Ebola Term Papers
Filoviridae is the only known virus family about which we have such profound ignorance. We do not even understand the maintenance strategies employed in nature by the agents, and we know much less about the resulting diseases, their pathogenesis, and detailed virology. The information gathered during control efforts directed toward recent epidemics has provided considerable fundamental information about filoviruses.
A number of colleagues, both in the laboratory and in the field, agreed to prepare reports reflecting recent research, thus permitting this supplement to the Journal of Infectious Diseases, which provides a single source for substantial new, peerreviewed information. We have somewhat arbitrarily divided the supplement into the categories of clinical observations; epidemiology and surveillance; ecology and natural history; virology and pathogenesis; experimental therapy; control, response, prevention; and conclusions. “Ebola,” however, is not just one Ebola: There are 4 distinguishable subtypes, whose phylogenetic tree is shown on page iii of this supplement [1–3]. Because the subtypes, which may even be different virus species, have differing properties, we have grouped the papers by the subtype discussed within each subject area.
Marburg, the First Known Filovirus
Biomedical science first encountered the virus family Filoviridae when Marburg virus appeared in 1967 . At that time, commercial laboratory workers with a severe and unusual disease were admitted to a hospital in Marburg, Germany. The attending physician recognized the distinctive clinical picture as additional cases appeared, and an investigation led to the isolation and identification of the immediate source of the virus as green monkeys imported from Africa for use in research and vaccine production. The monkeys, some of which had been shipped to Frankfurt, Germany, and Belgrade, Yugoslavia, were euthanatized, and the epidemic was contained with only 31 human cases and one generation of secondary transmission to health care workers and family members. Nevertheless, the bizarre morphology of the virions, the 23% human mortality, and the failure to identify the natural history of the virus left fear among many who were concerned with the role of viruses in human economy. Quarantine procedures were put in place in many countries to prevent the recurrence of disease introduced by imported monkeys , and tests were instituted to exclude Marburg virus from vaccine substrates . Fortunately, there have been only three detected recurrences of Marburg virus, all in humans traveling in rural Africa, and none of these has led to extensive transmission [7–9]. This brief history of Marburg virus presages the very similar course of events with Ebola virus.
Ebola, the Second Known Filovirus
Humans Meet Ebola Virus in Africa, 1976
In the late 1970s, the international community was again startled, this time by the discovery of Ebola virus  as the causative agent of major outbreaks of hemorrhagic fever in the Democratic Republic of the Congo (DRC)  and Sudan . International scientific teams that arrived to deal with these highly virulent epidemics found that transmission had largely ceased; however, they could reconstruct considerable data from the survivors. Medical facilities had been closed because of the high death toll among the staff, thus eliminating major centers for dissemination of infection through the use of unsterilized needles and syringes and the lack of barrier-nursing techniques. In contrast, patients in the affected villages were segregated through traditional methods of quarantine, a step that controlled the situation outside the clinics. Much of the information concerning these outbreaks has been previously summarized .
The international alarm and research efforts that arose in response to these outbreaks quickly dwindled when the only convincing evidence that Ebola virus infections were continuing among humans consisted of a small outbreak in the Sudan in 1979  and 1 case in Tandala, DRC, in 1977 .
Ebola Virus Visits the United States: The Virus Family Grows
In 1989, Ebola surprised us once more when it appeared in monkeys imported into a Reston, Virginia, primate facility outside of Washington, DC. Epidemics in cynomolgus monkeys (Macaca fascicularis) occurred in this facility and others through 1992 [16–17] and recurred in 1996, as reported in this supplement . Epidemiologic studies that were conducted in connection with both epidemics [19, 20] successfully traced the virus introductions to one Philippine exporter but failed to detect the actual source of the virus. Attempts to work in the remote areas where the monkeys were captured have been too dangerous due to political instability. We do know that this virus strain (EBO-R) has an apparent Asian origin and lesser pathogenicity than other Ebola subtypes for both macaques and humans [21, 22], but we are still not certain of its real origin. Nevertheless, current quarantine procedures for imported primates and vaccine requirements have protected the public [5, 6, 18].
The control of these introduced virus outbreaks in 1989 andchimpanzeeinbrid the 1990s stimulated laboratory studies to improve diagnosis of nonhuman primate infections [2, 23–28]. However, the materials necessary to definitively confirm the utility of these techniques for humans were lacking.
The African Ebola Epidemics of 1994–1996
After Ebola hemorrhagic fever (EHF) appeared in Africa in 1976–1979, it was not seen again until 1994. Was it “gone” during those 15 years? In one sense, certainly not—it was circulating in its natural reservoir. Was the virus causing sporadic human infections that remained undetected because the patients never contaminated hospitals to produce the savage nosocomial epidemics that brought Ebola virus to medical attention? During 1981–1985, Ebola virus surveillance was carried out concurrently with intensified efforts to understand monkeypox . This surveillance may have identified several cases and estimated the seroprevalence among the population; however, the findings are subject to caveats because of problems with the validity of laboratory tests . Serosurveillance in 1995 also suggested that human infections may have occurred from time to time .
During 1994–1996, no less than five independent active sites of Ebola virus transmission were identified: Côte d'Ivoire in 1994 ; DRC in 1995 ; and Gabon in 1994, 1995, and 1996 [3, 33–35]. The previously known Zaire subtype of Ebola virus (EBO-Z) and the newly discovered Côte d'Ivoire subtype (EBO-CI) were both involved, and as in previous African Ebola virus transmissions, the sites were in or near tropical forests, such as along riverine forests. Whether this hiatus after 1976–1979, which was followed by renewed human transmission, reflects actual Ebola virus activity or rather publicity combined with fortuitous entry of the virus into medical facilities (leading to recognition) is unknown; we believe the renewed quiescence of reported Ebola activity since 1996 argues for the former.
EBO-CI was discovered when ethologists in the Taï forest of Côte d'Ivoire noted that members of a chimpanzee troupe began to experience an unusually high mortality. One of the study group scientists became infected and was transferred to Basel, Switzerland, for definitive care . The clinical information derived from her hospitalization provides the best-studied clinical case of any Ebola virus infection . Furthermore, the circulation of virus in the well-defined region of the Taï forest reserve provides an excellent opportunity to study the Ebola reservoir question. Reports of the clinical case , the epidemiology in chimpanzees , and the pathogenesis in chimpanzees  are in this supplement.
EBO-Z was also circulating in Gabon , and at least 3 separate outbreaks in humans and nonhuman primates occurred . Thus, Gabon may well provide another site where the search for risk factors of human infection and the natural reservoir could be carried out. Notable among the epidemics were features such as the important role of a dead, naturally infected chimpanzee in bridging the virus to humans, the rapid control of human transmission when barrier-nursing measures were instituted and the continued circulation of virus without these precautions, and the deep forest exposures of index cases.
EBO-Z, Kikwit, DRC, 1995
The description of the large African EHF outbreaks in 1976 was largely based on retrospective information, so the Kikwit epidemic provided a better opportunity for more detailed investigations while the epidemic was in progress. Other differences were also present. For example, in 1995, the press and tabloid response in Kikwit was extraordinary and unanticipated. The last weeks of this epidemic took place in an unprecedented atmosphere of legitimate news reporting and tabloid exploitation. Largely because of the popular success of Richard Preston's book, The Hot Zone , there was tremendous public interest in both the information and misinformation that was generated by the media. Fortunately, careful mainstream journalists were accurate in carrying the best scientific information, and the World Health Organization (WHO) became a highly capable center for the dissemination of reliable facts about the epidemic . Large donations flowed into WHO and directly to the DRC; however, there were difficulties with the disbursement of relief supplies and resources, acquisition of appropriate types of materials, and triage of the contributions.
The clinical syndrome seen among patients in Kikwit resembled that seen in 1976 [13, 11], but bleeding was less common and other significant findings were identified, as reported by Bwaka et al. . Unfortunately, circumstances did not permit as close an evaluation as would have been desirable. It was possible, however, to make observations on eye complications , pregnancy , late sequelae , and an unusual case with mucormycosis complicating Ebola . As the epidemic progressed, mortality progressively declined from virtually 100% to 69% .
There is no known therapy for EHF. Late in the epidemic, this fact motivated a clinical experience with blood transfusions from survivors . Although no contemporaneous controls are available for comparison, only 1 of the 8 treated patients died. Comparison with the bulk of patients in the outbreak, taking into account the patient's age and sex, the day of treatment, and the stage of the epidemic, did not suggest any real benefit to the therapy . In addition, virologic analysis of the incomplete specimen set that was available did not lend support for efficacy. Nevertheless, it is useful to consider what was present in the transfused blood that might have been helpful. It is questionable whether antibodies would have had much effect (see below), but the activated allogeneic lymphocytes and the added volume of platelets, erythrocytes, and plasma were probably beneficial. If therapeutic studies are undertaken in patients in the future, it will be important to have randomized control serial laboratory samples and some consideration given to the potential immunostimulatory effects of allogeneic lymphocytes.
We assume that filoviruses, like other viruses causing hemorrhagic fevers, can latently or chronically infect their natural reservoir hosts . Primates seem to be susceptible hosts, and nonhuman primates may even provide a frequent link to humans. They are unlikely, however, to be the true reservoir hosts, given the high pathogenicity of filoviruses for African monkeys, macaques, chimpanzees, and perhaps great apes [4, 13, 16, 21, 34, 37, 38, 49, 50]. Furthermore, a direct search for chronic, persistent, or latent infection in monkeys was unsuccessful .
Marburg virus has been cultured from secretions or immunologically privileged sites 1–3 months after acute disease . In the 1995 Ebola outbreak in Kikwit, late transmission of disease was not detected in follow-up of contacts of several survivors . There was, however, evidence for Ebola virus RNA shed in semen and vaginal secretions for months [44, 52], although it was not possible to isolate virus. The only testicle examined from a fatal case showed clear-cut viral invasion .
Patients with persistent arthritis also had higher anti-Ebola IgG ELISA titers, suggesting increased or prolonged antigenic stimulation. Thus, although the question is not settled, persistence of virus or viral antigen or genomes for weeks into convalescence seems common, but long-term infection is apparently not likely.
IgG and IgM ELISAs [27, 27a] were used to evaluate the possibility of subclinical infections among family contacts , contacts of convalescent patients , medical staff , and local residents , and evidence suggested that a very low level of subclinical transmission occurred during the outbreak. Of interest, there was an appreciable seroprevalence among the residents of Kikwit and those of surrounding villages, which was thought to represent temporally distant infections .
Epidemiology and surveillance
The presence of the international teams allied with several organizations from the DRC during the end of the epidemic provided an opportunity for several studies to better define the transmission of Ebola virus among humans. Details of transmission in households  showed the important role of close contact and exposure to body fluids, particularly to care givers, who suffered the major burden of secondary infections. Touching cadavers at funerals was also an independent risk factor for disease and may well be related to the extensive skin involvement of Ebola virus, as discovered by Zaki et al. .
There is considerable misunderstanding concerning the potential for aerosol transmission of filoviruses. The data on formal aerosol experiments leave no doubt that Ebola and Marburg viruses are stable and infectious in small-particle aerosols, and experience of transmission between experimental animals in the laboratory supports this [49, 56–63]. Indeed, during the 1989–1990 epizootic of the Reston subtype of Ebola, there was circumstantial evidence of airborne spread of the virus, and supporting observations included suggestive epidemiology in patterns of spread within rooms and between rooms in the quarantine facility, high concentrations of virus in nasal and oropharyngeal secretions, and ultrastructural visualization of abundant virus particles in alveoli [17, 50]. However, this is far from saying that Ebola viruses are transmitted in the clinical setting by small-particle aerosols generated from an index patient . Indeed patients without any direct exposure to a known EHF case were carefully sought but uncommonly found . The conclusion is that if this mode of spread occurred, it was very minor.
Science Magazine Special Collection: Ebola
The Lancet: Ebola Research
A collection of published articles, mechanisms of desease, reports and letters.
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- Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study Summary | Full-text HTML | PDF
- Postexposure protection against Marburg haemorrhagic fever with recombinant vesicular stomatitis virus vectors in non-human primates: an efficacy assessment Summary | Full-text HTML | PDF
- Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys Summary | Full-text HTML | PDF
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