marburg virus disease marburg virus disease marburg virus disease (mvd; formerly marburg hemorrhagic fever) is a viral hemorrhagic fever in human and non-human primates caused by either of the two marburgviruses: marburg virus (marv) and ravn virus (ravv). its clinical symptoms are very similar to those of ebola virus disease (evd). marburg virus diseaseother namesmarburg hemorrhagic fevertransmission electron micrograph of marburg virusspecialtyinfectious diseases symptomsfever, weakness, muscle painusual onset2-21 days after exposurecausesmvrisk factorsdirect contact with bodily fluids of individuals infected with the virusdiagnostic methodblood testdifferential diagnosisebola virus diseasetreatmentthere is no treatment, only immediate supportive carefrequencyraredeaths24%-88% case fatality rate egyptian fruit bats are believed to be the normal carrier in nature and marburg virus rna has been isolated from them. 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 the onset of clinical symptoms. mhf presents with a high fever 104 °f (~40˚c) and a sudden, severe headache, with accompanying chills, fatigue, nausea, vomiting, diarrhea, pharyngitis, maculopapular rash, abdominal pain, conjunctivitis, and 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 and death. symptoms include bloody stools, ecchymoses, blood leakage from venipuncture sites, mucosal and visceral hemorrhaging, and possibly hematemesis. late organ phase: day 13 up to day 21+. symptoms bifurcate into two constellations for survivors and fatal cases. survivors will enter a convalescence phase, experiencing myalgia, fibromyalgia, hepatitis, asthenia, ocular symptoms, and 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. causes main article: marburgvirus genus marburgvirus: species and its mvd-causing viruses species name virus name (abbreviation) marburg marburgvirus* marburg virus (marv; previously mbgv) ravn virus (ravv; previously marv-ravn) "*" denotes the type species. mvd is caused by two viruses; marburg virus (marv) and ravn virus (ravv), family filoviridae. 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 fruit bat 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. 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. diagnosis marburg virus liver injury 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 sepsis, 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. classification 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. transmission the details of the initial transmission of mvd to humans remain incompletely understood. transmission most likely occurs from egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bushmeat, but the specific routes and body fluids involved are unknown. human-to-human transmission of mvd occurs through direct contact with infected bodily fluids such as blood. transmission events are relatively rare – there have been only 11 recorded outbreaks of marv between 1975 and 2011, with one event involving both marv and ravv. prevention main article: prevention of viral hemorrhagic fever 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. they 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 quarantine of confirmed or high probability cases, proper personal protective equipment, and sterilization and disinfection. endemic zones the natural maintenance hosts of marburgviruses 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 spread 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, and any possibly contaminated materials and utensils. patients should be isolated, but still are safe to be visited by family members. medical staff should be trained in 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, should 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. treatment 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 antifungals to treat secondary infections. prognosis prognosis is generally poor. 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 of a particularly virulent serotype 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. epidemiology below is a table of outbreaks concerning mvd from 1967 to 2023: marburg virus disease outbreaks year country virus human cases human deaths case fatality rate notes 1967 west germany yugoslavia marv 31 7 23% 1975 rhodesia south africa marv 3 1 33% 1980 kenya marv 2 1 50% 1987 kenya ravv 1 1 100% 1988 soviet union marv 1 1 100% 1990 soviet union marv 1 0 0% 1998–2000 democratic republic of the congo marv & ravv 154 128 83% 2004–2005 angola marv 252 227 90% 2007 uganda marv & ravv 4 1 25% 2008 uganda netherlands united states marv 2 1 50% 2012 uganda marv 18 9 50% 2014 uganda marv 1 1 100% 2017 uganda marv 3 3 100% 2021 guinea marv 1 1 100% 2022 ghana marv 3 2 66.66% 2023 equatorial guinea marv 40 35 88% 2023 tanzania marv 9 6 66% 1967 outbreak main article: 1967 marburg virus outbreak in west germany 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 were subsequently infected 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