Marburgviruses: An Update

Caterina M. Miraglia, DC, MLS(ASCP)


Lab Med. 2019;50(1):16-28. 

In This Article

Pathogenesis and Clinical Features

Filoviruses initially infect macrophages, dendritic cells, and fibroblastic stromal cells and disseminate to other areas of the body.[22] Unchecked, systemic viral replication leads to a potent, systemic inflammatory response, causing fever, coagulopathy, vascular leakage, and hypotension.[21] Decreased intravascular volume can occur, leading to electrolyte imbalances and decreased perfusion to organs and tissues.[41] Initiation of the extrinsic pathway of the coagulation cascade begins with expression of tissue factor, which activates Factor VII. Infected monocytes and macrophages overexpress tissue factor, activating the coagulation cascade, with resultant disseminated intravascular coagulation. Thrombocytopenia is also a pathological feature of filoviral disease, further contributing to hemostatic imbalances.[21] Death typically results from multiorgan failure and shock.[22]

The incubation period is 2 to 21 days,[41] with a rapid onset of nonspecific symptoms, including fever, malaise, myalgia/arthralgia, and headache. A centrally located maculopapular rash generally appears around day 5. As the disease progresses, the patient can develop abdominal pain, nausea, vomiting, diarrhea, and pharyngitis. Hemorrhagic manifestations may develop,[42] including petichiae, mucosal bleeding in multiple areas, and bleeding from venipuncture sites. Severe hemorrhage typically occurs in cases that are fatal and tends to be more localized to the gastrointestinal tract. Some patients do not exhibit hemorrhage during the clinical course of infection. In fatal cases, death usually occurs within 9 days from the time of onset of signs and symptoms.[43] It was noted during the 1998 to 2000 MVD outbreak in the Democratic Republic of Congo that mortality rates were higher in patients exhibiting conjunctival injection and hiccups.[10] The case fatality rate ranges from 23% to 90%.[42]

Studies using animals such as hamsters and NHPs have been conducted to study the pathological characteristics of MVD. Clinical record keeping during outbreaks has been insufficient,[44] and much is still unknown about the pathogenesis of the disease. Gaining a better understanding of MVD can assist with developing treatments and vaccines.[45] A version of the virus that has adapted to hamsters has been shown in a study[45] to accurately reflect the clinical manifestations observed in human MVD; the clinical course of disease in NHPs mirrors that of human infection. As such, these studies have provided valuable information regarding the pathological characteristics and pathogenesis of MVD. Table 2 provides a summary of the relevant clinical laboratory findings of these studies.[45–49]

Marburgviruses have the potential to be aerosolized and used as a weapon.[47] Because of this potential, researchers have conducted studies to determine the natural history of MVD when delivered to NHPs via the aerosol route. The viruses initially infect alveolar macrophages, with subsequent spread to the tracheobronchial and mediastinal lymph nodes.[48] Analysis of the lungs revealed edema, congestion, fibrin deposition, and alveolar histiocytosis. Necrotizing lymphadenitis of tracheobronchial and mediastinal lymph nodes occurred, with loss of lymphocytes in the germinal and B-cell regions of the tracheobronchial lymph nodes.[47–49] The results of a dose-response study to determine the quantity of viral exposure needed to produce clinical disease within NHPs demonstrated that intramuscular and aerosol admission routes and all doses (intramuscularly 1, 10, 100, 1,000, or 10,000 plaque-forming units, aerosol route 10 or 100 plaque-forming units) were lethal.[49]

Four clinical stages were observed with the aerosol route of infection in NHPs. The first was an incubation period lasting 3 to 4 days with lymphocytopenia and monocytopenia, and an early period of hours to days with onset of fever and viremia, followed by an overt clinical period with tachycardia, tachypnea, elevated liver transaminases, prothrombin time (PT), D-dimer and, lastly, a terminal period characterized by persistent hypotension, hypothermia, and mucosal bleeding. The mean time to death was 7.4 days.[47]

Genes that were upregulated in peripheral blood mononuclear cells in NHPs infected with MARV via the aerosol route included those involved in inflammation/cytokine responses, immune response, and wound healing. In the late stage of infection, increased expression of coagulation-associated genes was also noted. There was a stronger Th2 response (humoral), rather than Th1 (cell-mediated) immunity, which could contribute to the pathology of the disease.[50]

Cluster of differentiation (CD)4+ and CD8+ T-cells and activated T-cells substantially decreased during the course of infection in NHPs infected with MARV intramuscularly. Overall levels of B-cells and natural killer cells decreased; however, the number of activated cells increased later in the course of infection. Increases in cytokines and chemokines, including interferon (IFN)–γ and tumor necrosis factor, were observed in the spleen and blood. Peak cytokine levels occurred late in infection before death or euthanasia, analogous to the cytokine storm observed in patients with MVD before death.[51]