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ESSENTIALS OF DIAGNOSIS
Early stage EVD: a nonspecific febrile illness.
Later stage EVD: severe gastrointestinal symptoms, then neurologic symptoms and hypovolemic shock.
Hemorrhagic manifestations are late-stage manifestations.
Uveitis is prominent.
Travel and contact history from an Ebola-affected country raise suspicion.
Virus is detected with a RT-PCR.
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General Considerations
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Genus Ebolavirus is a single-stranded RNA virus in the Filoviridae family. Four different species of Ebolavirus have been identified to cause human disease. Fruit bats are possible reservoir for Ebolavirus. Zoonotic transmission to humans occurs via contact with the reservoir or an infected primate. Ebolavirus can continue to be transmitted among humans who have direct contact with infected body fluids. To acquire EVD, the virus must enter the body via mucous membranes, nonintact skin, sexual intercourse, breastfeeding, or needlesticks. Traditional burial practices in Africa (which entail considerable contact with the corpse) and unprotected direct care of persons with EVD are associated with highest transmission risk. Ebolavirus has been detected in semen up to 9 months after recovery from infection.
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EVD has a 2–21-day incubation period. Prior to manifestation of symptoms, Ebolavirus is not transmissible. Even at symptom onset, the risk of transmission is low but increases over time.
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The first Ebola outbreak occurred in 1976 as a simultaneous epidemic in the Democratic Republic of Congo and South Sudan. Subsequent outbreaks were confined to the Democratic Republic of Congo, Uganda, and Sudan until March 2014 when the first Ebola case in West Africa was identified in Guinea. Zaire ebolavirus was the associated species. This Ebola outbreak grew to be larger than all prior Ebola outbreaks combined. The number of EVD cases spread rapidly; there were at least 10 affected countries, especially Guinea, Liberia, and Sierra Leone. Many cases and deaths in these countries occurred among healthcare workers. In the United States, 11 persons were treated for Ebola. Most were healthcare workers who were evacuated to the United States and 4 patients were diagnosed in the United States. In total, 35 outbreaks of Ebola have occurred in Africa since 1976.
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Sierra Leone contained its last EVD outbreak as of March 2016. Guinea was declared free of EVD transmission in June 2016. Liberia declared the end of its last outbreak in June 2016. The WHO reports that the West African Ebola outbreak was associated with 28,616 cases and 11,310 deaths during the approximately 2-year interval of the outbreak between March 2014 and March 2016.
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Two outbreaks were reported in May and August of 2018, both in the Democratic Republic of Congo (where outbreaks also were reported in 2014 and 2017), and while the isolates from the two outbreaks were both the same species, complete genetic homogeneity between the isolates was not present. As of March 9, 2020, 3444 cases (3310 confirmed and 134 probable) and 2264 deaths were reported from 29 health zones in the Democratic Republic of Congo, including 171 cases among healthcare workers.
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A. Symptoms and Signs
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At symptom onset, early-stage EVD most typically presents as a nonspecific febrile illness. Along with fever, patients tend to experience headache, weakness, dizziness, malaise, fatigue, myalgia, and arthralgia. After 3–5 days, patients with later stage EVD may develop abdominal pain, severe nausea, vomiting, and diarrhea accompanying the febrile illness. This stage of the illness may continue for a week during which time neurologic symptoms gain prominence. Encephalitis is commonly observed and manifested as confusion, slowed cognition, agitation, and occasional seizures. Hypovolemic shock develops in most patients, but hemorrhagic manifestations (gastrointestinal bleeding, diffuse mucosal bleeding, conjunctival bleeding) develop in only 1–5% of patients. Respiratory symptoms are not typical for EVD, although interstitial pneumonia and respiratory failure are reported.
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B. Laboratory Findings
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During the first few days of symptoms, diagnosis may be made via several modalities, including antigen-capture ELISA, IgM ELISA, RT-PCR, or virus isolation. Blood samples obtained within the first 3 days of illness and tested by RT-PCR should be repeated if results are negative and clinical symptoms and signs persist. RNA levels peak a median of 7 days after illness onset. Later in the disease course or after recovery, IgM and IgG serologic tests may be sent. After about 10 days, IgM antibodies begin to develop, and, after approximately 2 weeks, an IgG antibody response develops. Postmortem diagnosis may be made by using immunohistochemistry, RT-PCR, or virus isolation.
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Given that filoviruses infect dendritic cells and then hepatocytes and renal cortical cells, laboratory findings typically include a low platelet count (and a thrombotic thrombocytopenic purpura syndrome has been postulated with the probable cause multifactorial), leukopenia, and transaminitis (aspartate aminotransferase [AST] greater than alanine aminotransferase [ALT]). As nonspecific symptoms progress to a severe systemic inflammatory response, coagulopathy with evidence of platelet dysfunction and disseminated intravascular coagulopathy (DIC) often develops. Whether DIC is a common cause of bleeding has not yet been firmly established because clinical measurements of fibrinogen, prothrombin time, fibrin split products, and platelets are not routinely taken in the communities where most outbreaks have occurred. Additional observed laboratory abnormalities include hypoalbuminemia, electrolytes imbalance, and increased serum creatinine level. Elevated blood urea nitrogen, AST, and creatinine upon presentation are associated with higher mortality.
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Differential Diagnosis
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The differential diagnosis varies with the stage of illness. Early-stage EVD is commonly mistaken for malaria, typhoid, and other viral illnesses. As gastrointestinal symptoms develop, health providers should also consider viral hepatitis, toxins, leptospirosis, and rickettsial diseases. In later stage EVD, bacterial, viral, and parasitic illnesses, including cholera and, in children, rotavirus infection can present with severe gastroenteritis and shock. Encephalitis must be differentiated from the confusion associated with uremia. Hemorrhagic manifestations raise suspicion for EVD but could be due to leukemia, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, or disseminated intravascular coagulation. Travel and contact history are crucial when considering the differential diagnosis in areas where Ebola is not endemic.
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Hypovolemic shock and multiorgan failure are the most common complications of EVD. Hemorrhage can occur in late stages. Rhabdomyolysis is reported frequently and may explain many of the associated laboratory abnormalities. Coinfections with malaria or bacteria (or both) are important considerations and can occur before presentation and during treatment of EVD. The virus is known to persist in immunologically privileged sites, such as the CNS, eye, and testes; however, viral relapse is uncommon. Post-EVD musculoskeletal pain, headache, auditory symptoms including hearing loss, and ocular symptoms (uveitis being the most common ocular finding) may develop. EVD survivors exhibit high rates of neuropsychological long-term sequelae including depression, anxiety, and posttraumatic stress disorder.
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Treatment is supportive. Several studies have shown that intravenous fluids can reduce the mortality rates to less than 50%. Despite the wide availability of oral rehydration salts, mortality approximates 70% in endemic areas. In these studies, the amount of intravenous fluid replacement was relatively less than what would be used in countries with developed health systems. Among patients treated in the United States or Europe, almost all received intravenous fluids, electrolyte supplementation, and empiric antibiotic therapy. Invasive or noninvasive mechanical ventilation and continuous renal replacement therapy are necessary in many cases. This increased level of care likely contributed to the decreased mortality (19%) among these patients. The use of individual air-conditioned biosecure cubicles is preferred to the burdensome protective equipment used during the 2014 West African outbreaks and allows for more time spent with patients.
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There are no approved medications for the treatment of EVD. Administration of convalescent plasma does not result in improved survival. Several drugs have advanced to clinical trials; however, some trials were terminated due to low enrollment or lack of efficacy. Monoclonal antibodies that have been tested include mAb114 (a monoclonal antibody isolated from a survivor of the 1995 outbreak in the Democratic Republic of the Congo), ZMapp (a cocktail of three chimeric monoclonal antibodies against Z ebolavirus), and REGN-EB3 (another cocktail of three monoclonal antibodies against Z ebolavirus). ZMapp showed some therapeutic benefit, but many of these patients received multiple agents and were not part of randomized controlled trials. The PREVAIL II study evaluated ZMapp for treatment of EVD and found it to be safe and well tolerated but failed to establish efficacy due to low enrollment numbers. REGN-EB3 is given as a single dose, does not require freezing, and shows efficacy in nonhuman primates, including reduction in mortality. Starting in November 2018, the Pamoja Tulinde Maisha (PALM) trial enrolled 681 Congolese patients to receive one of four investigational drugs: mAb114, ZMapp, REGN-EB3, or remdesivir (GS-5734; a novel nucleotide analog prodrug). In August 2019, the study’s independent data and safety monitoring board recommended stopping the trial early because preliminary results from 499 patients suggested that those taking REGN-EB3 or mAb114 had a greater chance of survival than patients who received the other two drugs (mortality with mAb-114 or REGN-EB3 was 6–11% compared to 24–33% mortality for those who received ZMapp or remdesivir).
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In the 2018 outbreak in the Democratic Republic of the Congo, the two antivirals used were remdesivir and the RNA-dependent RNA polymerase inhibitor favipiravir. Mathematical models show a high likelihood of efficacy for both agents against EVD if given within 3–4 days of infection, and the efficacy of remdesivir is theoretically 100% while that of favipiravir is 60%. Remdesivir has been administered under compassionate use to two Ebola patients, both of whom survived and is currently in phase 2 clinical development for the treatment of EVD and long-term clearance of Ebola virus in male survivors with virus persistence in semen (NCT02818582). Although both agents were effective in nonhuman primates and one study in man found favipiravir to be effective in patients with low to moderate viremia, a more recent trial of favipiravir in 99 participants found no difference in mortality for persons with low or high viral loads compared to historical controls.
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Aside from supportive treatment and experimental therapeutics, patients typically receive empiric antimalarial agents in endemic areas and broad-spectrum antibiotics. GS-5734 is an experimental medication that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in phase 2 clinical development for the treatment of EVD and long-term clearance of Ebola virus in male survivors with virus persistence in semen (NCT02818582).
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Children under 5 years of age and adults older than 40 have a high risk of death from EVD. Pregnancy is a risk factor for severe illness and death. In the 2014–2016 outbreak, the average maternal mortality was 86%. Immunosuppressed patients had shorter incubation time, rapid progression of disease, and poor outcomes. A higher baseline viral load was a strong predictor of mortality. In general, poor overall medical care confers a poor prognosis. Among survivors, protective antibodies persist for at least 10 years.
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Risk reduction should focus on preventing wildlife to human transmission and reducing human to human transmission by surveillance, early detection and isolation of cases, contact tracing, containment measures (disinfection, hygiene, and sanitation), strict droplet and contact precautions in health care setting, and reduction of sexual transmission in Ebola survivors. The WHO recommends that men avoid sexual activity or use barrier protection during intercourse for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus.
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There are two Ebola vaccines being used in the ongoing epidemic in the Democratic Republic of the Congo. The recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing Z ebolavirus (ZEBOV) glycoprotein is found to be highly effective in disease prevention after 10 days from receiving the vaccine. Side effects, such fever, myalgia, chills, fatigue, headaches, and oligoarthritis, developed in most of the persons who received the vaccine. rVSV-ZEBOV (marketed as Ervebo) showed promising results in phase III clinical trials (most study participants had persistent antibody levels at 1 year; NCT02503202). In addition, it was tested in a clinical trial conducted in Guinea during the 2014–16 Ebola outbreak in West Africa and was found to offer a high level of protection against Ebola (100% efficacy). rVSV-ZEBOV is the only Ebola vaccine candidate that has so far been able to demonstrate clinical effectiveness. It is being used in the ongoing outbreak in the Democratic Republic of the Congo (where more than 250,000 persons have been vaccinated as of November 11, 2019 including pregnant women and young children) and was approved by the European Medicines Agency (EMA) on November 11, 2019 and by the US FDA on December 19, 2019. The adenovirus/vaccinia virus vector vaccine is also deployed in the current outbreak in the Democratic Republic of the Congo; EMA approval for this vaccine is pending. The adenovirus/vaccinia virus vector vaccine is actually a two-dose series of two different vaccines, Ad26.ZEBOV (replication-incompetent recombinant adenovirus 26 expressing the ZEBOV [Mayinga strain] glycoprotein) and MVA-BN-Filo (a nonreplicating modified vaccinia Ankara-Bavarian Nordic virus vector expressing the glycoproteins of Zaire and Sudan ebolaviruses, Marburg virus, and the nucleoprotein of Tai Forest virus), given about 6 weeks apart (NCT03140774). This vaccine is being tested in a clinical trial in the Democratic Republic of the Congo at a dose that has shown 100% protective efficacy in nonhuman primate studies and that is well tolerated and immunogenic in extensive phase I–II trials. Nevertheless, concerns remain about public acceptance of an investigational two-dose vaccine when an approved one-dose vaccine (rVSV-ZEBOV) is already available.
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There are 11 other Ebola vaccines in various stages of clinical testing, including a recombinant Ebola virus glycoprotein nanoparticle formulated with a saponin-based Matrix-M adjuvant.
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Risk stratification may be useful in deciding when and to whom to administer antiviral postexposure prophylaxis. A high-risk exposure is defined as penetrating sharps injury from used device or through contaminated gloves or clothing, direct contact with an infected patient (alive or deceased) or their bodily fluids with broken skin or mucous membranes such as eyes, nose, or mouth. The ZEBOV vaccine was used in the setting of postexposure prophylaxis among healthcare workers and found to be effective, but the evidence is limited to case series. The vaccine-mediated immunity requires an average of 10 days to develop and might not be fast enough in certain cases to prevent infection.
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Current studies focus on isolation of cross-reactive monoclonal antibodies across Ebola virus species. The use of different preparations of combination monoclonal antibodies (ZMapp and MIL-77E) as postexposure prophylaxis during the West African outbreak failed to show statistical significance, and the conclusion was that the benefit was modest, at best. Newer forms of monoclonal antibodies include virus-like particles (VLP), mucin-deleted glycoproteins, and bispecific binding proteins (which bind Ebola proteins as well as those of related viruses such as the Sudan virus). The use of antiviral agents in postexposure prophylaxis is another alternative that, to date, also shows no clear survival benefit. The agent brincidofovir, for example, was not studied further because of inadequate sample size in Liberia.
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Persons living in or returning from a country with high rates of Ebola transmission should be monitored for 21 days and admitted to a health care facility when symptoms meeting the WHO case definition of a suspected EVD case develop, in accordance with the screening protocol designated by the respective country’s governmental health decision-making body.
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Bausch
DG
et al. Ebola vaccines: biomedical advances, human rights challenges. J Infect Dis. 2019 Oct 11. [Epub ahead of print]
[PubMed: 31603195]
+
Callaway
E. ‘Make Ebola a thing of the past’: first vaccine against deadly virus approved. Nature. 2019 Nov;575(7783):425–6.
[PubMed: 31745354]
+
Chertow
DS. Understanding long-term effects of Ebola virus disease. Nat Med. 2019 May;25(5):714–5.
[PubMed: 31036880]
+
Fischer
WA 2nd
et al. Ebola virus disease: an update on post-exposure prophylaxis. Lancet Infect Dis. 2018 Jun;18(6):e183–92.
[PubMed: 29153266]
+
Fries
L. A randomized, blinded, dose-ranging trial of an Ebola virus glycoprotein (EBOV GP) nanoparticle vaccine with matrix-M™ adjuvant in healthy adults. J Infect Dis. 2019 Oct 11. [Epub ahead of print]
[PubMed: 31603201]
+
Haddad
LB
et al. Pregnant women and the Ebola crisis. N Engl J Med. 2018 Dec 27;379(26):2492–3.
[PubMed: 30485156]
+
Ilunga Kalenga
O
et al. The ongoing Ebola epidemic in the Democratic Republic of Congo, 2018–2019. N Engl J Med. 2019 Jul 25;381(4):373–83.
[PubMed: 31141654]
+
Kuehn
B. Early success in Ebola trial. JAMA. 2019 Oct 15;322(15):1441.
[PubMed: 31613352]
+
Lötsch
F
et al. Neuropsychological long-term sequelae of Ebola virus disease survivors—a systematic review. Travel Med Infect Dis. 2017;18:18–23.
[PubMed: 28478336]
+
Shantha
JG
et al. An update on ocular complications of Ebola virus disease. Curr Opin Ophthalmol. 2017 Nov;28(6):600–6.
[PubMed: 28872492]