Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated Plasmodium falciparum malaria.

Tumor necrosis factor alpha (TNF-alpha) has been implicated in the pathology of experimental malaria. To establish its relevance to human malaria, we studied serum levels of two monocyte-derived cytokines, TNF-alpha and interleukin-6 (IL-6), as well as of the lymphocyte-derived mediator interferon gamma (IFN-gamma) in patients with malaria before and during antiparasitic treatment. One hundred twenty serum samples of 40 patients with malaria (Plasmodium falciparum [n = 32], Plasmodium vivax [n = 8]) were analyzed. IL-6 was measured by a highly sensitive and specific bioassay, TNF-alpha by immunoradiometric assay, and IFN-gamma by radioimmunoassay. Elevated cytokine levels could be detected in the majority of patients with P. falciparum malaria before treatment (31 of 32, 21 of 32, and 21 of 32 for TNF-alpha, IL-6, and IFN-gamma, respectively), but only in some patients with P. vivax malaria (four of eight, one of eight, and zero of eight for TNF-alpha, IL-6, and IFN-gamma, respectively). Serum concentrations of the monokines TNF-alpha and IL-6 correlated significantly with parasitic density (p less than 0.001). No such correlation was obtained with the circulating IFN-gamma concentration. The levels of monokines TNF-alpha and IL-6 were markedly elevated in 18 P. falciparum-infected patients with complicated clinical courses (median values for TNF-alpha 172 pg/mL, for IL-6 16 U/mL, peak values: 896 pg/mL and 1,000 U/mL, respectively). The correlation between TNF-alpha and IL-6 concentrations in serum (n = 40, r = 0.56, p = 0.0002) suggests co-ordinate production of those mediators. Organ impairment in human malaria was found to be correlated with the amount of circulating cytokine levels of TNF-alpha and IL-6. Thus, imbalances of the cytokine network in untreated P. falciparum infection serve as markers of severity of disease. Modulation of cytokine response could represent a novel approach to the treatment of severe organ dysfunctions in human malaria.