Cytokine Profiles in Malawian Children Presenting with Uncomplicated Malaria, Severe Malarial Anemia, and Cerebral Malaria

Abstract

Proinflammatory cytokines are involved in clearance of Plasmodium falciparum, and very high levels of these cytokines have been implicated in the pathogenesis of severe malaria. In order to determine how cytokines vary with disease severity and syndrome, we enrolled Malawian children presenting with cerebral malaria (CM), severe malarial anemia (SMA), and uncomplicated malaria (UCM) and healthy controls. We analyzed serum cytokine concentrations in acute infection and in convalescence. With the exception of interleukin 5 (IL-5), cytokine concentrations were highest in acute CM, followed by SMA, and were only mildly elevated in UCM. Cytokine concentrations had fallen to control levels when remeasured at 1 month of convalescence in all three clinical malaria groups. Ratios of IL-10 to tumor necrosis factor alpha (TNF-α) and of IL-10 to IL-6 followed a similar pattern. Children presenting with acute CM had significantly higher concentrations of TNF-α (P < 0.001), interferon gamma (IFN-γ) (P = 0.0019), IL-2 (P = 0.0004), IL-6 (P < 0.001), IL-8 (P < 0.001), and IL-10 (P < 0.001) in sera than healthy controls. Patients with acute CM had significantly higher concentrations of IL-6 (P < 0.001) and IL-10 (P = 0.0003) than those presenting with acute SMA. Our findings are consistent with the concept that high levels of proinflammatory cytokines, despite high levels of the anti-inflammatory cytokine IL-10, could contribute to the pathogenesis of CM.

Keywords: cytokines; malaria.

FIG 1

(A to J) Plots of log-transformed concentrations (picograms per milliliter) of different cytokines (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12p70) in serum samples collected from healthy controls (Control) and from patients with acute uncomplicated malaria (UCM), acute severe malarial anemia (SMA), and acute cerebral malaria (CM). (K and L) Plots of the ratios of log-transformed IL-10 to TNF-α and IL-10 to IL-6, respectively, during acute infection, showing medians and 10th and 90th percentiles.

FIG 2

(A to J) Plots of log-transformed concentrations (in picograms per milliliter) of different cytokines (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12p70) in serum samples collected from healthy controls (Control) and from patients with convalescent uncomplicated malaria (UCM-F), severe malarial anemia (SMA-F), and cerebral malaria (CM-F). (K and L) Plots of the ratios of log-transformed IL-10 to TNF-α and IL-10 to IL-6, respectively, during convalescence, showing medians and 10th and 90th percentiles.

FIG 3

Cytokine levels in children with CM and SMA who died or who survived. Plot of log-transformed concentrations (in picograms per milliliter) of different cytokines (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12p70) in serum samples collected from five children who died (D, red dots) and those children who survived (S, black dots) after presenting with acute CM and SMA, showing medians and 10th and 90th percentiles.