2019]. Available from: http://afro.who.int/health-topics/marburg-haemorrhagic-fever

World Health Organization. Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation – August 2014. Geneva: WHO; 2014. Available from: http://www.who.int/csr/disease/ebola/manual_EVD

World Health Organization. Interim Infection Prevention and Control Guidance for Care of Patients with Suspected or Confirmed Filovirus Haemorrhagic Fever in Health-Care Settings, with Focus on Ebola –December 2014. Geneva: WHO; 2014. Available from: http://www.who.int/csr/resources/publications/ebola/filovirus_infection…References

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