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Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children

Henry B Armah12, Nana O Wilson1, Bismark Y Sarfo3, Michael D Powell1, Vincent C Bond1, Winston Anderson4, Andrew A Adjei2, Richard K Gyasi2, Yao Tettey2, Edwin K Wiredu2, Jon Eric Tongren5, Venkatachalam Udhayakumar5 and Jonathan K Stiles1*

Author Affiliations

1 Morehouse School of Medicine, Department of Microbiology, Biochemistry and Immunology, Atlanta, Georgia, USA

2 University of Ghana Medical School, Department of Pathology, Accra, Ghana

3 Noguchi Memorial Institute for Medical Research, Department of Parasitology, Legon, Ghana

4 Howard University, Department of Biology, Washington DC, USA

5 Centers for Disease Control and Prevention (CDC), National Center for Zoonotic, Vector-Borne and Enteric Diseases, Division of Parasitic Diseases, Malaria Branch, Atlanta, GA, USA

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Malaria Journal 2007, 6:147  doi:10.1186/1475-2875-6-147

Published: 12 November 2007

Abstract

Background

Plasmodium falciparum can cause a diffuse encephalopathy known as cerebral malaria (CM), a major contributor to malaria associated mortality. Despite treatment, mortality due to CM can be as high as 30% while 10% of survivors of the disease may experience short- and long-term neurological complications. The pathogenesis of CM and other forms of severe malaria is multi-factorial and appear to involve cytokine and chemokine homeostasis, inflammation and vascular injury/repair. Identification of prognostic markers that can predict CM severity will enable development of better intervention.

Methods

Postmortem serum and cerebrospinal fluid (CSF) samples were obtained within 2–4 hours of death in Ghanaian children dying of CM, severe malarial anemia (SMA), and non-malarial (NM) causes. Serum and CSF levels of 36 different biomarkers (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, CRP, G-CSF, GM-CSF, IFN-γ, TNF-α, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, RANTES, SDF-1α, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-β1, PDGF bb and VEGF) were measured and the results compared between the 3 groups.

Results

After Bonferroni adjustment for other biomarkers, IP-10 was the only serum biomarker independently associated with CM mortality when compared to SMA and NM deaths. Eight CSF biomarkers (IL-1ra, IL-8, IP-10, PDGFbb, MIP-1β, Fas-L, sTNF-R1, and sTNF-R2) were significantly elevated in CM mortality group when compared to SMA and NM deaths. Additionally, CSF IP-10/PDGFbb median ratio was statistically significantly higher in the CM group compared to SMA and NM groups.

Conclusion

The parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1β, PDGFbb, IL-1ra, Fas-L, sTNF-R1, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.