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Marburg Virus Disease
Introduction
Marburgvirus (MARV), a highly pathogenic single-stranded RNA virus that belongs to the Filoviridae family, is the cause of Marburg virus disease (MVD), formerly known as Marburg fever, a rare but severe hemorrhagic fever with a high case-fatality rate (CFR), making it one of the most deadly pathogens.[1] First discovered in an outbreak in 1967 in Germany and Serbia (formerly Yugoslavia), the source of MVD was traced back to the importation of African green monkeys from Uganda. It was previously known as green monkey disease.[2] 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.[3][4][5][6][7][8]
The major animal reservoir was subsequently identified through epidemiological linkage as the fruit bat, Rousettus aegyptiacus.[9] Transmission is via inhalation or direct contact with contaminated excreta from bats; human-to-human transmission has been reported by direct contact with bodily fluids from sick patients, both in the healthcare and household settings.[10][11] Following the initial exposure, MARV enters the body, replicates, disseminates, and leads to a clinical syndrome characterized by fever, malaise, myalgia, and blood coagulation disorders.[12] These symptoms progress to hemorrhagic shock and multiorgan failure. The CFR has been reported to be up to 90%.[4]
Currently, no vaccine or specific treatment is available for MVD, 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 have a high index of suspicion to initiate treatment promptly and strive for the best patient outcomes. Having processes in place to immediately implement infection control measures is essential to protect close contacts and minimize transmission from sick patients.[13] Global and national public health preparedness and prevention strategies are necessary to respond quickly to prevent and manage outbreaks and limit their spread.
Etiology
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Etiology
MVD is caused by MARV, a highly pathogenic, enveloped, single-stranded, negative-sense RNA virus that belongs to the Filoviridae family.[12][14] 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.[15][16]
MVD is caused by 2 distinct viruses, the MARV and Ravn virus, which have 20% genetic divergence. MARV and Ravn virus belong to Orthomarburgvirus marburgense, a single species within the Orthomarburgvirus genera.[16] Orthoebolavirus and Orthomarburgvirus genera viruses cause MVD in humans and non-human primates (NHPs). MVD is characterized by severe and often fatal hemorrhagic fever syndrome with CFR up to 90% and dramatic clinical presentation of viral hemorrhagic fevers.[17] MARV also has other variants, e.g., the Marburg Mt. Elgon variant (MARV/MtE-Mus), also referred to as "Marburg Musoke" or "MARV/Mus, and the Marburg Angola variant (MARV/Ang)."[18] MARV/Ang is more virulent than MARV/Mus with higher CFR, and because of its higher virulence, it has now become the research standard for MARV studies.[19]
MARV is currently classified as a group 4 pathogen by the World Health Organization (WHO) because of its large public health significance, high CFR, absence of vaccination, no approved therapeutic options, and difficult-to-control natural reservoirs.[12]
Epidemiology
Marburg Virus Disease Transmission
MARV causes MVD. This highly pathogenic, enveloped, single-stranded, negative-sense RNA virus belongs to the Filoviridae family and was originally identified during an outbreak in 1967.[2][12][14] The duration of the incubation period ranges from 3 to 21 days but is usually 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 do not occur during the incubation period; they only occur after symptoms begin.
Precise identification of the MARV reservoirs and how MARV is transmitted has been difficult because obtaining samples from potential reservoirs during the outbreaks is complicated. The primary animal reservoir of MVD 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.[20] It remains uncertain whether the Egyptian fruit bat is the sole reservoir for MARV or if other bat species might also sustain the virus. Fruit bats have a subclinical infection with MARV and shed the virus, transmitting it to humans.[21] Human-to-human transmission can occur through contact with infected bodily fluids, such as blood, saliva, sweat, urine, stool, or breast milk.
The bat reservoir was identified through epidemiological studies initially during outbreaks and determining a common exposure for all the 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.[14] Notably, this outbreak demonstrated multiple independent, distinct virus strains, and the infections continued until the mine flooded.[22] Epidemiological testing of bats has been performed during non-outbreak settings during biosurveillance studies, and a considerable percentage of bats have been found to have a subclinical infection and to be shedding the virus.
Marburg Virus Disease Outbreaks
The first MVD outbreak occurred in August 1967 in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia (currently Serbia).[23] Thirty-seven people were infected, 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.[24]
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 MVD in Johannesburg, South Africa and died from disseminated intravascular coagulation; the 2 people he infected survived (33% CFR).[25] Subsequent outbreaks of MARV were reported in the DRC, Kenya, Uganda, Angola, Ghana, and Rwanda.[3][4][5][6][7] Of these, a few are described in more detail, eg 2 large, prolonged outbreaks occurred, the first in the DRC from 1998 to 2000 and the second in Angola from 2004 to 2005.[4] 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 people deaths (84% CFR).[4][5] In 2022, the first MARV outbreak was reported in Ghana.[3] 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 MVD in Rwanda, and 63 cases and 15 deaths have been reported up to date and are ongoing.[6]
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, such as 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.[26]
Pathophysiology
After direct contact with infected bodily fluids or direct contact with an infected animal or person, MARV enters the body through skin breaks or mucosal membranes.[27] The virus first infects monocytes, macrophages, and dendritic cells. It 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.[28] 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.[29] MARV and EBOV utilize similar mechanisms for entry into host cells. Glycoprotein is additionally involved in the inactivation of neutrophils and plays a role in immune suppression and evasion.[30]
Following attachment, endocytosis occurs, GP1 is cleaved by endosomal proteases, and the virus binds to an endosomal cholesterol transporter called Niemann-Pick C1.[31] The viral core is released into the cell cytoplasm, and transcription, translation, and replication occur.
History and Physical
A detailed medical and exposure history and a thorough clinical examination are 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) [12]
- People sick with MVD (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.[32] The clinical presentation of patients infected with MARV depends upon various factors, including strain virulence and host immunocompetent. After the incubation period, patients become acutely and abruptly ill and have nonspecific symptoms and signs, including high fever, chills, myalgias, arthralgia, headache, malaise, and even gastrointestinal symptoms. The clinical course is divided into 3 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 is after day 13.[14][32]
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, swings between hyperpyrexia and hypopyrexia may be present, and symptoms of hemorrhagic fever, including mucosal bleeding, hematemesis, hematochezia, petechiae, and bleeding nose and mouth and from venipuncture sites.[14] Disseminated intravascular coagulation will typically occur within a week of the illness. Severe cases develop hypotension, multiorgan failure, and shock.[12][32] 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.[14][32]
Evaluation
Laboratory abnormalities seen with MARV infection include increased liver enzymes, 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.[12]
Even though the diagnosis of MVD 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).[14]
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.[33]
Treatment / Management
Supportive Care and Prevention Measures
No treatments for the Marburg virus have been approved. Supportive care can significantly enhance clinical outcomes, including intravenous fluids, electrolyte replacement, supplemental oxygen, and blood or blood product transfusions.[14] The CDC and the WHO have developed infection prevention and control manuals to limit transmission in healthcare settings.[13]
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.[13]
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.[34] 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.[35] 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).[34][36](B3)
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 MVD.[37] 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.[38] Interferon-beta administration was also studied and found to prolong survival in monkeys.[39] (B3)
Other Treatments Under Investigation
Treatment with monoclonal antibodies has been studied in animal models, showing some promise, and is being considered for humans. Monoclonal antibodies produced from B cells from patients with MVD, eg, MR186 and MR191, have shown promise when tested on infected rhesus macaques, resulting in 80% to 100% survival in the macaques.[40]
Multiple trials and efforts are underway to develop an effective filovirus vaccine.[41] Many different vaccine modalities are undergoing investigation, including inactivated viruses, replication-incompetent vaccines, virus-like replicon particles, adenovirus vectors, DNA, virus-like particles, replication-competent vaccines, recombinant vesicular stomatitis virus, and mixed modality.[41] (B3)
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.
Differential Diagnosis
Clinical diagnosis is difficult in the early phase of MVD 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
Prognosis
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. Optimal management needs to occur in specialized biocontainment units.[14]
The WHO has published infection prevention and control guidelines, and they should be implemented as soon as MVD is considered.[13] All personnel with direct patient contact must adhere to the correct usage of PPE, hand hygiene, and minimal use of needles and sharps to avoid occupational exposure.[13] Control of future outbreaks remains a vital component in preventing further primary infections and secondary transmission. The variability in disease severity in the known outbreaks is thought to be due to the availability of medical care, infectious dose, infection route, the strain's virulence, and population health in general.
Complications
Complications of MVD 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.
Consultations
Managing a patient with MVD 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.
Deterrence and Patient Education
Patients located in or traveling to endemic regions of MVD 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 sick personnel once the disease is contracted should be emphasized.
Pearls and Other Issues
Local governments, public health departments, and international organizations, such as the WHO and US CDC, have managed most MVD 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 include 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 properly disposed of. Aerosol-generating procedures should be conducted cautiously, preferably in an airborne isolation room, and with the use of PPE, including respiratory protection.[26]
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 result in better patient outcomes. Healthcare workers must have a high index of suspicion to initiate treatment promptly and strive for the best patient outcomes. Having processes in place to immediately implement infection control measures to protect close contacts and minimize transmission from sick patients is essential.[13] Global and national public health preparedness and prevention strategies are necessary to respond quickly to prevent and manage outbreaks and limit their spread.
Enhancing Healthcare Team Outcomes
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.
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