Chapter 54 Ebola Hemorrhagic Fever
Definition and Cause
Ebola hemorrhagic fever (EHF) is a hemorrhagic disease of humans and nonhuman primates caused by the Ebola virus, a biosafety level (BSL) 4 biologic agent.20 Ebola hemorrhagic fever (EHF) was first described in 1976 during hemorrhagic fever outbreaks in the Democratic Republic of Congo (DRC, former Zaïre) and Sudan.17 Since then, its ecologic and epidemiologic characteristics largely remain a mystery.
Epizootiology
Ebolavirus (EBOV) and Margburgvirus make up the family Filoviridae; enveloped, nonsegmented, negative-stranded RNA viruses. There are currently five recognized species of Ebolavirus: Zaïre ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Côte d’Ivoire ebolavirus (CIEBOV), Reston ebolavirus (REBOV), and Bundibugyo ebolavirus.4,17,23
Viral Distribution
The geographic range of EBOV is associated with humid tropical forest ecosystems in sub-Saharan Africa and the Philippines.10 Confirmed human and animal outbreaks have occurred in Côte d’Ivoire (CIEBOV), Democratic Republic of Congo, Republic of Congo, Gabon (ZEBOV), Sudan (SEBOV), and Uganda (SEBOV and Bundibugyo ebolavirus). REBOV outbreaks in American and European primate facilities have been traced back to the Philippines. Serologic surveys and ecologic niche modeling have suggested that the virus may also be endemic in Cameroon, Madagascar, Mozambique, and Tanzania.14
Reservoirs
Studies have suggested that EBOV circulates in the environment at levels difficult to detect and that viral titers may be very low in naturally infected reservoir species.13,22 Tens of thousands of animals (bats, other vertebrates, and arthropods) have been tested from several central African countries since 1976, but live EBOV has not been isolated.17 There is a growing body of evidence to support certain bat species as reservoirs of EBOV. In studies in which dozens of plant, vertebrate, and invertebrate species were inoculated with EBOV, viral amplification occurred only in bats. EBOV gene sequences were detected in 13 bats of three species—hammer-headed fruit bat (Hypsignathus monstrosus), Franquet’s epauletted bat (Epomops franqueti), and little collared fruit bat (Myonycteris torquata). Recent detection of ZEBOV-specific IgG antibodies in 95 bats of six species (E. franqueti, H. monstrosus, M. torquata, Micropteropus pusillus [Peter’s dwarf epauletted fruit bat], Mops condylurus [Angolan free-tailed bat], and Rousettus aegyptiacus [Egyptian fruit bat]), indicate prior exposure to EBOV and may support the assertion that they are reservoirs of ZEBOV.12 Confirming bats as reservoir hosts will require additional evidence, including isolation of live virus from the animal, establishing persistence of infection, and confirming transmission to a target species.10
Epizootics
Captive Primates
On at least six different occasions since its discovery in 1989, REBOV was isolated from cynomolgus macaques (Macaca fascicularis) showing signs of viral hemorrhagic fever.15 The macaques had been imported to America and Europe from a single breeding facility in the Philippines.10 In one case, 82% of animals died and many were found to be coinfected with simian hemorrhagic fever virus. The significance of the coinfection is unknown. In almost all cases, affected macaques originated from a single breeding facility in Laguna Province, the Philippines. In 1996, an investigation at that facility reported a 14% mortality rate, with viral antigen detected in 32% of symptomatic and 4% of asymptomatic monkeys.3 Three of 301 cynomolgus macaques were positive for IgG antibodies.7 The source of infection for the macaques was not determined, but poor husbandry practices contributed to disease dissemination. Many macaques in both U.S. and Philippine centers were subsequently destroyed, and in 1997 the Laguna facility was closed. There have been no further REBOV cases reported in primates imported to the United States since that time.
Free-Ranging Primates
Chimpanzees (Pan troglodytes) and western lowland gorillas (Gorilla gorilla gorilla) appear to be dead-end hosts for ZEBOV infection. ZEBOV antigen was detected in 16 chimpanzee and gorilla carcasses discovered during epizootics associated with large great ape declines in central Africa.19,25 Based on temporal and spatial links between large-scale great ape mortality and confirmed ZEBOV epidemics and epizootics, case-fatality rates in great apes have been estimated at roughly 90%.24 The detection of Ebolavirus-specific IgG antibodies in 31 western lowland gorillas and chimpanzees suggests that they may survive infection or may be asymptomatically infected, or that assays are cross-reacting with an as yet unidentified, less virulent, strain of EBOV.4,14
Although the vastness and remoteness of the central African habitat makes precise great ape mortality impossible to determine, the impact of EHF on great ape populations appears dramatic.17,24 Some field researchers have observed rapid and astonishingly high mortality in resident ape populations. Large-scale ecologic surveys carried out over the past decade have indicated dramatic declines (up to 95%) in great ape populations in some regions. In all cases, these declines were spatially and/or temporally linked with human or animal ZEBOV outbreaks, in which hunting and habitat loss were ruled out as contributing factors.10 Given the context, it is reasonable to assume that the great ape declines were associated with EHF. The western lowland gorilla was reclassified as “critically endangered” by the International Union for the Conservation of Nature (IUCN), largely as a result of the threat of EHF.
Antibodies to ZEBOV were detected in eight wild-born monkeys of four species in Cameroon, Gabon, and the Republic of Congo, indicating virus circulation in nonhuman primates.14 Monkey morbidity and mortality have been spatially or temporally linked with human ZEBOV, although tests were negative for ZEBOV.10,25
CIEBOV was associated with the deaths of 12 chimpanzees in the Taï forest of Côte d’Ivoire in 1994.10 One chimpanzee was confirmed CIEBOV positive on immunohistochemistry (IHC) analysis, suggesting that chimpanzees are dead-end hosts.26 Antibodies to CIEBOV were detected in a red colobus monkey (Procolobus badius) following the outbreak. All affected chimps were observed consuming the monkey 6 days prior to the outbreak, suggesting the monkey as the source of infection of the chimpanzees.
Other Potential Hosts
Relatively little is known about EBOV susceptibility of other species that may serve as reservoir, incidental or dead-end hosts. Positive serologic findings in central African domestic hunting dogs have suggested that canines may be naturally and asymptomatically infected.3 Pigs (Potamochoerus porcus), duikers (various species), porcupines (Atherurus africanus), a civet (Civettictis civetta), sitatungas (Tragelaphus spekei), genets (Genetta spp.), an elephant (Loxodonta. africana), pythons (Python sebae), antelopes, rodents, a pangolin (Manis spp.), a mongoose (unspecified species), and a raptor have been reported dead in temporal or spatial coincidence with confirmed ZEBOV outbreaks in humans or nonhuman primates.10 Of the species that were tested for ZEBOV by polymerase chain reaction (PCR) assay, only a blue duiker (Cephalophus monticola) tested positive.19 A 50% decline in duiker populations was reported, coincident with ZEBOV outbreaks in humans and great apes in the Republic of Congo between 2000 and 2003, suggesting that duikers may be dead-end hosts for ZEBOV. Unconfirmed reports have also suggested the presence of EBOV in rodents (Mastomys, Mus, and Praomys spp.). In the Philippines, REBOV was recently isolated from domestic swine exhibiting a severe respiratory syndrome that were coinfected with porcine reproductive and respiratory syndrome virus.3 Given this lack of strong evidence, additional studies on potential Ebola virus hosts are needed.
Transmission
EBOV is transmitted through direct contact with body fluids of infected animals or persons.3,17 Increased risk of transmission occurs in the acute phase of infection, when patients are viremic. Once the virus is cleared, there is little risk of transmission. The exception may be with breast milk or semen, in which ZEBOV was detected in human patients at 15 and 91 days postinfection, respectively.
In a captive context, transmission is favored by poor husbandry conditions, poor compliance with infection control guidelines, and any other conditions that increase inter-animal contact.15 However, there is evidence of ZEBOV transmission between monkeys separated by a distance of 3 m, perhaps involving conjunctival exposure occurring via aerosolization from urination or cage cleaning.21
Human ZEBOV outbreaks in central Africa have been linked to the handling of infected great ape carcasses and the consumption of bats.12,17,18 Once in human communities, EHF spreads rapidly via person to person contact and in health care settings in which resources are limited or barrier nursing protocols are not implemented.10 There is no evidence of aerosol transmission in humans. Accidental laboratory exposures have been reported, usually involving needle sticks or torn gloves. Evidence of previous exposure in animal handlers has been documented, however, sometimes in the absence of any illness or identifiable accident.3
The route of initial infection of wild great apes has not been confirmed, but the prevailing theory suggests direct or indirect (fruit consumption in the same tree) contact with reservoir species (largely believed to be bats) at common feeding sites.10,16 Once EHF is initiated in the great ape population, viral transmission may be propagated by contact with an infected animal carcass and direct contact with other infected apes.19