presentation on ebola virus

European Centre for Disease Prevention and Control

An agency of the European Union

• Infectious disease topics
• Ebola virus disease
• Factsheet about Ebola virus disease

Factsheet about Ebola disease

Ebola disease is caused by a group of viruses within the genus Ebolavirus . This is a rare disease, but can cause outbreaks with high case fatality rates. So far, most outbreaks have occurred in sub-Saharan countries; the largest outbreak having occurred in three West African countries (Guinea, Liberia, and Sierra Leone) between 2013 and 2016, with over 28 000 cases and 11 000 deaths.

Ebola disease is not an airborne disease and is generally not considered to be contagious before the onset of symptoms. Transmission requires direct contact with the organs, blood, secretions or other bodily fluids of infected people/animals or their dead bodies. Therefore, the risk of infection is considered to be very low if strict infection prevention and control precautions are followed.

Clinical illness starts as a flu-like syndrome, often rapidly evolving to severe disease with haemorrhagic symptoms. Two vaccines against Ebola disease due to Zaire ebolavirus have been granted market authorisations by the EU. There are no licensed vaccines against Ebola disease due to the other ebolavirus species.

The pathogen

The Ebolavirus genus is a member of the  Filoviridae  family.

It includes four distinct species that are pathogenic to humans:  Zaire ebolavirus ,  Bundibugyo ebolavirus ,  Taï Forest ebolavirus   and  Sudan ebolavirus . All four species are found in Africa and cause serious illness in humans. In addition,  Reston ebolavirus can cause epizootics, but only causes asymptomatic infection in humans. So far, Reston ebolavirus outbreaks have only been reported in Asia.

Ebolaviruses are classified as a biosafety level 4 (BSL-4) pathogen and require special containment and barrier protection measures for laboratory personnel and  anyone taking care of potentially infected patients or handling dead bodies [1].

Clinical features and sequelae

In most cases, an infected patient experiences a sudden onset of flu-like illness, with

• general malaise and weakness
• muscle and joint pains

This is followed by

• progressive weakness
• diarrhoea (watery stools that sometimes contain 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 and confusion)
• vascular (conjunctival/pharyngeal injections)
• cutaneous (maculopapular rash)
• respiratory (cough, chest pain and shortness of breath) and can include complete exhaustion (prostration).

Haemorrhagic manifestations can also 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 the disease die from a combination of multi-organ failure and hypovolemic shock due to severe fluid losses. Based on one systematic review, the weighted case fatality rate (CFR) for Ebola disease (all species included but Reston ebolavirus ) was assessed to be 65.0% [95% CI (54.0–76.0%)] [2]. The CFR varies depending on the virus species, with Zaire ebolavirus exhibiting the highest fatality rate (75%), followed by Sudan ebolavirus (53%) [2].

In rare instances, infected individuals may remain asymptomatic or paucisymptomatic [2,3].

Transmission 

A spill-over from animal to human is a rare event, but subsequent human-to-human transmission can sustain large outbreaks. The typical incubation period ranges from 2 to 21 days and the mean incubation period has been estimated at 6.3 days [4]. Short incubation periods are likely due to exposure to highly contaminated materials (e.g. occupational exposure through needle-stick injuries).

Transmission modes

Ebolaviruses are highly transmissible by direct contact with the blood (e.g. through mucous membranes or broken skin), or other bodily fluids (e.g. saliva, urine or vomit) of infected people, their dead bodies, or any surfaces and materials soiled by infectious fluids [5].

Transmission can also occur through contact with infected animals (living or dead), including the consumption and/or handling of bushmeat (e.g. monkeys, apes, forest antelopes and bats) or by visiting caves or mines colonised by bats [6].

Healthcare workers can be infected by nosocomial transmissions which can occur as a result of contact with infected patients without wearing the proper protection. Healthcare settings can play a substantial role in the amplification of the disease, particularly at the beginning of an outbreak of Ebola disease before a definitive diagnosis is available and infection prevention and control (IPC) measures have been implemented [7]. The risk of infection can be significantly reduced through the appropriate use of infection control precautions and adequate barrier protection. This is especially important when performing invasive procedures.

Ebolaviruses can persist in immune-privileged sites (e.g. testicles, central nervous system and aqueous humour) of some survivors and, as a result, new transmissions can potentially arise, notably through sexual transmission [6,8,9].

Asymptomatic infections are a limited phenomenon and probably do not contribute significantly to human-to-human transmission [8-13].

The presence of the virus in the blood and, consequently, the organs and tissues of asymptomatic, infected or recovered individuals indicates that transmission of the virus via transfusion and transplantation is possible, although this has not been reported to date.

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 does not inactivate filoviruses.

Reservoirs of ebolaviruses

Several fruit bats of the Pteropodidae family in central and western Africa, particularly the hammer-headed bat species ( Hypsignathus monstrosus ), Franquet's epauletted fruit bat ( Epomops franqueti ) and the little collared fruit bat ( Myonycteris torquata ) are considered natural reservoirs for ebolaviruses [14].

In Africa, human infections have been linked to direct contact with wild gorillas, chimpanzees, monkeys, forest antelopes and porcupines found dead in the rainforest. Zaire ebolavirus and Sudan ebolavirus have been detected in the wild in the 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 has caused major outbreaks in macaque monkeys in the Philippines, while asymptomatic infections have been reported in pigs.

Epidemiology

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 was identified and named after a small river called Ebola, in the Mongala province. Later studies showed some differences between the virus isolated in the Democratic Republic of the Congo ( Zaire ebolavirus ) and the virus isolated in Sudan ( Sudan ebolavirus ). Multiple outbreaks of Ebola disease have been identified since its initial discovery [15].

Ebola disease due to Zaire ebolavirus is referred as Ebola virus disease. Large autochthonous outbreaks of Ebola virus disease have so far been reported in the Democratic Republic of the Congo, Gabon, Guinea, Liberia, the Republic of the Congo and Sierra Leone.

To date, the largest reported outbreak of Ebola virus disease occurred in the three West African countries (Guinea, Liberia and Sierra Leone) from 2013 through 2016, with over 28 000 cases and 11 000 deaths [15,16].

Ebola disease due to Sudan ebolavirus is referred as Sudan virus disease. Outbreaks of Sudan virus disease have been reported in Sudan and Uganda [15].

Ebola disease due to Bundibugyo ebolavirus and Taï Forest ebolavirus is referred to as Bundibugyo virus disease and Taï Forest virus disease, respectively. Outbreaks of Bundibugyo virus disease have been reported in the Democratic Republic of the Congo and Uganda; and outbreaks of Taï Forest virus disease have been reported in Côte d’Ivoire [15].

Sporadic imported cases of Ebola virus disease have also been reported in several non-endemic African and non-African countries. In some instances, short chains of transmission have occurred in countries such as Mali, Nigeria, Senegal, Uganda, South Africa, Spain, Italy, the United Kingdom and the United States [15].

Diagnostics

Laboratory tests on blood specimens detect viral material (viral genome or antigen) or specific antibodies. Ebola disease is diagnosed by the detection of ebolavirus ribonucleic acid (RNA) in whole blood, plasma or serum during the acute phase of illness, using reverse transcription polymerase chain reaction (RT-PCR) tests. 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 or urine [17,18]. 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. This poses a risk of sexual or mother-to-child transmission. Identification of acute infections based on serology is uncommon.

Only a few diagnostic tests are commercially available for Ebola disease and these are specific to Ebola virus disease. According to Directive 2000/54/EC of the European Parliament and of the Council, the ebolaviruses are group 4 biological agents [1]. Therefore, 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 level 4 laboratories (virus isolation). Any attempt at viral replication should be handled in biosafety level 4 laboratories [19] [20]. For inactivated samples, RT-PCR and ELISA testing can be performed at a laboratory with BSL-2 facilities.

Case management and treatment

Advances have been made in the treatment of the Ebola virus disease. Two drugs were trialled in the PALM study (‘Pamoja Tulinde Maisha’, which in Kiswahili means ‘Together Save Lives’) during the 2018–20 Ebola outbreak in the Democratic Republic of the Congo [20]. The study showed that both the drugs drastically reduce death rates of Ebola virus disease due to ZEBOV and can be used for both adults and children [21].

The first of the two treatments, Inmazeb (formerly REGN-EB3), is manufactured by Regeneron Pharmaceuticals. It is a mixture of three monoclonal antibodies (atoltivimab, maftivimab, and odesivimab-ebgn). The drug was approved for use in the US in October 2020 [22].

Ebanga (Ansuvimab-zykl), the second drug used in the PALM study, is manufactured by Ridgeback Biotherapeutics. It is a human monoclonal antibody (mAb114). The drug was approved for use in the US on 21 December 2020 [23].

To date there are no treatments approved against Ebola virus disease due to species other than ZEBOV.

Public health control measures

The goal of Ebola disease 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, through

• appropriate infection prevention and control (IPC) measures
• timely and comprehensive contact tracing
• disinfection of infectious materials
•  use of personal protective equipment.

In previous outbreaks, isolation of infected patients and the implementation of appropriate IPC measures has been shown to effectively stop the spread of disease.

Early and culturally-relevant community engagement and social mobilisation is essential for the support of outbreak response activities. This is also useful in enhancing the knowledge of affected populations on the risk factors of viral infection and the individual protective measures that they can adopt, especially regarding safe and dignified burial practices.

It is advisable to avoid habitats that may be populated by bats, such as caves or mines in areas/countries where ebolaviruses might be present. The handling or consumption of any type of bushmeat should be avoided, as should close contact with wild animals (such as monkeys, forest antelopes, rodents and bats - alive or dead).

Infection control, personal protection and prevention

Healthcare settings.

Healthcare workers have frequently been infected while treating patients with cases of suspected or confirmed Ebola disease. This occurs through close contact with patients where IPC measures are not strictly implemented or viral aetiology has not yet been recognised.

The appropriate use of infection control precautions and the application of strict barrier nursing procedures are critical to preventing nosocomial transmission. Implementation of appropriate infection control measures in healthcare settings, including use of personal protective equipment, will minimise the risk of transmission of ebolaviruses.

Sexual contact

For Zaire ebolavirus transmission by sexual contact has been documented and the World Health Organization (WHO) recommends that male survivors practise safe sex for at least 12 months after clinical recovery, unless their semen has tested negative on two separate occasions [6,25,26]. Sexual transmission events have also been reported in male survivors with documented Zaire ebolavirus RNA persistence in semen after 12 months [3,9], indicating the need to document the absence of the virus in semen through repeated testing after clinical recovery.

Substances of human origin

Individuals with evidence of Ebola disease should not donate blood and other substances of human origin (SoHO). Potentially exposed individuals (those being monitored, asymptomatic travellers or residents returning from an Ebola disease-affected area) should defer 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 of the donation of blood, cells and tissues is suggested for donors who have recovered from Ebola disease.

Organ donation from deceased individuals or live donors who have recovered from Ebola disease should be evaluated individually by assessing the urgency of the recipients’ need; obtaining donor laboratory tests to flag the presence of filovirus; acquiring informed consent from the recipient and performing specific post-transplant monitoring. The risk to healthcare workers should also be considered.

Significant developments have been made for the prevention of Ebola disease (Zaire ebolavirus) , with two vaccines now licensed for use in several countries [27].

The first of these vaccines is the Ervebo vaccine, which is a recombinant rVSVΔG-ZEBOV-GP live vaccine manufactured by Merck. It is a vector vaccine, expressing the surface glycoprotein of Zaire ebolavirus in a recombinant vesicular stomatitis virus construct [28]. It is administered as a single-dose vaccine by intramuscular injection, and was prequalified by WHO on 12 November 2019. This means that the vaccine meets the standards required by WHO in terms of quality, safety and efficacy, facilitating its procurement for at-risk countries.

The EU has authorised the use of the vaccine [29], as has the United States [30], Burundi, Central African Republic, the Democratic Republic of the Congo, Ghana, Guinea, Rwanda, Uganda and Zambia [31]. Over 40 000 individuals in the Democratic Republic of the Congo were vaccinated with Ervebo during the tenth and eleventh Ebola disease outbreaks, which occurred August 2018 − June 2020 and June − November 2020 respectively [32].

The second vaccine is a two-component vaccine manufactured by Janssen: the prime component is Zabdeno (Ad26.ZEBOV) and the booster component is Mvabea (MVA-BN-Filo) [33] [34]. These first and second components are vector vaccines using primate adenovirus and modified vaccinia Ankara (MVA) viruses as backbones, respectively. This two-dose vaccine regimen was licensed for use in the EU on 1 July 2020.

To date there are no vaccines approved against Ebola disease due to species other than Zaire ebolavirus .

Further reading

Institutional resources.

Technical guidance on risk assessment guidelines for diseases transmitted on aircraft (RAGIDA) - ECDC .

Ebola virus disease - WHO

Ebola and Marburg virus disease epidemics: preparedness, alert, control, and evaluation - WHO

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 - WHO

1. Consolidated text: Directive 2000/54/EC of the European Parliament and of the Council of 18 September 2000 on the protection of workers from risks related to exposure to biological agents at work (seventh individual directive within the meaning of Article 16(1) of Directive 89/391/EEC). Brussels: EC. Available at: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A02000L0054-20200624

2. Nyakarahuka L, Kankya C, Krontveit R, Mayer B, Mwiine FN, Lutwama J, et al. How severe and prevalent are Ebola and Marburg viruses? A systematic review and meta-analysis of the case fatality rates and seroprevalence. BMC Infect Dis. 2016 Nov 25;16(1):708. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27887599

3. Diallo MSK, Rabilloud M, Ayouba A, Toure A, Thaurignac G, Keita AK, et al. Prevalence of infection among asymptomatic and paucisymptomatic contact persons exposed to Ebola virus in Guinea: a retrospective, cross-sectional observational study. Lancet Infect Dis. 2019 Mar;19(3):308-16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30765243

4. Van Kerkhove MD, Bento AI, Mills HL, Ferguson NM, Donnelly CA. A review of epidemiological parameters from Ebola outbreaks to inform early public health decision-making. Sci Data. 2015;2:150019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26029377

5. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26589246

6. World Health Organization. Ebola virus disease fact sheet. Geneva: WHO; 2021. Available at: https://www.who.int/en/news-room/fact-sheets/detail/ebola-virus-disease

7. 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-S89. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30202878

8. Diallo B, Sissoko D, Loman NJ, Bah HA, Bah H, Worrell MC, et al. Resurgence of Ebola Virus Disease in Guinea Linked to a Survivor With Virus Persistence in Seminal Fluid for More Than 500 Days. Clin Infect Dis. 2016 Nov 15;63(10):1353-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27585800

9. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30500321

10. Glynn JR, Bower H, Johnson S, Houlihan CF, Montesano C, Scott JT, et al. Asymptomatic infection and unrecognised Ebola virus disease in Ebola-affected households in Sierra Leone: a cross-sectional study using a new non-invasive assay for antibodies to Ebola virus. Lancet Infect Dis. 2017 Jun;17(6):645-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28256310

11. Mbala P, Baguelin M, Ngay I, Rosello A, Mulembakani P, Demiris N, et al. Evaluating the frequency of asymptomatic Ebola virus infection. Philos Trans R Soc Lond B Biol Sci. 2017 May 26;372(1721) Available at: https://www.ncbi.nlm.nih.gov/pubmed/28396474

12. Group PIS, Sneller MC, Reilly C, Badio M, Bishop RJ, Eghrari AO, et al. A Longitudinal Study of Ebola Sequelae in Liberia. N Engl J Med. 2019 Mar 7;380(10):924-34. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30855742

13. Schindell BG, Webb AL, Kindrachuk J. Persistence and Sexual Transmission of Filoviruses. Viruses. 2018 Dec 2;10(12) Available at: https://www.ncbi.nlm.nih.gov/pubmed/30513823

14. Emanuel J, Marzi A, Feldmann H. Filoviruses: Ecology, Molecular Biology, and Evolution. Adv Virus Res. 2018;100:189-221. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29551136

15. Centers for Disease Control and Prevention. History of Ebola Virus Disease (EVD) Outbreaks. Atlanta: US CDC; 2022. Available at: https://www.cdc.gov/vhf/ebola/history/chronology.html

16. European Centre for Disease Prevention and Control. Ebola outbreak in West Africa (2013-2016). Stockholm: ECDC Available at: https://www.ecdc.europa.eu/en/ebola-and-marburg-fevers/threats-and-outbreaks/ebola-outbreak

17. Vetter P, Fischer WA, 2nd, Schibler M, Jacobs M, Bausch DG, Kaiser L. Ebola Virus Shedding and Transmission: Review of Current Evidence. J Infect Dis. 2016 Oct 15;214(suppl 3):S177-S84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27443613

18. 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;10(2):e0004475. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26927697

19. Centers for Disease Control and Prevention. Biosafety in Microbiological and Biomedical Laboratories (BMBL) 6th Edition. Atlanta: US CDC. Available at: https://www.cdc.gov/labs/BMBL.html

20. Health and Safety Executive. The Approved List of biological agents, Advisory Committee on Dangerous Pathogens. London: HSE; 2021. Available at: https://www.hse.gov.uk/pUbns/misc208.pdf

21. World Health Organisation. Update on Ebola drug trial: two strong performers identified, 12 Aug 2019. Geneva: WHO. Available at: https://www.who.int/news/item/12-08-2019-update-on-ebola-drug-trial-two-strong-performers-identified

22. Dyer O. Two Ebola treatments halve deaths in trial in DRC outbreak. BMJ. 2019 Aug 13;366:l5140. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31409588

23. US Food and Drug Administration. FDA Approves First Treatment for Ebola Virus, 14 Oct 2020. Maryland: FDA. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-ebola-virus

24. US Food and Drug Administration. FDA approves treatment for ebola virus, 21 Dec 2020. Maryland: FDA. Available at: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-ebola-virus

25. World Health Organization. Interim advice on the sexual transmission of the Ebola virus disease, 21 Jan 2016. Geneva: WHO. Available at: https://www.who.int/publications/m/item/interim-advice-on-the-sexual-transmission-of-the-ebola-virus-disease

26. World Health Organization. Clinical care for survivors of Ebola virus disease: interim guidance. Geneva: WHO; 2016. Available at: https://apps.who.int/iris/handle/10665/204235

27. World Health Organization. Ebola virus disease: Vaccines, 11 Jan 2020. Geneva: WHO. Available at: https://www.who.int/news-room/questions-and-answers/item/ebola-vaccines

28. Regules JA, Beigel JH, Paolino KM, Voell J, Castellano AR, Hu Z, et al. A Recombinant Vesicular Stomatitis Virus Ebola Vaccine. N Engl J Med. 2017 Jan 26;376(4):330-41. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25830322

29. European Medicines Agency (EMA). Ervebo, 12 Dec 2019. Amsterdam: EMA. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/ervebo

30. US Food and Drug Administration. First FDA-approved vaccine for the prevention of Ebola virus disease, marking a critical milestone in public health preparedness and response, 19 Dec 2019. Maryland: FDA. Available at: https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health

31. World Health Organization (WHO). Ebola Vaccine Frequently Asked Questions, 11 Jan 2020. Available at: www.who.int/news-room/questions-and-answers/item/ebola-vaccines

32. World Health Organization - Regional Office for Africa. 11th Ebola outbreak in the Democratic Republic of the Congo declared over, 18 Nov 2020. Brazzaville: WHO; 2020. Available at: https://staging.afro.who.int/countries/democratic-republic-of-congo/news/1th-ebola-outbreak-democratic-republic-congo-declared-over

33. European Medicines Agency (EMA). Zabdeno. Amsterdam: EMA; 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/zabdeno

34. European Medicines Agency (EMA). Mvabea. Amsterdam: EMA; 2020. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/mvabea

Ebola: Clinical Presentation, Evaluation, and Infection Prevention

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“Please note special time of this COCA Call.”

This COCA Call will be held on Friday, March 27, 2020

On September 20, 2022, the Ministry of Health of Uganda officially declared an outbreak of Ebola disease caused by Sudan ebolavirus (SUDV). This is the fifth outbreak caused by SUDV in Uganda since 2000. No probable or confirmed cases related to this outbreak have yet been reported in the United States.

During this COCA Call, subject matter experts from the Centers for Disease Control and Prevention (CDC) will discuss signs and symptoms of Ebola, disease progression, importance of alternative diagnoses or treatments, and the utility of a CDC clinical consult. Presenters will also review specimen handling and testing biosafety, and infection prevention and control recommendations.

Mary Choi, MD, MPH CDR, U.S. Public Health Service Medical Officer, Viral Special Pathogens Branch Division of High-Consequence Pathogens and Pathology National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention

Trevor Shoemaker, PhD, MPH Epidemiologist Division of High-Consequence Pathogens and Pathology National Center for Emerging and Zoonotic Diseases Centers for Disease Control and Prevention

Amy Valderrama, PhD, RN, FAAN CAPT, U.S. Public Health Service Nurse Epidemiologist Division of Healthcare Quality Promotion National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention

Brian Harcourt, PhD CDR, U.S. Public Health Service Biosafety Officer, Viral Special Pathogens Branch Division of High-Consequence Pathogens and Pathology National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention

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• Ebola virus disease Information for Clinicians in U.S. Healthcare Settings | For Clinicians | Ebola (Ebola Virus Disease) | Ebola Hemorrhagic Fever | CDC
• Screening Patients | For Clinicians | Ebola Virus Disease | CDC
• Information for Healthcare Workers | Viral Hemorrhagic Fevers (VHFs) | CDC
• What is Ebola Virus Disease? | Ebola (Ebola Virus Disease) | CDC
• Signs and Symptoms | Ebola Hemorrhagic Fever | CDC
• Transmission | Ebola Hemorrhagic Fever | CDC
• Infection Prevention and Control Recommendations for Hospitalized Patients Under Investigation (PUIs) for Ebola Virus Disease (EVD) in U.S. Hospitals | Ebola Virus Disease | Clinicians | Ebola (Ebola Virus Disease) | CDC
• Guidance for Collection, Transport and Submission of Specimens for Ebolavirus Testing | For Laboratory Personnel | Ebola (Ebola Virus Disease) | CDC
• Cleaning and Decontamination | Cleaning and Decontamination | Public Health Planners | Ebola (Ebola Virus Disease) | CDC

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Clinical presentation and management of severe Ebola virus disease

Affiliation.

• 1 1 Division of Pulmonary & Critical Care Medicine, Department of Medicine, and.
• PMID: 25369317
• DOI: 10.1513/AnnalsATS.201410-481PS

Clinicians caring for patients infected with Ebola virus must be familiar not only with screening and infection control measures but also with management of severe disease. By integrating experience from several Ebola epidemics with best practices for managing critical illness, this report focuses on the clinical presentation and management of severely ill infants, children, and adults with Ebola virus disease. Fever, fatigue, vomiting, diarrhea, and anorexia are the most common symptoms of the 2014 West African outbreak. Profound fluid losses from the gastrointestinal tract result in volume depletion, metabolic abnormalities (including hyponatremia, hypokalemia, and hypocalcemia), shock, and organ failure. Overt hemorrhage occurs infrequently. The case fatality rate in West Africa is at least 70%, and individuals with respiratory, neurological, or hemorrhagic symptoms have a higher risk of death. There is no proven antiviral agent to treat Ebola virus disease, although several experimental treatments may be considered. Even in the absence of antiviral therapies, intensive supportive care has the potential to markedly blunt the high case fatality rate reported to date. Optimal treatment requires conscientious correction of fluid and electrolyte losses. Additional management considerations include searching for coinfection or superinfection; treatment of shock (with intravenous fluids and vasoactive agents), acute kidney injury (with renal replacement therapy), and respiratory failure (with invasive mechanical ventilation); provision of nutrition support, pain and anxiety control, and psychosocial support; and the use of strategies to reduce complications of critical illness. Cardiopulmonary resuscitation may be appropriate in certain circumstances, but extracorporeal life support is not advised. Among other ethical issues, patients' medical needs must be carefully weighed against healthcare worker safety and infection control concerns. However, meticulous attention to the use of personal protective equipment and strict adherence to infection control protocols should permit the safe provision of intensive treatment to severely ill patients with Ebola virus disease.

Keywords: Ebola virus disease; critical illness; disease outbreaks; infection control; intensive care.

Publication types

• Acute Kidney Injury / etiology
• Acute Kidney Injury / therapy
• Blood Coagulation Disorders / etiology
• Blood Coagulation Disorders / therapy
• Brain Diseases / etiology
• Brain Diseases / therapy
• Cardiopulmonary Resuscitation
• Catheterization, Central Venous
• Clinical Laboratory Techniques
• Critical Care / ethics
• Critical Illness*
• Hemorrhagic Fever, Ebola / diagnosis*
• Hemorrhagic Fever, Ebola / therapy*
• Hemorrhagic Fever, Ebola / transmission
• Infection Control
• Infectious Disease Transmission, Patient-to-Professional / prevention & control
• Malnutrition / etiology
• Malnutrition / therapy
• Monitoring, Physiologic
• Pain Management
• Patient Discharge
• Protective Devices
• Respiratory Insufficiency / etiology
• Respiratory Insufficiency / therapy
• Shock / etiology
• Shock / therapy
• Social Support
• Terminal Care
• Water-Electrolyte Imbalance / etiology
• Water-Electrolyte Imbalance / therapy
• World Health Organization

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Treatment of Ebola-related critical illness

Peter kiiza.

1 Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5 Canada

4 Canadian Forces Health Services Group, Toronto, 10 Yukon Lane, North York, ON M3K 0A1 Canada

N. K. J. Adhikari

2 Institute for Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON Canada

3 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON Canada

R. A. Fowler

5 2075 Bayview Avenue, Room D478, Toronto, ON M4N 3M5 Canada

To explore contemporary clincial case management of patients with Ebola virus disease.

A narrative review from a clinical perspective of clinical features, diagnostic tests, treatments and outcomes of patients with Ebola virus disease.

Substantial advances have been made in the care of patients with Ebola virus disease (EVD), precipitated by the unprecedented extent of the 2014–2016 outbreak. There has been improved point-of-care diagnostics, improved characterization of the clinical course of EVD, improved patient-optimized standards of care, evaluation of effective anti-Ebola therapies, administration of effective vaccines, and development of innovative Ebola treatment units. A better understanding of the Ebola virus disease clinical syndrome has led to the appreciation of a central role for critical care clinicians—over 50% of patients have life-threatening complications, including hypotension, severe electrolyte imbalance, acute kidney injury, metabolic acidosis and respiratory failure. Accordingly, patients often require critical care interventions such as monitoring of vital signs, intravenous fluid resuscitation, intravenous vasoactive medications, frequent diagnostic laboratory testing, renal replacement therapy, oxygen and occasionally mechanical ventilation.

With advanced training and adherence to infection prevention and control practices, clinical interventions, including critical care, are feasible and safe to perform in critically ill patients. With specific anti-Ebola medications, most patients can survive Ebola virus infection.

Take-home messages

Introduction.

Ebola virus disease (EVD) has long been perceived as a rare Equatorial viral illness that leads to hemorrhagic fever and near certain death. Until recently there was a common view that little could be done for patients other than isolation and limited supportive care—a reasoning premised on the expected futility of care for patients with an illness of historically high mortality rate and a concern for risk of infection to healthcare workers [ 1 – 3 ]. However, over the past 5 years, alongside the West African outbreak, there has been improved characterization of the clinical course, recognition that Ebola frequently leads to a unique critical illness with multisystem organ failure [ 1 – 8 ], and that patients with Ebola virus that can be supported, treated and cured [ 5 , 9 – 11 ].

Historical case-weighted mortality fell from approximately 70% in outbreaks prior to 2014, to 39% in the West African outbreak and 18.5% in patients with EVD who were treated in Europe and USA [ 12 , 13 ]. Mortality has remained over 50% in the most recent outbreaks in the Democratic Republic of the Congo (DRC) [ 13 ]. Treatment has shifted from a focus upon isolation and oral rehydration (‘minimal-touch’) to one of optimized care involving rapid diagnostic testing, frequent or continuous monitoring of vital signs, individualized enteral and intravenous fluid treatment, intravenous vasoactive medications, supplemental oxygen, occasional mechanical ventilation, renal replacement therapy and now, specific and effective antiviral therapies [ 9 – 12 , 14 – 18 ].

In this review, we highlight the need for clinicians to be able to recognize and manage Ebola-related organ dysfunction, and highlight that advanced supportive care is necessary of treatment for severely ill patients with EVD.

Epidemiology

Ebolaviruses fall under the order Mononegavirales and the filoviridae family, and whose viral genome comprises a single negative stranded RNA with negative polarity. Within the genus of Ebolavirus, 6 species have been identified, though only 4— Zaire Ebola virus, Bundibugyo virus, Sudan virus and Tai Forest virus —are known to cause disease in humans; no serious illness has been reported from Bombali or Reston ebolavirus [ 19 , 20 ]. Non-human primates (NHP) and bats are considered the natural reservoirs of Ebola virus, with the virus capable of causing zoonotic outbreaks.

Since the first recognized EVD outbreak in 1976, approximately 30 others have occurred [ 13 , 19 ], with the majority happening in equatorial sub-Saharan Africa. Previously, most outbreaks have occurred in rural and remote areas, and have been of relatively short duration. However, in 2014–2016, EVD spread throughout West Africa (predominantly Guinea, Liberia and Sierra Leone), fueled in part by a fragile pre-existing health system and lack of human resource capacity, and led to the world’s largest outbreak (28,610 cases with 11,308 deaths and a case fatality ratio of 39%) [ 13 ]. Since the West African outbreak, the Democratic Republic of the Congo (DRC) has faced three more EVD outbreaks. In the most recent, centered in Northeastern DRC, as of January 04, 2020, there have been 2233 deaths out of 3386 cases—the second largest Ebola outbreak in history [ 17 , 21 ]. Now characterized as a public health emergency of international concern [ 17 ] there is a need for clinicians to be prepared to treat patients in both endemic or exported regions.

Clinical presentation

Demographics.

Ebola virus (EV) can infect people of all ages—from infants to elderly—and infection can affect fetal development and viability. In previous outbreaks, 10-year age group-incidence for EVD increased linearly from infancy peaking at the 35–45 years age group and falling thereafter [ 22 ]. Attack rates have traditionally been higher among women and middle-aged people and lower in children and the elderly, probably due to differences in exposure risks. The current DRC outbreak has been epidemiologically notable for higher than previously recognized infections among children [ 17 ].

Transmission

Most human-to-human Ebola transmission is by direct exposure of the mucous membranes or non-intact skin to infectious body fluids such as blood, vomitus, stool, or with contaminated materials [ 19 ]. Inoculation of the virus into the body via needle stick or sharps injuries can occur in healthcare settings. Droplet or aerosol transmission is unlikely except under specific conditions such as when carrying out procedures in non-ventilated rooms on patients with high viral loads that increase the risk respiratory spread, such as bronchoscopy [ 23 ]. Survivors from previous outbreaks have shown persistent Ebola virus in some bodily fluids, such as semen in males, up to 500 days after recovery [ 24 ]; however, the viability and infectivity of the virus isolated from these sites is less certain.

Pathophysiology

Ebola virus gains entry into the body mainly via the mucous membranes (eyes, nose, and mouth). Its viral glycoprotein enhances receptor binding and attachment to the endosomes of cells [ 23 ]. The virus attacks dendritic cells, monocytes and macrophages, which then migrate to the lymph nodes where early viral replication and dissemination occurs before the onset of symptoms. Ebola virus disseminates to infect a broad range of cells including endothelial cells, hepatocytes, fibroblasts, and the adreno-cortical cells, among others. Ebola virus uses its structural and membrane proteins through a number of mechanisms to evade the host immune response [ 23 , 25 , 26 ]. Tissue damage happens via numerous but closely related mechanisms such as direct viral cytopathy, endothelial dysfunction, coagulation disruption, and likely, the host’s own inflammatory response [ 23 ]. Infected patients undergo a cell-mediated immune activation, however, patients that succumb to EVD may have a more limited functional T-cell-mediated response [ 4 , 27 ].

Clinical suspicion of EVD should arise when considering a patient’s clinical syndrome and recent likelihood of exposure in an area where the virus is known to circulate [ 28 ]. An epidemiological history should include any recent (within 21 days) travel to an area with ongoing Ebola transmission, or contact history with infected persons or dead or possibly infected animals.

After exposure to Ebola virus, an incubation period of 3–21 days (mean 12.7, SD 4.3 days) [ 29 ] ensues where symptoms (Fig.  1 ) might present [ 30 ]. It is not uncommon for viral RNA to be undetectable by reverse transcriptase-polymerase chain reaction (RT-PCR) in the first 1–3 days after symptom onset. This necessitates re-testing all patients in whom clinical suspicion persists even after initial plasma RT-PCR results are negative if symptoms have been present for fewer than a few days [ 14 ].

A meta-analysis of proportion of 6168 EVD patients presenting with symptoms compared to reference data. Blue indicates a meta-analysis approximate with low or moderate heterogeneity, red is for a high heterogeneity of pooled estimates, and grey is the WHO reference data.

Adapted from Rojek AM et al. [ 30 ]

Several observational studies [ 12 , 16 , 31 , 32 ], have grouped the progression of EVD illness into three stages (Table ​ (Table1). 1 ). In the initial phase, most patients’ symptoms include a non-specific febrile illness with headache, fever, myalgia and general malaise, with or without a maculopapular rash. These early symptoms often overlap with those of common diseases in the tropics (such as malaria, typhoid fever, and other bacterial and arboviral infections), complicating clinical diagnosis [ 7 ].

Stages of Ebola virus disease presentation.

Adapted from Malvy et al. and Dickson et al. [ 4 , 16 ]

Some patients will progress to the second phase with asthenia and gastro-intestinal illness, including nausea, anorexia, abdominal pain, odynophagia, emesis and then watery diarrhea. This stage can range from mild symptoms to a severe state of illness characterized by intravascular volume depletion and electrolyte derangement [ 6 , 32 ], hypotension, metabolic acidosis, hepatitis, pancreatitis, hypoglycemia and renal injury. Patients are typically with a high viral load and are correspondingly infectious in this phase of illness [ 14 ].

In the third phase of illness [ 4 ], multi-organ failure may occur, with acute kidney failure, hepatic failure, cardiac dysfunction and shock, altered level of consciousness, seizures, coagulopathy (petechiae, ecchymoses, at venipuncture sites and bleeding from mucosal membranes and peri-partum) or death [ 30 – 33 ].

Diagnostic testing for Ebola

The WHO recommends confirmation of EVD by RT-quantitative PCR [ 34 ]. There are over a dozen RT-PCR processing platforms, but only a few have had their limits of detection (LOD) verified by independent assessors, including the WHO endorsed Cepheid Xpert ® assay, which targets nucleoprotein and glycoprotein antigens on the Ebola virus [ 34 – 36 ]. For screening suspected EVD patients in remote settings without access to PCR testing, WHO recommends use of highly sensitive and specific rapid diagnostic tests (RDTs). Table ​ Table2 2 outlines various RDTs available, with only a few, such as ReEBOV, Ebola eZYSCREEN and OraQuick, having undergone clinical validation [ 35 , 37 – 40 ]. Laboratory testing for alternative or co-infections such as malaria and bacterial infections should be considered [ 8 , 12 , 23 , 31 ], since these are often assumed to co-exist with Ebola in severely ill patients and may lead to over-prescription of antimalarials or antibiotics unless rapid tests (for malaria) and cultures (for bacterial infections) can rule these out.

RDTs for the detection of Ebola virus.

Adapted from Tembo et al. [ 35 ]

Clinical validation refers to field testing for specificity and sensitivity on blood specimens containing varying amounts of Ebola virus, with the specific RDT results compared to the polymerase chain reaction gold standard test [ 37 – 40 ]

BDBV, Bundibugyo ebolavirus ; GP, glycoprotein; Ig G, immunoglobulin G; Ig M, immunoglobulin M; VP, matrix protein; NP, nucleoprotein; NR, not reported; RESTV, Reston ebolavirus ; SUDV, Sudan ebolavirus ; TAFV, Taï Forest ebolavirus ; EBOV, Zaire ebolavirus

Laboratory abnormalities

Early in the course of EVD illness, leukocyte and lymphocyte counts often fall due to impaired immune response, while hemoglobin and hematocrit levels increase along with intravascular volume depletion [ 23 ]. Elevation in aspartate amino transferase (AST), alanine aminotransferase (ALT), and total serum bilirubin is common, generally believed to be due to direct viral cytopathic effect on hepatocytes [ 4 , 12 , 23 ]. Contributory pathology from rhabdomyolysis or myositis leads to high serum creatine kinase and AST levels [ 12 , 23 ]. Elevated prothrombin time and activated partial thromboplastin time and increased d -dimers occur among patients with progressive illness [ 4 , 8 , 12 , 23 ].

During the most severe phase of illness (Table ​ (Table3), 3 ), patients might have hyper- or hyponatremia, hyper- or hypokalemia, hypocalcemia and hypomagnesemia as a result severe vomiting and diarrhea; hypoglycemia secondary to reduced oral intake or depleted glycogen stores, and hypoalbuminemia, acute kidney injury, and both anion gap (lactate- or urea-associated) or non-anion gap (diarrhea-related bicarbonate losses) metabolic acidosis. [ 4 , 8 , 12 , 23 ].

Laboratory abnormalities observed in EVD patients by stage.

Adapted with permission [ 23 ]

An overriding principle in providing EVD care is to ensure healthcare worker (HW) safety through strict infection prevention and control (IPC) practices. HWs involved in EVD care should adhere to both standard and transmission-based (contact and droplet) precautions for their safety [ 14 ]. Recommended personal protective equipment (PPE) when providing direct patient care includes: face shield/googles; fluid-resistant medical/surgical gown, surgical masks or N-95 respirators that maintain their shape and consistency in hot and humid environments; two pairs of gloves; waterproof apron; fluid-impermeable protective feet covering and a head cover [ 14 , 41 ]. A buddy (two person) system while providing care, and PPE adherence supervisors are both advisable. Vaccination of frontline HWs should be a standard of clinical practice [ 16 , 42 ].

Pre-exposure prophylaxis

Preliminary data on vaccination of populations at increased risk of infection, such as HWs, contacts of patients and contacts of contacts, with the rVSV ZEBOV-Gp, while utilizing the ring vaccination strategy in West Africa has shown a vaccine efficacy of 97.5% in people vaccinated at least 10 days before potential exposure, and an 88.1% efficacy in all the other analyses of EVD onset irrespective of timing [ 43 ]. Subsequently, a 26 vectored glycoprotein/MVA-BN (Ad26.ZEBOV/MVA-BN) vaccine developed by Johnson & Johnson has been deployed for evaluation in the current outbreak in DRC.

The care for critically ill EVD patients is best offered in individual patient treatment rooms inside a facility that has the following features: a sectioned unit with separate areas for low risk patients in whom EVD has not been confirmed and who are not demonstrating ‘wet’ symptoms (vomiting and diarrhea); patients who have wet symptoms but as yet unconfirmed infection; and a section for confirmed EVD patients. Each section should have waste disposal areas; unidirectional flow of materials and personnel from the lowest risk zones to higher risk zones; and capacity to accommodate medical technologies such as oxygen delivery systems, mechanical ventilators and renal replacement systems [ 41 ]. Diagnostic laboratory testing should be either at the point of care and with a well-coordinated and timely system of safe transportation of samples to a dedicated laboratory equipped to process such specimens. There should be physical barriers to limit access to Ebola assessment and treatment areas to essential and trained personnel. However, there should be visual accessibility to patients by family and friends who provide important psychological support to patients.

Heath workers’ use of impermeable PPE while caring for EVD patients with infectious “wet’ symptoms puts them at increased risk for heat strain especially in hot and humid areas. This limitation can have the unintended consequence of reducing the time HWs can spend with patients and can limit the quality of care [ 2 , 10 , 16 ]. Thus, temperature and humidity control for HWs is an important element of caring for patients. This has been accomplished in the field through caring for patients in climate controlled hospitals, or through novel engineering solutions with individual patient rooms such as found in the (Alliance for International Medical Action—ALIMA) biosecure cubes (Fig.  2 ) that consist of transparent and air conditioned patient rooms, and come fitted with specialized ports to enable patient access and monitoring while in minimal PPE [ 10 , 44 ].

A medical advisor for the Alliance for International Medical Action demonstrating a Biosecure Emergency Care Unit for outbreaks of infectious diseases.

Photo credit: Etinosa Yvonne/ALIMA [ 44 ]

Basic supportive care

Following the 2014–2016 EVD outbreak, a number of observational studies postulated that delivery of improved supportive care would reduce mortality from EVD [ 1 – 9 , 12 , 31 , 32 ]. Basic supportive care recommendations [ 11 ] include: systematic monitoring and documentation of clinical signs and symptoms; a clinician to patient ratio of 1:4 but with emphasis placed on maximizing patient contact time; patient–family audio-visual communication; psychosocial care; provision of oral rehydration therapy to correct or prevent hypovolemia; parenteral fluids for patients unable to achieve sufficient enteral hydration; measurement of serum biochemistry with correction of identified electrolyte abnormalities; oxygen administration to achieve normal oxygen saturation; intravenous vasoactive medications for patients with fluid-resistant hypotension and organ hypoperfusion; pain management, antiemetics, and anxiolytics; nutritional support customized to patient assessment including treatment of hypoglycemia with intravenous glucose when necessary; and microbiological analysis to guide antimicrobial use, and in absence of such capacity, a low threshold for empirical use of broad-spectrum antibiotics and antimalarials, depending on the geographical context and symptoms [ 9 – 12 , 14 , 44 , 45 ]. Provision of supportive care to patients will inevitably require a multi-disciplinary team of HWs: nurses, physicians, IPC personnel, laboratory personnel, and ideally, nutritionists, social and community workers, and psychologists. These recommendations derived from observational studies that generally found improved outcomes later in the outbreak compared to the beginning, attributed to improvements in multiple domains of care, including clinical monitoring and fluid administration [ 46 ].

Advanced supportive care

Data collected from patient cohorts admitted in Ebola Treatment Centres in Africa [ 4 , 30 ] and in Europe and the USA [ 12 ] posited that approximately 50% of patients in either setting were critically ill and required advanced supportive care interventions. Described below is the management of common complications observed in patients with EVD.

Metabolic disturbance and renal injury has been observed as a complication of EVD in over 50% of patients in cohorts of patients during the West African outbreak [ 6 – 8 , 12 , 16 , 23 ] and is likely multifactorial in etiology, including hypovolemia, hypotension and hypoperfusion, direct viral damage to the endothelium and renal tubular cells [ 6 , 12 – 14 , 23 , 31 ], and occasional toxicity due to rhabdomyolysis or medications. Interventions include careful monitoring of urine output, maintaining adequate renal perfusion with fluids and vasoactive agents, avoiding nephrotoxic drugs and diuretics in hypovolemic patients, and treatment of other underlying cause(s) [ 10 – 12 , 16 ]. Electrolyte disturbances such as hyperkalemia have commonly been reported in the context of Ebola-related renal injury. Temporizing measures for complications of acute kidney injury should be available, such as bicarbonate for metabolic acidosis, intravenous short-acting insulin and dextrose for hyperkalemia, and a diuretic trial in oliguric volume-replete patients. Where facilities and expertise are available, renal replacement therapy should be offered [ 11 , 12 , 16 ], as feasibility of delivering dialysis has been demonstrated in both resource-rich and resource-limited settings [ 12 , 16 , 47 ].

Cardiovascular complications have included arrhythmias and may often respond to normalization of serum electrolytes. Hypotension due to hypovolemia, vasodilation or impaired myocardial performance unresponsive to fluid resuscitation require intravenous vasopressor or inotropic support.

Coagulation abnormalities have included thrombocytopenia, vitamin K deficiency or liver-injury-related effects to the intrinsic and extrinsic pathways of coagulation, and rarely, disseminated intravascular coagulation. Clinical monitoring and measurement of blood counts and coagulation profiles can help to guide treatment with vitamin K and tranexamic acid, transfusion with red blood cells, platelets or plasma [ 11 , 23 , 44 ]. Early placement of a durable intravenous catheter of sufficient diameter to allow blood sampling (e.g., a peripherally inserted central catheter) facilitates safe blood sampling and administration of intravenous fluids or medications [ 12 , 16 ].

Clinicians should anticipate that a proportion of patients will develop hypoxic or hypercapneic respiratory failure. Etiologies may be diverse, relating to pulmonary vascular leak and inflammatory insults, volume overload, impaired myocardial performance, pulmonary infections, decreased level of consciousness and aspiration, severe metabolic acidosis or hypoventilation syndromes. Over 70% of patients with EVD treated in Europe or USA required some form of respiratory support—invasive or non-invasive mechanical ventilation [ 12 ] or supplemental oxygen [ 1 , 9 – 12 , 16 , 23 ] .

Neurological complications such as altered mental status (confusion or coma), seizures, agitation and encephalopathy were reported in over 30% of patients treated in Europe, USA and West Africa [ 12 , 30 ]. Interventions include treating underlying causes such as hypoglycemia, electrolyte imbalance, hepatic dysfunction, uraemia and viral or bacterial encephalitis or meningitis; and use of anticonvulsants, sedatives and antipsychotics as appropriate [ 11 , 12 , 14 , 15 ].

Medical treatments

Supportive care remains the cornerstone of patient treatment. A number of direct acting anti-Ebola agents were proposed and evaluated during the West African Ebola outbreak. Most were tested using methodologically weak study designs that precluded determination of efficacy, and await further evaluation [ 44 , 45 ]. A systematic review [ 48 ] evaluated the potential effect of different anti-Ebola therapies on clinical outcomes of EVD patients. All but one of the studies were limited by their non-randomized designs. ZMapp (a cocktail of three monoclonal antibodies), was the only anti-Ebola therapy whose efficacy was tested in a randomized control trial against standard care. In the 72 enrolled patients, mortality in the intervention group was 22% vs 37% in the control group (confidence interval for risk difference, − 36 to 7%). Although ZMapp achieved a 91.2% posterior probability of superiority over standard care, it failed to reach the pre-set threshold of 97.5% probability to establish efficacy.

Health authorities and the WHO R&D blueprint under the ethical framework of monitored emergency use of unregistered and investigational interventions (MEURI) recommended expanded access to investigational therapies, including three monoclonal antibodies (MAb114, ZMapp, and REGN-EB3) and one antiviral agent (remdesivir) in the 2018–2019 DRC Ebola outbreak (Table ​ (Table4) 4 ) [ 44 , 49 ].

Current anti-Ebola therapies being implemented under compassionate use in the DRC

AST, Aspartate aminotransferase; ALT, alanine aminotransferase; DSMB, data and safety monitoring board; GP, glycoprotein; IM, intramuscular; HW, healthcare worker; Ig G, immunoglobulin G; IV, intravenous; MAbs, monoclonal antibodies; NIAID, National Institute of Allergy and Infectious Diseases; NHP, non-human primates; PCR Ct-value, polymerase chain reaction-Cycle threshold value; oSOC, optimized standard of care; SAEs, Serious Adverse Events; SD, standard deviation; TEAEs, treatment-emergent adverse effects

REGN-EB3 is a cocktail of three monoclonal antibodies (REGN-3470, -3471, and -3479, all humanized from mice) targeting non-overlapping epitopes of Ebola virus. REGN-EB3 previously showed promise in reducing mortality in infected NHPs even when single doses of up to 150 mg/kg were administered 5 days post EVD infection. REGN-EB3 was also found to be well tolerated when it was tested in randomized placebo-controlled phase 1 trial involving 18 human participants [ 50 ].

VRC-EBOMAB092-00-AB (MAb114) is a single human monoclonal antibody (isolated from a human survivor) that targets a highly conserved epitope on the receptor-binding domain of the Ebola virus glycoprotein, thus preventing its interaction with the host cell receptor protein and blocking viral entry. In pre-clinical studies involving NHPs challenged with lethal doses of Ebola virus, single 50 mg/kg or 30 mg/kg doses of MAb114 given 5 days after viral exposure offered complete protection. In a subsequent human phase 1, open-label, dose escalation trial, MAb114 was given to 18 participants. MAb114 was well tolerated in all participants, with no reported site infusion reactions or serious adverse effects [ 51 ].

In a subsequent randomized controlled trial ( n  = 681) conducted under challenging field conditions, the safety and effectiveness of three drugs (MAb114, remdesivir, and REGN-EB3) was compared to the control drug ZMapp in Ebola patients receiving optimized standard of care (consisting of intravenous fluid resuscitation, daily clinical laboratory testing, correction of hypoglycemia and other electrolyte abnormalities, and use of broad-spectrum antibiotics and antimalarials, whenever indicated) [ 49 , 52 ]. The trial was stopped early after MAb114 and REGN-EB3 were found to be superior to ZMapp in reducing 28-day mortality, with event rates of 35.1% for MAb114 [risk difference (RD) vs. ZMapp, − 14.6%, 95% CI − 25.2 to − 1.7%) and 33.5% for REGN-EB3 (RD vs. ZMapp, 17.8%, 95% CI − 28.9 to − 2.9%). Mortality among patients receiving ZMapp was 49.7% and among those receiving remdesivir was 53.1%. However, mortality rates in patients with high viral loads or those with organ dysfunction (high creatinine or transaminases) remained high (> 60% for all interventions), even in a trial setting of optimized standard of care. This observation validates the need for advanced supportive interventions tailored to patient-specific critical care needs whenever feasible, and continued research into refining more effective anti-Ebola therapeutics, either newer drug compounds or combinations of the current ones [ 52 ].

Management of patients with Ebola has evolved substantially over the past decade, from a clinical perspective of isolation and provision of oral rehydration therapy to one of treating the syndromic illness, specific patterns of organ dysfunction with oral and intravenous volume repletion, management of life-threatening electrolyte disturbances, support of renal dysfunction with dialysis, cardiovascular dysfunction with intravenous vasoactive medications, and oxygen and mechanical ventilation for respiratory failure. With attention to the provision of care for patients, mortality has dropped from 70 to 40% in resource-challenged Ebola Treatment Centre context and is under 20% in resource-rich environments. With the promise of effective vaccine and specific anti-Ebola virus medications, we now understand that most patients can be safely supported, treated and cured.

Compliance with ethical standards

The authors declare that they have no conflict of interests.

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