Marburg Fever

Etiology

Marburg virus disease (MVD) is caused by Marburg virus (MARV), a highly pathogenic, enveloped, single-stranded, negative-sense RNA virus that belongs to the Filoviridae family.[5][6] Genera in this family include Marburgvirus, Ebolavirus (EBOV), Cuevavirus, Thamnovirus, and Striavirus.[7] 

Only viruses in the Marburgvirus or Ebolavirus genera are known to cause disease in humans and are most well known because of their high case-fatality rates and dramatic clinical presentation.[8] There is one species within the Marburgvirus genera, called Marburg Marburgvirus, which encompasses two viruses: the Marburg virus and Ravn virus (RAVV). Marburg virus can further be broken down into variants with a less genomic difference; Marburg Muskoke, Marburg Angola, Ci67, Ozolin, and isolates within a variant (Pop, Ci67).[9] 

MARV is currently classified as a Group 4 pathogen by the World Health Organization (WHO), indicating high individual and community risk.[5]

Epidemiology

The first outbreak of Marburg virus disease (MVD) occurred in August 1967 in Marburg and Frankfurt, Germany, and Belgrade, Yugoslavia.[10] Multiple laboratory workers were infected, with the source being traced back to African Green monkeys (Cercopithecus aethiops) imported from Uganda. 31 cases were observed to develop severe disease, 7 of which died (23% case fatality rate). Because most cases occurred in Marburg, the virus was named after that city. During the 1967 outbreak, a possible sexual transmission was suspected during the convalescence phase, as a virus antigen was detected in the patient's semen.[11] 

The following case was eight years later, when an Australian traveler who had hitchhiked through Zimbabwe was hospitalized in St. Johannesburg, South Africa, infected two other people, and died.[12] The secondary cases recovered (33% case fatality rate). After that, small outbreaks of MARV have been reported in Kenya and Uganda. Most noteworthy were two large outbreaks in the Democratic Republic of Congo (DRC) from 1998 to 2000, and Angola, from 2004 to 2005. The outbreak in the DRC involved 154 cases with 128 deaths (83% case fatality rate), while the largest cluster in Angola involved 252 cases with 227 deaths (90% case fatality rate). During the Angola outbreak, the infection was postulated to spread through contaminated transfusion equipment on the pediatric ward.[13] 

The genomic analysis likely discovered only a single introduction of the virus into the population at risk and subsequent human-to-human transmission with no identified source of infection. According to the CDC, other countries reporting outbreaks of Marburg disease include Guinea, Kenya, and Serbia.

The animal reservoir of MVD is the Egyptian fruit bat (Rousettus aegyptiacus), which demonstrates little to no clinical disease.[14] The virus replicates and sheds from bats without displaying overt signs of infection, allowing for maintenance and dissemination of the virus.[15] The identification of the host was discovered through epidemiological linkage to outbreaks, with almost all primary infections being linked to humans entering caves that contain bats. For example, the large outbreak in the DRC was related to gold mining in Goroumbwa cave in Durba.[6] Notably, this outbreak demonstrated multiple independent, distinct virus strains, and infections continued until the mine flooded.[16] 

It is unclear whether the Egyptian fruit bat is the only exclusive reservoir for MARV or if other bat species could also perpetuate the virus. The virus spreads from animal hosts, either from bats or another intermediate host such as non-human primates to humans, but the exact route and specific fluid involved is unknown. The transmission through person-to-person contact can occur through blood or other infected bodily fluids (e.g., saliva, sweat, urine, stool, breast milk, etc.).

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.[17] 

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 (APC), an inflammatory response involving the release of inflammatory cytokines and 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 coagulation cascades.[18] This leads to disseminated intravascular coagulation, causing abnormal blood clotting throughout the body with devastating effects. 

MARV glycoprotein (GP) is the most important attachment factor on the viral surface responsible for mediating binding and entry into host cells. GP has two components: the GP surface unit (GP1), which binds to cellular receptors, and an internal fusion loop (GP2), which inserts into the cell membrane.[19] MARV and EBOV utilize similar mechanisms for entry into host cells. GP is additionally involved in the inactivation of neutrophils and plays a role in immune suppression and evasion.[20] 

Following attachment, endocytosis occurs, GP1 is cleaved by endosomal proteases, and the virus binds to an endosomal cholesterol transporter called Niemann-Pick C1 (NPC1).[21] The viral core is released into the cell cytoplasm, and transcription, translation, and replication occur.

History and Physical

Patients most at risk of exposure include those that have close contact with:

• Excrements of the fruit bats (for example, recent travel to endemic regions in Africa, or those who enter caves and mines inhabited by Rousettus aegyptiacus)[5]
• People sick with the Marburg virus (for example, family members or hospital staff who care for infected patients)
• Non-human primates (NHP) infected with Marburg virus

Following exposure and infection with MARV, there is a 3 to 21 day incubation period. After incubation, the course is then broken down into three phases: the initial generalization phase, the early organ phase, and a late organ phase or convalescence phase. In the generalization phase, patients begin experiencing flu-like, non-specific symptoms such as high fever, chills, myalgias, joint pain, headache, and malaise. Some patients will additionally experience gastrointestinal symptoms. Intensity increases on days 5 to 7, and a maculopapular, erythematous, non-pruritic rash is a common feature.[6] 

The early organ phase involves conjunctivitis, swings between hyper- and hypo-pyrexia, and symptoms of hemorrhagic fever, including mucosal bleeding, hematemesis, hematochezia, petechiae, and bleeding from venipuncture sites.[5] In later stages of the disease, patients develop neurological symptoms such as agitation, seizures, confusion, and coma. Past day 13, patients enter the late organ/convalescence phase and either succumb to the disease or have an extended period of recovery and rehabilitation.

Evaluation

Laboratory abnormalities seen with MARV infection include increases in alanine and aspartate aminotransferase (ALT and AST) and increased serum creatinine levels. Lymphopenia, thrombocytopenia, and disseminated intravascular coagulation (DIC) encompass the hematological findings within the first week of symptoms.[5]

According to the CDC, diagnosis can be made using antigen-capture enzyme-linked immunosorbent assay (ELISA) testing, polymerase chain reaction (PCR), and IgM-capture ELISA within a few days of symptom onset. GP-based ELISA assays have been developed to detect species-specific antibodies, but PCR remains the preferred method for distinguishing between different virus variants and aiding in the early identification of the disease. IgG-capture ELISA can be used later in the course of the disease or after recovery. Virus isolation must be completed in a high containment laboratory such as a biosafety level 4 laboratory.

Typical diagnostic samples include bodily fluids such as blood as well as tissue specimens at autopsy. In the United States, clinicians should immediately contact their state health department for further advice on specimen testing and managing patients under investigation.[22]

Treatment / Management

As of now, there are no approved treatments for the Marburg virus. During outbreaks, supportive care has been the mainstay of treatment: the CDC and the WHO have developed a manual for infection control. Key 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 patients' rooms. Although there are no currently approved treatments, there are several pharmaceutical agents in development.

Galidesivir (BCX4430) is an antiviral, synthetic nucleoside analog that inhibits viral RNA-dependent RNA polymerase.[23] RNA polymerase plays a crucial role in the viral replication process. Rodent models infected with Marburg virus either through intraperitoneal injection or exposure to aerosolized virus received post-exposure 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 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.[24] A phase 1, double-blind, placebo-controlled, dose-ranging study was completed in 32 subjects and published in 2021 to evaluate the single-dose safety, tolerability, and pharmacokinetics of BXC4430 (NCT03800173). (B3)

Other antivirals that have been investigated include favipiravir, a synthetic guanidine nucleoside, and remdesivir, a prodrug of an adenosine analog. A significant survival benefit has not yet been demonstrated. Interferon-beta administration was also studied and found to prolong survival in monkeys.[25] (B3)

Treatment with antibodies has been studied in animal models and is planned in humans. A human monoclonal, MR 191-N, was tested in rhesus macaques. After infection, they were treated with 50 mg/kg given IV on days 4 and 7. In the first study, 3/3 animals survived, and in the second study, 4/5.[26] 

Antibodies have been used in humans with Ebola virus disease and led to improved outcomes. Specifically, a three-antibody cocktail called ZMapp was tested during the West Africa outbreak and the recent Ebola outbreak in the DRC. It is possible to consider monoclonal antibodies in Marburg virus disease as well, given the similarities between the two diseases. 

Multiple trials and efforts are underway to develop an effective filovirus vaccine.[27] Many different vaccine modalities are undergoing investigation, including inactivated virus, replication-incompetent vaccines, virus-like replicon particles (VRPs), adenovirus vector, DNA, virus-like particles (VLPs), replication-competent vaccines, recombinant vesicular stomatitis virus, and mixed modality.[27] (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 disease as symptoms are nonspecific and similar to a multitude of other infectious diseases. The differential diagnosis for Marburg fever may include, but is not limited to:

• Ebola virus disease
• Lassa fever
• Dengue
• Malaria
• Typhoid fever
• Rickettsial illness
• Shigellosis
• Meningitis

Prognosis

As there is no current approved treatment for the Marburg virus and only supportive care can be provided, the prognosis of the disease remains poor with a high case fatality rate. Optimal management needs to occur in specialized biocontainment units.[6] 

All personnel with direct patient contact must adhere to the correct usage of personal protective equipment (PPE), hand hygiene, and minimal use of needles and sharps to avoid occupational exposure. Control of future outbreaks remains a vital component in preventing further primary infections as well as secondary transmission. The variability in disease severity in the known outbreaks is thought to be due to availability of medical care, infectious dose, route of infection, the virulence of the strain, and population health in general.

Complications

Complications of Marburg virus disease include signs and symptoms of hemorrhagic fever, multi-system organ failure, shock, and ultimately death. Transmission to others remains a significant concern, and proper PPE and prophylactic measures are necessary while caring for infected patients and handling the deceased. Additionally, given the immunosuppression induced by Marburg virus infection, secondary infections should be considered and treated appropriately.