Elevated levels of methaemoglobin in Tanzanian children with severe and uncomplicated malaria

Abstract

Elevated levels of methaemoglobin, the ferric form of haemoglobin incapable of oxygen transport, have been previously found during Plasmodium vivax infections and in acidotic infants. We measured methaemoglobin in the following 5 groups of children with P. falciparum malaria admitted to Muhimbili Medical Centre, Dar es Salaam, Tanzania. (i) Cerebral malaria (CM) with unrousable coma (n = 50), including 32 with complete recovery (CMCR) and 18 with death or neurological sequelae (CMDS); (ii) malaria with severe anaemia but without severe respiratory distress (SA; n = 6); (iii) uncomplicated malaria (UM; n = 37); (iv) asymptomatic parasitaemia (AP; n = 5); and (v) healthy controls (HC; n = 34). Mean methaemoglobin levels were elevated in all groups with malaria, forming up to 16.4% of circulating haemoglobin. The degree of methaemoglobinaemia correlated with disease severity and severity of anaemia. Mean methaemoglobin levels in children with AP, UM, SA, CMCR and CMDS were 3.3%, 4.1%, 5.6%, 4.7% and 5.8% respectively; the mean levels in those with clinical disease were significantly higher than those in healthy controls (2.0%). Methaemoglobinaemia > 10% was found in 5.4%, 16.7%, 12.5%, and 22.2% of those with UM, SA, CMCR and CMDS, respectively. In the presence of parasite sequestration, impaired tissue perfusion, and a reduction in oxygen carrying capacity of blood due to anaemia, a further reduction in oxygen carrying capacity from even a modest concentration of methaemoglobin is likely to exacerbate tissue hypoxia, perhaps critically so in a minority of anaemic and acidotic patients with severe falciparum malaria.

Study of Methaemoglobin in Malaria Patients

“…increase in hypoxia and vice versa which is ultimately associated with increased mortality. This result is consistent with the fact that reduction in oxygen carrying capacity of blood in malaria is not only due to a decrease in the quantity of haemoglobin, but also due to a qualitative impairment in the ability of remaining haemoglobin to carry oxygen [11]. It can be presumed that the level of MetHb is more in complicated malaria due to involvement of more number of erythrocyte population than in uncomplicated malaria.…”

“…In a similar manner, P. falciparum infected erythrocyte of malaria male individuals contained significantly (p \ 0.05) higher methaemoglobin concentration than the female group. Furthermore, Anstey et al [11] documented elevated MetHb concentration of Tanzanian children with severe and uncomplicated malaria. The degree of methaemoglobinaemia was correlated with disease severity and severity of anemia.…”

A central role for free heme in the pathogenesis of severe malaria: the missing link?

“…In keeping with this notion, 20-40% of children infected by Plasmodium falciparum in sub-Saharan countries present undetectable levels of plasma Hp [40]. Presumably, for this reason, cellfree metHb does accumulate in the plasma of individuals suffering from severe malaria [41,42], which should lead to the prompt release of its heme prosthetic groups (Fig. 1).…”

“…There is indirect evidence, however, to suggest that this might be the case. Individuals developing severe malaria have high levels of plasma metHb [41,42]. As metHb releases free heme, the prediction is that free heme should accumulate in the plasma of these individuals, a hypothesis we are currently testing.…”

Methemoglobin incites primaquine toxicity through single-electron oxidation and modification

“…During malaria, lysis of infected RBCs releases hemoglobin (Hb), hemin, hemozoin, and other toxic metabolites into the serum [19] . The released Hb is readily being oxidized to form ferryl Hb and MetHb [20] .…”