Marburg virus disease
|Transmission electron micrograph of the Marburg virus|
|Group:||Group V ((-)ssRNA)|
|Marburg virus disease|
|Classification and external resources|
Marburg virus disease (MVD) is the name for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). MVD is a viral hemorrhagic fever (VHF), and the clinical symptoms are indistinguishable from Ebola virus disease (EVD).
Marburg virus disease (MVD) is the official name listed in the World Health Organization's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg, where MARV was first discovered.
Signs and symptoms 
The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A maculopapular rash, petechiae, purpura, ecchymoses, and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension, disseminated intravascular coagulation, and focal tissue necroses.
Clinical phases of Marburg Hemorrhagic Fever's presentation are described below. Note that phases overlap due to variability between cases.
- Incubation: 2–21 days, averaging 5–9 days.
- Generalization Phase: Day 1 up to Day 5 from onset of clinical symptoms. MHF presents with a high fever (~40˚C) and a sudden, severe headache, with accompanying chills, fatigue, nausea, vomiting, diarrhea, pharyngitis, maculopapular rash, abdominal pain, conjunctivitis, & malaise.
- Early Organ Phase: Day 5 up to Day 13. Symptoms include prostration, dyspnea, edema, conjunctival injection, viral exanthema, and CNS symptoms, including encephalitis, confusion, delirium, apathy, and aggression. Hemorrhagic symptoms typically occur late and herald the end of the early organ phase, leading either to eventual recovery or worsening & death. Symptoms include bloody stools, ecchymoses, blood leakage from venipuncture sites, mucosal & visceral hemorrhaging, and possibly hematemesis.
- Late Organ Phase: Day 13 up to Day 21+. Symptoms bifurcate into two constellations for survivors & fatal cases. Survivors will enter a convalescence phase, experiencing myalgia, fibromyalgia, hepatitis, asthenia, ocular symptoms, & psychosis. Fatal cases continue to deteriorate, experiencing continued fever, obtundation, coma, convulsions, diffuse coagulopathy, metabolic disturbances, shock and death, with death typically occurring between Days 8 and 16.
|Species name||Virus name (Abbreviation)|
|Marburg marburgvirus*||Marburg virus (MARV; previously MBGV)|
|Ravn virus (RAVV; previously MARV-Ravn)|
|"*" denotes the type species.|
Marburgviruses are endemic in arid woodlands of equatorial Africa. Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines. In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian rousettes (Rousettus aegyptiacus) caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys. Finally, a major risk factor for acquiring marburgvirus infection is occupational exposure, i.e. treating patients with MVD without proper personal protective equipment.
Contrary to Ebola virus disease (EVD), which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.
Like all mononegaviruses, marburgvirions contain non-infectious, linear nonsegmented, single-stranded RNA genomes of negative polarity that possesses inverse-complementary 3' and 5' termini, do not possess a 5' cap, are not polyadenylated, and are not covalently linked to a protein. Marburgvirus genomes are approximately 19 kb long and contain seven genes in the order 3'-UTR-NP-VP35-VP40-GP-VP30-VP24-L-5'-UTR. The genomes of the two different marburgviruses (MARV and RAVV) differ in sequence.
Like all filoviruses, marburgvirions are filamentous particles that may appear in the shape of a shepherd's crook or in the shape of a "U" or a "6", and they may be coiled, toroid, or branched. Marburgvirions are generally 80 nm in width, but vary somewhat in length. In general, the median particle length of marburgviruses ranges from 795–828 nm (in contrast to ebolavirions, whose median particle length was measured to be 974–1,086 nm ), but particles as long as 14,000 nm have been detected in tissue culture. Marburgvirions consist of seven structural proteins. At the center is the helical ribonucleocapsid, which consists of the genomic RNA wrapped around a polymer of nucleoproteins (NP). Associated with the ribonucleoprotein is the RNA-dependent RNA polymerase (L) with the polymerase cofactor (VP35) and a transcription activator (VP30). The ribonucleoprotein is embedded in a matrix, formed by the major (VP40) and minor (VP24) matrix proteins. These particles are surrounded by a lipid membrane derived from the host cell membrane. The membrane anchors a glycoprotein (GP1,2) that projects 7 to 10 nm spikes away from its surface. While nearly identical to ebolavirions in structure, marburgvirions are antigenically distinct.
The marburgvirus life cycle begins with virion attachment to specific cell-surface receptors, followed by fusion of the virion envelope with cellular membranes and the concomitant release of the virus nucleocapsid into the cytosol. The virus RdRp partially uncoats the nucleocapsid and transcribes the genes into positive-stranded mRNAs, which are then translated into structural and nonstructural proteins. Marburgvirus L binds to a single promoter located at the 3' end of the genome. Transcription either terminates after a gene or continues to the next gene downstream. This means that genes close to the 3' end of the genome are transcribed in the greatest abundance, whereas those toward the 5' end are least likely to be transcribed. The gene order is therefore a simple but effective form of transcriptional regulation. The most abundant protein produced is the nucleoprotein, whose concentration in the cell determines when L switches from gene transcription to genome replication. Replication results in full-length, positive-stranded antigenomes that are in turn transcribed into negative-stranded virus progeny genome copies. Newly synthesized structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane. Virions bud off from the cell, gaining their envelopes from the cellular membrane they bud from. The mature progeny particles then infect other cells to repeat the cycle.
MVD is clinically indistinguishable from Ebola virus disease (EVD), and it can also easily be confused with many other diseases prevalent in Equatorial Africa, such as other viral hemorrhagic fevers, falciparum malaria, typhoid fever, shigellosis, rickettsial diseases such as typhus, cholera, gram-negative septicemia, borreliosis such as relapsing fever or EHEC enteritis. Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis, scrub typhus, plague, Q fever, candidiasis, histoplasmosis, trypanosomiasis, visceral leishmaniasis, hemorrhagic smallpox, measles, and fulminant viral hepatitis. Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia, hemolytic uremic syndrome, snake envenomation, clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura, hereditary hemorrhagic telangiectasia, Kawasaki disease, and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patient's exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects. Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA, which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore.
There are currently no Food and Drug Administration-approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons, vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious, but not very contagious. Importantly, and contrary to popular belief, marburgviruses do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on behavior modification, proper personal protective equipment, and sterilization/disinfection.
In endemic zones 
The natural maintenance hosts of marburg viruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source.
During outbreaks 
Since marburgviruses are not spreading via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids, or possibly contaminated materials and utensils. Patients ought to be isolated but still have the right to be visited by family members. Medical staff should be trained and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, ought to be discouraged or modified, ideally with the help of local traditional healers.
In the laboratory 
Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment. Laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.
There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration, administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation, administration of procoagulants late in infection to control hemorrhaging, maintaining oxygen levels, pain management, and administration of antibiotics or antimycotics to treat secondary infections. Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. Novel, very promising, experimental therapeutic regimens rely on antisense technology: phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome could prevent disease in nonhuman primates.
Prognosis is generally poor (average case-fatality rate of all MVD outbreaks to date = 82%). If a patient survives, recovery may be prompt and complete, or protracted with sequelae, such as orchitis, hepatitis, uveitis, parotitis, desquamation or alopecia. Importantly, MARV is known to be able to persist in some survivors and to either reactivate and cause a secondary bout of MVD or to be transmitted via sperm, causing secondary cases of infection and disease.
Of the 252 people who contracted Marburg during the 2004–2005 outbreak in Angola, 227 died, for a case fatality rate of 90%.
Although all age groups are susceptible to infection, children are rarely infected. In the 1998–2000 Congo epidemic, only 8% of the cases were children less than 5 years old.
|Year||Virus||Geographic location||Human cases/deaths (case-fatality rate)|
|1967||MARV||Marburg and Frankfurt, West Germany; and Belgrade, Yugoslavia||31/7 (23%)|
|1975||MARV||Rhodesia and Johannesburg, South Africa||3/1 (33%)|
|1988||MARV||Koltsovo, Soviet Union||1/1 (100%) [laboratory accident]|
|1990||MARV||Koltsovo, Soviet Union||1/0 (0%) [laboratory accident]|
|1998–2000||MARV + RAVV||Durba and Watsa, Democratic Republic of the Congo||154/128 (83%)|
|2007||MARV + RAVV||Uganda||4/1 (25%)|
|2008||MARV||Uganda, Netherlands, Colorado||2/1 (50%)|
1967 outbreak 
MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main, and in Belgrade, Yugoslavia. The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines. The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine, Emil von Behring. The company, which at the time was owned by Hoechst, was originally set up to develop sera against tetanus and diphtheria. Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment. Secondary cases involved two physicians, a nurse, a post-mortem attendant, and the wife of a veterinarian. All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients.  A popular science account of this outbreak can be found in Laurie Garrett’s book The Coming Plague.
1975 cases 
In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe). He died in a hospital in Johannesburg, South Africa. His girlfriend and an attending nurse subsequently came down with MVD, but survived.
1980 cases 
A case of MARV infection occurred in 1980 in Kenya. A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma) at the base of Mount Elgon (which contains Kitum Cave), became infected by unknown means and died shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston’s book The Hot Zone (the French man is referred to under the pseudonym “Charles Monet”, whereas the physician is identified under his real name Shem Musoke).
1987 case 
In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu, Kenya. He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa, where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston’s book The Hot Zone (the boy is referred to under the pseudonym “Peter Cardinal”).
1988 laboratory infection 
In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs. The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR (today Russia). Very little information is publicly available about this MVD case because Ustinov’s experiments were classified. A popular science account of this case can be found in Ken Alibek’s book Biohazard.
1990 laboratory infection 
Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor") in Koltsovo, USSR, when a scientist contracted MARV by unknown means.
1998–2000 outbreak 
A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa, Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine.
2004–2005 outbreak 
In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola, which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity. Contact tracing was complicated by the fact that the country's roads and other infrastructure have been devastated after nearly three decades of civil war and the countryside remained littered with land mines. Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died.
2007 cases 
In 2007, four miners became infected with marburgviruses in Kamwenge District, Uganda. The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection.
2008 cases 
On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda suffered of MVD due to MARV infection, and had been admitted to a hospital in the Netherlands. The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin. At the time, serologic testing was negative for viral hemorrhagic fever. She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA.
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Further reading 
- Klenk, Hans-Dieter (1999), Marburg and Ebola Viruses. Current Topics in Microbiology and Immunology, vol. 235, Berlin, Germany: Springer-Verlag, ISBN 978-3-540-64729-4
- Klenk, Hans-Dieter; Feldmann, Heinz (2004), Ebola and Marburg Viruses: Molecular and Cellular Biology, Wymondham, Norfolk, UK: Horizon Bioscience, ISBN 978-0-9545232-3-7
- Kuhn, Jens H. (2008), Filoviruses: A Compendium of 40 Years of Epidemiological, Clinical, and Laboratory Studies. Archives of Virology Supplement, vol. 20, Vienna, Austria: SpringerWienNewYork, ISBN 978-3-211-20670-6
- Martini, G. A.; Siegert, R. (1971). Marburg Virus Disease. Berlin, Germany: Springer-Verlag. ISBN 978-0-387-05199-4.
- Ryabchikova, Elena I.; Price, Barbara B. (2004), Ebola and Marburg Viruses: A View of Infection Using Electron Microscopy, Columbus, Ohio, USA: Battelle Press, ISBN 978-1-57477-131-2
|Wikimedia Commons has media related to: Marburg virus|
- ViralZone: Marburg virus
- Centers for Disease Control, Infection Control for Viral Haemorrhagic Fevers In the African Health Care Setting.
- Center for Disease Control, Marburg Haemorrhagic Fever.
- Center for Disease Control, Known Cases and Outbreaks of Marburg Haemorrhagic Fever
- Ebola and Marburg haemorrhagic fever (10 July 2008) factsheet from European Centre for Disease Prevention and Control
- World Health Organization, Marburg Haemorrhagic Fever.
- Red Cross PDF
- Virus Pathogen Database and Analysis Resource (ViPR): Filoviridae