High plasma erythropoietin levels are associated with prolonged coma duration and increased mortality in children with cerebral malaria

Abstract

Background: Elevated endogenous plasma erythropoietin (EPO) levels have been associated with protection from acute neurologic deficits in Kenyan children with cerebral malaria (CM). Based on these findings and animal studies, clinical trials of recombinant human EPO (rHuEPO) have been started in children with CM. Recent clinical trials in adults with acute ischemic stroke have demonstrated increased mortality with rHuEPO treatment. We conducted a study in children with CM to assess the relationship of endogenous plasma and cerebrospinal fluid (CSF) EPO levels with mortality and acute and long-term neurologic outcomes.

Methods: A total of 210 children between 18 months and 12 years of age with a diagnosis of CM, were enrolled at Mulago Hospital, Kampala, Uganda. Plasma (n = 204) and CSF (n = 147) EPO levels at admission were measured by radioimmunoassay and compared with mortality and neurologic outcomes.

Results: After adjustment for age and hemoglobin level, a 1-natural-log increase in plasma EPO level was associated with a 1.74-fold increase in mortality (95% confidence interval, 1.09-2.77, P = .02). Plasma and CSF EPO levels also correlated positively with coma duration (P = .05 and P = .02, respectively). Plasma and CSF EPO levels did not differ in children with vs those without acute or long-term neurologic deficits. Plasma EPO levels correlated positively with markers of endothelial and platelet activation and histidine-rich protein-2 levels, but remained associated with mortality after adjustment for these factors.

Conclusions: High endogenous plasma EPO levels are associated with prolonged coma duration and increased mortality in children >18 months of age with CM.

Keywords: cerebral malaria; erythropoietin; mortality; neurologic deficits.

Figure 1.

Study profile. Abbreviations: CSF, cerebrospinal fluid; EPO, erythropoietin; LP, lumbar puncture.

Figure 2.

Hemoglobin and erythropoietin (EPO) levels in children with cerebral malaria who survived vs those who died. EPO levels (log-transformed) and hemoglobin level are depicted for children who died and survived. Solid and dashed lines show average EPO level for each hemoglobin level for children who survived (S) vs children who died (D), respectively. In 19 of the 23 children who died, EPO values were higher than the mean EPO value of survivors for the same hemoglobin level.