Ebola Virus 

Ebola virus is one of at least 30 known viruses capable of causing viral hemorrhagic fever syndrome. Although agents that cause viral hemorrhagic fever syndrome constitute a geographically diverse group of viruses, to date, all are RNA viruses with a lipid envelope, all are considered zoonoses, all damage the microvasculature, resulting in increased vascular permeability, and all are members of one of four families: Arenaviridae, Bunyaviridae, Flaviviridae, and Filoviridae. Although some of the hemorrhagic fever viruses are normally spread by ticks or mosquitoes, all but one (ie, Dengue hemorrhagic fever) are capable of being spread by aerosols, making these viruses potential bioterrorism agents.

The family Filoviridae resides in the order Mononegavirales and contains the largest genome within the order. Originally considered members of the family Rhabdoviridae, Ebola virus and the antigenically distinct Marburg virus now comprise the family Filoviridae.

Epidemiology

Ebola and Marburg viruses are responsible for well-documented outbreaks of severe human hemorrhagic fever, with resultant case mortality rates ranging from 23% for Marburg virus (Marburg, Germany; 1967) to 89% for Ebola virus (Democratic Republic of the Congo [DRC]; formerly Zaire; Dec 2002 to Apr 2003). Ebola virus (Reston, Va; 1989) has also caused a highly lethal disease in cynomolgus macaques (Macaca fascicularis) imported into Reston, Va, from the Philippines, but it caused no deaths among 4 infected employees who worked at the primate facility that housed these animals.

Ultrastructure and pathogenesis

The 5 distinguishable species (formerly referred to as subtypes) of Ebola virus and the single species of Marburg virus comprise the known members of the family Filoviridae. Although some controversy remains regarding the question of whether the 5 genetically distinguishable Ebola viruses are separate species or separate subtypes, present nomenclature classifies the Ebola viruses into 5 separate species. The currently identified species include Sudanebolavirus (SEV), Zaire ebolavirus (ZEV) , Ivory Coast ebolavirus (also referred to as Côte d'Ivoire Ebola virus [CIEV]), Restonebolavirus (REV), and, the most recently identified, Bundibugyo ebolavirus (BEV).

Filoviruses share a characteristic filamentous form with a uniform diameter of approximately 80 nm but display great variation in length. Filaments may be straight, but they are often folded on themselves. Ebola virus has a nonsegmented negative-stranded RNA genome containing 7 structural and regulatory genes. The Ebola genome codes for 4 virion structural proteins (VP30, VP35, nucleoprotein, and a polymerase protein [L]) and 3 membrane-associated proteins (VP40, glycoprotein [GP], and VP24). The GP gene is positioned fourth from the 3' end of the 7 linearly arranged genes.

Following infection, human and nonhuman primates experience an early period of rapid viral multiplication that, in lethal cases, is associated with an ineffective immunological response. Although a full understanding of Ebola must await further investigations, part of the pathogenesis has been elucidated. Most Filovirus proteins are encoded in single reading frames; the surface GP is encoded in 2 frames (open reading frame [ORF] I and ORF II). The ORF I (amino-terminal) of the gene encodes for a small (50-70 kd), soluble, nonstructural secretory glycoprotein (sGP) that is produced in large quantities early in Ebola infection.^[1]

The sGP binds to neutrophil CD16b, a neutrophil-specific Fc g receptor III, and inhibits early neutrophil activation. The sGP also may be responsible for the profound lymphopenia that characterizes Ebola infection. Thus, sGP is believed to play pivotal roles in the ability of Ebola to prevent an early and effective host immune response. One hypothesis is that the lack of sGP production by Marburg virus may explain the reduced virulence with this agent as compared to that of African-derived Ebola.

Leroy et al reported their observations of 24 close contacts of symptomatic patients actively infected with Ebola.^[2] Eleven of the 24 contacts developed evidence of asymptomatic infection associated with viral replication. Viral replication was proven by the authors' ability to amplify positive-stranded Ebola RNA from the blood of the asymptomatic contacts. A detailed study of these infected but asymptomatic individuals revealed that they had an early (4-6 d after infection) and vigorous immunologic response with production of interleukin-1 beta, interleukin-6, and tumor necrosis factor, resulting in enhanced cell-mediated and humoral-mediated immunity. In patients who eventually died, proinflammatory cytokines were not detected even after 2-3 days of symptomatic infection.

A second glycoprotein of 120-150 kd, transmembrane glycoprotein, is incorporated into the Ebola virion and binds to endothelial cells but not to neutrophils. Ebola virus is known to invade, replicate in, and destroy endothelial cells. Destruction of endothelial surfaces is associated with disseminated intravascular coagulation, and this may contribute to the hemorrhagic manifestations that characterize many, but not all, Ebola infections.

Clinical infection in human and nonhuman primates is associated with rapid and extensive viral replication in all tissues. Viral replication is accompanied by widespread and severe focal necrosis. The most severe necrosis occurs in the liver, and this is associated with the formation of Councilman-like bodies similar to those seen in yellow fever. In fatal infections, the host's tissues and blood contain large numbers of Ebola virions, and their tissues and body fluids are highly infectious.

Presently, 5 distinct species have been identified, each named for the location where it caused documented human or animal disease. Two Africa species, Sudanebolavirus and Zaire ebolavirus, have been responsible for most of the reported deaths caused by filoviruses. Clinical disease due to African-derived Ebola virus is severe and, with the exception of 2 patients infected with Ivory Coast ebolavirus who survived, is associated with a mortality rate of 65% (Sudan, 1979) to 89% (DRC, Dec 2002 to Apr 2003).

A fourth species, Restonebolavirus, was first isolated in 1989 in monkeys imported from a single Philippine exporter. A virtually identical isolate imported from the same Philippine exporter was detected in 1992 in Siena, Italy. The fifth species, also of African lineage, is Bundibugyo ebolavirus, which caused an outbreak in Uganda in 2007-2008, with a mortality rate of 25%.

Between 1994 and 1997, a stable strain of Ebola caused 3 successive outbreaks of hemorrhagic fever in Gabon (mortality rate range of 60%-74%).^[3] Because the Gabon strain shares a greater than 99% homology of the nucleoprotein and GP gene regions with Ebola virus Zaire (EBO-Z), it has not been considered a distinct species.

One likely reservoir for filoviruses has been identified. In 1996, members of the National Institute for Virology of South Africa went to Kikwit, Zaire, (now the DRC) and evaluated the infectivity of Ebola for 24 species of plants and 19 species of vertebrates and invertebrates.^[4] Insectivorous bats, Tadarida pumila, and fruit bats, Epomophorus wahlbergi, were found to support Ebola virus replication without dying. Furthermore, serum Ebola titers in infected fruit bats reached as high as 10 million fluorescent focus-forming units per milliliter, and feces contained viable Ebola virus.

Mechanisms of dispersion

African-derived Filovirus infections are characterized by transmission from an unknown host (possibly bats) to humans or nonhuman primates, presumably via direct contact with body fluids such as saliva or blood or other infected tissues. Evidence in nonhuman primates indicates that Sudan ebolavirus and Zaire ebolavirus may be transmitted by contact with mucous membranes, conjunctiva, pharynx and gastrointestinal surfaces, small breaks in the skin, and, at least experimentally, by aerosol.^[5]

Dogs have been shown to acquire asymptomatic Ebola infections, possibly by contact with virus-laden droplets of urine, feces, or blood of unknown hosts.^[6] Of epidemiologic significance was the observation that seroprevalence rates in dogs rose in a linear fashion as sampling approached areas of human cases, reaching as high as 31.8%. Thus, an increase in canine seroprevalence may serve as an indicator of increasing Ebola circulation in primary vectors within specific geographical areas.

Human infection with African-derived strains has often occurred in caregivers, either family or medical, or in family members who have prepared dead relatives for burial. Late stages of Ebola are associated with the presence of large numbers of virions in body fluids, tissues, and, especially, skin. Individuals who come into contact with patients infected with Ebola without proper barrier protection are at high risk of becoming infected. A recent report from the DRC identified Ebola virus RNA in 100% of oral secretions in patients with Ebola virus RNA in their serum. Both serum and oral secretions were tested with reverse-transcriptase polymerase chain reaction (RT-PCR). Thus, oral secretions may be capable of transmitting Ebola virus.

The first recorded outbreak occurred in Yambuku, DRC, in 1976, where 316 patients were infected. In the largest recorded urban outbreak to date (DRC, 1995; 318 cases), admission to a hospital acted to greatly amplify the frequency of transmission. The lack of proper barrier protection (gloves, fluid-resistant gowns, and proper sanitation) and the use and reuse of contaminated medical equipment, especially needles and syringes, resulted in rapid nosocomial spread of infection. Only after adequate barrier protection and alteration in burial rituals were implemented was the outbreak contained.

Unlike Asian-derived Ebola (ie, the Reston species traced to a Philippine supplier of primates), African-derived species appear to be spread more often by direct contact than by the respiratory route. However, the Reston species has repeatedly been demonstrated to spread among nonhuman primates and possibly from primates to humans via the respiratory route. Fortunately, although the Reston species has been documented to cause infection in humans, it does not appear to be pathogenic to humans.

Frequency

United States

Ebola is not endemic in the United States. However, several human infections with the Reston strain of Ebola have been acquired by animal care workers at primate holding facilities within the United States. Fortunately, the Reston strain has not demonstrated pathogenic effects in humans. Others at potential risk are laboratory workers who work with infected animals or with the virus in tissue culture.

International

Individuals considered at risk for Ebola hemorrhagic fever include persons with a travel history to sub-Saharan Africa, persons who have recently cared for infected patients, and animal workers who have worked with primates infected with African-derived Ebola subtypes.

Table 1. History of Ebola Virus Sudan Outbreaks^a (Open Table in a new window)

^a Data taken from the Centers for Disease Control and Prevention and The World Health Organization.

^b Occurred following a laboratory accident.

Table 2. History of Ebola Virus Zaire Outbreaks^a (Open Table in a new window)

^a Data taken from the Centers for Disease Control and Prevention and The World Health Organization.

Table 3. History of Ebola Virus Côte-d’Ivoire Outbreaks (No Deaths Reported)^a (Open Table in a new window)

^a Data taken from the Centers for Disease Control and Prevention and The World Health Organization.

Table 4. History of Ebola Virus Reston Outbreaks (No Deaths Reported)^a (Open Table in a new window)

^a Data taken from the Centers for Disease Control and Prevention and The World Health Organization.

^b Humans infected based on serologic evidence, but without clinical disease.

^c Associated with pig farming.^{[7, 8]}

Table 5. History of Ebola Virus Bundibugyo Outbreak^a (Open Table in a new window)

^a Data taken from the Centers for Disease Control and Prevention and The World Health Organization.

Mortality/Morbidity

With the exception of Reston ebolavirus, morbidity and mortality rates among patients who present with clinical illness are very high and vary with the species of Ebola.

• The most highly lethal Ebola species is Zaire ebolavirus, which has been reported to have a mortality rate as high as 89%.
• Sudan ebolavirus also has a high reported mortality rate, ranging from 41%-65%.

Race

• No evidence exists for a racial predilection in Ebola infection. Because most cases have occurred in sub-Saharan Africa, most patients have been black.

Sex

• No sex predilection exists.

  • Ebola virus infection has no sexual predilection, but direct exposure among men and women differ in the manner in which they are exposed.
  • Men, by the nature of their work exposure in forest and savanna regions, may be at increased risk of acquiring a primary infection from gathering "bush meat" (dead carcasses of primates) for food, as well as an unknown vector or vectors. Evidence in Africa and the Philippines are compatible with bats being a principal vector of Ebola virus.
  • Because women provide much of the direct care for ill family members and are involved in the preparation of the bodies of the deceased, they may be at increased risk of acquiring Ebola infection based on these activities.
  • However, men and women who are medical health care providers seem to share a high and equal risk of infection.

Age

• In the 1995 outbreak in Kikwit, DRC, infection rates in children were significantly less than in adults. During this outbreak, only 27 (8.6%) of the 315 patients diagnosed with Ebola were aged 17 years or younger. This apparent sparing of children occurs even though 50% of the population of the DRC is younger than 16 years.
• Although definitive evidence is lacking, epidemiologic evidence suggests that children are less likely to come into direct contact with ill patients than adults.
• Other viral hemorrhagic syndromes, such as Crimean-Congo hemorrhagic fever and Hantavirus infections, also show a predominance of adult patients and a relative sparing of young children.