Ebola Virus Disease

Etiology

Ebola viruses, named after the Ebola River, emerged in 1976. The viruses appear episodically in animal populations in regions close to the African equator. They are highly transmissible between humans and primates, including chimpanzees, apes, and gorillas.[7] Ebolavirus and Ebola virus antibodies can also be found in bats, which are considered asymptomatic reservoirs.[7][6] Although bats with Ebola virus antibodies have been discovered in surveillance studies during outbreaks, establishing a causal relationship with human illness remains unproven.[8] 

Filoviridae family members to Ebolavirus are the Marburgvirus, extremely virulent in humans, and the Cuevavirus, which thus far has only been found in bats in Spain and Hungary.[9][1] The 5 subtypes of Ebola virus that cause clinical disease in humans are named based on topographic discovery: Zaire/Ebola (EBOV), Bundibugyo (BDBV), Sudan (SUDV), and more recently, Tai Forest (TAFV), and Bombali (BOMV).[10][7] No appreciable difference in virulence is observed across outbreaks induced by different subtypes.[3] Other filoviruses have been identified, but to date, these do not infect humans or do not cause clinical illness in humans. 

The renaming of Ebola virus terms over time has complicated the filovirus taxonomy. Since 2018, Ebola virus, Ebola virus disease (EVD), and EBOV have explicitly referred to the Zaire subtype of Ebola viruses.[1] Ebola virus (species Zaire ebolavirus) has caused most Ebola virus outbreaks and is thus the most studied of the Ebolavirus types. 

Electron microscopy of blood samples demonstrates the Ebola virus structure. The EBOV virion is surrounded by an envelope with glycoprotein (GP_1,2) spikes.[3] The single-stranded, negative-sense RNA core is packaged in the virion capsule with 4 proteins: NP, VP35, VP30, and L. These proteins and glycoproteins are important components of Ebola pathophysiology and immunogenicity. 

Epidemiology

Since its discovery, over 25 EVD outbreaks have occurred; many were confined to rural areas in Sudan, the Democratic Republic of Congo, Gabon, the Republic of the Congo, and Uganda.[11] Ebola virus disease has claimed the lives of over 15,000 people.[12] Hunting and eating bushmeat is a risk for contracting Ebola viruses.[13] Transmission in the community from the patient to family and community members and during funeral practices can be rapid.[14]

The most recent outbreak of Ebola virus disease occurred from April to September 2022 in the Democratic Republic of the Congo.[15] The largest and longest epidemic (late 2013 to 2016) spanned Western Africa, with cases also found in parts of Europe and the United States. Healthcare systems in some countries were overwhelmed, shedding light on the lack of preparedness for epidemics. Most reported cases outside of Africa were healthcare workers providing aid in regions with an active outbreak, who had strict travel restrictions and effective quarantine strategies; only a few travelers were infected due to direct human contact.

The case fatality rate of Ebola virus disease without supportive care or other treatments may be as high as 90%.[7] With heightened awareness, increased education on the importance of seeking medical care, and early detection, the average mortality rate has now reduced to approximately 50%. Persons are only infectious when experiencing symptoms of the infection, such as fever, chills, nausea, or vomiting, or when people come in contact with contaminated objects or infected deceased persons.[3] Due to its high case-fatality rate, the virus is a feared biowarfare agent.[16]

Transmission

Infected humans and non-human primates transmit Ebola viruses through direct contact with bodily fluids, including saliva, blood, urine, feces, sweat, breast milk, or semen, and contact with objects (or fomites).[1][7] The virus usually enters the new host through mucosal membranes and perhaps skin. It can occasionally happen percutaneously. Ebola viruses can persist in body fluids for prolonged periods. For example, in semen, Ebola virus has been isolated for up to 82 days [17] and detected via PCR up to 101 days after initial symptoms.[18] Cases of sexual transmission of Ebola viruses from semen and from pregnant mothers to their fetuses have occurred.[18][32080199] 

Once it has entered the host, the virus incubates for an asymptomatic, noncontagious period, usually lasting several days to a few weeks. Patients are contagious once they start exhibiting signs and symptoms. The amount of time a virus can survive outside the human body is unknown. Most often, the bedding, clothes, and medical utensils utilized by patients are all burned or disposed of as medical waste to avoid contamination and the risk of spreading the virus.[19] Some traditional funerals in affected countries include opportunities to touch the bodies and personal items of persons who have died, which can contribute to the spread of the disease.[20]

Pathophysiology

Once the Ebola virus infects the host, there is an incubation period of 2 to 21 days, with a mean of 8 to 10 days.[7] The virus penetrates the host cell membrane by binding with GP_1,2, which triggers endocytosis. Once inside the cell, the virus releases its nucleocapsid into the host cell cytoplasm. VP30 initiates viral RNA replication [32080199] and serves as a regulatory protein; phosphorylation of VP30 by transcribed viral proteins turns off VP30 and ceases viral protein synthesis. Due to this unique function, VP30 has been identified as a target for vaccine development. The matrix protein VP40 is also produced and packaged into exosomes and is involved in host immune system suppression. Virus release from the cell is by budding from the cell membrane; this can cause direct damage to the cell and cell death. EBOV-specific cellular and humoral immune responses develop but are often outpaced by virus-host cell interactions. The process is not fully understood and continues to be investigated. 

Mononuclear cells are among the cells that are first targeted by the virus.[7] The destruction of these cells results in the release of cytokines and reactive oxygen species responsible for edema and hypovolemic shock.[7] Destruction of other tissue cells results in myalgias from myositis, hepatitis, and acute kidney injury from renal tubular dysfunction.[1] Immune-mediated cell damage causes further injury, leading to dysfunction in multiple vital organs such as the lungs, heart, kidney, and liver.[21] The combined effects lead to multi-system organ failure. Death can occur quickly from the onset of symptoms, often within 6 days.[14] For survivors, long-term consequences have been identified, including hepatitis, encephalitis, uveitis, and spinal cord injury.[7] 

Hemorrhagic responses are complex and involve disruption of the coagulation cascade through platelet aggregation, which sequesters platelets, causing bleeding and clotting simultaneously.[22] Liver damage also reduces the production of clotting factors.[22]

History and Physical

Persons infected with an Ebola virus present with sudden fever, malaise, headache, anorexia, and myalgias.[23] This is often followed by nausea, abdominal pain, vomiting, and diarrhea.[1][23] Red eyes, sore throat, and hiccups may also occur.[32080199] A maculopapular rash and hemorrhagic features such as bleeding from mucosal membranes, skin, eyes, nose, and ears may appear later in this early phase.[1][32080199] Shortness of breath and cough commonly occur as the syndrome progresses, as do neurologic symptoms, including confusion and prostration.[32080199][23][1] 

The primary and most crucial evaluation is serial patient assessments with careful attention to vital signs and volume status.[1] Patients should be assessed for signs of dehydration, including mucous membranes and skin turgor. Fluid losses are often severe, averaging between 3 and 5 liters daily, but up to 10 liters/day.[24] On physical exam, a patient presenting early in illness may be noted to be relatively stable with prodromal symptoms. In contrast, patients later in infection, with higher viral loads, may be severely ill and in shock.

Most people with these symptoms do not have Ebola virus disease. However, clinical suspicion should be high in epizootic areas worldwide if the World Health Organization has declared an outbreak of international concern. 

History includes:

• Travel to an area with an Ebola outbreak within 2 to 21 days of symptom onset.
• Contact with an ill person with suspected or confirmed Ebola or any contact with any object that might have come in contact with body fluids within the last 21 days.
• Contact with semen from an Ebola Disease survivor
• Any breach in Infection Prevention and Control procedures if caring for a suspected or confirmed Ebola case 
• Participation in certain activities while in an active outbreak region:
  • Attending a funeral or preparing a body for funeral or burial
  • Working or visiting a health facility or laboratory
  • Visiting a traditional healer
  • Contact with bats or animals
  • Working or visiting a mine or cave. 

If risk factors exist in the context of consistent signs and symptoms, the patient should be immediately isolated in a single room with a private bathroom or bedside commode, and Hospital Infection Prevention and Control should be contacted.

A careful history of sick and close contacts must be obtained for follow-up by local or state health authorities. Any suspected or confirmed cases of Ebola must be reported to the local or state health department as soon as possible, considering the need to stabilize and treat the patient.

Evaluation

Laboratory Testing

Laboratory tests to consider in patients diagnosed with Ebola virus disease or a person under investigation (PUI) for Ebola virus disease are:

• Complete blood count testing is essential for evaluating hemoglobin, platelet, and leukocyte counts. Bleeding due to coagulopathy can result in severe anemia, resulting in the need for transfusion. Bacterial co-infections are also often present.[7]
• A comprehensive metabolic panel helps evaluate acute kidney injury, electrolyte abnormalities (such as hyponatremia, hyperkalemia, and hypokalemia), elevated liver enzymes, and hypoglycemia that is often present.[25]
• An arterial blood gas should be drawn to evaluate for acid-base disturbances.[25]
• Creatine kinase testing should be sent to evaluate for rhabdomyolysis.[7]
• A urinalysis should be done to assess for renal dysfunction.[7]
• A basic coagulation profile, including prothrombin time, active partial thromboplastin time, fibrinogen, and international normalized ratio (INR), should be drawn and monitored to evaluate for signs of coagulopathy.[7]
• A blood type and screen should be tested preemptively; a blood transfusion may be necessary to support the patient.[7]
• A diagnostic test to evaluate for the presence of Ebola virus.[7]

Diagnostic Testing

Several molecular testing methods are available. RT-PCRs evaluate for the presence of the nucleoprotein or envelope glycoprotein.[26] These tests require an inactivation phase and must be performed in biosafety level 4 isolation.[26] Some reagents need to be kept at -20°C.[26] Additionally, the test requires a dedicated area and careful attention, as some byproducts of testing can contaminate the test. Testing generally requires 3 to 4 hours to perform. Although RT-PCRs are the most sensitive tests, the limitations of the safety requirements and equipment needed make this problematic in resource-limited settings. They are instead often found in reference laboratories. Automated nucleic acid tests are easier and quicker to perform. A comparative study comparing the RT-PCR method and an automated nucleic acid test, the FilmArray test, showed 85% agreement between the 2 tests.[27]

Several rapid lateral flow assays with quicker turnaround times than PCR testing are also available. A meta-analysis that compared rapid tests to RT-PCR showed a pooled sensitivity of 85% and a pooled specificity of 95%.[28] Some rapid tests have a sensitivity as low as 77%.[29] Although more sensitive and specific tests are needed, these remain potent tools in rural areas with limited resources and an epidemic setting.

Serologic tests can be helpful. However, the earliest that Ebola IgM can be detected is 6 days after the onset of the illness.[30] Due to the nature of Ebola virus disease, patients may have died before IgM would be detectable.

Radiography

Chest x-rays should be done to evaluate for pulmonary edema secondary to capillary leak syndrome.[31]

Treatment / Management

Infection Prevention and Control

The importance of employing immediate, effective Infection Prevention and Control (IPC) for patients with Ebola virus disease cannot be understated. The reproduction number of EBOV is estimated to be between 1.51 and 2.53, meaning for every patient infected with EBOV, between 1 and 3 additional people are expected to be infected.[32]  Effective IPC is paramount to controlling the spread of EVD. In endemic areas in West Africa, patients are often directed to Ebola Treatment Units (ETUs) that have tight protocols for testing and isolation.[33] However, patients may first seek treatment at any healthcare facility or not at all. This is sometimes due to the belief that the ETUs were the source of the infection.[34] In areas with inadequate contact tracing, people infected with an Ebola virus may present to facilities that do not have adequate IPC measures. This can amplify spread, as happened in the West African EVD epidemic between late 2013 and 2016.[33] In this epidemic, more than 800 healthcare workers died of EVD; most of these occurred where adequate IPC precautions were not employed.[25]The ability to screen patients for symptoms and signs consistent with EVD, practical training on IPC, facilities to isolate patients with EVD and those under investigation, and swift reporting of patients suspected of having Ebola to public health agencies are crucial to an effective IPC effort to control the disease.[33](A1)

The first case seen in the United States was in a community hospital in Dallas, Texas, in 2014.[35] Two nurses were infected while caring for the patient.[35] Following this, extra engineering controls were added for the medical intensive care unit to contain the virus, including zippered fabric walls to denote where PPE was required and the implementation of unidirectional entry and exit from the unit to decrease contamination of PPE.[35] Strict PPE was also implemented for laboratory personnel testing materials from patients with EVD or those under investigation.[35] 

A Cochrane review found evidence about optimal PPE to be uncertain, with tradeoffs between effectiveness, comfort, and errors in donning and doffing.[36] Modifying PPE design may be effective. Spoken instructions during doffing, double gloving, glove disinfection, and following CDC guidance may improve effectiveness and compliance. The Centers for Disease Control and Prevention recommend:(A1)

• single-use, impermeable gowns or coveralls
• either a powered, air-purifying respirator (PAPR) or an N95 respirator with a hood from head to shoulders and a disposable face shield (in case an aerosol-generating procedure needs to be performed emergently)
• two pairs of single-use gloves with extended cuffs
• single-use boot covers
• a single-use apron

PPE donning should occur with a trained observer who utilizes a written checklist and can ensure that PPE is worn correctly. PPE should be doffed in a designated area and placed in an infectious waste container. PPE should be inspected for any defects during the doffing process. Consistent and correct use of PPE and rapid initiation of isolation precautions effectively stop the chain of transmission; unfortunately, access to PPE has historically not been available in some areas affected by Ebola virus disease.[37]

The virus particle is resilient to inactivation. The virus is sensitive to sodium hypochlorite, gamma irradiation, high-dose ultraviolet light, and heat treatment (60 minutes at 60 °C or boiling for 5 minutes).[7](B3)

Public Health Follow-up

Both suspected and confirmed cases of Ebola virus disease are reported to local or state health officials as appropriate to the location. A suspect case is one in which a patient's signs, symptoms, and risk factors are consistent with Ebola virus disease but without confirmatory testing.[CDC. Ebola Disease] A confirmed case is one in which laboratory confirmation has been made. Close contacts include anyone in direct contact with a person confirmed or suspected to be sick with Ebola or objects that may be contaminated with their bodily fluids. 

Health officials will individually follow all close contacts for 21 days. They will also report the case to the CDC, as Ebola is internationally reportable under international health regulations.   

International travel bans and exit screenings upon departure from countries with active Ebola outbreaks have previously been implemented to prevent further spread.[38] However, this may limit the ability of aid workers to reach affected countries and promote more circuitous routes into and out of affected areas, which may decrease the effectiveness of infection prevention efforts.[39]

Supportive Care

The cornerstone of management and treatment for patients infected with an Ebola virus and exhibiting symptoms of Ebola virus disease is supportive care. Oral rehydration is highly recommended for all patients able to drink.[25] Parenteral fluid replacement is recommended in patients unable to take an adequate amount of fluids via the oral route or for those patients whose ongoing fluid losses are greater than their oral intake.[25] Vital signs and careful assessment of fluid status should be done at regular intervals to assess whether fluids should be adjusted.[25] Assessing electrolytes and renal function is recommended as electrolyte abnormalities, such as hypokalemia, hyperkalemia, and hyponatremia, are independent predictors of mortality in patients with Ebola virus disease.[40][25] Adequate staffing ratios to enable quick recognition of status changes, communicating with family and friends to decrease psychological distress, and adequate analgesics to relieve pain are also recommended.[25] Additionally, broad-spectrum antibiotics should be administered to patients with severe illness as bacterial co-infections are often present.[25](A1)

Therapeutics

The Pamoja Tulinde Maisha (PALM) trial solidified ansuvirimab and REGN-EB3 as preferred treatments for EVD over ZMapp and remdesivir.[31774950] Further information on this trial is below under "Pertinent Studies and Ongoing Trials." Ansuvirmab (MAb114) is an IgG1 monoclonal antibody that binds to the Ebola virus receptor binding domain.[41] It was approved by the US Food and Drug Administration (FDA) for Ebola treatment in December 2020.[42] REGN-EB3 combines 3 monoclonal antibodies that target Ebola virus glycoproteins: atolivimab, maftivimab, and odesivimab.[43] This drug obtained FDA approval in the United States in October 2020.[43]

Vaccinations

The live vesicular stomatitis virus-vectored vaccine against EBOV (r-VSV-ZEBOV) encodes a glycoprotein against EBOV.[44] Partial and maximal protection against death due to EBOV is achieved within 3 and 7 days, respectively, after one dose of vaccine in non-human primates.[44] The single-dose regimen makes it ideal for outbreak control for EBOV, using ring vaccination of primary and secondary contacts. It has been used effectively as post-exposure prophylaxis when more recent antibody therapies were unavailable.[44] In large human clinical trials, vaccine efficacy is 97.5% to 100% when given pre-exposure.[44] In a randomized clinical trial, 76% of adults and 87% of children receiving r-VSV-ZEBOV pre-exposure continued to have a detectable antibody response at twelve months.[45] The vaccination received US FDA approval for use in patients older than twelve months in August 2023. (A1)

Ad26.ZEBOV encodes a viral glycoprotein and utilizes an adenovirus 26 vector.[7] This is usually followed by a dose of MVA-BN-FILO, which encodes Ebola, Marburg, Sudan, and Tai Forest viruses using a modified vaccinia vector.[45][7] Forty-one percent of patients who received the Ad26.ZEBOV vaccination followed by the MVA-BN-FILO 56 days later had an antibody response twelve months post-vaccination.[45](A1)

Differential Diagnosis

Ebola virus disease should be differentiated from other causes of hemorrhage in the febrile patient and common viral illnesses presenting with similar prodromes and gastrointestinal symptoms.

Hemorrhage in the Febrile Patient

• Marburg virus
• Crimean-congo hemorrhagic fever
• Lassa fever
• Rift Valley fever
• Dengue
• Bunyavirus

Similar Prodromal Symptoms

• Malaria
• Typhoid fever
• Measles
• Leptospirosis
• Influenza
• COVID-19 infection

Gastroenteritis

• Shigella
• Rotavirus
• Norovirus

Pertinent Studies and Ongoing Trials

The Partnership for Research on EBOV in Liberia II (Prevail II) study was a randomized controlled trial performed in 2015 that randomized 72 patients to receive either ZMapp or only supportive care.[46] 37% of patients randomized to the supportive care arm died, compared to 22% in the ZMapp arm.[46] This study established that ZMapp was likely beneficial over only supportive care.

The Pamoja Tulinde Maisha (PALM) study was a randomized, controlled study performed in 2019 that evaluated EBOV patients receiving one of 4 agents:[47]

• Ansuvirmab (MAb114) is an IgG1 monoclonal antibody that binds to the Ebola virus receptor binding domain.[41] 
• REGN-EB3 combines 3 monoclonal antibodies: atolivimab, maftivimab, and odesivimab.[43] These monoclonal antibodies target Ebola virus glycoproteins.[43]  
• Remdesivir is a pro-drug of a nucleoside analog that terminates RNA synthesis by inhibiting RNA-dependent RNA polymerase.[48] This pro-drug was initially developed to treat hepatitis C but was found to have wide-spectrum activity against RNA viruses.[49] This treatment was found to have activity in Ebola virus-infected primates.[49]
• ZMapp is a mixture of monoclonal antibodies optimized from other monoclonal antibody cocktails. It showed early promise in the Partnership for Research on Infectious Diseases and Vaccines in Liberia (PREVAIL) II trial.[50][46]

In this trial, 673 people were randomized and included in the final analysis to receive one of the 4 treatments in equal ratios.[47] Based on the preliminary results of the trial revealing significantly lower mortality in the REGN-EB3 and Mab114 groups, further participants were randomized to receive either REGN-EB3 or Mab114, while remdesivir and ZMapp were no longer offered in the trial.[47] Mortality was 33.5% in the REGN-EB3 group, 35.1% in the Mab114 group, 49.7% in the ZMapp group, and 53.1% in the remdesivir group.[47]

In the trial, mortality at 28 days was 35.1% in patients treated with ansuvirimab, 33.5% in the REGN-EB3 group, compared to 49.7% in the ZMapp group.[47] There was no significant difference in mortality between remdesivir and ZMapp.[47] 

Prognosis

The recovery rate of Ebola virus depends on early intervention and access to adequate healthcare with continuous supportive care and close-interval patient reassessment. Supportive care is essential to correct dehydration, anemia, and respiratory support if needed. Even with optimal treatment, the mortality rate remains high. Fatality rates vary depending on the outbreak: the earliest outbreak in 1976 had an 88% mortality rate for EBOV and 60% for SUDV, while more recent outbreaks have shown fatality rates as low as 40%, likely reflecting improved supportive care.[21]

Complications

The main complications caused by the Ebola virus are profound hypovolemia, hemorrhage, and multisystem organ failure, leading to shock and death.[1] Psychiatric illness is common in EVD survivors.[51] Most survivors experience the trauma of watching others die in ETUs and may sense reluctance of healthcare workers to provide care due to concerns about contracting the virus.[51]

Due to prolonged viral presence in semen and known sexual transmission, the World Health Organization recommends semen Ebola RT-PCR testing monthly starting 3 months after infection, with condom use or abstinence until 2 consecutive tests are negative at least one week apart.[18]