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Marburg virus disease, or Marburg fever, caused by the highly pathogenic Marburgvirus (MARV), is a rare but severe hemorrhagic fever with a high case-fatality rate, transmitted through contact with excreta of the fruit bat Rousettus aegyptiacus (the natural reservoir of MARV), infected individuals’ bodily fluids, or exposure in healthcare and laboratory settings. This course reviews the characteristic features of this disease, which presents after an incubation period of 3 to 21 days, beginning with nonspecific symptoms such as fever, myalgia, and headache, progressing to gastrointestinal symptoms, hemorrhagic manifestations, and, in severe cases, multiorgan failure and shock. Participants will gain an in-depth understanding of this rare virus and the importance of prompt diagnosis to prevent the high morbidity and mortality associated with this condition. Public health preparedness, supportive management, including fluid replacement and blood transfusions, which remains the primary treatment for this condition, as well as stringent infection control measures critical to limiting the spread of the disease and managing and containing outbreaks effectively, are also explored. This activity for healthcare professionals is designed to enhance the learner's competence in recognizing the clinical features of the Marburg virus disease, performing the recommended evaluation, and implementing an appropriate interprofessional management approach to improve patient outcomes. Objectives: Identify the risk factors for Marburg virus transmission. Select appropriate diagnostic studies to evaluate patients with clinical features of Marburg virus disease. Implement current evidence-based management for patients infected with Marburg virus disease. Apply interprofessional team strategies to improve care coordination and outcomes for patients infected with Marburg virus disease. Access free multiple choice questions on this topic.

Marburgvirus (MARV), a highly pathogenic single-stranded RNA virus that belongs to the Filoviridae family, is the cause of Marburg virus disease. Marburg virus disease is a rare but severe hemorrhagic fever with a high case-fatality rate (CFR), making it one of the most deadly pathogens.[1][2] According to the World Health Organization (WHO), the fatality rate is 88%. The WHO first identified MARV during an outbreak in 1967 in Germany and Serbia (then part of Yugoslavia). The source of Marburg virus disease was traced back to the importation of African green monkeys from Uganda, and therefore, Marburg virus disease was previously known as green monkey disease.[3] Outbreaks have since been reported in Ghana, Guinea, Kenya, South Africa, Angola, Tanzania, the Democratic Republic of the Congo (DRC), Equatorial Guinea, Uganda, and Rwanda.[4][5][6][7][8][9][10] The major animal reservoir was subsequently identified through epidemiological linkage as the fruit bat, Rousettus aegyptiacus.[11] Transmission occurs via inhalation or direct contact with contaminated excreta from bats. Human-to-human transmission has been reported through direct contact with bodily fluids from sick patients, both in healthcare and household settings.[12][13] Following the initial exposure, MARV enters the body, replicates, and disseminates, leading to a clinical syndrome characterized by fever, malaise, myalgia, and blood coagulation disorders.[14] These symptoms progress to hemorrhagic shock and multiorgan failure. The CFR has been reported to be as high as 90%.[5] Currently, no vaccine or specific treatment is available for Marburg virus disease, although new treatments may be promising. Due to the severity of the disease and the high CFR, this is a global public threat. Therefore, early recognition and supportive care are essential as they can result in better patient outcomes. Healthcare workers must maintain a high index of suspicion to initiate treatment promptly and strive for optimal patient outcomes. Having processes in place to immediately implement infection control measures is crucial for protecting close contacts and minimizing the transmission of infections from sick patients.[15] Global and national public health preparedness and prevention strategies are necessary to respond quickly, prevent and manage outbreaks, and limit their spread.

Marburg virus disease is caused by MARV, a highly pathogenic, enveloped, single-stranded, negative-sense RNA virus that belongs to the Filoviridae family.[14][16] Genera in the Filoviridae family include those that infect mammals, Orthoebolavirus (formerly Ebolavirus), Orthomarburgvirus (formerly Marburgvirus), Cuevavirus, and Dianlovirus; those that infect fish, Oblavirus, Loebevirus, Thamnovirus, and Striavirus; and lastly, Tapjovirus, which infects reptiles.[17][18] Marburg virus disease is caused by 2 distinct viruses, the MARV and the Ravnvirus, which have 20% genetic divergence. MARV and Ravnvirus belong to Orthomarburgvirus marburgense, a single species within the Orthomarburgvirus genus.[18] Orthoebolavirus and Orthomarburgvirus genera cause Marburg virus disease in humans and nonhuman primates. Marburg virus disease is characterized by severe and often fatal hemorrhagic fever syndrome with CFR up to 90% and dramatic clinical presentation of viral hemorrhagic fevers.[19] MARV also has other variants, eg, the Marburg Mt. Elgon variant (MARV/MtE-Mus), also referred to as "Marburg Musoke" or "MARV/Mus, and the Marburg Angola variant (MARV/Ang)."[20] MARV/Ang is more virulent than MARV/Mus with higher CFR, and because of its higher virulence, MARV/Ang has now become the research standard for MARV studies.[21] MARV is currently classified as a group 4 pathogen by the WHO because of its considerable public health significance, high CFR, absence of vaccination, no approved therapeutic options, and difficult-to-control natural reservoirs.[14]

Marburg Virus Disease Transmission MARV causes Marburg virus disease. This highly pathogenic, enveloped, single-stranded, negative-sense RNA virus belongs to the Filoviridae family and was originally identified during an outbreak in 1967.[3][14][16] The duration of the incubation period ranges from 3 to 21 days, with an average of 5 to 10 days. The length of the incubation period is related to the route of infection and the infectious dose. Viral shedding and transmission typically begin after symptoms appear, rather than during the incubation period. Precise identification of the MARV reservoirs and the mechanism of MARV transmission has been challenging due to the difficulty of obtaining samples from potential reservoirs during outbreaks. The primary animal reservoir of Marburg virus disease was identified as the Egyptian fruit bat (Rousettus aegyptiacus). However, to date, other bat species have also been reported, eg, Chiroptera and Hipposideros caffer, but they are responsible, most likely to a lesser degree.[22] Whether the Egyptian fruit bat is the sole reservoir for MARV or if other bat species might also sustain the virus remains unclear. Fruit bats have a subclinical infection with MARV and shed the virus, which they transmit to humans.[23] Human-to-human transmission can occur through contact with infected bodily fluids, eg, blood, saliva, sweat, urine, stool, or breast milk. The bat reservoir was initially identified through epidemiological studies during outbreaks, which helped determine a shared exposure among all cases. This was the case during the large outbreak in the DRC from 1998 to 2000, during which young male gold miners were exposed to the Rousettus aegyptiacus bats while working in a Goroumbwa cave in Durba, from which they contracted MARV and then passed it on to family members and others in the community.[16] Notably, this outbreak demonstrated multiple independent, distinct virus strains, and the infections continued until the mine flooded.[24] Epidemiological testing of bats has been conducted during non-outbreak settings in biosurveillance studies, and a considerable percentage of bats have been found to harbor subclinical infections and shed the virus. Marburg Virus Disease Outbreaks

The bat reservoir was initially identified through epidemiological studies during outbreaks, which helped determine a shared exposure among all cases. This was the case during the large outbreak in the DRC from 1998 to 2000, during which young male gold miners were exposed to the Rousettus aegyptiacus bats while working in a Goroumbwa cave in Durba, from which they contracted MARV and then passed it on to family members and others in the community.[16] Notably, this outbreak demonstrated multiple independent, distinct virus strains, and the infections continued until the mine flooded.[24] Epidemiological testing of bats has been conducted during non-outbreak settings in biosurveillance studies, and a considerable percentage of bats have been found to harbor subclinical infections and shed the virus. Marburg Virus Disease Outbreaks The first Marburg virus disease outbreak occurred in August 1967 in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia (currently Serbia).[25][26] Thirty-seven people were infected, including laboratory workers as well as healthcare workers caring for them. The source was traced back to African Green monkeys (Cercopithecus aethiops) imported from Uganda. Thirty-one cases developed severe disease, 7 of which died (23% CFR). Because most cases occurred in Marburg, the virus was named after that city. During this 1967 outbreak, a possible sexual transmission was suspected during the convalescence phase, as MARV was detected in the patient's semen.[27]

The first Marburg virus disease outbreak occurred in August 1967 in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia (currently Serbia).[25][26] Thirty-seven people were infected, including laboratory workers as well as healthcare workers caring for them. The source was traced back to African Green monkeys (Cercopithecus aethiops) imported from Uganda. Thirty-one cases developed severe disease, 7 of which died (23% CFR). Because most cases occurred in Marburg, the virus was named after that city. During this 1967 outbreak, a possible sexual transmission was suspected during the convalescence phase, as MARV was detected in the patient's semen.[27] The next case, and the first case reported from Africa, was 8 years later, in 1975, when the index case, an Australian traveler who had hitchhiked through Zimbabwe (formerly Rhodesia), was hospitalized with Marburg virus disease in Johannesburg, South Africa, and died from disseminated intravascular coagulation; the 2 people he infected survived (33% CFR).[28] Subsequent outbreaks of MARV were reported in the DRC, Kenya, Uganda, Angola, Ghana, and Rwanda.[4][5][6][7][8] Of these, a few are described in more detail, including two large, prolonged outbreaks that occurred: the first in the DRC from 1998 to 2000, and the second in Angola from 2004 to 2005.[5] The outbreak in the DRC involved 154 cases with 128 deaths (83% CFR), while the largest cluster in Angola involved 422 reported cases and 356 deaths (84% CFR).[5][6] In 2022, the first MARV outbreak was reported in Ghana.[4] In 2023, the first outbreak was reported from Tanzania. In September 2024, the Rwandan Ministry of Health announced the confirmation of the first-ever outbreak of Marburg virus disease in Rwanda, and 63 cases and 15 deaths have been reported to date and are ongoing.[7] Most of these outbreaks have been and are currently being managed by the local governments, Ministries of Health, local public health departments, and international organizations, eg, the WHO, the Africa Centre for Disease Control and Prevention, and the United States Centers for Disease Control (CDC). Contact tracing, active surveillance, and implementation of infection prevention and control measures within the healthcare system and in the community have all been measures used to contain the outbreaks.[29]

After direct contact with infected bodily fluids or direct contact with an infected animal or person, MARV enters the body through breaks in the skin or mucosal membranes.[30] The virus first infects monocytes, macrophages, and dendritic cells. The virus then moves to the liver, lymph nodes, and spleen for early replication and further dissemination. Due to the extensive involvement of antigen-presenting cells, an inflammatory response involving the release of inflammatory cytokines, chemokines, and lymphoid depletion in the spleen occurs. Systemic inflammation plays a critical role in the disease process. The release of inflammatory cytokines and chemokines, such as prostacyclin and nitric oxide, triggers the coagulation cascade.[31] This leads to disseminated intravascular coagulation, causing abnormal blood clotting throughout the body with devastating effects. MARV glycoprotein is the most crucial attachment factor on the viral surface and is responsible for mediating binding and entry into host cells. Glycoprotein has 2 components: the glycoprotein surface unit (GP1), which binds to cellular receptors, and an internal fusion loop (GP2), which inserts into the cell membrane.[32] MARV and EBOV utilize similar mechanisms for entry into host cells. Glycoproteins are additionally involved in the inactivation of neutrophils and play a role in immune suppression and evasion.[33] Following attachment, endocytosis occurs, and GP1 is cleaved by endosomal proteases. The virus binds to an endosomal cholesterol transporter called Niemann-Pick C1.[34] The viral core is released into the cell cytoplasm, and transcription, translation, and replication occur.

A detailed medical and exposure history, along with a thorough clinical examination, is crucial for all patients seeking medical care. A detailed exposure history should be obtained, including travel to endemic areas, entrance into caves, encounters with bats, and contact with laboratories researching viral hemorrhagic fevers or humans or NHPs who had confirmed or suspected hemorrhagic fever. Patients most at risk of exposure include those who have close contact with the following: Excrements of the fruit bats (eg, recent travel to endemic regions in Africa or those who enter caves and mines inhabited by Rousettus aegyptiacus) [14] People sick with Marburg virus disease (eg, family members or hospital staff who care for infected patients) NHP infected with MARV People who work at laboratory facilities that study viral hemorrhagic fevers Following exposure and infection with MARV, an incubation period of 3 to 21 days begins.[35] The clinical presentation of patients infected with MARV depends on various factors, including strain virulence and the host's immunocompetence. After the incubation period, patients become acutely and abruptly ill, exhibiting nonspecific symptoms and signs, including high fever, chills, myalgias, arthralgia, headache, malaise, and gastrointestinal symptoms. The clinical course is divided into three phases: the first generalized phase, from days 1 to 4; the early organ phase, from day 5 to 13; and the late organ phase, or convalescence phase, which occurs after day 13.[16][35]

Following exposure and infection with MARV, an incubation period of 3 to 21 days begins.[35] The clinical presentation of patients infected with MARV depends on various factors, including strain virulence and the host's immunocompetence. After the incubation period, patients become acutely and abruptly ill, exhibiting nonspecific symptoms and signs, including high fever, chills, myalgias, arthralgia, headache, malaise, and gastrointestinal symptoms. The clinical course is divided into three phases: the first generalized phase, from days 1 to 4; the early organ phase, from day 5 to 13; and the late organ phase, or convalescence phase, which occurs after day 13.[16][35] In the generalized phase, sudden onset flu-like, nonspecific symptoms develop, including high fever, chills, myalgias, arthralgias, headache, and malaise. Some patients will additionally experience gastrointestinal symptoms and will rapidly become more debilitated with nausea, vomiting, abdominal pain, and diarrhea within 2 to 5 days. During the early organ phase, between days 5 and 7, a maculopapular, erythematous, nonpruritic rash appears, and petechiae can be seen. Conjunctivitis injection can be seen, and swings between hyperpyrexia and hypopyrexia may be present. Symptoms of hemorrhagic fever, including mucosal bleeding, hematemesis, hematochezia, petechiae, and bleeding from the nose and mouth, as well as from venipuncture sites, may also be present.[16] Disseminated intravascular coagulation will typically occur within a week of the illness. Severe cases develop hypotension, multiorgan failure, and shock.[14][35] In the later stages of this phase, patients develop neurological symptoms, eg, agitation, seizures, confusion, and coma. Patients enter the late organ/convalescence phase after day 13, and they either succumb to the disease or have an extended period of recovery and rehabilitation.[16][35]

Laboratory abnormalities associated with MARV infection include elevated liver enzymes, eg, alanine and aspartate aminotransferase, and increased serum creatinine levels. Lymphopenia, thrombocytopenia, prolonged prothrombin time, and disseminated intravascular coagulation characterize the hematological findings within the first week of symptoms.[14] Even though the diagnosis of Marburg virus disease can be made using either antigen-capture enzyme-linked immunosorbent assay (ELISA) testing, polymerase chain reaction (PCR), or IgM-capture ELISA within a few days of symptom onset, PCR remains the preferred method because it can detect the virus early in the disease and can distinguish between different virus variants. IgG-capture ELISA can be used later in the course of the disease or to detect past infection because it takes longer to develop antibodies. Virus isolation must be completed in a high-containment laboratory (eg, a biosafety level 4).[16] Typical diagnostic samples include bodily fluids such as blood. Tissue specimens can be used at autopsy. Clinicians should immediately contact their state health department to report the diagnosis and for further advice on specimen testing and managing patients under investigation.[36]

Supportive Care and Prevention Measures No treatments for the Marburg virus have been approved. Supportive care can significantly enhance clinical outcomes, including the administration of intravenous fluids, electrolyte replacement, supplemental oxygen, and blood or blood product transfusions.[16] The CDC and the WHO have developed infection prevention and control guidelines to limit the transmission of infections in healthcare settings.[15] Essential infection control precautions include placing patients in an individual room with a closed door, using proper personal protective equipment (PPE), using disposable patient care equipment when possible, limiting the use of needles and sharps, avoiding aerosol-generating procedures, performing hand hygiene frequently, monitoring and managing potentially exposed personnel, and preventing the entry of visitors into the patient's rooms.[15] Pharmaceutical Antiviral Agents Although no currently approved treatments exist, several pharmaceutical agents are in development. Galidesivir (BCX4430) is an antiviral, synthetic nucleoside analog that inhibits viral RNA-dependent RNA polymerase.[37] RNA polymerase plays a crucial role in the viral replication process. Rodent models infected with MARV either through intraperitoneal injection or exposure to aerosolized virus received postexposure intramuscular administration of BCX4430, which conferred protection when initiated within 48 hours. Additionally, the efficacy of BCX4430 was explored in cynomolgus macaques. The macaques were infected with lethal doses of wild-type MARV and then administered BXC4430 intramuscularly twice daily for 14 days. While the control succumbed to the virus, all animals treated beginning 24 to 48 hours after infection survived.[38] A phase 1, double-blind, placebo-controlled, dose-ranging study was completed in 32 subjects to evaluate the single-dose safety, tolerability, and pharmacokinetics of BXC4430 (NCT03800173).[37][39]

Although no currently approved treatments exist, several pharmaceutical agents are in development. Galidesivir (BCX4430) is an antiviral, synthetic nucleoside analog that inhibits viral RNA-dependent RNA polymerase.[37] RNA polymerase plays a crucial role in the viral replication process. Rodent models infected with MARV either through intraperitoneal injection or exposure to aerosolized virus received postexposure intramuscular administration of BCX4430, which conferred protection when initiated within 48 hours. Additionally, the efficacy of BCX4430 was explored in cynomolgus macaques. The macaques were infected with lethal doses of wild-type MARV and then administered BXC4430 intramuscularly twice daily for 14 days. While the control succumbed to the virus, all animals treated beginning 24 to 48 hours after infection survived.[38] A phase 1, double-blind, placebo-controlled, dose-ranging study was completed in 32 subjects to evaluate the single-dose safety, tolerability, and pharmacokinetics of BXC4430 (NCT03800173).[37][39] Other antivirals that have been investigated include favipiravir, a synthetic guanidine nucleoside, and remdesivir, a prodrug of an adenosine analog. Remdesivir has inhibitory activity against several lineages of RNA viruses, and some efficacy has been shown in animal models for the treatment of Marburg virus disease.[40] Combination treatment with remdesivir and MR186 showed promising outcomes in monkeys, even when at a late stage of their illness, reversing the signs of disease.[41] Interferon-beta administration was also studied and found to prolong survival in monkeys.[42] Other Treatments Under Investigation Treatment with monoclonal antibodies has been studied in animal models, showing promise, and is being considered for use in humans. Monoclonal antibodies produced from B cells of patients with Marburg virus disease, eg, MR186 and MR191, have shown promise when tested on infected rhesus macaques, resulting in 80% to 100% survival in the macaques.[43] Multiple trials and efforts are underway to develop an effective filovirus vaccine.[44] Many different vaccine modalities are undergoing investigation, including inactivated viruses, replication-competent vaccines, virus-like replicon particles, adenovirus vectors, DNA, virus-like particles, replication-incompetent vaccines, recombinant vesicular stomatitis virus, and mixed modality.[44]

Multiple trials and efforts are underway to develop an effective filovirus vaccine.[44] Many different vaccine modalities are undergoing investigation, including inactivated viruses, replication-competent vaccines, virus-like replicon particles, adenovirus vectors, DNA, virus-like particles, replication-incompetent vaccines, recombinant vesicular stomatitis virus, and mixed modality.[44] Clinical trials were accelerated following the 2013 Ebola virus epidemic as the need for effective vaccination grew. However, challenges and hindrances associated with vaccine design remain, as more data is needed to determine the utility and efficacy of these vaccines.

Clinical diagnosis is difficult in the early phase of Marburg virus disease, as symptoms are nonspecific and similar to a multitude of other infectious diseases. The differential diagnoses for Marburg fever include: Ebola virus disease Lassa fever Dengue Malaria Typhoid fever Rickettsial illness Shigellosis Meningitis

As no current treatment for the Marburg virus has been approved, and only supportive care can be provided, the prognosis of the disease remains poor, with a high CFR. Optimally, patients should be treated within specialized biocontainment units.[16] The WHO has published guidelines on infection prevention and control, which should be implemented as soon as Marburg virus disease is considered.[15] All personnel with direct patient contact must adhere to the correct use of PPE, proper hand hygiene, and minimal use of needles and sharps to prevent occupational exposure.[15] Control of future outbreaks remains a vital component in preventing further primary infections and secondary transmission. The variability in disease severity in known outbreaks is thought to be due to the availability of medical care, infectious dose, route of infection, the strain's virulence, and overall population health.

Complications of Marburg virus disease include signs and symptoms of hemorrhagic fever, multisystem organ failure, shock, and ultimately death. Transmission to others remains a significant concern, and active surveillance, containment, avoidance of contact with sick persons and bodily fluids, proper PPE, and prophylactic measures are necessary while caring for infected patients and handling the deceased. Additionally, secondary infections should be considered and treated appropriately, given the immunosuppression induced by MARV infection.

Managing a patient with Marburg virus disease or an outbreak of MARV should involve infectious disease physicians, microbiologists, pharmacists, internal medicine physicians, the intensive care team, and the local Departments of Public Health. The WHO, CDC, the African Centers for Disease Control and Prevention, the UK Health Security Agency, and similar international public health bodies should be involved early to limit the spread and provide technical knowledge and assistance.

Patients located in or traveling to endemic regions of Marburg virus disease must be adequately educated on recognizing signs and symptoms of the disease, preventing infection, and avoiding contact with bats, which can harbor the disease. Quarantine instructions and isolation of personnel who are sick once the disease is contracted should be emphasized.

Local governments, public health departments, and international organizations, eg, the WHO and CDC, have managed most Marburg virus disease outbreaks. Contact tracing, active surveillance, and implementation of infection prevention and control measures within the healthcare system and in the community have all been measures used to contain the outbreaks. Avoidance of physical contact with persons who are ill, no contact with blood and bodily fluids, hand hygiene, and use of PPE, which includes gowns, gloves, masks, face shields, and goggles, are all measures that should be implemented. All precautions should be taken when managing infected patients, including their transfer to other medical facilities. Corpses infected with MARV should be disposed of properly. Aerosol-generating procedures should be conducted cautiously, preferably in an airborne isolation room, and with the use of PPE, including respiratory protection.[29] Due to the severity of the disease and the high CFR, this is a global public threat. Early recognition and supportive care are essential, as they can lead to better patient outcomes. Healthcare workers must maintain a high index of suspicion to initiate treatment promptly and strive for optimal patient outcomes. Having processes in place to immediately implement infection control measures to protect close contacts and minimize transmission from sick patients is essential.[15] Global and national public health preparedness and prevention strategies are necessary to respond quickly to prevent and manage outbreaks and limit their spread.

Effective management of MVD demands a collaborative, interprofessional approach to enhance patient-centered care, safety, and outcomes. Physicians and advanced practitioners play a vital role in recognizing early symptoms, initiating diagnostic testing, and providing evidence-based supportive care, such as fluid replacement and management of complications. Nurses are essential in monitoring patients, administering treatments, and strictly adhering to infection control protocols, including proper use of personal protective equipment and implementing biocontainment measures to prevent the spread of the virus. Pharmacists contribute by ensuring the safe use of investigational drugs and staying informed on emerging therapies to support clinical decision-making. Strong interprofessional communication and coordinated teamwork are critical to implementing effective containment strategies. This includes isolating infected patients, limiting exposure, and using specialized biocontainment units when available. Continuous education is key as new research and treatment options evolve, ensuring that healthcare teams remain prepared to provide optimal care. By maintaining a unified approach and staying informed, healthcare professionals can improve patient outcomes, reduce mortality, and minimize the public health impact of MVD.