EBOLA VIRUS DISEASE
• Detection of viral RNA in the blood by reverse transcriptase- polymerase chain reaction (RT-PCR) beginning 3 days after the onset of symptoms.
• Repeat testing may be necessary for patients with illness duration shorter than 3 days.
• Details on specimen collection and handling can be found on the Centers for Disease Control and Prevention (CDC), and World Health Organization (WHO) websites.
• Intensive fluid management to correct volume losses and electrolyte abnormalities.
• Aggressive use of antiemetics, antidiarrheals, and rehydration solutions.
• Respiratory and hemodynamic support.
• Blood products for management of coagulopathy.
• Evaluate and treat any concomitant infections.
• There are no approved antiviral therapies. However, a number of experimental treatments, including monoclonal antibodies, convalescent serum, small-molecule antivirals, and short interfering RNAs are available.
• Strict infection control measures, with contact and droplet precautions, must be used.
• Personnel trained in the correct use of personal protective equipment (PPE) should care for the patients.
Filoviridae, derived from the Latin word “filum,” meaning threadlike, is a family of viruses with a filamentous structure that can cause severe hemorrhagic fever and fulminant septic shock. Filoviruses have been divided into two genera: Ebola-like viruses with five species —Zaire, Sudan, Ivory Coast, Bundibugyo, and Reston; and Marburg-like viruses with a single species—Marburg, which has caused outbreaks in Central Africa. Using paleoviruses (genomic fossils) found in mammals, we can extrapolate that the viruses probably diverged several thousand years ago, and that the family itself is at least tens of millions of years old.
Of the five Ebola virus species only four—Zaire, Sudan, Ivory Coast, Bundibugyo—cause disease in humans. Since its first recognition in 1976, Zaire ebolavirus has caused multiple outbreaks in Central Africa. It is the causative agent of the 2014 West African epidemic, with an initial estimated case fatality rate as high as 70%, although as the epidemic evolved, lower fatality rates in the range of 30% to 40% were observed. The 2014 epidemic began in Guinea, when a 2-year-old child became infected in late 2013, and Zaire ebolavirus subsequently spread to Liberia, Sierra Leone, Nigeria, Senegal, and Mali. The epidemic resulted in over 28,000 cases and 11,000 deaths, with more than 800 infections occurring in health care workers. Sudan virus has been associated with a case-fatality rate of approximately 50% in four epidemics, which occurred in Sudan and Uganda between 1970 and 2004. Ivory Coast virus has been identified as the cause of illness in one person following exposure during a necropsy on a chimpanzee found dead in the Tai Forest. Bundibugyo virus, most closely related to the Ivory Coast species, emerged in Uganda in 2007, causing an outbreak with a case fatality rate of approximately 30%. Reston virus, discovered after an outbreak of lethal infection in macaques imported into the United States in 1989, is maintained in animal reservoirs in the Philippines.
Outbreaks generally begin when an individual becomes infected through contact with the tissue or body fluids of an infected animal. The virus then spreads to others who come into contact with the infected individual’s blood, skin, or other body fluids. Prior to the 2014 epidemic in West Africa, outbreaks occurred in remote regions with low population density and were controlled within short periods. However, the recent epidemic has shown that movement of infected individuals facilitates the extensive and rapid spread of the virus.
Transmission occurs most commonly through direct contact of broken skin or mucous membranes with virus-containing body fluids from an infected person, the most infectious being blood, feces, and vomit. During the early phase of illness, the level of virus in the blood is typically quite low, but then increases rapidly to very high levels in advanced stages of the illness, when patients become highly infectious. In fact, corpses of persons who die from Ebola are highly infectious, and ritual washing of bodies at funerals has played a significant role in the spread of infection. The virus has also been detected in urine, semen, saliva, breast milk, tears, and sweat, and can persist in some of these fluids much longer than in blood. To prevent sexual transmission the WHO recommends that men either abstain from sex, or use condoms for three months after onset of symptoms.
Ebola virus may also be transmitted though contact with contaminated surfaces where the virus can remain infectious from hours to days.
Transmission to health care workers may occur when appropriate PPE is not used, especially when caring for severely ill patients in advanced stages of illness. During the 2014 outbreak in West Africa, a large number of health care workers became infected. In Sierra Leone, the incidence of confirmed cases at the peak of the epidemic was about 100-fold higher in health care workers than in the general population. Several factors have contributed to the high rates of infections among health providers, including failure to recognize infection among patients and corpses, limited availability and training in the use of appropriate PPE, and inadequate management of contaminated waste and burial of corpses. Although there is no evidence of respiratory transmission, the virus is highly infectious when released in laboratory experiments as a small-particle aerosol, and therefore health care workers may be at risk if exposed to aerosols generated during procedures.
Human infection can occur through contact with infected wild animals during hunting, butchering, and preparing meat, with several episodes having occurred following contact with infected gorillas or chimpanzees. To prevent infection, food products should be properly cooked to inactivate the virus, and basic hygiene measures should be followed. Direct transmission of virus infection from bats to wild primates or humans has not been proven, although Ebola RNA sequences and antibodies have been detected in bats in Central Africa. Bats likely form a major reservoir.
Ebolavirus is a negative-sense, single-stranded RNA virus resembling rhabdoviruses and paramyxoviruses in its genome organization and replication mechanisms. The tubular virions contain the nucleocapsid surrounded by an outer envelope, which is derived from the host cell membrane and studded with viral glycoprotein spikes. The virions attach to host cell receptors through the spikes and are then endocytosed into vesicles. Initially, productive infection occurs primarily in dendritic cells, monocytes, and macrophages, resulting in impaired interferon production and release of proinflammatory cytokines, which have secondary effects on innate and adaptive immune responses, inflammation, and vascular integrity. Neutrophils are activated, with resultant degranulation, and lymphocytes undergo apoptosis. The virus then spreads to regional lymph nodes resulting in further rounds of replication, followed by dissemination to the liver, spleen, thymus, and other lymphoid tissues.
When the virus infects cells, it hijacks the cell and forces it to become a virus-producing factory, churning out new copies of the virus, which results in a loss of cellular function and eventual cell death by apoptosis. As the disease progresses, there is extensive tissue necrosis accompanied by a systemic inflammatory response induced by the release of various cytokines, chemokines, and proinflammatory mediators; and a severe coagulopathy triggered by the release of tissue factors. This systemic inflammatory response may contribute to gastrointestinal dysfunction, and ultimately there is a multisystem failure caused by the damage to vascular and coagulation systems.
Clinical Manifestations and Laboratory Findings
Patients with Ebola virus disease (EVD) typically have an abrupt onset of symptoms 5 to 10 days after exposure, with a range of 2 to 21 days. The first phase of the illness is characterized by high fever, chills, headaches, myalgia, and malaise. The second phase is marked by gastrointestinal symptoms, which develop by day 3 to 5, and includes watery diarrhea, nausea, vomiting, and abdominal pain.
Patients may also develop chest pain, hiccups, shortness of breath, conjunctival injection, and rash. The rash is usually diffuse erythematous, maculopapular, involving the face, neck, trunk, and arms. Respiratory symptoms such as cough are rare. Common neurologic symptoms include delirium—manifested by confusion, slowed cognition, or agitation, and less frequently, seizures.
The final phase, beginning in the second week, is marked by either progression to shock and death, or gradual recovery. Fatal disease is characterized by development of multisystem failure usually as a consequence of massive fluid losses that lead to shock, loss of consciousness, and renal failure. Major bleeding, typically hemorrhage from the gastrointestinal tract, is infrequent and seen in less than 5% during the terminal phase of illness. Patients who survive begin to improve during the second week of illness, with a prolonged convalescence marked by weakness and fatigue. About half of the survivors are plagued by chronic debilitating joint pain and a quarter experience eye problems. The virus can persist in the eye for months, leading to uveitis, cataracts, and sometimes blindness.
During acute illness patients typically develop leukopenia, lymphopenia, thrombocytopenia, serum transaminase elevations, and proteinuria. They may develop renal insufficiency and electrolyte disturbances as a result of the gastrointestinal losses. Severe cases develop coagulation abnormalities with prolonged prothrombin and partial thromboplastin times, and elevated fibrin degradation products, consistent with disseminated intravascular coagulation.
The approach to evaluating patients depends upon whether or not appropriate signs and symptoms are evident, and if an exposure occurred within 21 days prior to the onset of symptoms. Infection control precautions must be used for all symptomatic patients with an identifiable risk for EVD. All symptomatic patients should be isolated in a single room with a private bathroom, and implementation of contact and droplet precautions. Only essential personnel who are well-trained in the use of PPE should interact with the patient.
Phlebotomy and laboratory testing should be limited to essential tests. Both the CDC and the WHO have provided detailed recommendations for approach to the evaluation of persons who may have been exposed to the virus.
Rapid diagnostic tests are the most commonly used tests for diagnosis. Viral RNA is generally detectable by RT-PCR in the blood 3 days after the onset of symptoms. Repeat testing may be necessary for patients with illness duration shorter than 3 days. A negative RT-PCR test greater than or equal to 72 hours after the onset of symptoms rules out EVD. Details on specimen collection and handling can be found on the CDC website. For clinicians outside the United States, the WHO has issued guidance for the collection and shipment of specimens from patients with suspected disease.
Acute onset of febrile illness in a person who lives in, or has recently been in West or Central Africa may be caused by a variety of local infectious diseases, which must be considered in the differential diagnosis. Malaria may have similar findings and might occur concurrently. Examination of blood smears and rapid antigen tests are typically used to diagnose malaria. Typhoid is characterized by fever and abdominal pain, and diagnosed by blood cultures.
Patients with Lassa fever may develop a severe clinical syndrome resembling EVD and progress to fatal shock. The illness is restricted to West Africa, where it is transmitted through exposure to the aerosolized excretions of rodents, and diagnosed by RT-PCR testing and/or serology. Clinical manifestations of Marburg virus disease are similar to EVD, and cases have been identified in Central Africa. The diagnosis is made by RT-PCR. Patients with influenza may have a similar initial presentation, but respiratory signs and symptoms are prominent.
Good supportive care can significantly improve the chances of recovery from EVD. Mortality rates have been as low as 18% among those cared for in the US and Europe, receiving careful fluid and electrolyte management, nutritional support and critical care. Large volumes of intravenous fluids and electrolytes are often needed to correct dehydration and electrolyte abnormalities resulting from gastrointestinal losses. Supportive care is required for complications such as shock, hypoxia, hemorrhage, and multiorgan failure. Patients may develop secondary bacterial infections, which may require concurrent management with antimicrobials. Infection prevention and control measures are critical; all bodily fluids and tissues must be considered potentially infectious. The illness is associated with high rates of pregnancy-associated hemorrhage and fetal death. The Centers for Disease Control and Prevention and the American College of Obstetrics and Gynecology have issued recommendations for the care of pregnant women with EVD. However, there are no definitive data to recommend cesarean section versus vaginal delivery or the preferred timing for delivery.
No FDA-approved antiviral drugs or therapeutic vaccines are available, although several are currently in development. Two antiviral nucleoside agents, favipiravir (T-705, Avigan)5 and brincidofovir (CMX001)5 have been used in patients with EVD. Favipiravir inhibits the replication of a wide range of RNA viruses, including influenza, and is currently being evaluated in Ebola-infected macaques. Brincidofovir is being developed for the treatment of poxvirus, cytomegalovirus, and other DNA virus infections, but has also demonstrated in vitro activity against Ebola virus.
Ebola-specific agents in development include ZMapp (a combination of humanized monoclonal antibodies),5 TKM-Ebola (a short interfering RNA molecule [siRNA]),5 phosphorodiamidate morpholino oligomers (PMO, a type of antisense oligonucleotide),5 and BCX4430 (a nucleoside analog).5 Plasma from patients who have recovered from the disease was used to treat patients during the 2014 outbreak, but no clinical trials have been conducted to date. Clinicians may contact the CDC’s Emergency Operations Center for additional information on use of experimental therapeutics for treatment of EVD.
There is no FDA-approved vaccine available for Ebola, although several vaccines are in various stages of development, and some have shown efficacy against virus challenge in laboratory primates. A vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising candidate that was rapidly escalated into efficacy trials in Africa. In August 2015 the Lancet published an interim analysis showing that rVSV-ZEBOV appears to provide 100% protection against the virus.
The trial was carried out in Guinea and used a ‘ring’ design in which contacts of infected people are vaccinated, as are any subsequent contacts of those people.
Recommendations for travelers to an area affected by an Ebola outbreak or those residing in such an area are as follows:
• Practice careful hand hygiene and avoid contact with an infected person’s blood or body fluids, including personal items that may have come in contact with blood and body fluids.
• Avoid unprotected contact with the body of a deceased person who was infected with EVD.
• Avoid contact with bats and nonhuman primates, including blood, bodily fluids, and tissues from these animals.
• Monitor health for 21 days after return from an Ebola endemic region, and seek medical care immediately if any symptoms develop.
Health care workers at risk for exposure to Ebola must wear PPE and notify appropriate health officials at their institutions if they have unprotected contact with the blood or bodily fluids of a person infected with EVD. Finally institutions must have proper infection control and sterilization measures in place for handling of biohazardous materials. Clinicians may contact the CDC for additional information on use of experimental therapeutics and vaccines for prophylaxis following a high-risk occupational exposure to Ebola virus.
Local authorities may have specific regulations for management of asymptomatic individuals with Ebola virus exposure. This includes self-monitoring versus direct observation by a health official, and the need for quarantine. In general, asymptomatic persons who have had an exposure should be monitored for 21 days after the last known exposure, and should immediately report the development of fever or other clinical manifestations suggestive of EVD to the health authorities.
1. Bah E.I., Lamah M.C., Fletcher T., et al. Clinical presentation of patients with Ebola virus disease in Conakry, Guinea. N Engl J Med. 2015;372:40–47.
2. Chertow D.S., Kleine C., Edwards J.K., et al. Ebola virus disease in West Africa—clinical manifestations and management. N Engl J Med. 2014;371:2054–2057.
3. Henao-Restrepo A.M. Longini IM, Egger M, et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet. 2015;S0140– 6736(15):61117–61125.
4. Schieffelin J.S., Shaffer J.G., Goba A., et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371:2092–2100.
5. United States Centers for Disease Control and Prevention (CDC). Ebola (Ebola virus disease). Available at http://www.cdc.gov/vhf/ebola/.
6. WHO Ebola Response Team. Ebola virus disease in West Africa —the first 9 months of the epidemic and forward projections. N Engl J Med. 2014;371:1481–1495.
7. World Health Organization (WHO). Ebola. Available at http://www.who.int/csr/disease/ebola/en/.
5 Investigational drug in the United States.