Rift valley fever viral load correlates with the human inflammatory response and coagulation pathway abnormalities in humans with hemorrhagic manifestations

Rift Valley fever virus is an arbovirus that affects both livestock and humans throughout Africa and in the Middle East. Despite its endemicity throughout Africa, it is a rare event to identify an infected individual during the acute phase of the disease and an even rarer event to collect serial blood samples from the affected patient. Severely affected patients can present with hemorrhagic manifestations of disease. In this study we identified three Ugandan men with RVFV disease that was accompanied by hemorrhagic manifestations. Serial blood samples from these men were analyzed for a series of biomarkers specific for various aspects of human pathophysiology including inflammation, endothelial function and coagulopathy. There were significant differences between biomarker levels in controls and cases both early during the illness and after clearance of viremia. Positive correlation of viral load with markers of inflammation (IP-10, CRP, Eotaxin, MCP-2 and Granzyme B), markers of fibrinolysis (tPA and D-dimer), and markers of endothelial function (sICAM-1) were all noted. However, and perhaps most interesting given the fact that these individuals exhibited hemorrhagic manifestations of disease, was the finding of a negative correlation between viral load and P-selectin, ADAMTS13, and fibrinogen all of which are associated with coagulation pathways occurring on the endothelial surface.
Author summary Rift Valley fever virus is an emerging virus of public health significance. In endemic areas up to 60% of the population are seropositive by adulthood. This implies that most of the individuals living in these endemic areas become infected with this virus at some point in their lifetime. This highly prevalent virus is poorly understood likely secondary to lack of diagnostic capacity in affected areas. In fact, the majority of cases are undocumented and spontaneously resolve. However, in some individuals the disease can be very severe and at times associated with hemorrhage or encephalitis. In this report we identify three men infected during the acute stage who also exhibited hemorrhagic manifestations. These men had elevated cytokine and chemokine levels consistent with immune activation. Our data show that biomarkers of fibrinolysis correlated positively with virus while biomarkers of coagulation correlated negatively with virus, suggesting that opposing hemostatic pathways are altered during disease, and that they correct with resolution of viremia.