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.



23 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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    2. In response to Marc’s comment, I think it is not necessarily true that increased population in the natural habitat of the potential reservoirs equals to more exposure/cases. It is very likely that before humans start to reside in the area, it will be modified to some extent to make it “livable”. In this sense, the area may no longer be considered as a suitable habitat by the wildlife as well as the reservoir hosts. The most important factor that facilitates disease transmission does not have to be the proximity between human beings and the reservoirs/vectors, but the overlapping of their habitats/territories and the social landscape of human beings (as mentioned in the post) because humans are very mobile.

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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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    2. I wonder if in the future we will have to be concerned with evolving strands of this virus. Also is there a possibility that those that have not been found in humans will eventually come to affect humans.

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    3. This is a very good point, there are many strands already identified, and the fact that it is able to infect many different hosts shows that it is evolving. Have different strands of Ebola been found in areas in the Americas that are similar to that in Africa?

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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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  8. There is an ongoing outbreak of ebola right now. It seems to be a continuation of the same outbreak mentioned by A.F.C.E de Wert. Unfortunately, Dr. Walsh, both Liberia and Sierra Leone, according to the WHO and reporting by Jonathan Paye-Layleh of the Associated Press, have confirmed Ebola cases. You had mentioned the difficulty in eliminating/eradicating diseases that have non-human reservoirs. I do, however, believe that there are efforts that might help limit zoonotic transmission. Part of the problem, I feel, is lack of information/education.

    While zoonotic transmission will be much more difficult to control, human-human, especially in the nosocomial instance, can be limited with proper infection control measures. This does, of course, assume the presence of resources, such as gloves, masks, etc as mentioned in the blog.
    The hunters, who tend to serve as the critical index cases should be better educated about the modes of transmission of this virus. While we cannot remove their sustenance products, the hunters themselves might find innovative ways to reduce the risk of transmission. Proper information about effective ways to prevent transmission, especially in the "bush" setting, could also help prevent many secondary cases, as opposed to everyone running away due to the fear that is doubtless associated with the disease.
    The report by Paye-Layleh is located at http://abcnews.go.com/International/wireStory/liberian-official-deaths-linked-ebola-24170004

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  9. I really like the way this discussion was started about how infamous this disease has become, though people know very little about it. I was not aware ebola virus could live in animals. let alone bats and pigs. I wonder why they are not susceptible to the virus. Also,it was interesting to me that the reservoir, after all this time, is still in question. It seems there are several variables which are currently unknown about this virus.

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  10. Ebola has been the headline news recently in the international health realm and this recent outbreak has been more alarming than in the past. Since March 2014, there has been 759 cases in Guinea, Sierra Leone and Liberia for a disease that usually in isolated areas. However, what has exacerbated the situation is not only the lack of more public awareness but also the infrastructure for public health efforts. There is a sense of mistrust of health workers and even active resistance reported with rock throwing. Ebola isn't easily spread though and although it takes 2-21 days from exposure to symptoms, the person isn't contagious until they show the symptoms. This allows for a better way of containment then. However, there is no cure or vaccine for Ebola and most of the cure is supportive with IV and treating the symptoms. Thus, the main efforts should focus on the public health aspect of gaining the trust of the communities and spreading more awareness in order to prevent the problem from spreading even more.
    http://www.cnn.com/2014/06/26/health/ebola-outbreak-west-africa/index.html

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    1. Not necessarily true that Ebolavirus cannot be transmitted until symptoms are present. Be careful of your data sources.

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  11. The Ebola virus seems to affect individuals in a wide area, and it is actually very helpful that a map is available showing the geographical spread of the virus. Due to the constant warfare that forces individuals to constantly relocate, has the virus been able to spread in refugee camps?

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  12. Racquel BreretonJuly 16, 2014 at 1:32 PM

    As voiced by a few posts, the issue with Ebola virus is lack of information. While there have been great strides in containment of outbreaks, there is still much ambiguity about the disease. This was reflected in David Bausch's encounter with Ebola in Gabon's 2001 outbreak relayed in "Outbreak Investigations Around the World". It is difficult making a diagnosis as the disease manifests differently in individuals. But I do believe communication and community awareness can prove great tools in preventing outbreaks. It is challenging to advertise the health implications associated with contact with infected wild primates in a community that so heavily relies on bush hunting for sustenance. Perhaps it may be more effective and practical to encourage better contact precautions to healthcare workers. However, this also presents a challenge as the issue often lies in lack of a continuous supply of PPE rather than negligence.

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  13. Ebola Hemorrhagic Fever is one of the most deadly diseases known to man. At one point it was believed the death rate was approximately 90% (Ebola Zaire) during its first discovery in 1976. After reading the book “Hot Zone”, Ebola sparked an interest of mine, since it seemed to be unique compared to other viral infections. The rapid onset of Ebola roughly somewhere between 2-21 days leaves little time for ample treatment, and deteriorates its host. Symptoms include: intense aches and pain, internal hemorrhaging (usually very severe), and bleeding from orifices. Transmission of Ebola comes from contact with blood or stool of infected vehicles. Note one species of Ebola , Reston Ebolavirus is believed to be airborne transmission, however no human cases of infections were reported.

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  14. Even though parts of Southeast Asia share similar geographic settings as the dry Savanna region of Africa, I wonder why regions in Africa share the biggest burden of EBV. I wonder if removing the practice of bush hunting would completely eliminate the fruitbat to human transmission.

    Since current EBV strain seems more resilient and is likely becoming a pandemic, I wonder what prevention and control measures were missed in the initial steps for this current outbreak.

    As we enter into the influenza season in addition to current enterovirus outbreak in the US, it seems like it’s everyone responsibility to step up in applying all the prevention and control measures advised.

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  15. Ebola is recently coming back to the front page news and I feel it might be a much bigger of a problem that is still brewing under the surface.

    Even thought measures been taken by lots of countries and health organization, it seems that even in developed countries this infection might be hard to contain, as these measure are general and not specific, hugely time/money consuming and needs attention to details, while as humans were make the same mistakes whether in developed or developing countries during these procedures, which is apparent in the recent case of the Spanish nurse who got infected caring for two Ebola patients who came recently from Africa, even though she have been using all the procedures from masks, body suits ..etc, and only have been twice in the patients rooms.Her dog also got infected and have been put to sleep. So how she got infected ? did she failed to follow the right procedures, even thought she is a highly trained nurse in a specialized Spanish hospital that treat infectious disease and contain them which point to a human mistake, or that we don’t fully appreciate/ understand how and when the infection is transmitted.

    Since there is not a lot of details about the incubation, latent phase of the disease, the different strains of the virus, and how each differs in the ways of transmission, symptoms, signs, speed of fatality, we can’t efficiently inform the public and use the right measures.

    Ebola have not been transmitted to the developed world before, and these developed countries and urban cities has a different and much bigger problem to contain a disease like that, because in urban cities, communication and contacts happens in a much larger and different scale than in a rural African community. A person, fly, use the train, the bus, a taxi and go to the gym, have dinner with friends and family in a restaurant, see a doctor or go to the emergency room, and get in contact with 10’s and even hundreds of people in one day.
    For example, In an urban city like New York city, where millions of its inhabitants use the subway system daily, a real scenario would be like that: a person who is infected, comes from JFK airport by plan, takes the AirTrian to Jamaica station, then E, F and/or R subway lines to 42 street Times Square Manhattan then transfer to another subway line or use shuttle to another train system line NJtrain in Penn station or Metro North or LIRR trains from Grand Central or the Port Authority bus terminal, stay in the food court of the station for 15 to 20 minutes waiting for the train, and finally go home to his family, and second day to go to work and use the same trains/subway circle again, this person looks like he has the flu, he coughs in his hand multiple time and maybe as an informed person he maybe a couple of times he coughs/sneezes in his sleeves to avoid transmission of the flu/cold viruses, in all these trips he stand up hold the train poles, touch the door, the seat. How many hundreds of people will touch the same surfaces that he touches and get exposed to his droplets and fluids in about 5 or 10 minutes after that?
    Also add to this the short incubation period, which is a good thing in that we can detect the diseased earlier but a bad thing since the virus kills the patient in few days and there is no ample time for treatment and fatality is very high, more than 50%.

    Since the flu/cold season is here, it would make it much more difficult to start to isolate all persons with fever and muscle/joint pains/aches and waste huge resources in isolating people with false positive signs and symptoms and attest them for Ebola and waste a lot of money and time, and as in SARS virus outbreak before, people tended to take few ibuprofen pills before they land their plane so that they will not show any fever for screeners which is counter productive, and in the mean time you do not want to loose any number of true cases as they will spread the infection. So the question is how to balance sensitivity and specificity in a situation like that.

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    1. Usama, I agree with you that a universally appropriate protocol is needed for dissemination of information to the public as well as prevention and treatment measures. In the case of the Spanish nurse, I don't know how she got infected, but I have been following the news coverage of the two Texas nurses infected with Ebola and sources claim that their exposure may have been due to wearing too much protective equipment. Given the fact that the nurses were new to Ebola and the protective measures required, there was opportunity for error. There may have been problems in disrobing that led to a breach. Doctors without Borders and similar groups that have been providing treatment in the Ebola epicenter have been able to do so with minimal incidence of exposure because they received adequate training and may be more experienced than the nurses in Texas and Spain. These women, who never expected to one day care for an Ebola infected individual, were suddenly thrust into that situation. Although it may be expensive and time consuming, ideally, a large enough proportion of the entire hospital workforce should be trained extensively in treating Ebola patients while minimizing potential for secondary transmission.

      This outbreak has definitely highlighted the delicate balance of sensitivity and specificity. As of late, there has been plenty of talk about whether to instate mandatory isolation for Americans who recently traveled to West Africa to treat Ebola patients. Isolation may reduce the number of secondary transmissions but I don't think mandatory seclusion is necessary because a person is infectious only when symptomatic, and I'm sure that health care workers returning from that region would already be watching for symptoms out of self interest.

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