Chloroquine as a Therapeutic Option for Mild Post Malaria Anaemia

Pathogenesis of Malaria Anaemia

Although the pathogenesis of malaria anaemia is not completely understood (1), mechanisms that have been proposed include immune and non-immune-mediated hemolysis of parasitized and non-parasitized red blood cells, bone marrow dysfunction and iron delocalisation (2-4). Plasmodium falciparum infection is associated with changes in the cell membranes of infected and uninfected erythrocytes causing alterations in membrane permeability and susceptibility to early hemolysis. It is also associated with bone marrow dysfunction probably due to malaria-induced abnormalities in erythroid progenitors, CFU-e and BFU-e (5,6). Jason et a (l7) have shown that malaria exerts a pro-inflammatory immune response in children and is associated with release of cytokines which act at various levels of the erythropoietic pathway to cause anaemia. These cytokines include human tumour necrosis factor (TNF)(8), interleukin (IL)-12, IL-10, IL-6 and IL-4 (7,9), and interferon-γ (IFN-γ) (9). In addition to the absolute concentrations of the cytokines, the balance between opposing anti- and pro-inflammatory responses may determine the clinical characteristics of malaria, including the level of anaemia (7) e.g. high TNF/IL-10 ratio may contribute to the reversible bone marrow suppression seen in malaria patients (10,11). Several investigators have reported the persistence of a fall in haemoglobin after successful treatment of malaria1 (2). Although the precise mechanism for this persistent anaemia is unclear, it is likely to be multifactorial. Studies conducted among Gambian children1 (3), French adults (14), and Thai adults (15) show that cytokine levels remain elevated for one to four weeks after a successful treatment for malaria; and Camacho et al (12) reported more than 80% of Thai adults with malaria had persisting anaemia on days 7, 14, and 21 after successful treatment, while 55% were still anaemic on day 28. On day 28, 46% of these subjects had hypoproliferative erythropoiesis while 7% had ineffective erythropoiesis (12). Although the study did not explore the mechanisms behind these findings, it is likely that persisting elevation of inflammatory cytokines reported by earlier workers (13-15) could be contributory. Greenberg and colleagues (16) have suggested that unusually strong and prolonged Th-1 response in conjunction with an inadequately developed Th-2 response may contribute to persistent anaemia after clearance of parasitaemia. Other workers have reported that persistent microscopically undetectable parasitaemia following successful treatment with an antimalarial was associated with protracted bone marrow suppression (17).

Macrophages and Malaria Anaemia Macrophages are responsible for the removal of senescent red blood cells from the body. They process these erythrocytes to release the heme iron which is then transported to the peripheral tissues including the bone marrow. The mononuclear phagocyte system plays two major roles in iron metabolism (18) - iron recycling from senescent erythrocytes and serving as a large storage depot for excess iron. This macrophageal recycling accounts for most of the 20-24mg of iron required daily for haemoglobin production. The cytokines released as part of the body's response to infection with Plasmodium cause the macrophages to release oxygen and nitrogen radicals leading to oxidative damage to parasitized and non-parasitized red blood cells, enhancing their removal from the circulation and contributing to anaemia (19). In addition, malaria-induced inflammation impedes release of iron from the macrophage-monocyte system hampering the supply of iron to the erythropoietic tissues. This causes considerable delocalisation of iron within the macrophage/monocyte system which makes iron unavailable to the marrow cells for erythropoiesis (18). The clinical practice of administration of iron for malaria anaemia is a result of the observation that serum iron is often low in such patients, as demonstrated in several animal and human studies (20,21). That the hypoferraemia observed in malaria could be largely due to iron sequestration in the macrophages is supported by reports of decreased peripheral iron levels despite normal or increased bone marrow iron (22,23).

Iron supplementation versus macrophageal iron mobilization The recent controversy regarding routine iron supplementation of children in malaria endemic areas with high prevalence of anaemia has further highlighted the need for alternative therapeutic regimens in children with malaria-associated anaemia. The genesis of the 'iron supplementation controversy' arose from several reports of increased morbidity and mortality from malaria and other infections in children from malaria endemic regions supplemented with iron. Recent evidence (reviewed by Prentice et al, Position paper for WHO Expert Consultation, Lyon, June 2006) suggests that the risk of adverse outcomes is less in more anaemic children. However, a growing body of evidence points to the poor rationale for giving iron supplements to children with mild malaria anaemia. First, during acute malaria, there is reduced iron absorption (Doherty et al. submitted, AJCN, 2006) and at least initially, erythropoietic iron supply is likely to come from reticuloendothelial macrophages rather than iron supplements. Secondly, the hypoferreamia associated with malaria has been shown to be due to iron delocalisation rather than absolute iron lack, reviewed in 18. Finally, a number of studies have found little or no benefit of giving iron supplements to children with malaria anaemia compared to other alternative regimens (24-27). While the management of moderate to severe malaria anaemia (Hb <80g/L) is not in contention, the management of mild anaemia remains an enigma because iron supplementation in these children, apart from providing questionable benefit, might in fact be harmful. Results from a large clinical trial of routine iron supplementation of children in an area of both iron deficiency and malaria transmission in Tanzania showed that among 24,076 children recruited those who received iron and folic acid, with or without zinc, were significantly more likely to die or experience adverse events than children who did not receive iron and folic acid (28).

Presently, there are no clear guidelines on the management of children with mild malaria anaemia. Mild anaemia in malaria endemic areas is likely due to either or both malaria and iron deficiency but distinguishing the iron delocalization of malaria from iron deficiency is difficult. It is important to optimize a child's iron nutrition to promote optimal cognitive development (29); however iron supplementation of this group is potentially dangerous hence the urgent need for alternative management strategies for a very common clinical scenario in Africa. Such interventions should take into consideration the complex pathogenesis of malaria anaemia including the mechanisms of iron flux and macrophageal iron delocalization during Plasmodium falciparum infection. It is likely that reduction of malaria-induced macrophageal iron sequestration and inflammation will enhance erythropoietic recovery post-malaria. We hypothesize that the anti-inflammatory, anti-macrophageal iron loading and anti-malarial effects of chloroquine could make it a useful drug in the management of mild post malaria anaemia by reducing macrophageal iron sequestration and interrupting the malaria-induced inflammatory process.