Where malaria surveillance and health care is inadequate, iron supplements given without food can increase the severity of malarial infections. The likely explanation is that the rate of iron influx into the plasma from high-dose oral supplements exceeds the rate of iron binding to transferrin and a quantity of non-transferrin-bound iron (NTBI) is formed. It is proposed that NTBI increases the intensity of malarial infections by increasing the sequestration of malaria-infected red cells in the capillaries of the brain and intestine, causing more cerebral malaria and further increasing the permeability of the intestinal barrier to the passage of pathogens. Bacteremia is frequently reported in children with severe malaria. At the same time, high iron doses stimulate the growth of pathogenic bacteria in the stool, further increasing the potential for bacteremia. The normal immune response to malaria, as well as other infections and inflammatory disorders, is to prevent further microbial growth by stimulating hepcidin synthesis and preventing the passage of iron into the plasma. Iron absorption is decreased and the efficacy of the iron interventions would be expected to be lower in the presence of infections.

1.
Wander K, Shell-Duncan B, McDade TW: Evaluation of iron deficiency as a nutritional adaptation to infectious disease: an evolutionary medicine perspective. Am J Hum Biol 2009;21:172–179.
2.
Ganz T: Molecular control of iron transport. J Am Soc Nephrol 2007;18:394–400.
3.
Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, Othman MK, Kabole FM: Effects of routine prophylactic supplementation with iron and folic acid on admis- sion to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet 2006;367:133–143.
4.
Prentice AM, Ghattas H, Doherty C, Cox SE: Iron metabolism and malaria. Food Nutr Bull 2007;28:S524–S539.
5.
Oppenheimer SJ: Iron and its relation to immunity and infectious disease. J Nutr 2001;131:616S–633S, discussion 633S–635S.
6.
Tielsch JM, Khatry SK, Stoltzfus RJ, Katz J, LeClerq SC, Adhikari R, Mullany LC, Shresta S, Black RE: Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial. Lancet 2006;367:144–152.
7.
Ojukwu JU, Okebe JU, Yahav D, Paul M: Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas. Cochrane Database Syst Rev 2009, p. CD006589.
8.
World Health Organization: Conclusions and recommendations of the WHO Consultation on prevention and control of iron deficiency in infants and young children in malaria-endemic areas. Food Nutr Bull 2007;28:S621–S627.
9.
Hershko C, Graham G, Bates GW, Rachmilewitz EA: Non-specific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol 1978;40:255–263.
10.
Hutchinson C, Al-Ashgar W, Liu DY, Hider RC, Powell JJ, Geissler CA: Oral ferrous sulphate leads to a marked increase in pro-oxidant nontransferrin-bound iron. Eur J Clin Invest 2004;34:782–784.
11.
Dresow B, Petersen D, Fischer R, Nielsen P: Non-transferrin-bound iron in plasma following administration of oral iron drugs. Biometals 2008;21:273–276.
12.
Hershko C: Mechanism of iron toxicity. Food Nutr Bull 2007;28:S500–S509.
13.
Brissot P, Wright TL, Ma WL, Weisiger RA: Efficient clearance of non-transferrin-bound iron by rat liver: implications for hepatic iron loading in iron overload states. J Clin Invest 1985;76:1463–1470.
14.
Hurrell R: Iron and malaria: absorption, efficacy and safety. Int J Vitam Nutr Res 2010;80:279–292.
15.
Miller LH, Baruch DI, Marsh K, Doumbo OK: The pathogenic basis of malaria. Nature 2002;415:673–679.
16.
Chakravorty SJ, Craig A: The role of ICAN-1 in Plasmodium falciparum cytoadherence. Eur J Cell Biol 2005;84:15–27.
17.
Kartikasari AE, Georgiou NA, Visseren FL, van Kats-Renaud H, van Asbeck BS, Marx JJ: Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera. FASEB J 2006;20:353–355.
18.
Oundo JO, Muli F, Kariuki S, Waiyaki PG, Iijima Y, Berkley J, Kokwaro GO, Ngetsa CJ, Mwarumba S, Torto R, Lowe B: Non-typhi salmonella in children with severe malaria. East Afr Med J 2002;79:633–639.
19.
Seydel KB, Milner DA Jr, Kamiza SB, Molyneux ME, Taylor TE: The distribution and intensity of parasite sequestration in comatose malawian children. J Infect Dis 2006;194:208–205.
20.
Zimmermann MB, Chassard C, Rohner F, Goran EKN, Nindjin C, Dostal A, Utzinger J, Ghattas H, Lacroix C, Hurrell RF: The effects of iron fortification on the gut microbiota in African children a randomized controlled trial in Cote d’Ivoire. Am J Clin Nutr 2010;92:1406–1415.
21.
Doherty CP, Cox SE, Fulford AJ, Austin S, Hilmers DC, Abrams SA, Prentice AM: Iron incorporation and post-malaria anaemia. PLoS One 2008;3:e2133.
22.
Cercamondi CI, Egli IM, Ahouandjinou E, Dossa R, Zeder C, Salami L, Tjalsma H, Wiegerinck E, Tanno T, Hurrell RF, Hounhoutgan J, Zimmermann MB: Afebrile Plasmodium falciparum parasitemia decreases absorption of fortification iron but does not affect systemic iron utilization a double stable-isotope study in young Beninese women. Am J Clin Nutr 2010;92:1385–1392.
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