Clinical aspects of Marburg hemorrhagic fever

Abstract

Marburg virus belongs to the genus Marburgvirus in the family Filoviridae and causes a severe hemorrhagic fever, known as Marburg hemorrhagic fever (MHF), in both humans and nonhuman primates. Similar to the more widely known Ebola hemorrhagic fever, MHF is characterized by systemic viral replication, immunosuppression and abnormal inflammatory responses. These pathological features of the disease contribute to a number of systemic dysfunctions including hemorrhages, edema, coagulation abnormalities and, ultimately, multiorgan failure and shock, often resulting in death. A detailed understanding of the pathological processes that lead to this devastating disease remains elusive, a fact that contributes to the lack of licensed vaccines or effective therapeutics. This article will review the clinical aspects of MHF and discuss the pathogenesis and possible options for diagnosis, treatment and prevention.

Figure 1. Geographical distribution and epidemiological information regarding known Marburg hemorrhagic fever cases/outbreaks

The sites of known Marburg virus outbreaks are indicated as black circles, while the sites of imported outbreaks are marked as blue stars with lines indicating the source location from which the virus was imported. Laboratory accidents are indicated by green stars. The associated outbreak dates are indicated next to the outbreak location. The epidemiological information associated with each of these outbreaks is listed in Table 1.

Figure 2. Clinical observations, laboratory findings and suitable diagnostic approaches during the course of Marburg hemorrhagic fever

The top panel shows the symptoms associated with each of the three clinical phases of Marburg hemorrhagic fever (generalization phase, boxed in green; early organ phase, boxed in blue; late organ phase, boxed in red; and convalescence phase, boxed in yellow). The middle panel shows the current methods for diagnostic detection and their application with regard to clinical stages of disease. For reverse transcription PCR, IgM and IgG, the numbers indicate the latest date at which detection has been achieved, while ND indicates that this value has not yet been determined. The lower panel describes the major laboratory findings of Marburg hemorrhagic fever and the times at which they can be measured. The times at which the most anomalous (minimum or maximum values, as appropriate) are observed are indicated by asterisks. ND: Not determined; SGOT: Serum glutamic oxaloacetic transaminase; SGPT: Serum glutamic pyruvic transaminase.

Figure 3. Marburg hemorrhagic fever pathogenesis model

Primary targets cells for Marburg virus infection are macrophages and dendritic cells. In dendritic cells, infection leads to ‘paralysis’ of the innate response and dysregulation of costimulation of lymphocytes. Macrophage infection leads to the production of proinflammatory mediators such as TNF-α, which may induce bystander apoptosis in lymphocyte populations, thereby contributing to lymphopenia and immunosuppression. Together with IL-6, macrophage-derived TNF-α also induces changes in vascular permeability. In addition, the production of TF by infected macrophages leads to dysregulation of coagulation (e.g., DIC), which is further reinforced by hepatocyte infection, leading to decreased synthesis of liver-derived clotting factors. Infection of adrenal cortical cells results in hypotension and metabolic disorders, which together with immunosuppression and coagulopathy contribute to multiorgan failure and shock. DIC: Disseminated intravascular coagulation; GP: Glycoprotein; TF: Tissue factor; TRAIL: TNF-related apoptosis-inducing ligand.