#94083: Ebola Virus Disease

Ebola virus is a nonsegmented negative-strand RNA virus that varies greatly in size and form, with the filamentous form being the most characteristic [34]. The Ebola virus core structure consists of the RNA genome wrapped in nucleoprotein (the nucleocapsid) and other proteins having distinct functions in the replication cycle. The particle is enveloped within a lipid bilayer (the viral envelope) derived from the host cell. Spikes on the surface of the particle are formed by a transmembrane glycoprotein that mediates viral entry into the host cell.

Ebola virus is thought to gain entry to the human host through mucous membranes or skin abrasions, after which it binds to receptors on the surface of macrophages, monocytes, and dendritic cells [2]. Infected macrophages and monocytes migrate to regional lymph nodes, where continued viral replication and cellular propagation of infection occurs. From lymph nodes, infected monocytes, macrophages, and free virions spread through the lymphatic system to the blood stream, liver, spleen, and adrenal glands. Amplification of infection at these distant sites leads to focal areas of tissue necrosis and the release of ever-increasing numbers of virions into the general circulation [2]. The trophism of Ebola virus extends to multiple cell types, including endothelial cells, fibroblasts, hepatocytes, and adrenocortical cells.

The rapid pace of virus replication and dissemination results not only from the direct effect of virus on host cells, but also from mechanisms Ebola virus employs to evade host immune responses. [2,34]. These mechanisms include antagonism of the type I interferon response, inhibition of antigen presentation to CD8 and CD4 T cells, and suppression of T-cell activation, impeding the linkage between innate and adaptive immune responses [34]. Although Ebola virus does not invade lymphocytes, widespread and massive lymphocyte apoptosis develops early in the course of EVD [2].

Infected macrophages elaborate a variety of inflammatory mediators (cytokines and chemokines) that act in various ways to produce severe multisystem injury. These include cell-surface expression of tissue factors that activate the coagulation cascade and cytokine-mediated vascular endothelial injury, which together lead to disseminated intravascular coagulation (DIC), hypotension, and multi-organ failure [2]. This syndrome resembles the septic shock caused by gram-negative bacillary endotoxemia.

As noted, EVD is an acute, severe, multisystem viral infection that is highly contagious and often fatal [1,3,8,9,33]. The onset of symptoms is usually 5 to 7 days after exposure, though the observed incubation period varies from 2 to 21 days. Illness begins abruptly with fever, chills, and malaise, followed soon after by the rapid onset of weakness, myalgia, headache, vomiting, diarrhea, and abdominal pain. An erythematous maculopapular rash, appearing first on the buttocks and trunk, then more generalized, is often seen between the 5th and 7th day of illness [8]. Other findings include pharyngitis, lymph node enlargement, hepatomegaly, and abdominal tenderness.

Early laboratory abnormalities include neutropenia, lymphocytopenia, thrombocytopenia, and mild-to-moderate elevations of hepatic aminotransferase enzymes. Hemoglobin and hematocrit values are elevated secondary to fluid losses and hemoconcentration. At peak illness, total white blood cell counts rebound, anemia develops, and a variety of metabolic abnormalities emerge, including hypoalbuminemia, hypoglycemia, and elevated blood urea nitrogen [34].

With disease progression, patients experience profound weakness, postural hypotension, prostration, confusion, and bleeding abnormalities. Hemorrhagic manifestations, seen in fewer than half of affected patients, include petechiae, ecchymoses, bleeding from the gums, and blood in vomitus and stool [1,8,33]. Hemorrhagic complications are evidence of ongoing thrombocytopenia and the development of DIC. Metabolic acidosis and electrolyte abnormalities, principally hypokalemia, are common.

The diagnosis of acute EVD is difficult because early symptoms and signs are nonspecific and may suggest other, more common febrile illnesses such as malaria or typhoid fever. The clinical criteria for a presumed case of EVD have been established by the CDC and are as follows [20]:

In the event of a confirmed or suspected case of EVD, the patient should be isolated, diagnostic specimens collected, and public health authorities notified.

For clinical purposes, early confirmation of the diagnosis of EVD relies on detection of viral genomic material or demonstration of virus-specific antigen in a sample of blood (Table 2). Ebola virus is detectable in blood within one to three days after onset of initial symptoms by use of the reverse transcriptase polymerase chain reaction (RT-PCR). Virus detection in blood samples remains positive for 10 days or more after onset of illness. If the initial diagnostic evaluation occurs more than three days after onset of illness, a subsequent specimen for RT-PCR may be necessary to confidently exclude EVD.

An enzyme-linked immunosorbent assay (ELISA), for detection of viral antigen, is also available. This assay is slightly less sensitive than RT-PCR, usually becoming positive three to five days after onset of illness.

In 2019, the U.S. Food and Drug Administration (FDA) allowed marketing of a new rapid diagnostic test for Ebola virus [25]. The OraQuick Ebola Rapid Antigen Test uses blood samples from symptomatic patients or cadaveric oral fluid to identify Ebola antigens; the results are available within 30 minutes. For living patients, the test is intended for use in patients suspected of and with signs or symptoms consistent with EVD and when the patient meets the CDC's Ebola virus epidemiologic criteria, such as history of residence in or travel to a geographic region with active EVD transmission at the time of travel [25]. Negative results do not rule out Ebola virus infection, and definitive identification of EVD requires additional testing and confirmation.

Specimen collection and transfer for diagnostic purposes is a serious biohazard risk. Workers have been exposed to the disease during this process, especially when strict infection control policies are not followed and enforced [3]. The CDC provides guidance for collection, transport, and submission of specimens for Ebola virus testing, last updated December 2022 [21]. If a diagnosis of EVD is considered, clinicians should coordinate with their clinical laboratory, local public health officials, and the CDC to ensure appropriate precautions are taken to prevent spread and coordinate care. The CDC's Viral Special Pathogens Branch (VSPB) is available at any time for consultations on EVD by calling (770) 488-7100.

The CDC recommends that Ebola testing be conducted only for persons who have both consistent signs or symptoms and risk factors as follows [21]:

Patients with EVD should be admitted to a single-bed room separate from the usual patient care areas, preferably one with an adjacent anteroom for donning and removing PPE. Ideally, care should be provided by an interprofessional team (physician and nursing staff) designated for this purpose. The team members should have critical care experience or advanced knowledge and training in the care of severely ill and highly infectious patients. Adherence to strict isolation, standard contact precautions, proper utilization of PPE, and effective environmental decontamination practices are essential for limiting transmission and protecting healthcare workers [6,11].

A multidisciplinary guidelines panel strongly recommends, with moderate confidence, administering patients with Ebola virus disease oral rehydration solution in an adequate amount rather than nonstandardized rehydration.

(https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31795-6/fulltext Last Accessed: March 21, 2024)

Strength of Recommendation: Strongly in favor

Because survivors can produce infectious virions for prolonged periods, strict barrier isolation in a private room away from traffic patterns should be maintained throughout the illness. The patient's urine, stool, sputum, and blood, along with any objects that have come in contact with the patient or the patient's body fluids (such as laboratory equipment), should be disinfected with a 0.5% sodium hypochlorite solution [6].

There is no satisfactory antiviral agent for treatment of EVD. Care is supportive and initial management goals include fluid resuscitation, prevention of intravascular volume depletion, and correction of electrolyte and other metabolic abnormalities [9,11]. Severe hypokalemia and varying degrees of lactic acidosis are common. Vigilance is required for fluid resuscitation that matches losses from vomiting and diarrhea, preventing complications of shock (e.g., metabolic acidosis, acute renal failure, acute lung injury).

In 2019, the FDA approved the first vaccine for the prevention of EVD [23]. The Ebola vaccine rVSV-ZEBOV (Ervebo) is a live, attenuated, vectored vaccine based on a recombinant vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein [33]. This vaccine is administered as a single injection for protection against Ebola virus species Zaire ebolavirus only, which has caused the largest, most deadly Ebola outbreaks to date [39]. The use of Ervebo vaccine was initially restricted to individuals 18 years of age and older. In September 2023, after randomized trials had established safety and immunogenicity, FDA approval extension of the indication for use of Ervebo to include individuals 12 months of age and older [47].

The approval of Ervebo is supported by a study conducted in Guinea during the 2014–2016 outbreak in individuals 18 years of age and older [27]. The study was a randomized cluster (ring) vaccination study in which 3,537 contacts and contacts of contacts of individuals with laboratory-confirmed EVD received either "immediate" or 21-day "delayed" vaccination with Ervebo. This noteworthy design was intended to capture a social network of individuals and locations that might include dwellings or workplaces where a patient spent time while symptomatic, or the households of individuals who had contact with the patient during that person's illness or death. In a comparison of cases of EVD among 2,108 individuals in the "immediate" vaccination arm and 1,429 individuals in the "delayed" vaccination arm, Ervebo was determined to be 100% effective in preventing Ebola cases with symptom onset greater than 10 days after vaccination. No cases of EVD with symptom onset greater than 10 days after vaccination were observed in the "immediate" cluster group, compared with 10 cases of EVD in the 21-day "delayed" cluster group.

Pre-exposure prophylaxis Ervebo vaccination is recommended for healthcare personnel at potential occupational risk of exposure to Zaire ebolavirus. This recommendation includes workers who are responding to an EVD outbreak, those involved in the care and transport of patients with suspect or confirmed EVD, and laboratorians and support staff at facilities handling specimens that may contain Ebola virus [39,44].

On August 8, 2014, the WHO declared the West Africa Ebola epidemic a Public Health Emergency of International Concern, thereby invoking the powers of the 2005 International Health Regulations (IHR). In response to a potential pandemic, the IHR requires all countries to develop a national preparedness program, conduct surveillance, exercise public health measures, and report any internationally significant event [4]. The director-general of the WHO further urged those countries with active Ebola transmission to declare a national emergency, activate disaster management plans, and establish emergency operation centers.

With international support, a coordinated effort emerged in West Africa with a strategy for clinical care and infection control aimed at curbing the spread of the epidemic. Public health countermeasures included isolation and quarantine, social distancing, public education, travel restrictions, and enhanced protection of healthcare workers [4]. These measures embrace the following recognized priorities for an effective infection control program:

By the end of April 2016, the West Africa Ebola epidemic had been contained and the outbreak rapidly diminished over the ensuing weeks. According to data at the CDC, there had been 28,616 cases (suspected, probable, and confirmed) and 11,310 deaths [13].

Apart from the horrific burden of illness and death, the socioeconomic impact of the Ebola epidemic was enormous. It is estimated that during 2015, the countries of Guinea, Liberia, and Sierra Leone sustained a combined loss of $2.2 billion in gross domestic product. In addition, the epidemic resulted in lower investment, a decline in private sector growth, and reduced cross-border trade in goods and services [31].

The impact of the Ebola outbreak on the healthcare system was especially troubling. Healthcare workers caring for patients with EVD were among those at highest risk for contracting the infection. From the start of the outbreak through November 2015, a total of 881 confirmed cases of EVD in health workers were reported in Guinea, Liberia, and Sierra Leone, and there were 513 reported deaths [31]. Liberia lost 8% of its doctors, nurses, and midwives to Ebola; Sierra Leone and Guinea lost 7% and 1% of their healthcare workers, respectively [31]. The reduction in the healthcare workforce, combined with reduced access to services and setbacks in care for other indigenous infection, is estimated to have resulted in an additional 10,600 deaths from human immunodeficiency virus, tuberculosis, and malaria.

Children suffered not only from the disease but also because of the impact of the epidemic on the family and the educational process [31]. Approximately 20% of all EVD cases occurred in children younger than 15 years of age. Recovery plan data from the three countries most affected estimate that more than 17,000 children were orphaned because of Ebola. All schools closed for a period of 33 to 39 weeks, and by the time they reopened, an estimated 1,848 hours of instruction had been lost [31].

The cost of the international response to the West Africa Ebola epidemic reached $3.611 billion (in U.S. dollars) by December 2015. The U.S. government allocated approximately $2.369 billion, including $798 million to the CDC, $632 million to the U.S. Department of Defense, and $939 million to the Agency for International Development [31].

The risk of the Ebola virus transmission during air travel is low because, unlike infections such as influenza or tuberculosis, this virus is not spread by inhalation of aerosolized particles from an infected person. Moreover, a person only becomes infectious after having developed symptoms of illness, and transmission of the virus requires direct physical contact with bodily fluids in a manner likely to be extraordinarily rare for travelers on a commercial flight.

There is the possibility that a newly infected traveler from an epidemic zone could enter the United States during the (asymptomatic) incubation period, only to become ill (and thus infectious) some days later. Such a case occurred in October 2014, when a man became ill and was hospitalized in Dallas, Texas, several days after arriving from Liberia. Shortly before his departure from Guinea he had provided bodily assistance to a severely ill woman who subsequently was diagnosed with EVD. This was the first case of EVD to be diagnosed in the United States and was followed shortly by two secondary cases among the hospital nurses who had cared for the patient. This series of events spawned a national discourse on the potential risks from Ebola and on the measures required for effective protection of healthcare workers and control of transmission in the event of an index case [14]. This in turn lead to enhanced assistance to West Africa and to the implementation of a program for identification and surveillance of potentially infected travelers entering this country [15].

On October 6, 2014, the CDC issued a Health Alert Notice Advisory to remind healthcare personnel and health officials to [16]:

Early recognition is critical to controlling the spread of Ebola virus. Healthcare personnel should examine the patient's travel history and consider the possibility of Ebola in patients who present with fever, myalgia, headache, abdominal pain, vomiting, diarrhea, or unexplained bleeding or bruising. If a patient reports a history of recent travel to one of the affected West African countries and is symptomatic, immediate action should be taken [16].

An active early warning approach, under the framework of a surveillance response system, for veterinary and human populations is a key element for prevention in all countries. The institution of electronic-based reporting systems based on advances in information and communication technologies is also an important tool for surveillance [17].

Another crucial component during an outbreak is to understand cultural practices and customs that can affect behavioral attitudes toward Ebola outbreaks. Lack of understanding about EVD and misinformation concerning hospitalization, treatment, and transmission frustrated attempts to curtail the epidemic in West Africa. Myth, rumor, and fear frequently led to avoidance of healthcare centers, refusal of hospitalization, concealing of sick family members at home, and reliance upon local custom and traditional healers. These factors, taken together, contributed to a heightened mortality risk and served to perpetuate spread of the infection [17,26].

A multidisciplinary guidelines panel strongly recommends, with moderate confidence, an Ebola treatment unit staffing ratio of at least one clinician to four patients, including the following considerations—patient assessment at least three times per day and continuous (24 hours per day) monitoring of patients to allow prompt recognition of and reaction to acute changes in condition.

(https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31795-6/fulltext Last Accessed: March 21, 2024)

Strength of Recommendation: Strongly in favor

Most U.S. hospitals are capable of admitting a patient to a private room (with bathroom) and observing standard isolation and Contact Precautions. With advanced planning in conformity with CDC infection control recommendations and with the availability of critical care specialists, most should be able to safely and effectively care for a patient with EVD [6].

Healthcare personnel should perform hand hygiene frequently, including before and after all patient contact, contact with potentially infectious material, and before putting on and taking off PPE, including gloves. Healthcare facilities should ensure that supplies for performing hand hygiene are available.

Acceptable hand hygiene in healthcare settings includes both washing with soap and water or using alcohol-based hand rubs. If hands are visibly soiled, use soap and water, not alcohol-based hand rubs.

Specimens should be obtained when a patient meets the criteria for person under investigation (PUI) including patients with clinical signs, symptoms, and epidemiologic risk factors for Ebola virus disease. If the first specimen is obtained one to three days after the onset of symptoms and tests negative and the patient remains symptomatic without another diagnosis, a later specimen is needed to rule out Ebola virus infection.

Staff who collect specimens from PUIs should wear appropriate PPE and should refer to Guidance on Personal Protective Equipment To Be Used by Healthcare Workers During Management of Patients with Ebola Virus in U.S. Hospitals, Including Procedures for Putting On (Donning) and Removing (Doffing) (online at https://www.cdc.gov/vhf/ebola/healthcare-us/ppe/guidance.html).

For adults, two samples of whole blood, each a minimum volume of 4 mL, is preferable. For pediatric patient samples, a minimum of 1 mL whole blood should be collected in pediatric-sized collection tubes. Blood must be collected in plastic collection tubes. Do not transport or ship specimens in glass containers or in heparinized tubes.

Whole blood preserved with ethylenediaminetetraacetic acid (EDTA) is preferred, but whole blood preserved with sodium polyanethol sulfonate, citrate or with clot activator is also acceptable. Do not separate and remove serum or plasma from the primary collection container.

Public health authorities will determine where ebolavirus testing will occur. Presumptive testing for Ebola virus and Sudan virus is available at select reference laboratories throughout the United States, Specimens should be packaged and transported at 2°–8°C with cold-packs to the final testing destination. Specimens other than blood may be submitted after consultation with CDC by calling the Emergency Operations Center at 770-488-7100.

If necessary, short-term storage of specimens before shipping should be at 2–8°C. Specimens sent to the CDC for testing must be sent on dry ice and must arrive in time to be tested within seven days of the date of specimen collection.

Real-time RT-PCR testing for Ebola virus is available at over 60 LRN laboratories located throughout the United States. LRN laboratories are currently using an FDA-approved Emergency Use Only (EUA) assay to detect the Ebola (Zaire species) virus. Samples that test positive using this assay are considered presumptive positive for Ebola Zaire RNA by real-time RT-PCR and should be submitted to CDC for additional evaluation.

PPE to be worn during transport within the facility should be determined by a site-specific risk assessment and may vary among facilities. Recommendations for PPE include disposable fluid-resistant closed lab coat, disposable gloves, covered legs and closed-toed shoes.

Before removing patient specimens from the site of care, it is advisable to plan the route of the sample from the patient area to the location where it will be packed for shipping to avoid high traffic areas.

Before removing patient specimens from the site of care, the outside of the specimen containers should be decontaminated with an approved disinfectant. Recommended disinfectants are those known to kill non-enveloped viruses and can be found in List L of the Environmental Protection Agency (EPA) Disinfectants for Use Against the Ebola Virus. This list of registered disinfectants meets the CDC's criteria for use against the Ebola virus on hard, non-porous surfaces.

In compliance with OSHA Bloodborne Pathogens Standard, specimens should be placed in a durable, leak-proof secondary container. After placing in a secondary container, specimens should be hand-carried to the laboratory or packing area. DO NOT use any pneumatic tube system (automated or vacuum specimen delivery system) for transporting specimens.

Samples from patients who are PUIs or confirmed to have Ebola virus infection should be packaged and shipped as Category A infectious substances in accordance with the Department of Transportation's (DOT's) Hazardous Materials Regulations. All persons packing and shipping infectious substances must be trained and certified in compliance with DOT or the International Air Transport Association (IATA) requirements every two years.

Specimens collected for Ebola virus testing should be packed and shipped without attempting to open collection tubes or aliquot specimens. Opening the tubes destroys the vacuum seal and thus increases the risk of leakage during transport. Specimens for shipment should be packaged following the basic triple packaging system, which consists of (1) a primary container (a sealable specimen container) wrapped with absorbent material, (2) a secondary container (watertight, leak-proof), and (3) an outer shipping package. For questions about (packaging) transportation regulations, contact the U.S. DOT Hazardous Materials Information Center at 1-800-467-4922.

The CDC will not accept specimens without prior consultation and approval. The CDC's Viral Special Pathogens Branch (VSPB) is available 24/7 by calling CDC Emergency Operations Center at (770) 488-7100 and requesting VSPB's on-call epidemiologist. The following steps should be followed by persons certified to ship infectious substances.

Community awareness of risk factors for Ebola infection and the protective measures individuals can take is an important way to reduce human transmission and interrupt the epidemic spread of EVD. During outbreaks in Africa, public health education efforts have focused on:

The CDC has published guidance for personal protection and prevention of the spread of EVD for those living in or traveling to a region where Ebola virus is potentially present or to an area experiencing an outbreak of EVD [39]. These methods of protection emphasize that one should avoid general and sexual contact with all body fluids, clothing bedding, and other items that may have come in contact with the sick or persons known or suspected of having EVD. In addition, one should avoid contact with bats, forest antelopes, and nonhuman primates, including blood, fluids, or raw meat prepared from these or unknown animals (also known as bushmeat).

As noted, the Ebola virus vaccine is a replication-competent, live, attenuated recombinant vesicular stomatitis virus vaccine encoded for Zaire ebolavirus glycoprotein. It is known as rVSV/G-ZEBOV-GP Ebola vaccine (brand name Erbevo), manufactured by Merck. This vaccine is safe and effective against Zaire ebolavirus, the cause of the largest and most deadly Ebola outbreaks to date [40]. It is not possible to become infected with Ebola from vaccination, as the vaccine only contains a gene from the core particle, not the whole virus. Adverse effects following vaccination are typically mild and include headache, fatigue, myalgia, and fever. The duration of protection against Ebola virus is unknown. It is also not known whether it is effective when administered concurrently with antiviral medication, monoclonal antibody therapy, or plasma transfusion [40]. Erbevo is FDA-approved for the prevention of disease caused by Ebola virus (EBOV; species Zaire ebolavirus) in individuals 12 months of age and older as a single dose administration [47].

In February 2020, the Advisory Committee on Immunization Practices recommended pre-exposure vaccination with Ervebo for adults in the United States who are at potential risk of exposure to Zaire ebolavirus. Ervebo is not currently marketed in the United States but is stockpiled in the Strategic National Stockpile and is made available through the CDC for pre-exposure vaccination of individuals who fall into one of the three occupational categories [40]:

Continuing outbreaks of EVD, which come with high morbidity and mortality, are a tragedy for local communities, place an enormous burden on public health resources of affected countries, and pose a potential threat to global health stability. In response to this challenge, a consortium of agencies under the auspices of the WHO have sought to develop safe and effective Ebola virus vaccines applicable to adults and children. Such a vaccine, administered on a community-wide basis in response to an index case, would facilitate a ring strategy of containment designed to limit spread and shorten the outbreak. Two candidate vaccine regimens have received WHO prequalification status and were evaluated for this purpose during recent EVD outbreaks. One is rVSV-ZBOV vaccine (Ervebo) and the other is a combination of an adenovirus type-26—vectored vaccine encoding the ZEBOV glycoprotein followed by a booster dose of a modified vaccinia Ankara virus strain (MVA-BN-Filo) [48,49].

The WHO PREVAC Study Team has published results of two randomized, placebo-controlled trials evaluating three Ebola vaccine strategies in adults and children. The trials were conducted simultaneously in 2018 and enrolled 1,400 adults and 1,401 children (1- to 17 years of age) who were randomized to receive two injections of either Ebola vaccine or placebo in one of three regimens. Study participants were volunteers at sites in Guinea, Liberia, Sierra Leone, and Mali. All vaccine regimens were found to be safe and immunogenic in adults and children [49]. Serum IgG binding antibodies against the Ebola virus surface glycoprotein were evident by day 14 after vaccination and continued to be detectable, at varying levels depending on the regimen, in both age groups for one year. The trials were unable to assess protection from disease as there were no incident cases of EVD among vaccine or placebo group participants during the study period. However, the authors note that prior studies show that levels of glycoprotein-binding antibodies strongly correlate with neutralizing antibody titers in nonhuman and humans [49].