Ebola hemorrhagic Fever: novel biomarker correlates of clinical outcome

Abstract

Background: Ebola hemorrhagic fever (EHF) outbreaks occur sporadically in Africa and result in high rates of death. The 2000-2001 outbreak of Sudan virus-associated EHF in the Gulu district of Uganda led to 425 cases, of which 216 were laboratory confirmed, making it the largest EHF outbreak on record. Serum specimens from this outbreak had been preserved in liquid nitrogen from the time of collection and were available for analysis.

Methods: Available samples were tested using a series of multiplex assays to measure the concentrations of 55 biomarkers. The data were analyzed to identify statistically significant associations between the tested biomarkers and hemorrhagic manifestations, viremia, and/or death.

Results: Death, hemorrhage, and viremia were independently associated with elevated levels of several chemokines and cytokines. Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator. Finally, samples from nonfatal cases had higher levels of sCD40L.

Conclusions: These novel associations provide a better understanding of EHF pathophysiology and a starting point for researching new potential targets for therapeutic interventions.

Keywords: Ebola virus; Gulu; biomarkers; hemorrhage; hemorrhagic fever virus.

Figure 1.

Viremia as a function of clinical outcome. Patients with fatal outcomes had higher viral loads. TCID₅₀, median tissue-culture infective dose.

Figure 2.

Cytokines and chemokines associated with a fatal outcome (black bars) or hemorrhagic manifestations (red bars). *P ≤ .05. Abbreviations: IL-1α, interleukin 1α; IL-1RA, interleukin 1 receptor antagonist; IL-6, interleukin 6; IP-10, interferon γ–inducible protein 10; MCP-1, monocyte chemoattractant protein 1; MCSF, macrophage colony-stimulating factor; sCD40L, soluble CD40 ligand; SE, standard error.

Figure 3.

Markers of inflammation associated with a fatal outcome (black bars) or hemorrhagic manifestations (red bars). *P ≤ .05. Abbreviations: SE, standard error; sICAM, soluble intracellular adhesion molecule 1.

Figure 4.

Markers of coagulation and fibrinolytic pathways associated with a fatal outcome (black bars), hemorrhagic manifestations (red bars) or viremia (blue bars). *P ≤ .05. A simplified model of the coagulation/fibrinolytic pathway is also depicted. Proteins that are known to play a major role in the pathways are noted. Arrows indicate activation while bars indicate inhibition. *, analytes assessed in the study; #, analytes associated with death.