Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India.
BACKGROUND
Plasmodium falciparum in a subset of patients can lead to cerebral malaria (CM), a major contributor to malaria-associated mortality. Despite treatment, CM mortality 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 is mediated by alterations in cytokine and chemokine homeostasis, inflammation as well as vascular injury and repair processes although their roles are not fully understood. The hypothesis for this study is that CM-induced changes in inflammatory, apoptotic and angiogenic factors mediate severity of CM and that their identification will enable development of new prognostic markers and adjunctive therapies for preventing CM mortalities.


METHODS
Plasma samples (133) were obtained from healthy controls (HC, 25), mild malaria (MM, 48), cerebral malaria survivors (CMS, 48), and cerebral malaria non-survivors (CMNS, 12) at admission to the hospital in Jabalpur, India. Plasma levels of 30 biomarkers ((IL-1beta, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGF basic protein, G-CSF, GM-CSF, IFN-gamma, IP-10, MCP-1 (MCAF), MIP-1alpha, MIP-1beta, RANTES, TNF-alpha, Fas-ligand (Fas-L), soluble Fas (sFas), soluble TNF receptor 1 (sTNF-R1) and soluble TNF receptor 2 (sTNFR-2), PDGF bb and VEGF)) were simultaneously measured in an initial subset of ten samples from each group. Only those biomarkers which showed significant differences in the pilot analysis were chosen for testing on all remaining samples. The results were then compared between the four groups to determine their role in CM severity.


RESULTS
IP-10, sTNF-R2 and sFas were independently associated with increased risk of CM associated mortality. CMNS patients had a significantly lower level of the neuroprotective factor VEGF when compared to other groups (P < 0.0045). The ratios of VEGF to IP-10, sTNF-R2, and sFas distinguished CM survivors from non survivors (P < 0.0001).


CONCLUSIONS
The results suggest that plasma levels of IP-10, sTNF-R2 and sFas may be potential biomarkers of CM severity and mortality. VEGF was found to be protective against CM associated mortality and may be considered for adjunctive therapy to improve the treatment outcome in CM patients.
Jain
Vidhan
V
National Institute of Malaria Research (ICMR), Jabalpur, India. vidhanjain78@yahoo.com
Armah
Henry B
HB
Tongren
Jon E
JE
Ned
Renée M
RM
Wilson
Nana O
NO
Crawford
Sara
S
Joel
Pradeep K
PK
Singh
Mrigendra P
MP
Nagpal
Avinash C
AC
Dash
A P
AP
Udhayakumar
Venkatachalam
V
Singh
Neeru
N
Stiles
Jonathan K
JK
D000293:Adolescent; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D054357:Chemokine CXCL10 / Q000097:blood*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007194:India / Q000453:epidemiology; D016015:Logistic Models; D016779:Malaria, Cerebral / Q000097:blood / Q000401:mortality* / Q000469:parasitology / Q000503:physiopathology; D008297:Male; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood*; D012720:Severity of Illness Index; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D019014:fas Receptor / Q000097:blood*
D043925:Angiogenesis Inducing Agents; D015415:Biomarkers; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C491901:FAS protein, human; D047889:Receptors, Tumor Necrosis Factor, Type II; D042461:Vascular Endothelial Growth Factor A; D019014:fas Receptor