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-1beta, 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-gamma, TNF-alpha, IP-10, MCP-1 (MCAF), MIP-1alpha, MIP-1beta, RANTES, SDF-1alpha, CXCL11 (I-TAC), Fas-ligand [Fas-L], soluble Fas [sFas], sTNF-R1 (p55), sTNF-R2 (p75), MMP-9, TGF-beta1, 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-1beta, 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.


CONCLUSIONS
The parasite-induced local cerebral dysregulation in the production of IP-10, 1L-8, MIP-1beta, 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.
Armah
Henry B
HB
Morehouse School of Medicine, Department of Microbiology, Biochemistry and Immunology, Atlanta, Georgia, USA. hbaarmah@hotmail.com
Wilson
Nana O
NO
Sarfo
Bismark Y
BY
Powell
Michael D
MD
Bond
Vincent C
VC
Anderson
Winston
W
Adjei
Andrew A
AA
Gyasi
Richard K
RK
Tettey
Yao
Y
Wiredu
Edwin K
EK
Tongren
Jon Eric
JE
Udhayakumar
Venkatachalam
V
Stiles
Jonathan K
JK
D015415:Biomarkers / Q000097:blood* / Q000134:cerebrospinal fluid*; D018946:Chemokine CCL5 / Q000097:blood / Q000134:cerebrospinal fluid; D054357:Chemokine CXCL10 / Q000097:blood / Q000134:cerebrospinal fluid; D019742:Chemokines, CC / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D019040:E-Selectin / Q000097:blood / Q000134:cerebrospinal fluid; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D005869:Ghana; D006801:Humans; D007118:Immunoassay; D007223:Infant; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood / Q000134:cerebrospinal fluid; D016209:Interleukin-8 / Q000097:blood / Q000134:cerebrospinal fluid; D016779:Malaria, Cerebral / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000401:mortality; D008297:Male; D011379:Prognosis; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000134:cerebrospinal fluid
D015415:Biomarkers; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019040:E-Selectin; D053222:Fas Ligand Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha