Increase hemoglobin level in severe malarial anemia while controlling parasitemia: A mathematical model

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine produced by immune cells; it can play a protective or deleterious role in response to pathogens. The intracellular malaria parasite secretes a similar protein, PMIF. The present paper is concerned with severe malarial anemia (SMA), where MIF suppresses the recruitment of red blood cells (RBCs) from the spleen and the bone marrow. This suppression results in a decrease of the hemoglobin (H_b) in the blood to a dangerous level. Indeed, SMA is responsible for the majority of death-related malaria cases. Artesunate is the first line of treatment of SMA; it accelerates the death of infected RBCs (iRBCs), thereby decreasing parasitemia. However, artesunate does not increase the level of H_b, and, in some cases, post-artesunate hemolytic anemia requires blood transfusion. In order to avoid this situation, we explore combining artesunate with another drug so that the H_b level is increased to healthy levels while parasitemia is still controlled. In this paper we show, by a mathematical model, that increasing the H_b levels while controlling parasitemia in malarial anemia can be done with the experimental drug Epoxyazadiradione (Epoxy) in combination with artesunate. Epoxy acts as MIF inhibitor and thus has the potential to increase the H_b level. Simulations of the model show that the two drugs compliment each other: while artesunate is primarily responsible for decreasing parasitemia, Epoxy is primarily responsible for increasing the hemoglobin level.