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Anaemia, iron deficiency and susceptibility to infections
Journal of Infection (2014) xx, 1e5
www.elsevierhealth.com/journals/jinf
Anaemia, iron deficiency and susceptibility to infections € l Boele van Hensbroek* Femke A.M. Jonker, Michae Global Child Health Group, Department of Global Health, Emma Children’s Hospital/AMC, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands Available online - - -
KEYWORDS Anaemia; Iron deficiency; Iron supplementation; Infection risk; Immune system; Children
Summary Anaemia, iron deficiency and infections are three major causes of childhood morbidity and mortality throughout the world, although they predominantly occur in resource limited settings. As the three conditions may have the same underlying aetiologies, they often occur simultaneously and may interact. Being an essential component in erythropoiesis, iron is also essential for proper functioning of the host immune system as well as an essential nutrient for growth of various pathogens, including non-typhoid salmonella. This has resulted in a treatment dilemma in which iron is needed to treat the iron deficient anaemia and improve the immune system of the host (child), but the same treatment may also put the child at an increased, potentially fatal, infection risk. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Anaemia, iron deficiency and infections are three major causes of childhood morbidity and mortality throughout the world, although they predominantly occur in resource limited settings such as sub-Saharan Africa. As the three conditions may have the same underlying aetiologies, they often occur simultaneously and may interact. For example, iron deficiency can lead to anaemia and may also increase susceptibility to infection by suppressing the immunological response to pathogens.1 Conversely, treatment of iron deficiency has also been associated with an increased incidence of infection.2e7 After a short introduction on childhood anaemia, iron deficiency and infection risk, this chapter
will highlight some outstanding research questions which arise from their complex interaction.
Anaemia Anaemia is defined as a reduction in the amount of circulating haemoglobin8 resulting in a decrease in oxygen carrying capacity. Anaemia in children is a global public health problem especially affecting young children with a prevalence rate that can be as high as 70% in some communities.8 In sub-Saharan Africa severe anaemia is a major contributor to under 5 years mortality rates.9 Three mechanisms may lead to the development of anaemia, namely: an increased red blood cell destruction;
* Corresponding author. Tel.: þ31 205668220. E-mail addresses: [email protected] (F.A.M. Jonker), [email protected] (M. Boele van Hensbroek). http://dx.doi.org/10.1016/j.jinf.2014.08.007 0163-4453/ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
2
F.A.M. Jonker, M. Boele van Hensbroek
an impaired red blood cell production, and/or acute or chronic blood loss. Anaemia may have multiple aetiologies and should be considered as a syndrome rather than a specific disease. Since iron is essential for synthesis of haemoglobin, iron deficiency is often considered the primary cause of anaemia. As a consequence the terms anaemia, iron deficiency and iron deficiency anaemia are often interchanged. Besides confusing definitions, this approach is incorrect as anaemia can occur with sufficient iron stores and iron deficiency does not necessarily lead to anaemia, as in the initial stages of iron deficiency erythropoiesis is not restricted. For this reason anaemia and iron deficiency should be considered as distinct conditions. The possible aetiologies important in the development of anaemia are multiple, including: infections such as malaria,10 hookworm8 and HIV8; drugs such as antibiotics,11 tuberculostatics12 and antiretroviral drugs13; genetic disorders such as G6PD, alpha-thalassaemia and sickle cell disease14; and micronutrient deficiencies (iron, vitamin B12, folic acid and vitamin A). Despite the fact that multiple aetiologies contribute to the development of childhood anaemia in resource limited settings, the management of anaemia in these settings is often only focused on treatment and prevention of malaria and iron deficiency.
Iron deficiency Iron is essential for many biochemical processes including electron transfer reactions, gene regulation, binding and transport of oxygen, and regulation of cell growth and differentiation. Iron deficiency is defined as a state in which there are no available iron stores due to disturbance of the normally stable cycle of iron metabolism.15 Iron deficiency is considered to be the most common nutritional disorder worldwide, with children and pregnant women most at risk. As it may cause anaemia, affect the immune system and delay cognitive development, iron deficiency is a critical problem in child health.1,15 There are different factors and pathways that may disturb iron homeostasis and induce iron deficiency (Fig. 1). Physiological causes of iron deficiency include periods of increased demand during periods of rapid growth as during the first years of life, as well as inadequate supply (nutritional iron deficiency) or both so that diet does not cover physiological
requirements.16 This is an important cause of iron deficiency in sub-Saharan Africa, where limited bioavailability of iron from staple foods is common.8 Pathological iron deficiency can follow increased blood loss (e.g. gastrointestinal blood loss) due to enteric parasitic infections including hookworm.17,18 In addition to actual iron shortage, normal physiological systems for transporting iron to target tissues may be impaired in the presence of adequate iron stores.19 During the acute phase of an infection a pro-inflammatory cytokine response causes a decrease in intestinal iron absorption and decreased release from body iron stores.20 Such functional iron deficiency is discussed further below. High pressure of infection contributes to the high prevalence of (functional) iron deficiency in sub-Saharan Africa.
Iron deficiency and infection Iron deficiency limiting immunity Iron deficiency may increase risks of infection as iron is required for normal immune function including bactericidal activity of macrophages (iron is a critical component) of peroxide- and nitrous oxide-generating cellular enzymes1 and also for T-cell numbers and function. In Malawian HIV-infected anaemic children receiving iron supplementation, an increase in circulating CD-4 positive T-cell numbers was observed.21 Galan and colleagues (1992) reported reduced interleukin-2 production by activated lymphocytes in iron-deficient subjects.
Iron and pathogens Iron is also an essential nutrient for many pathogens. The specific strategies microbes use to sequester iron from the host depend considerably on whether the pathogen adopts a predominately intracellular or extracellular lifestyle as well as its preferred iron source.22 In a recent in vitro study, growth, adhesion, cellular invasion and epithelial translocation of Salmonella typhimurium were all increased in response to iron as was the growth of other pathogenic bacteria leading to the conclusion that the availability of iron may be correlated with virulence for several pathogens.23
Iron deficiency as an immune defence
Figure 1
Aetiology of iron deficiency.
The bacteriostatic effects of iron-binding proteins were first described in the mid-twentieth century.24 This “hypoferremia of infection,” a host-defence mechanism, is now known to be mediated largely by hepcidin a small 20e25 amino acid peptide predominantly expressed in hepatocytes in the liver.25e27 Hepcidin is also produced by other cell types (at much lower levels), including renal tubular, myocardial, retinal, alveolar and pancreatic cells, monocytes, neutrophils, and adipocytes.28e34 Through binding to the cellular iron transporter, ferroportin, in the small intestine, macrophages and bone marrow, hepcidin induces internalization and degradation of ferroportin and regulates cellular iron efflux.35 There are several factors that down regulate hepcidin expression including reduced iron
Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
Anaemia, iron deficiency and susceptibility to infections levels, increased erythropoiesis and hypoxia.36,37 Conversely it is up-regulated in association with increased iron levels and during inflammation35 (Fig. 2) thus withholding iron from possible pathogens by limiting absorption of iron from the intestinal tract and reducing the release of iron from stores; in other words generating functional iron deficiency. Several other hepcidin-independent defence mechanisms of this kind exist; cytokines such as interferon gamma (IFN-g), tumour necrosis factor alpha (TNF-a), interleukin-1 (IL-1), and IL-6 modulate iron metabolism to further strengthen iron-withholding defences.22 Activation of phagocytes at the site of infection also limits iron availability to intracellular pathogens.22 In addition to systemic induction of hypoferremia, innate immune effectors further sequester iron locally at infectious foci. The iron binding proteins transferrin, lactoferrin, and ferritin participate in the acute-phase response and represent a host defence against potential pathogens. The presence of lactoferrin in breast milk and other epithelium-protecting secretory fluids, together with its release by neutrophils at foci of infection, further support this theory38 which is further underpinned by clinical studies indicating that iron deficiency is associated with a reduced risk of malaria infection.39e42
Iron supplementation and infection In the late 1970s a positive association between iron supplementation and increased infection risk was observed.2 Nevertheless the benefit of iron supplementation was considered to outweigh possible increased infection risk. When in 2006, a large trial in Zanzibar reported that iron supplementation increased (mainly malaria related) morbidity and mortality in iron replete children,3 the World Health Organization restricted its recommendations for iron supplementation to children with proven iron deficient anaemia.4 In this context, it should be noted that evaluation of the safety of iron supplementation was not the primary objective of the Zanzibari trial. Recently, the safety of iron supplementation in HIV-infected anaemic children was evaluated. An increased risk of malaria infection was observed, although the investigators did not show
Figure 2
Regulatory pathways of hepcidin.
3 any increased risk of bacterial infections and observed a trend towards decreased incidence of respiratory infections.21 In another paediatric study, iron supplementation was associated with a potentially more pathogenic gut microbiota profile, mainly Salmonella spp.43 No significant increase in incidence of infection was observed although the sample size of the study was limited.44
The dilemma Clearly iron deficiency presents a conundrum: should one treat iron deficiency, which will, among other benefits, improve the function of the immune system, but which may also increase the likelihood of (potentially fatal) infections? This dilemma has been debated for over 40 years and a consensus has yet to be reached. Although a Cochrane meta-analysis reviewing iron supplementation in children in malaria endemic areas concluded that iron supplementation did not adversely affect children when adequate malaria surveillance was provided,45 the authors noted limited data on several aspects including baseline iron status and more recent studies which show a strong positive relationship between iron and susceptibility to malaria21 were not included. In addition, it is important to appreciate that iron status can be difficult to assess and is often poorly defined, particularly when infections are prevalent; studies investigating the effect of iron status on risk of infection are therefore difficult to compare. Other issues also contribute to the lack of consensus. Evolution forces a fine balance between provision of adequate iron for function of the biological systems of the host while hiding it by sequestration from potential pathogens. Thus the effects of iron supplementation are likely to be context-specific. Exposure to pathogens differs by location in the body and the pathogenic potential of different microbial species given iron likewise varies widely as has already been noted for malaria39,40 and respiratory infections.21 Whether a pathogen is intra- or extra cellular may be important in its relation to iron status. Risks related to intracellular pathogens such as Mycobacterium tuberculosis can be affected by host iron status.46 Non-typhoid Salmonella (NTS), also intra-cellular, benefits from sophisticated iron acquisition systems and it has been suggested that this pathogen may be responsible for part of the increased risk for malaria-associated morbidity and mortality with iron supplementation,46 although other factors including host genetic background, may also contribute.38,47 It is clear that the relationships between infections and iron deficiency are complex and bi-directional and that studies describing association may easily be confounded. While iron deficiency may have a protective effect, infections may themselves induce iron deficiency. Either indirectly, through increased hepcidin/cytokine production in response to inflammation48e51 or directly, for example through gastro-intestinal blood loss in hookworm infection. Studies showing that iron status affects risk of infection39,40 are likely to be context and population specific. For example in severely anaemic children hepcidin levels may be low even during concurrent severe infections, negating any protective effect of inhibited iron absorption and
Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
4 potentially increasing infection risk, while in non-severely anaemic children a contrary effect can be seen.52 The number of outstanding questions related to iron deficiency, anaemia and susceptibility to infections remains large. Consequently, good evidence-based guidelines for anaemia and iron deficiency treatment and prevention, are lacking. In order to develop them, there is an urgent need for more reliable data on the influence of iron status and iron supplementation on infection risk and anaemia resolution, using well-validated biomarkers.
F.A.M. Jonker, M. Boele van Hensbroek
16.
17.
18.
Conflict of interest None.
19.
References 20. 1. Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr 2001;131(2S-2): 568Se79S. 2. Murray MJ, Murray AB, Murray MB, Murray CJ. The adverse effect of iron repletion on the course of certain infections. Br Med J 1978;2(6145):1113e5. 3. Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, 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 Jan 14;367(9505):133e43. 4. WHO. Conclusions and recommendations of the WHO consultation on prevention and control of iron deficiency in infants and young children in malariaendemic areas. World Health Organization website Available: http://www.who.int/ nutrition/publications/micronutrients/FNBvol28N4supdec07. pdf [accessed: June 2006]. 5. Franchini M, Targher G, Capra F, Montagnana M, Lippi G. The effect of iron depletion on chronic hepatitis C virus infection. Hepatol Int 2008;2(3):335e40. 6. Nairz M, Theurl I, Ludwiczek S, Theurl M, Mair SM, Fritsche G, et al. The co-ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol 2007 Sep;9(9): 2126e40. 7. Ratledge C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb) 2004;84(1e2):110e30. 8. WHO. Worldwide prevalence of anaemia 1993e2005; 2005. Available: www.who.int/entity/wormcontrol/documents/ joint_statements/en/ppc_unicef_finalreport.pdf. 9. Phiri KS, Calis JC, Faragher B, Nkhoma E, Ng’oma K, Mangochi B, et al. Long term outcome of severe anaemia in Malawian children. PLoS One 2008;3(8):e2903. 10. Menendez C, Fleming AF, Alonso PL. Malaria-related anaemia. Parasitol Today 2000;16(11):469e76. 11. Ahmed SG, Ibrahim UA. Bone marrow morphological features in anaemic patients with acquired immune deficiency syndrome in Nigeria. Niger Postgrad Med J 2001;8(3):112e5. 12. Knox-Macaulay HH. Tuberculosis and the haemopoietic system. Baillieres Clin Haematol 1992;5(1):101e29. 13. Shah I. Adverse effects of antiretroviral therapy in HIV-1 infected children. J Trop Pediatr 2006;52(4):244e8. 14. Flint J, Harding RM, Boyce AJ, Clegg JB. The population genetics of the haemoglobinopathies. Baillieres Clin Haematol 1998;11(1):1e51. 15. WHO. Iron deficiency aneamia, assessment, prevention and control, a guide for programme managers; 2001. Available:
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http://www.who.int/nutrition/publications/micronutrients/ anaemia_iron_deficiency/WHO_NHD_01.3/en/index.html. Duggan C, John B, Watkins W, Walker A. Nutrition in pediatrics 4, basic science, clinical applications; 2012. p. 84e98. Albonico M, Stoltzfus RJ, Savioli L, Tielsch JM, Chwaya HM, Ercole E, et al. Epidemiological evidence for a differential effect of hookworm species, Ancylostoma duodenale or Necator americanus, on iron status of children. Int J Epidemiol 1998 Jun;27(3):530e7. Jonker FA, Calis JC, Phiri K, Brienen EA, Khoffi H, Brabin BJ, et al. Real-time PCR demonstrates Ancylostoma duodenale is a key factor in the etiology of severe anemia and iron deficiency in Malawian pre-school children. PLoS Negl Trop Dis 2012;6(3):e1555. WHO. Assessing the iron status of populations, second edition of the World Health Organization; 2004. Available: http:// www.who.int/nutrition/publications/micronutrients/ anaemia_iron_deficiency/9789241596107/en/index.html. Trey JE, Kushner I. The acute phase response and the hematopoietic system: the role of cytokines. Crit Rev Oncol Hematol 1995;21(1e3):1e18. Esan MO, van Hensbroek MB, Nkhoma E, Musicha C, White SA, Ter Kuile FO, et al. Iron supplementation in HIV-infected Malawian children with anemia: a double-blind, randomized, controlled trial. Clin Infect Dis 2013 Dec;57(11):1626e34. Cassat JE, Skaar EP. Iron in infection and immunity. Cell Host Microbe 2013;13(5):509e19. Kortman GA, Boleij A, Swinkels DW, Tjalsma H. Iron availability increases the pathogenic potential of Salmonella typhimurium and other enteric pathogens at the intestinal epithelial interface. PLoS One 2012;7(1):e29968. Schade AL, Caroline L. Raw hen egg white and the role of rion in growth inhibition of shigella dysenteriae, staphylococcus aureaus escherichia coli and saccharomyces cerevisiae. Science 1944;100(2584):14e5. Nicolas G, Bennoun M, Devaux I, Beaumont C, Grandchamp B, Kahn A, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A 2001 Jul 17;98(15): 8780e5. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276(11):7806e10. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001 Mar 16; 276(11):7811e9. Bekri S, Gual P, Anty R, Luciani N, Dahman M, Ramesh B, et al. Increased adipose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology 2006 Sep;131(3):788e96. Gnana-Prakasam JP, Martin PM, Mysona BA, Roon P, Smith SB, Ganapathy V. Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor4 pathway independent of Hfe. Biochem J 2008;411(1): 79e88. Isoda M, Hanawa H, Watanabe R, Yoshida T, Toba K, Yoshida K, et al. Expression of the peptide hormone hepcidin increases in cardiomyocytes under myocarditis and myocardial infarction. J Nutr Biochem 2010 Aug;21(8):749e56. Kulaksiz H, Theilig F, Bachmann S, Gehrke SG, Rost D, Janetzko A, et al. The iron-regulatory peptide hormone hepcidin: expression and cellular localization in the mammalian kidney. J Endocrinol 2005 Feb;184(2):361e70. Merle U, Fein E, Gehrke SG, Stremmel W, Kulaksiz H. The iron regulatory peptide hepcidin is expressed in the heart and
Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
Anaemia, iron deficiency and susceptibility to infections
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regulated by hypoxia and inflammation. Endocrinology 2007; 148(6):2663e8. Nguyen NB, Callaghan KD, Ghio AJ, Haile DJ, Yang F. Hepcidin expression and iron transport in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 2006;291(3):L417e25. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 2007 Jul;117(7):1926e32. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004 Dec 17;306(5704):2090e3. Kroot JJ, Tjalsma H, Fleming RE, Swinkels DW. Hepcidin in human iron disorders: diagnostic implications. Clin Chem 2011; 57(12):1650e69. Nicolas G, Bennoun M, Porteu A, Mativet S, Beaumont C, Grandchamp B, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A 2002 Apr 2;99(7):4596e601. Drakesmith H, Prentice AM. Hepcidin and the iron-infection axis. Science 2012;338(6108):768e72. Gwamaka M, Kurtis JD, Sorensen BE, Holte S, Morrison R, Mutabingwa TK, et al. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin Infect Dis 2012 Apr;54(8):1137e44. Jonker FA, Calis JC, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, et al. Iron status predicts malaria risk in Malawian preschool children. PLoS One 2012;7(8):e42670. Kabyemela ER, Fried M, Kurtis JD, Mutabingwa TK, Duffy PE. Decreased susceptibility to Plasmodium falciparum infection in pregnant women with iron deficiency. J Infect Dis 2008; 198(2):163e6. Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Back R, Kortok M, et al. Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis 2004 Aug 1;190(3):439e47.
5 43. Zimmermann MB, Chassard C, Rohner F, N’goran EK, Nindjin C, Dostal A, et al. 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 Dec; 92(6):1406e15. 44. Dewey KG, Baldiviez LM. Safety of universal provision of iron through home fortification of complementary foods in malaria-endemic areas. Adv Nutr 2012;3(4):555e9. 45. Okebe JU, Yahav D, Shbita R, Paul M. Oral iron supplements for children in malaria-endemic areas. Cochrane Database Syst Rev 2011;(10):CD006589. 46. van Santen S, de MQ, Swinkels DW, van der Ven AJ. The iron link between malaria and invasive non-typhoid Salmonella infections. Trends Parasitol 2013;29(5):220e7. 47. McDermid JM, Prentice AM. Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV. Clin Sci (Lond) 2006;110(5):503e24. 48. Fuchs D, Hausen A, Reibnegger G, Werner ER, WernerFelmayer G, Dierich MP, et al. Immune activation and the anaemia associated with chronic inflammatory disorders. Eur J Haematol 1991 Feb;46(2):65e70. 49. Cercamondi CI, Egli IM, Ahouandjinou E, Dossa R, Zeder C, Salami L, et al. 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 Dec;92(6):1385e92. 50. Doherty CP, Cox SE, Fulford AJ, Austin S, Hilmers DC, Abrams SA, et al. Iron incorporation and post-malaria anaemia. PLoS One 2008;3(5):e2133. 51. Nweneka CV, Doherty CP, Cox S, Prentice A. Iron delocalisation in the pathogenesis of malarial anaemia. Trans R Soc Trop Med Hyg 2010;104(3):175e84. 52. Prentice AM, Doherty CP, Abrams SA, Cox SE, Atkinson SH, Verhoef H, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood 2012 Feb 23;119(8).
Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
www.elsevierhealth.com/journals/jinf
Anaemia, iron deficiency and susceptibility to infections € l Boele van Hensbroek* Femke A.M. Jonker, Michae Global Child Health Group, Department of Global Health, Emma Children’s Hospital/AMC, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands Available online - - -
KEYWORDS Anaemia; Iron deficiency; Iron supplementation; Infection risk; Immune system; Children
Summary Anaemia, iron deficiency and infections are three major causes of childhood morbidity and mortality throughout the world, although they predominantly occur in resource limited settings. As the three conditions may have the same underlying aetiologies, they often occur simultaneously and may interact. Being an essential component in erythropoiesis, iron is also essential for proper functioning of the host immune system as well as an essential nutrient for growth of various pathogens, including non-typhoid salmonella. This has resulted in a treatment dilemma in which iron is needed to treat the iron deficient anaemia and improve the immune system of the host (child), but the same treatment may also put the child at an increased, potentially fatal, infection risk. ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Introduction Anaemia, iron deficiency and infections are three major causes of childhood morbidity and mortality throughout the world, although they predominantly occur in resource limited settings such as sub-Saharan Africa. As the three conditions may have the same underlying aetiologies, they often occur simultaneously and may interact. For example, iron deficiency can lead to anaemia and may also increase susceptibility to infection by suppressing the immunological response to pathogens.1 Conversely, treatment of iron deficiency has also been associated with an increased incidence of infection.2e7 After a short introduction on childhood anaemia, iron deficiency and infection risk, this chapter
will highlight some outstanding research questions which arise from their complex interaction.
Anaemia Anaemia is defined as a reduction in the amount of circulating haemoglobin8 resulting in a decrease in oxygen carrying capacity. Anaemia in children is a global public health problem especially affecting young children with a prevalence rate that can be as high as 70% in some communities.8 In sub-Saharan Africa severe anaemia is a major contributor to under 5 years mortality rates.9 Three mechanisms may lead to the development of anaemia, namely: an increased red blood cell destruction;
* Corresponding author. Tel.: þ31 205668220. E-mail addresses: [email protected] (F.A.M. Jonker), [email protected] (M. Boele van Hensbroek). http://dx.doi.org/10.1016/j.jinf.2014.08.007 0163-4453/ª 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved. Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
2
F.A.M. Jonker, M. Boele van Hensbroek
an impaired red blood cell production, and/or acute or chronic blood loss. Anaemia may have multiple aetiologies and should be considered as a syndrome rather than a specific disease. Since iron is essential for synthesis of haemoglobin, iron deficiency is often considered the primary cause of anaemia. As a consequence the terms anaemia, iron deficiency and iron deficiency anaemia are often interchanged. Besides confusing definitions, this approach is incorrect as anaemia can occur with sufficient iron stores and iron deficiency does not necessarily lead to anaemia, as in the initial stages of iron deficiency erythropoiesis is not restricted. For this reason anaemia and iron deficiency should be considered as distinct conditions. The possible aetiologies important in the development of anaemia are multiple, including: infections such as malaria,10 hookworm8 and HIV8; drugs such as antibiotics,11 tuberculostatics12 and antiretroviral drugs13; genetic disorders such as G6PD, alpha-thalassaemia and sickle cell disease14; and micronutrient deficiencies (iron, vitamin B12, folic acid and vitamin A). Despite the fact that multiple aetiologies contribute to the development of childhood anaemia in resource limited settings, the management of anaemia in these settings is often only focused on treatment and prevention of malaria and iron deficiency.
Iron deficiency Iron is essential for many biochemical processes including electron transfer reactions, gene regulation, binding and transport of oxygen, and regulation of cell growth and differentiation. Iron deficiency is defined as a state in which there are no available iron stores due to disturbance of the normally stable cycle of iron metabolism.15 Iron deficiency is considered to be the most common nutritional disorder worldwide, with children and pregnant women most at risk. As it may cause anaemia, affect the immune system and delay cognitive development, iron deficiency is a critical problem in child health.1,15 There are different factors and pathways that may disturb iron homeostasis and induce iron deficiency (Fig. 1). Physiological causes of iron deficiency include periods of increased demand during periods of rapid growth as during the first years of life, as well as inadequate supply (nutritional iron deficiency) or both so that diet does not cover physiological
requirements.16 This is an important cause of iron deficiency in sub-Saharan Africa, where limited bioavailability of iron from staple foods is common.8 Pathological iron deficiency can follow increased blood loss (e.g. gastrointestinal blood loss) due to enteric parasitic infections including hookworm.17,18 In addition to actual iron shortage, normal physiological systems for transporting iron to target tissues may be impaired in the presence of adequate iron stores.19 During the acute phase of an infection a pro-inflammatory cytokine response causes a decrease in intestinal iron absorption and decreased release from body iron stores.20 Such functional iron deficiency is discussed further below. High pressure of infection contributes to the high prevalence of (functional) iron deficiency in sub-Saharan Africa.
Iron deficiency and infection Iron deficiency limiting immunity Iron deficiency may increase risks of infection as iron is required for normal immune function including bactericidal activity of macrophages (iron is a critical component) of peroxide- and nitrous oxide-generating cellular enzymes1 and also for T-cell numbers and function. In Malawian HIV-infected anaemic children receiving iron supplementation, an increase in circulating CD-4 positive T-cell numbers was observed.21 Galan and colleagues (1992) reported reduced interleukin-2 production by activated lymphocytes in iron-deficient subjects.
Iron and pathogens Iron is also an essential nutrient for many pathogens. The specific strategies microbes use to sequester iron from the host depend considerably on whether the pathogen adopts a predominately intracellular or extracellular lifestyle as well as its preferred iron source.22 In a recent in vitro study, growth, adhesion, cellular invasion and epithelial translocation of Salmonella typhimurium were all increased in response to iron as was the growth of other pathogenic bacteria leading to the conclusion that the availability of iron may be correlated with virulence for several pathogens.23
Iron deficiency as an immune defence
Figure 1
Aetiology of iron deficiency.
The bacteriostatic effects of iron-binding proteins were first described in the mid-twentieth century.24 This “hypoferremia of infection,” a host-defence mechanism, is now known to be mediated largely by hepcidin a small 20e25 amino acid peptide predominantly expressed in hepatocytes in the liver.25e27 Hepcidin is also produced by other cell types (at much lower levels), including renal tubular, myocardial, retinal, alveolar and pancreatic cells, monocytes, neutrophils, and adipocytes.28e34 Through binding to the cellular iron transporter, ferroportin, in the small intestine, macrophages and bone marrow, hepcidin induces internalization and degradation of ferroportin and regulates cellular iron efflux.35 There are several factors that down regulate hepcidin expression including reduced iron
Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007
Anaemia, iron deficiency and susceptibility to infections levels, increased erythropoiesis and hypoxia.36,37 Conversely it is up-regulated in association with increased iron levels and during inflammation35 (Fig. 2) thus withholding iron from possible pathogens by limiting absorption of iron from the intestinal tract and reducing the release of iron from stores; in other words generating functional iron deficiency. Several other hepcidin-independent defence mechanisms of this kind exist; cytokines such as interferon gamma (IFN-g), tumour necrosis factor alpha (TNF-a), interleukin-1 (IL-1), and IL-6 modulate iron metabolism to further strengthen iron-withholding defences.22 Activation of phagocytes at the site of infection also limits iron availability to intracellular pathogens.22 In addition to systemic induction of hypoferremia, innate immune effectors further sequester iron locally at infectious foci. The iron binding proteins transferrin, lactoferrin, and ferritin participate in the acute-phase response and represent a host defence against potential pathogens. The presence of lactoferrin in breast milk and other epithelium-protecting secretory fluids, together with its release by neutrophils at foci of infection, further support this theory38 which is further underpinned by clinical studies indicating that iron deficiency is associated with a reduced risk of malaria infection.39e42
Iron supplementation and infection In the late 1970s a positive association between iron supplementation and increased infection risk was observed.2 Nevertheless the benefit of iron supplementation was considered to outweigh possible increased infection risk. When in 2006, a large trial in Zanzibar reported that iron supplementation increased (mainly malaria related) morbidity and mortality in iron replete children,3 the World Health Organization restricted its recommendations for iron supplementation to children with proven iron deficient anaemia.4 In this context, it should be noted that evaluation of the safety of iron supplementation was not the primary objective of the Zanzibari trial. Recently, the safety of iron supplementation in HIV-infected anaemic children was evaluated. An increased risk of malaria infection was observed, although the investigators did not show
Figure 2
Regulatory pathways of hepcidin.
3 any increased risk of bacterial infections and observed a trend towards decreased incidence of respiratory infections.21 In another paediatric study, iron supplementation was associated with a potentially more pathogenic gut microbiota profile, mainly Salmonella spp.43 No significant increase in incidence of infection was observed although the sample size of the study was limited.44
The dilemma Clearly iron deficiency presents a conundrum: should one treat iron deficiency, which will, among other benefits, improve the function of the immune system, but which may also increase the likelihood of (potentially fatal) infections? This dilemma has been debated for over 40 years and a consensus has yet to be reached. Although a Cochrane meta-analysis reviewing iron supplementation in children in malaria endemic areas concluded that iron supplementation did not adversely affect children when adequate malaria surveillance was provided,45 the authors noted limited data on several aspects including baseline iron status and more recent studies which show a strong positive relationship between iron and susceptibility to malaria21 were not included. In addition, it is important to appreciate that iron status can be difficult to assess and is often poorly defined, particularly when infections are prevalent; studies investigating the effect of iron status on risk of infection are therefore difficult to compare. Other issues also contribute to the lack of consensus. Evolution forces a fine balance between provision of adequate iron for function of the biological systems of the host while hiding it by sequestration from potential pathogens. Thus the effects of iron supplementation are likely to be context-specific. Exposure to pathogens differs by location in the body and the pathogenic potential of different microbial species given iron likewise varies widely as has already been noted for malaria39,40 and respiratory infections.21 Whether a pathogen is intra- or extra cellular may be important in its relation to iron status. Risks related to intracellular pathogens such as Mycobacterium tuberculosis can be affected by host iron status.46 Non-typhoid Salmonella (NTS), also intra-cellular, benefits from sophisticated iron acquisition systems and it has been suggested that this pathogen may be responsible for part of the increased risk for malaria-associated morbidity and mortality with iron supplementation,46 although other factors including host genetic background, may also contribute.38,47 It is clear that the relationships between infections and iron deficiency are complex and bi-directional and that studies describing association may easily be confounded. While iron deficiency may have a protective effect, infections may themselves induce iron deficiency. Either indirectly, through increased hepcidin/cytokine production in response to inflammation48e51 or directly, for example through gastro-intestinal blood loss in hookworm infection. Studies showing that iron status affects risk of infection39,40 are likely to be context and population specific. For example in severely anaemic children hepcidin levels may be low even during concurrent severe infections, negating any protective effect of inhibited iron absorption and
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4 potentially increasing infection risk, while in non-severely anaemic children a contrary effect can be seen.52 The number of outstanding questions related to iron deficiency, anaemia and susceptibility to infections remains large. Consequently, good evidence-based guidelines for anaemia and iron deficiency treatment and prevention, are lacking. In order to develop them, there is an urgent need for more reliable data on the influence of iron status and iron supplementation on infection risk and anaemia resolution, using well-validated biomarkers.
F.A.M. Jonker, M. Boele van Hensbroek
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Conflict of interest None.
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Please cite this article in press as: Jonker FAM, Boele van Hensbroek M, Anaemia, iron deficiency and susceptibility to infections, J Infect (2014), http://dx.doi.org/10.1016/j.jinf.2014.08.007