Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome

[Emily]

http://jid.oxfordjournals.org/content/210/4/558.full

J Infect Dis. (2014) 210 (4): 558-566. doi: 10.1093/infdis/jiu088 First published online: February 12, 2014

Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome

Anita K. McElroy1,2,
Bobbie R. Erickson1,
Timothy D. Flietstra1,
Pierre E. Rollin1,
Stuart T. Nichol1,
Jonathan S. Towner1 and
Christina F. Spiropoulou1

- Author Affiliations

1Viral Special Pathogens Branch, Centers for Disease Control and Prevention
2Division of Pediatric Infectious Disease, Emory University School of Medicine, Atlanta, Georgia

Correspondence: Christina Spiropoulou, PhD, 1600 Clifton Rd NE, MS G14, Atlanta, GA 30333
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.

Full text at link. :tiphat: Interesting to me was that the paper points out that no significant correlation between hemorrhage and death has been found in outbreaks of EBOV and BDBV infections. (In other words, the blood loss is not the driver of fatalities.) Also the higher levels of sCD40L in survivors was a surprise apparently.

 

[Vibrant62]

Re: Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome

sCD40L is a zinc dependent matrix metalloproteinase, and levels were significantly higher in survivors.

Dont know if there are any clues in here?

http://en.wikipedia.org/wiki/Matrix_metalloproteinase

 

[Emily]

Re: Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome

I'm not sure if I even have a tiny understanding of all this, but I think sCD40L is a soluble platelet-derived mediator that links inflammation, hemostasis and vascular dysfunction...because it says so here:

http://www.ncbi.nlm.nih.gov/pubmed/22151659
J Thromb Haemost. 2012 Feb;10(2):207-16. doi: 10.1111/j.1538-7836.2011.04589.x.
High sCD40L levels early after trauma are associated with enhanced shock, sympathoadrenal activation, tissue and endothelial damage, coagulopathy and mortality.

That could explain why high sCD40L levels were a surprise in survivors of ebola.

But the matrix metalloproteinase you mentioned looks like it might be stimulated by CD40L so maybe those levels would also be raised if CD40L levels are high?

http://www.nature.com/nri/journal/v13/n9/fig_tab/nri3499_F1.html

Here's another study talking about CD40L in asymptomatic infections:

http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2249.2001.01517.x/full

Clinical & Experimental Immunology
Volume 124, Issue 3, pages 453?460, June 2001
Early immune responses accompanying human asymptomatic Ebola infections
E. M. Leroy?, S. Baize?, P. Debre2, J. Lansoud-Soukate1 and E. Mavoungou1
Article first published online: 20 DEC 2001
DOI: 10.1046/j.1365-2249.2001.01517.x
Abstract

In a recent study we identified certain asymptomatic individuals infected by Ebola virus (EBOV) who mounted specific IgG and early and strong inflammatory responses. Here, we further characterized the primary immune response to EBOV during the course of asymptomatic infection in humans. Inflammatory responses occurred in temporal association with anti-inflammatory phase composed by soluble antagonist IL-1RA, circulating TNF receptors, IL-10 and cortisol. At the end of the inflammatory process, mRNA expression of T-cell cytokines (IL-2 and IL-4) and activation markers (CD28, CD40L and CTLA4) was up-regulated, strongly suggesting T-cell activation. This T-cell activation was followed by EBOV-specific IgG responses (mainly IgG3 ang IgG1), and by marked and sustained up-regulation of IFNγ, FasL and perforin mRNA expression, suggesting activation of cytotoxic cells. The terminal down-regulation of these latter markers coincided with the release of the apoptotic marker 41/7 NMP in blood and with the disappearance of viral RNA from PBMC, suggesting that infected cells are eliminated by cytotoxic mechanisms. Finally, RT-PCR analysis of TCR-Vβ repertoire usage showed that TCR-Vβ12 mRNA was never expressed during the infection. Taken together, these findings improve our understanding about immune response during human asymptomatic Ebola infection, and throw new light on protection against Ebola virus.