Wednesday, December 19, 2012

Marburg Hemorrhagic Fever


This week we are going to cover the second of the two Filoviruses included in our extended series on the viral hemorrhagic fevers: Marburg virus. Marburg hemorrhagic fever is another very serious disease, and it is clinically indistinguishable from Ebola hemorrhagic fever. Indeed, because the virology, epidemiology, and clinical symptoms are so similar between these two diseases, much of this discussion will be quite similar to what has been covered on Ebola hemorrhagic fever.

Marburg virus is named after the city of Marburg, Germany, which is where one of the first epidemics was identified following exposure to imported infected monkeys in 1967.

The Pathogen. Marburg hemorrhagic fever (MHF) is caused by Marburg virus (MARV), whose species name is Marburg marburgvirus and is in the Filoviridae family.



Like all the Filoviridae, MARV ranges between 790 and 1400 nanometers long (though MARV is typically about 200 nanometers shorter than the ebolaviruses) and 80 nanometers  in diameter  They are enveloped viruses with helical capsids and linear, negative-sense single-stranded RNA genomes.

Marburg virus structure (published by ViralZone)

Monocytes, macrophages, dendritic cells, liver cells, and endothelial cells are the primary target cells of MARV. 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 Reservoir. The natural reservoir host for MARV 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 MARV.

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.

The Egyptian fruit bat, Rousettus aegyptiacus, has been identified as a natural reservoir host for MARV.

Rousettus aegyptiacus

Like the reservoir fruit bats discussed for ebolaviruses, these bats are frugivores and are nocturnal. However, the Egyptian fruit bat is relatively small for a megabat, and it also uses echolocation, which is unique to Rousettus spp. among the megabats. These bats are gregarious and roost in large colonies in trees and caves.


Egyptian fruit bats can exploit very diverse ecological habitats, but stay away from desert landscapes. They are distributed extensively across subregions of Africa and narrow corridors of the Middle East. They can also be found in South Asia in Pakistan and northern India.

The Disease. Marburg hemorrhagic fever (MHF) 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 MHF 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 Nature Reviews Immunology 7, 556-567 (July 2007) illustrates these key features of MARV 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 MARV.

The Epidemiology and the Landscape. Marburg 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 MARV is depicted in the following two map sets and the descriptions below each, all of which was published in Emerging Infectious Diseases 2004 Jan (http://wwwnc.cdc.gov/eid/article/10/1/03-0125.htm):


Summary of known and predicted geography of filoviruses in Africa. (A) Known occurrence points of filovirus hemorrhagic fevers (HFs) identified by virus species. (B) Geographic projection of ecologic niche model based on all known filovirus disease occurrences in Africa. (C) Geographic projection of ecologic niche model based on all known Ebola HF occurrences (i.e., eliminating Marburg HF occurrences). (D) Geographic projection of ecologic niche model based on all known occurrences of Marburg HF (i.e., eliminating Ebola HF occurrences). Darker shades of red represent increasing confidence in prediction of potential presence. Open squares, Ebola Ivory Coast; circles, Ebola Zaire; triangles, Ebola Sudan; dotted squares, Marburg HF 


Projection of filovirus ecologic niche models onto southeastern Asia and the Philippines to assess the degree to which possible Philippine distributional areas are predictable on the basis of the ecologic characteristics of African filovirus hemorrhagic fever (HF) occurrences. (A) Projection of model for Marburg HF occurrences (Figure 1D) to southeastern Asia. (B) Projection of model for all filovirus disease occurrences (Figure 1B) to southeastern Asia (the projection of models for Ebola HF occurrences is identical to this map). Inset: detail of projection to the island of Mindanao, in the Philippines. Darker shades of red represent increasing confidence in prediction of potential presence.

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 depiction of the ecology and landscape epidemiology of ebolaviruses, but applies equally to MARV:


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 MHF. 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 MHF are typically focused on outbreak containment and control, and in only the second 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 MHF 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 Filoviruses, including Ebola virus and Marburg virus, have 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 MARV foci and the possible interception of human contact with these cites before transmission occurs.

2 comments:

  1. Sheaba D. -

    MHF seems to share many characteristics with the various hemorrhagic fevers discussed on this site, in terms of the symptoms listed and the virology. Some of the symptoms of MHF also bear many similarities to diseases like typhoid and malaria, so if only one case occurs as opposed to a series of cases, a misdiagnosis is possible. I assume that the patients’ travel history and their exposure to wildlife (bats and excrement) are thoroughly examined by the doctor before making a diagnosis.
    For a disease that has such a high mortality rate, it is grim to note that there are no ways to prevent MHF outside of outbreak containment (secondary transmission).

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  2. Although MHF bares resemblance to typhoid and malaria as sheaba mentioned in terms of fever aches and chills,the subsequent symptoms seem to be a lot worse with bleeding occurring from the mouth nose and gums. What's more, there are no substantial ways to treat MHF other than isolation of the primary infected person. Perhaps if public health organizations could increase awareness about how infection is spread, the mortality rate could decrease.

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