Iron Metabolism, Malaria, and Other Infections: What Is All the Fuss About? 1,2

Transcription

1 The Journal of Nutrition Symposium: Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries The Critical Role of Research to Guide Policy and Programs Iron Metabolism, Malaria, and Other Infections: What Is All the Fuss About? 1,2 Andrew M. Prentice* MRC International Nutrition Group, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; and MRC Keneba, The Gambia Abstract This article briefly describes how iron lies at the center of a host-pathogen battle for nutrients and why there are many theoretical reasons to suspect that administration of supplemental iron might predispose to infection. This is supported by in vitro and small animal studies, but meta-analysis of human epidemiological and intervention studies has found little evidence for most disease outcomes. Supplemental iron does appear to increase susceptibility to malaria as measured by a variety of malariometric indices. However, even in malarious areas, iron appears beneficial in iron-deficient subjects. The concerns about iron supplementation programs for children seem to be confined to Sub-Saharan Africa and to areas of high malaria endemicity, where it will be necessary to adopt a cautious approach to supplementation based either on screening out iron-replete children or combining iron administration with effective disease-control strategies. J. Nutr. 138: , Introduction Iron deficiency and iron deficiency anemia (IDA) are estimated to be the most widespread of all nutritional deficiencies (1), and, as a consequence, iron is probably the most widely administered of all compounds both through preventative campaigns involving mass administration and by individual prescription. WHO and International Nutritional Anemia Consultative Group guidelines for combating IDA have been widely adopted by most less-developed countries, and efforts to enhance the efficiency of implementation were gathering pace until results of the Pemba trial, showing an increase in serious adverse events among children receiving iron, were published (2) and then widely publicized. Because Pemba is an area of hyperendemic malaria, and because a very similar trial in malaria-free Nepal found no such adverse effect (3), the result has been generally ascribed to an adverse interaction between iron administration and malaria. As discussed by Stoltzfus in an accompanying article (4), the detrimental effect was confined to children who were iron replete, suggesting that it is an excess of iron that generated the adverse interaction. This article examines the issues surrounding iron and infections with special attention to malaria. 1 Published as a supplement to The Journal of Nutrition. Presented as part of the symposium Infant and Young Child Iron Deficiency and Iron Deficiency Anemia in Developing Countries: The Critical Role of Research to Guide Policy and Programs given at the 2008 Experimental Biology meeting on April 7, 2008, in San Diego, CA. The symposium was sponsored by the American Society for Nutrition. The symposium was chaired by Chessa Lutter and Rebecca Stoltzfus. 2 Author disclosures: A. Prentice, no conflicts of interest. * To whom correspondence should be addressed. andrew.prentice@ lshtm.ac.uk. The critical role of iron in host and pathogen biology There are multiple reasons to conclude that, among the 40 or so nutrients essential to human health, iron plays the most critical role in relation to the host s interactions with pathogens (viruses, bacteria, and protozoa) (5,6). In brief the evidence can be summarized as follows (see also Fig. 1): 1) althoughironisa highly abundant element, it is highly insoluble at physiological ph and in the oxidative conditions of life, and therefore, it is difficult to acquire; 2) iron has very useful redox characteristics that have resulted in its incorporation in a very wide range of enzyme and oxygen transport systems; 3) these same redox characteristics also make free iron potentially very harmful because of the generation of free radicals; 4) humans have evolved a range of transport, sequestration, and storage systems for iron (e.g., transferrin, lactoferrin, ferritin, haptoglobin, hemopexin) that appear well adapted to prevent iron causing localized tissue damage; 5) these systems are up-regulated by the acute-phase response to infection causing a depletion of iron in the systemic circulation down to ; mol/l (teleologically interpreted as a defense mechanism by depriving pathogens of iron); 6) both in vitro and in vivo (small animal) experiments clearly demonstrate that addition of iron (in various forms including as heme) overcomes the bacteriostatic and bacteriocidal effects of iron-binding proteins; 7) in response to these human adaptations, bacteria, in particular, have evolved an astonishing range of siderophores and related iron acquisition molecules with very strong iron-binding capabilities (e.g., mol/l for enterobactin); 8) in many bacteria, the so-called islands of high pathogenicity within their genome are enriched in iron acquisition genes; and 9) genetic detective work strongly indicates that microorganisms have had to acquire specialist methods for iron retrieval before they could colonize humans /08 $8.00 ª 2008 American Society for Nutrition. doi: /jn

2 FIGURE 1 These factors combine to place iron at the center of the hostpathogen battleground for nutrients and suggest that optimizing iron status may involve a very delicate balance; a deficit of iron will impair host function (including immunity), but an excess may favor the growth and pathogenicity of microorganisms (7). This is the biological background against which we should judge the epidemiological evidence linking iron administration to an increased susceptibility to infections. Iron and infections: what is the evidence? The data from Pemba suggesting that iron administration can increase a person s vulnerability to infection are by no means new. As long ago as the 1850s, the Parisian physician Trousseau warned his students of the mortal consequences of administering iron to TB patients (8), and there are much-quoted data suggesting that refeeding malnourished refugees and consequent hyperferremia caused a recrudescence of malaria and other infections (9,10). In consequence of these and other data, the WHO Guidelines for Treatment of Severely Malnourished Children advise withholding of iron until wide-spectrum antibiotics have been used to control bacterial infections. There is also emerging evidence to suggest that iron plays diverse roles in viral infections (11), and we have recently shown that elevated ferritin levels strongly predict earlier mortality in HIV patients (12). To examine whether these occasional findings are supported by the totality of evidence, Gera and Sachdev (13) conducted a meta-analysis of 28 randomized controlled trials of iron intervention. Outcomes were all infections, respiratory tract infections, diarrhea, and malaria. Risk of diarrhea was found to be marginally significantly elevated with a relative risk of 1.11 (95% CI ). The risk of other infections was not significantly altered. Results of the Pemba and Nepal trials (2,3) were not available when the Gera meta-analysis was conducted. Stoltzfus et al. (14) Evidence implicating iron as a key player in host-pathogen interactions. have since updated and critically reviewed the evidence on possible effects of iron and iron plus folic acid on infections and included both the Pemba and Nepal main studies and the Pemba substudy. Their summary indicates that the evidence for harmful effects is minimal. In particular, the very marginal negative effect on diarrhea noted in the Gera summary is offset by slight (but nonsignificant) protective effects in Pemba and Nepal. There has been 1 further trial published since the Stoltzfus review. This examined the effects of iron supplementation on incidence of malaria in Peru and showed a 49% increase in malaria episodes (Plasmodium vivax) in children over 5 y of age but had no significant effect on diarrhea or respiratory tract infections in any age group (15). Meta-analyses such as these should be interpreted with caution because most of the studies included have not disaggregated their data according to the baseline iron status of the children. The Pemba substudy analysis indicates that positive effects in iron-deficient children may be balanced by negative effects in iron-replete children, thus tending toward a neutral result within any population that contains a range of iron status. It is critical that future study designs and analysis plans take into account iron status. Iron and malaria Following the Pemba trial a key question facing researchers is: What are the potential mechanisms by which iron status could affect parasite invasion or growth and hence the clinical sequelae of infection? Most discussion of this question revolves around the blood stages of the parasite with virtually nothing known about factors that might impact on the liver stages, and this would be an important target for future research. At present there are 4 regularly cited suggestions as to possible means by which iron status might influence susceptibility to malaria. The first is simply through alterations in iron availability for parasite growth and replication. In its erythrocytic stages, the 2538 Symposium

3 malaria parasite presents some paradoxes in relation to its iron acquisition. Heme iron, although available in abundance, appears not to be utilized by plasmodia and must be detoxified through formation of the hemazoin complex, which contains 2.2 mol/l iron (16). It appears that the parasite is dependent on the very small pool of labile iron in the cytoplasm and hence might be sensitive to external (nutritional) influences on the concentration of iron in this compartment (16). A second possibility is that iron supplementation might enhance susceptibility by stimulating erythropoiesis because there is evidence that parasites have a preference for reticulocytes. However, this is only true of P. vivax and would not explain effects on P. falciparum as has sometimes been erroneously claimed. A third possibility is that zinc protoporphyrin (a product of iron-deficient erythropoiesis) may inhibit hemozoin formation and hence generate a toxic environment in a manner analogous to an antimalarial drug action (17). The final possibility would be through iron s influence on host immunity. Epidemiological and intervention evidence linking iron and malaria Surprisingly, there have been rather few studies examining whether iron-deficient/anemic individuals are more or less vulnerable to malaria (Fig. 2). Two studies showed an increased susceptibility to malaria in individuals with high serum ferritin (18,19). Other studies have shown both increased (20) and decreased (21) susceptibility associated with higher hemoglobin levels. Confounding in such studies can easily arise from different proportions of hemaglobinopathies, which might be associated with both hemoglobin and protection from malaria. The evidence from iron supplementation trials is more robust (Fig. 3) and has been reviewed in detail elsewhere (22 24). Of 15 studies reviewed most recently (24), 6 showed no effect of iron supplements on malaria risk; of these, 3 included large proportions of anemic subjects (74 94%), and 1 only included children with Hb,50 g/l. Other studies that stratified by baseline hemoglobin level found that the greatest benefits occurred in the most anemic subgroups, a finding that is in line with Stoltzfus s interpretation of the Pemba data (4). Three studies showed an increase in clinical malaria attacks in the iron-supplemented groups, and a further 6 studies found nonsignificant increases in malaria outcomes. One of the striking differences between study populations with significant increases in malaria outcomes and those with nonsignificant effects is access to health care and active treatment of malaria incident cases. In fact, all but 1 of the trials that found no effect on malaria outcomes provided access to health care facilities or active follow-up and treatment of malaria incident cases. This implies that the potential detrimental effects of iron supplementation may be curtailed by concurrent effective treatment of malaria infections. However, Verhoef et al. (25) and Nwanyanwu et al. (26) have shown potential treatment failure effects of combining sulfadoxine/ pyrimethamine (SP) with iron in the treatment of preexisting malaria, suggesting that antimalarial therapy should precede supplementation. In summary, the data from Pemba are generally in line with other studies that have previously hinted at likely detrimental effects of iron administration but have been able to show the adverse effects with much greater certainty as a consequence of the very large sample size. Balancing risks and benefits other pros and cons of iron administration Anemia. Anemia is by far the most common clinical and epidemiological indicator for preventative and/or therapeutic iron, and there is no doubt that, under almost all conditions, administration of iron (given with or without folic acid, and sometimes with vitamin B-12) does achieve an increase in hemoglobin. However, effect sizes of,1 SD are usual, and this generally leaves a residual deficit of ;1 SD compared with wellnourished women and children from affluent populations even when treatment is combined with antihelminthics and antimalarials. The reason for the residual deficit is unclear. Effects on cognition and development. The positive and lasting effects of iron on the mental and motor development of infants and children are reviewed in the accompanying paper from this symposium by Beard (27). Iron and oxidative stress/tissue damage. Animal studies appear to confirm the theoretical concerns that excess iron may induce oxidative damage as measured by increases in lipid peroxidation, DNA damage, and colitis. Human studies also show evidence for raised thiobarbituric acid reactive substances when iron is given at.60 mg/d, that iron chelation can decrease thiobarbituric acid reactive substances, and that iron stores correlate with DNA damage. Effects on growth. In a meta-analysis of 25 studies (19 supplementation, 6 fortification) Sachdev et al. (28) showed very small and mostly nonsignificant effects of iron on growth. Weight-for-age was increased by 0.13 SD (P ¼ 0.04, nonsignificant after adjustments), and height-for-age was unaffected. Disaggregation of the data showed a positive effect on weightfor-age in malarious areas and a negative effect on height-for-age in developed countries when iron was given for longer than 6 mo. Two studies have been widely quoted as raising concerns relating to iron and growth (29). In Swedish infants there was a significant decrease in length and head circumference between 4 and 9 mo in the group receiving iron (29). A study of Honduran infants by the same investigators showed decreased length (4 6 mo) in iron-replete subjects (29). This latter finding has been confirmed by a study from India (30). FIGURE 2 malaria. Observational studies: Iron status and susceptibility to Putative interactions with zinc and copper metabolism. Theoretical concerns that iron administration may inhibit absorption of copper and/or zinc were widely held some years Iron metabolism, malaria and other infections 2539

4 FIGURE 3 Meta-analysis and reviews of iron supplementation. ago but have not been borne out by experimental data and hence have largely subsided. Summary of the critical issues In summary, iron lies at the center of the host-pathogen battle for nutrients, and there are many theoretical reasons to suspect that extra iron might predispose to infection. This is supported by in vitro and small animal studies, but meta-analysis of human epidemiological and intervention studies has found little evidence for most disease outcomes. Supplemental iron does appear to increase susceptibility to malaria as measured by a variety of malariometric indices. However, even in malarious areas, iron appears beneficial (strongly so) in iron-deficient subjects. The concerns about iron supplementation programs for children seem to be confined to Sub-Saharan Africa and to areas of high malaria endemicity, where it will be necessary to adopt a cautious approach to supplementation based either on screening out iron-replete children or combining iron administration with effective disease control strategies. Other articles in this symposium include references (1,4,27,31). Literature Cited 1. Chaparro CM. Setting the stage for child health and development: prevention of iron deficiency in early infancy. J Nutr. 2008;138: Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, Dhingra U, Kabole I, Deb S, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial. Lancet. 2006; 367: 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, placebocontrolled trial. Lancet. 2006;367: Stoltzfus RJ. Developing countries: the critical role of research to guide policy and programs research needed to strengthen science and programs for the control of iron deficiency and its consequences in young children. J Nutr 2008;138: Prentice AM, Ghattas H, Cox SE. Host-pathogen interactions: can micronutrients tip the balance? J Nutr. 2007;137: McDermid JM, Prentice AM. Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP Symposium (SLC11A1) on host-pathogen interactions in tuberculosis and HIV. Clin Sci (Lond). 2006;110: Doherty CP, Weaver LT, Prentice AM. Micronutrient supplementation and infection: a double-edged sword? J Pediatr Gastroenterol Nutr. 2002;34: Trousseau A. True and false chlorosis. Lectures on Clinical Medicine. 1872;5: Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. BMJ. 1978;2: Murray MJ, Murray NJ, Murray AB, Murray MB. Refeeding-malaria and hyperferraemia. Lancet. 1975;1: Drakesmith H, Prentice AM. Viral infection and iron metabolism. Nat Rev Microbiol. 2008;6: McDermid JM, Jaye A, Schim van der Loeff MF, Todd J, Bates C, Austin S, Jeffries D, Awasana AA, Whittle HC, Prentice AM. Elevated iron status strongly predicts mortality in West African adults with HIV infection. J Acquir Immune Defic Syndr. 2007;46: Gera T, Sachdev HP. Effect of iron supplementation on incidence of infectious illness in children: systematic review. BMJ. 2002;325: Stoltzfus RJ, Heidkamp R, Kenkel D, Habicht JP. Iron supplementation of young children: learning from the new evidence. Food Nutr Bull. 2007;28 Suppl 4:S Richard SA, Zavaleta N, Caulfield LE, Black RE, Witzig RS, Shankar AH. Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. Am J Trop Med Hyg. 2006;75: Scholl PF, Tripathi AK, Sullivan DJ. Bioavailable iron and heme metabolism in Plasmodium falciparum. Curr Top Microbiol Immunol. 2005;295: Iyer JK, Shi L, Shankar AH, Sullivan DA. Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum. Mol Med. 2003;9: Snow RW, Byass P, Shenton FC, Greenwood BM. The relationship between anthropometric measurements and measurements of iron status and susceptibility to malaria in Gambian children. Trans R Soc Trop Med Hyg. 1991;85: Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Back D, Kortok M, Chemtai AK, Marsh K, Williams TN. Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis. 2004;190: Oppenheimer SJ, Gibson FD, Macfarlane SB, Moody JB, Harrison C, Spencer A, Bunari O. Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans R Soc Trop Med Hyg. 1986;80: Shipton D. Association between haemoglobin level and susceptibility to malaria: a study of Gambian children. MSc Thesis. London: London School of Hygiene and Tropical Medicine; Shankar AH. Nutritional modulation of malaria morbidity and mortality. J Infect Dis. 2000;182 Suppl 1:S37 53.

5 23. Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr. 2001;131:616S 33S. 24. Prentice AM, Ghattas H, Doherty C, Cox SE. Iron metabolism and malaria. Food Nutr Bull. 2007;28 Suppl 4:S Verhoef H, West CE, Nzyuko SM, de Vogel S, van der Valk R, Wanga MA, Kuijsten A, Veenemans J, Kok FJ. Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. Lancet. 2002;360: Nwanyanwu OC, Ziba C, Kazembe PN, Gamadzi G, Gandwe J, Redd SC. The effect of oral iron therapy during treatment for Plasmodium falciparum malaria with sulphadoxine-pyrimethamine on Malawian children under 5 years of age. Ann Trop Med Parasitol. 1996;90: Beard JL. Why iron deficiency is important in infant development. J Nutr. 2008;138: Sachdev H, Gera T, Nestel P. Effect of iron supplementation on physical growth in children: systematic review of randomised controlled trials. Public Health Nutr. 2006;9: Dewey KG, Domellöf M, Cohen RJ, Landa Rivera L, Hernell O, Lönnerdal B. Iron supplementation affects growth and morbidity of breast-fed infants: results of a randomized trial in Sweden and Honduras. J Nutr. 2002;132: Majumdar I, Paul P, Talib VH, Ranga S. The effect of iron therapy on the growth of iron-replete and iron-deplete children. J Trop Pediatr. 2003;49: Lutter CK. Iron deficiency in young children in low-income countries and new approaches for its prevention. J Nutr. 2008;138: Iron metabolism, malaria and other infections 2541