Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation

Abstract

Background

Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection.

Methods

This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6–24 months; hemoglobin < 11 g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12 mg/day) as part of a micronutrient powder for 84 days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint.

Findings

Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~ 10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49 days of iron supplementation relative to baseline ( p < 0.001), paralleling increases in erythropoiesis.

Interpretation

These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria.

Funding

National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Highlights

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  P. falciparum laboratory and field strains invade and grow less efficiently in RBCs from anemic children.

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  Deficits in invasion and growth for erythrocytic stage P. falciparum are reversed when RBCs are used from anemic children receiving iron supplementation for 49 and 84 days.

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  The population level impact of protection against malaria from anemia was greater than that for sickle-cell trait.

The long-term consequences of anemia are severe, and it is easily treatable. However, concerns remain about the safety of iron supplements, particularly for children in malaria-endemic countries lacking adequate access to health services. We used RBCs from Gambian children before, during, and after 12 weeks of daily iron supplementation for in vitro P. falciparum assays. P. falciparum invasion and growth was decreased in anemic RBCs and increased after 49 days of iron supplementation relative to baseline ( p < 0.001), paralleling increases in young RBCs, which the parasite prefers. The parasite growth protection from anemia was substantial, providing greater population level impact than sickle-cell trait.