Molecular Biology and Pathogenesis of Crimean–Congo Hemorrhagic Fever Virus

Annette A Kraus; Ali Mirazimi

Disclosures

Future Virology. 2010;5(4):469-479. 

In This Article

Clinical & Pathological Findings

Humans are the only known hosts that develop disease after infection with CCHFV. The infection can result in CCHF, a severe hemorrhagic fever that is characterized by fever, prostration, severe hemorrhages and, potentially, death. The disease progression is rapid and can be subdivided into four different stages: incubation, prehemorrhagic, hemorrhagic and the convalescence phase.[8] It should be noted that duration and symptoms in these different phases vary significantly between individuals.[25] The pathogenesis of CCHF is only poorly characterized for several reasons, for example the fact that infections occur sporadically and in areas where facilities are limited for performing complete autopsies, virus handling requires biosafety level 4 containment laboratories and there is a lack of available animal models of disease.

In fatal cases, platelet counts can be extremely low, even from an early stage of illness. Increases in aspartate and alanine aminotransferase levels in the serum, and prolongation of prothrombin and partial thromboplastin times has also been observed.[26] The primary pathophysiological events appear to be leakage of erythrocytes and plasma through the vasculature into tissues.[1] Endothelial damage can contribute to coagulopathy by deregulated stimulation of platelet aggregation, which, in turn, activates the intrinsic coagulation cascade, ultimately leading to clotting factor deficiency, causing hemorrhages. In the case of CCHF, vascular leakage may be caused either by destruction of endothelial cells or by disruption of tight junctions that constitute the endothelial barrier between cells. Moreover, it is unclear whether these events are a direct consequence of infection or whether virus-induced host factors cause the endothelial dysfunction.[40] However, in an epithelial cell line model, CCHFV neither caused disruption of tight junctions nor necrosis/apoptosis of cells.[41] This suggests that the hemorrhages and coagulation disturbances may be caused indirectly, possibly by high levels of proinflammatory cytokines. Key players in disease progression are the cytokines IL-10, -1, -6 and TNF-α.[42] Recently, Ergonul and coworkers demonstrated significantly higher levels of IL-6 and TNF-α in CCHFV patients with fatal outcome compared with the nonfatal cases.[43] Another observation was a correlation between high levels of IL-6 and TNF-α with the onset of disseminated intravascular coagulation in patients. However, elevated levels of IL-10 were not observed in these patients and the levels of IL-10 were negatively correlated to the disseminated intravascular coagulation scores. In another study, Papa et al. confirmed that high TNF-α levels correlate with the severity of CCHF, but they suggested that IL-6 could be found in both mild and severe cases.[44] The only fatal case in this study had high levels of both IL-6 and TNF-α.[44] Another interesting observation is the elevated levels of neopterin in patients with Dengue fever or Ebola hemorrhagic fever.[45,46] Neopterin derivates are produced by macrophages and dendritic cells upon stimulation by interferons.[47] Neopterin is a useful tool to assess the intensity of cell-mediated immune response[47] and a recent study noted a correlation between elevated levels of neopterin in CCHFV patients and disease severity.[48]

All of these results suggest that capillary fragility, a common feature of CCHF, is caused by multiple host-induced mechanisms in response to CCHFV infection. Endothelial damage would cause the characteristic rash and contribute to hemostatic failure. Interestingly, some authors have noticed similarities between various viral hemorrhagic fevers and septic shock caused by severe bacterial infections.[49]

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