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

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-1 beta, IL-I ra, 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-gamma, TNF-alpha, IP-10, MCP-I (MCAF), MIP-I alpha, MIP-I beta, RANTES, SDF-I alpha, CXCLII (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-beta I, 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-Ira, IL-8, IP-10, PDGFbb, MIP-I beta, Fas-L, sTNFR1, 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-I beta, PDGFbb, IL-I ra, Fas-L, sTNF-RI, and sTNF-R2 may be involved in CM neuropathology, and their immunoassay may have potential utility in predicting mortality in CM.