Monday, November 26, 2012

Ebola Hemorrhagic Fever


This week we introduce the Filoviridae family of viruses, with perhaps its most infamous member: Ebola virus. This virus has gained popular attention because of its severe outbreaks, which are typically associated with a very high mortality. Unfortunately this attention has usually been amplified by sensationalism in news media and film. While this hemorrhagic fever is undoubtedly a very serious disease and needs to be treated as such, this post will strive to describe only what is currently known and avoid hyperbole.

Ebola virus is named after the Ebola River in the Democratic Republic of Congo, which is one of the two places documented outbreaks first occurred in 1976. At the time, the Democratic Republic of Congo was known as Zaire, while the other outbreak occurred in the Sudan. These two outbreaks occurred almost simultaneously but were caused by two distinct species of the virus, as described below. There have been about 25 outbreaks in central Africa since, and including, the first, and these have occurred on an annual or biannual basis since 1994. Some years, like 2012, have seen multiple outbreaks.

The Pathogen. Ebola hemorrhagic fever (EHF) is caused by by one of five species of Ebolavirus. These species are Bundibugyo ebolavirus, Coite d'Ivoire ebolavirus (CIEBOV), Sudan ebolavirus (SEBOV), Reston ebolavirus (REBOV), and Zaire ebolavirus (ZEBOV), which is the specific virus denoted by the name Ebola virus (EBOV). Through the remainder of this discussion we will simply refer generically to EBOV.


The ebolaviruses, and the Filoviridae, are typically between 790 and 1400 nanometers long and 80 nanometers  in diameter  They are enveloped viruses with helical capsids and linear, negative-sense single-stranded RNA genomes.

Ebolavirus structure (published by ViralZone)

Monocytes, macrophages, dendritic cells, liver cells, and endothelial cells are the primary target cells of ebolaviruses. Virus is present in many tissues including kidney, liver, spleen, lymph nodes, and blood, as well as most body secretions. The viruses enter the cells by endocytosis, or by phagocytosis in the case of macrophages. The graphic below published by the Research Center for Zoonosis Control at Hokkaido University, nicely depicts the life cycle of ebolaviruses. 


The Reservoir. The natural reservoir host for EBOV remains unknown. However, several outbreak-associated and outbreak-independent seroepidemiology field investigations, as well as laboratory animal studies, strongly suggest that fruit bats are important natural reservoir hosts for EBOV

These are the the so-called megabats, i.e. the family Pteropodidae in the suborder known as Megachiroptera. 

Megabat, or "fruit bat": Spectacled flying-fox (Pteropus conspicillatus)

Many of these bats are quite large relative to the other suborder of bats, the Microchiroptera, but this is not a defining feature as some species of megabats are as small or smaller than some microbats. An important  distinction between these suborders is that megabats do not use echolocation (with the exception of the genus Rousettus) for navigation in flight and finding prey. Moreover, the megabats typically have very good vision. Megabats subsist solely on nectar and fruit, which is why they are commonly collectively referred to as "fruit bats", while most microbats eat insects and some will eat small vertebrates (reptiles, mammals, fish), mammalian blood or fruits and nectar.

There are three species distributed across tropical Africa that have demonstrated EBOV infection without disease. The first is Hypsignathus monstrosus, known commonly as the Hammer-headed bat:

 Hypsignathus monstrosus

The Hammer-headed bat has a long but very narrow distribution across the tropical belt of African rain forest:


These bats are exclusively fruit eating and are nocturnal. They roost in the tree canopy of forested habitat during the day, but are not selective about tree species other than they must be sufficiently high (20 to 30 meters).

The second of these potential important EBOV reservoirs is Epomops franqueti, which is known as the Franquet's Epauletted fruit bat:

Epomops franqueti

These bat ares distributed across a wide, but slightly shorter, area of central Africa:


These bats can be found across a wide variety of landscapes, including wet, dry, and mangrove forests, swamps, and dry savanna. These bats are also nocturnal and frugivorous, but they are solitary and maintain diurnal roosts at a height of around 5 meters. 

The third possible reservoir is Myonycteris torquata, known as the Little Collared fruit bat.

Myonycteris torquata

These bats have a geographic distribution similar to the Franquet's Epauletted fruit bat in central Africa: 


However, the Little Collared fruit bat is somewhat more ecologically specialized in that it prefers wet lowland forests and wet savanna. These bats are also nocturnal frugivores.

The Disease. Ebola hemorrhagic fever (EHF) is characterized by an abrupt onset presenting with myalgia,  fever, and chills. Abdominal pain and/or nausea with diarrhea and/or vomiting are also common. There are two important features of EHF that are critical in its pathogenesis: 1) endothelial damage mediated by both the virus and the up-regulation of toxic cytokines, which leads to extensive vascular leakage, and 2) disseminated intravascular coagulation, which leads to severe thrombocytopenia. The graphic below published in the Lancet Student (doi:10.1016/S0140-6736(10)60667-8Cite) illustrates these key features of EBOV pathogenesis:


Hemorrhage, often severe, thus ensues and can be seen at several sites within approximately 5 to 7 days of the onset of symptoms. Bleeding from the nose, gums, and eyes is common, and extensive gastrointestinal hemorrhage will often manifest as frank blood in the stool or hematemesis. Dehydration is very common.Significant lesions can be found in multiple organs including the kidneys, spleen, liver, and lymph nodes. Mortality is high, typically ranging from 50% to 90% depending on the species and strain of Ebolavirus.

The Epidemiology and the Landscape. Ebola virus is transmitted via contaminated body fluids. Direct and indirect contact, and droplet transmission are the primary specific routes of viral spread between humans, and between other animals and humans. Health care settings and subsistence hunting define the two primary paradigms for human infection, and therefore both human to human and zoonotic transmission are viable and important routes of human infection.

The global distribution of EBOV human and animal outbreaks, seroprevalence and presumed reservoir host range is depicted in the map below produced by the World Health Organization:


Interestingly, the map demonstrates a very wide potential reservoir host distribution across much of South and Southeast Asia and Oceania, which includes several additional fruit bat species in the Pteropodidae family not described above. Moreover, REBOV has been found extensively in monkeys and domestic pigs in the Philippines, though no human infections have yet been observed.

The graphic below, and the description underneath, were published in the journal, Emerging Infectious Diseases (http://wwwnc.cdc.gov/eid/article/11/2/04-0533_article.htm). This is a nice depiction of the ecology and landscape epidemiology of ebolaviruses, as we currently understand them:


Schematic representation of the Ebola cycle in the equatorial forest and proposed strategy to avoid Ebola virus transmission to humans and its subsequent human-human propagation. Ebola virus replication in the natural host (a). Wild animal infection by the natural host(s) (b), no doubt the main source of infection. Wild animal infection by contact with live or dead wild animals (c). This scenario would play a marginal role. Infection of hunters by manipulation of infected wild animal carcasses or sick animals (d). Three animal species are known to be sensitive to Ebola virus and to act as sources of human outbreaks: gorillas, chimpanzees, and duikers. Person-to-person transmission from hunters to their family and then to hospital workers (e). The wild animal mortality surveillance network can predict and might prevent human outbreaks. Medical surveillance can prevent Ebola virus propagation in the human population.

As you can see from this depiction, the physical and social landscapes are both important in the epidemiology of EHF. In particular, 1) the interface between human subsistence economies and sylvan habitat generates critical index cases, and 2) the bare-essential act of care-giving, either in the home or in a clinical setting, generates the propagative secondary cases.

Control and Prevention. Control and prevention of EHF are typically focused on outbreak containment and control, and in only one of the two primary paradigms of transmission described above. As such, this translates to blocking nosocomial transmission by employing good barrier protection and patient isolation to prevent spread from infected patients to health care personnel and/or other non-infected patients in a hospital or health care setting. This is the central component to EHF control and prevention as outbreaks often generate many secondary cases by human to human transmission during the care of infected individuals.

Blocking transmission at the source of index cases is very difficult because there is no way that a primary source of subsistence, i.e. bush hunting, can be removed as a public health intervention for a community whose basis of existence is a subsistence economy. Nevertheless, the Wild Animal Mortality Monitoring Network is an important surveillance instrument that has been developed to survey animal carcasses in sylvan habitat where EBOV has been identified in order to help predict and prevent future outbreaks. While of limited geographic and temporal implementation, the use of this kind of surveillance could be quite useful for the future identification of sylvan EBOV foci and the possible interception of human contact with these cites before transmission occurs.



10 comments:

  1. I was researching online, and found out that the latest reported Ebola outbreak was in August, 2012 in Western Uganda. I believe it is the same strain as the Sudan ebolavirus. Does anyone else know if there is a more recent outbreak or one that is more sever in recent history?

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  2. Russel Sharif (MPH)December 7, 2012 at 11:49 PM

    What I found is that the incubation period for Ebola HF ranges from 2 to 21 days. The onset of illness is abrupt and is characterized by fever, headache, joint and muscle aches, sore throat, and weakness, followed by diarrhea, vomiting, and stomach pain. A rash, red eyes, hiccups and internal and external bleeding may be seen in some patients. Researchers do not understand why some people are able to recover from Ebola HF and others are not. However, it is known that patients who die usually have not developed a significant immune response to the virus at the time of death. So we have to do more research on this virus to protect the people from this fatal disease.

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    1. I understand the blocking transmission at the primary source is impossible because of the limited resources and option available to those with the greatest risk for exposure. My thought is that constant human expansion and encroachment into natural habitat increases our exposure to the natural reservoir. My question is, as the population in these areas increase in the future would we expect to see increases in the cases of EBOV? And if so, perhaps constraining ourselves from rapid expansion and disrupting ecosystems would decrease our chances of contracting these fatal diseases. With this, perhaps rates of bushmeat hunting would eventually decrease since a rapidly expanding population would increase the rates of subsistence living. To sum it up, I feel a few of these diseases are a result of large population increases and lack of resources to support it.

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  3. @ Flynn, the outbreak in Uganda ran from July to November 2012. It was responsible for 34 deaths.

    There is a recent suspected outbreak of Ebola in the republic of congo, with at least 6 reported cases in May 2013. The affected area is 700 miles from the Ugandan border, making it possible it a potential source of the Congo outbreak.

    http://www.voanews.com/content/suspected-ebola-fever-surfaces-in-drc/1671512.html

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  4. These individuals have since tested negative for Ebola virus.

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  5. I thought it was interesting that Congo and Sudan had an outbreak almost simultaneously, yet the outbreaks were caused by two different species of the ebola virus.

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    1. Sheaba Daniel

      According to info that I read on the CDC site, there have been at least 5 strains of the Ebola virus identified so far, with the latest identified in 2007, which includes the symptom of vomiting.
      Also, the site also mentions that the natural reservoir of Ebola has not been confirmed as of yet, though there is much speculation that the natural reservoir may be fruit bats (testing revealed that fruit bats in specific areas of Ebola outbreaks generate an immune response to Ebola despite not producing any symptoms).

      I also find it interesting that Ebola is able to infect a wide range of hosts, from humans, to primates, rodents and bats. Further research is required to find the mechanism by which the Ebola virus enters the cells of its host.

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  6. As discussed in the post, the natural reservoir for Ebola virus is unknown but evidence points to fruit bats. I think this is the factor that makes eradication the most difficult for this infection. Since there is no definitive answer as to the natural reservoir it seems that any attempt to control this infection would be to no avail. It is unfortunate that another way of infection is via nosocomial infection. Since this is an easily avoidable mode of transmission it seems like it would be easy to control. However, in areas where Ebola virus is prevalent the lack of resources is preventing the stop of nosocomial infections. Some health care providers run out of barrier protecting equipment like gloves, masks, and goggles. As populations grow and expand I wonder how that will influence the spread of this infection. I imagine that resources will continue to be limited in these areas and the nosocomial infections will continue to be a problem.

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  7. Today (24 March 2014), someone in Liberia told me, that there is an outbreak of Ebola going on in Sierra Leone. People fear that this contagious disease might spread into bordering areas of Liberia because of the intense traveling between the stricken Sierra Leonean area and some LIberian counties. Do you know if this is true?

    A.F.C.E. de Wert

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    1. Ebola cases have not yet been confirmed outside of Guinea, though some ill patients are under investigation in both Sierra Leone and Liberia.

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