Skip to main content
Top
Published in: Malaria Journal 1/2018

Open Access 01-12-2018 | Research

Malaria causes long-term effects on markers of iron status in children: a critical assessment of existing clinical and epidemiological tools

Published in: Malaria Journal | Issue 1/2018

Login to get access

Abstract

Background

Most epidemiological studies on the interplay between iron deficiency and malaria risk classify individuals as iron-deficient or iron-replete based on inflammation-dependent iron markers and adjustment for inflammation by using C-reactive protein (CRP) or α-1-acid glycoprotein (AGP). The validity of this approach and the usefulness of fibroblast growth factor 23 (FGF23) as a proposed inflammation-independent iron marker were tested.

Methods

Conventional iron markers and FGF23 were measured in children with acute falciparum malaria and after 1, 2, 4, and 6 weeks. Children, who were transfused or received iron supplementation in the follow-up period, were excluded, and iron stores were considered to be stable throughout. Ferritin levels 6 weeks after admission were used as a reference for admission iron status and compared with iron markers at different time points.

Results

There were long-term perturbations in iron markers during convalescence from acute malaria. None of the tested iron parameters, including FGF23, were independent of inflammation. CRP and AGP normalized faster than ferritin after malaria episodes.

Conclusion

Malaria may bias epidemiological studies based on inflammation-dependent iron markers. Better markers of iron status during and after inflammation are needed in order to test strategies for iron supplementation in populations at risk of malaria.
Literature
1.
go back to reference Halterman JS, Kaczorowski JM, Aligne CA, Auinger P, Szilagyi PG. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics. 2001;107:1381–6.PubMed Halterman JS, Kaczorowski JM, Aligne CA, Auinger P, Szilagyi PG. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics. 2001;107:1381–6.PubMed
3.
go back to reference Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011;141:740S–6S.PubMedPubMedCentral Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr. 2011;141:740S–6S.PubMedPubMedCentral
4.
go back to reference Doom JR, Georgieff MK. Striking while the iron is hot: understanding the biological and neurodevelopmental effects of iron deficiency to optimize intervention in early childhood. Curr Pediatr Rep. 2014;2:291–8.PubMedPubMedCentral Doom JR, Georgieff MK. Striking while the iron is hot: understanding the biological and neurodevelopmental effects of iron deficiency to optimize intervention in early childhood. Curr Pediatr Rep. 2014;2:291–8.PubMedPubMedCentral
5.
go back to reference Jonker FAM, Boele van Hensbroek M. Anaemia, iron deficiency and susceptibility to infections. J Infect. 2014;69(Suppl 1):S23–7.PubMed Jonker FAM, Boele van Hensbroek M. Anaemia, iron deficiency and susceptibility to infections. J Infect. 2014;69(Suppl 1):S23–7.PubMed
6.
go back to reference Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Bäck R, Kortok M, et al. Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis. 2004;190:439–47.PubMed Nyakeriga AM, Troye-Blomberg M, Dorfman JR, Alexander ND, Bäck R, Kortok M, et al. Iron deficiency and malaria among children living on the coast of Kenya. J Infect Dis. 2004;190:439–47.PubMed
7.
go back to reference 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;54:1137–44.PubMedPubMedCentral 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;54:1137–44.PubMedPubMedCentral
8.
go back to reference Jonker FAM, Calis JCJ, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, et al. Iron status predicts malaria risk in Malawian preschool children. PLoS ONE. 2012;7:e42670.PubMedPubMedCentral Jonker FAM, Calis JCJ, van Hensbroek MB, Phiri K, Geskus RB, Brabin BJ, et al. Iron status predicts malaria risk in Malawian preschool children. PLoS ONE. 2012;7:e42670.PubMedPubMedCentral
9.
go back to reference Moya-Alvarez V, Cottrell G, Ouédraogo S, Accrombessi M, Massougbodgi A, Cot M. High iron levels are associated with increased malaria risk in infants during the first year of life in Benin. Am J Trop Med Hyg. 2017;97:497–503.PubMedPubMedCentral Moya-Alvarez V, Cottrell G, Ouédraogo S, Accrombessi M, Massougbodgi A, Cot M. High iron levels are associated with increased malaria risk in infants during the first year of life in Benin. Am J Trop Med Hyg. 2017;97:497–503.PubMedPubMedCentral
10.
go back to reference Barffour MA, Schulze KJ, Coles CL, Chileshe J, Kalungwana N, Arguello M, et al. High iron stores in the low malaria season increase malaria risk in the high transmission season in a prospective cohort of rural Zambian children. J Nutr. 2017;147:1531–6.PubMed Barffour MA, Schulze KJ, Coles CL, Chileshe J, Kalungwana N, Arguello M, et al. High iron stores in the low malaria season increase malaria risk in the high transmission season in a prospective cohort of rural Zambian children. J Nutr. 2017;147:1531–6.PubMed
11.
go back to reference Das BS, Thurnham DI, Das DB. Influence of malaria on markers of iron status in children: implications for interpreting iron status in malaria-endemic communities. Br J Nutr. 1997;78:751–60.PubMed Das BS, Thurnham DI, Das DB. Influence of malaria on markers of iron status in children: implications for interpreting iron status in malaria-endemic communities. Br J Nutr. 1997;78:751–60.PubMed
12.
go back to reference Kung’u JK, Wright VJ, Haji HJ, Ramsan M, Goodman D, Tielsch JM, et al. Adjusting for the acute phase response is essential to interpret iron status indicators among young Zanzibari children prone to chronic malaria and helminth infections. J Nutr. 2009;139:2124–31.PubMed Kung’u JK, Wright VJ, Haji HJ, Ramsan M, Goodman D, Tielsch JM, et al. Adjusting for the acute phase response is essential to interpret iron status indicators among young Zanzibari children prone to chronic malaria and helminth infections. J Nutr. 2009;139:2124–31.PubMed
13.
go back to reference 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;367:133–43.PubMed 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;367:133–43.PubMed
15.
go back to reference Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6:748–73.PubMed Kell DB, Pretorius E. Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics. 2014;6:748–73.PubMed
16.
go back to reference Namaste SM, Aaron GJ, Varadhan R, Peerson JM, Suchdev PS, BRINDA Working Group. Methodologic approach for the biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. Am J Clin Nutr. 2017;106:333S–47S.PubMedPubMedCentral Namaste SM, Aaron GJ, Varadhan R, Peerson JM, Suchdev PS, BRINDA Working Group. Methodologic approach for the biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. Am J Clin Nutr. 2017;106:333S–47S.PubMedPubMedCentral
17.
go back to reference Drakesmith H. Next-generation biomarkers for iron status. Nestle Nutr Inst Workshop Ser. 2016;84:59–69.PubMed Drakesmith H. Next-generation biomarkers for iron status. Nestle Nutr Inst Workshop Ser. 2016;84:59–69.PubMed
18.
go back to reference 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;119:1922–8.PubMedPubMedCentral 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;119:1922–8.PubMedPubMedCentral
19.
go back to reference Jonker FAM, Calis JCJ, Phiri K, Kraaijenhagen RJ, Brabin BJ, Faragher B, et al. Low hepcidin levels in severely anemic Malawian children with high incidence of infectious diseases and bone marrow iron deficiency. PLoS ONE. 2013;8:e78964.PubMedPubMedCentral Jonker FAM, Calis JCJ, Phiri K, Kraaijenhagen RJ, Brabin BJ, Faragher B, et al. Low hepcidin levels in severely anemic Malawian children with high incidence of infectious diseases and bone marrow iron deficiency. PLoS ONE. 2013;8:e78964.PubMedPubMedCentral
20.
go back to reference Braithwaite V, Prentice AM, Doherty C, Prentice A. FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. Int J Pediatr Endocrinol. 2012;2012:27.PubMedPubMedCentral Braithwaite V, Prentice AM, Doherty C, Prentice A. FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. Int J Pediatr Endocrinol. 2012;2012:27.PubMedPubMedCentral
22.
go back to reference Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, et al. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS ONE. 2008;3:e4000.PubMedPubMedCentral Kweku M, Liu D, Adjuik M, Binka F, Seidu M, Greenwood B, et al. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. PLoS ONE. 2008;3:e4000.PubMedPubMedCentral
23.
go back to reference WHO. Guidelines for the treatment of malaria. 3rd ed. Geneva: World Health Organization; 2015. p. 1–317. WHO. Guidelines for the treatment of malaria. 3rd ed. Geneva: World Health Organization; 2015. p. 1–317.
24.
go back to reference Gibbs WN. The methylene blue reduction test: evaluation of a screening method for glucose-6-phosphate dehydrogenase deficiency. Am J Trop Med Hyg. 1974;23:1197–202.PubMed Gibbs WN. The methylene blue reduction test: evaluation of a screening method for glucose-6-phosphate dehydrogenase deficiency. Am J Trop Med Hyg. 1974;23:1197–202.PubMed
25.
go back to reference Kurtzhals JA, Rodrigues O, Addae M, Commey JO, Nkrumah FK, Hviid L. Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria. Br J Haematol. 1997;97:169–74.PubMed Kurtzhals JA, Rodrigues O, Addae M, Commey JO, Nkrumah FK, Hviid L. Reversible suppression of bone marrow response to erythropoietin in Plasmodium falciparum malaria. Br J Haematol. 1997;97:169–74.PubMed
26.
go back to reference Thurnham DI, Northrop-Clewes CA, Knowles J. The use of adjustment factors to address the impact of inflammation on vitamin A and iron status in humans. J Nutr. 2015;145:1137S–43S.PubMedPubMedCentral Thurnham DI, Northrop-Clewes CA, Knowles J. The use of adjustment factors to address the impact of inflammation on vitamin A and iron status in humans. J Nutr. 2015;145:1137S–43S.PubMedPubMedCentral
27.
go back to reference Namaste SM, Rohner F, Huang J, Bhushan NL, Flores-Ayala R, Kupka R, et al. Adjusting ferritin concentrations for inflammation: biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. Am J Clin Nutr. 2017;106:359S–71S.PubMedPubMedCentral Namaste SM, Rohner F, Huang J, Bhushan NL, Flores-Ayala R, Kupka R, et al. Adjusting ferritin concentrations for inflammation: biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. Am J Clin Nutr. 2017;106:359S–71S.PubMedPubMedCentral
28.
go back to reference Grant FKE, Suchdev PS, Flores-Ayala R, Cole CR, Ramakrishnan U, Ruth LJ, et al. Correcting for inflammation changes estimates of iron deficiency among rural Kenyan preschool children. J Nutr. 2012;142:105–11.PubMed Grant FKE, Suchdev PS, Flores-Ayala R, Cole CR, Ramakrishnan U, Ruth LJ, et al. Correcting for inflammation changes estimates of iron deficiency among rural Kenyan preschool children. J Nutr. 2012;142:105–11.PubMed
29.
go back to reference Thurnham DI, McCabe LD, Haldar S, Wieringa FT, Northrop-Clewes CA, McCabe GP. Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis. Am J Clin Nutr. 2010;92:546–55.PubMed Thurnham DI, McCabe LD, Haldar S, Wieringa FT, Northrop-Clewes CA, McCabe GP. Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis. Am J Clin Nutr. 2010;92:546–55.PubMed
30.
go back to reference Elin RJ, Wolff SM, Finch CA. Effect of induced fever on serum iron and ferritin concentrations in man. Blood. 1977;49:147–53.PubMed Elin RJ, Wolff SM, Finch CA. Effect of induced fever on serum iron and ferritin concentrations in man. Blood. 1977;49:147–53.PubMed
31.
go back to reference Birgegård G, Hällgren R, Venge P, Wide L. Serum ferritin during inflammation. A study on myocardial infarction. Acta Med Scand. 1979;206:361–6.PubMed Birgegård G, Hällgren R, Venge P, Wide L. Serum ferritin during inflammation. A study on myocardial infarction. Acta Med Scand. 1979;206:361–6.PubMed
32.
go back to reference van Iperen CE, Kraaijenhagen RJ, Biesma DH, Beguin Y, Marx JJ, van de Wiel A. Iron metabolism and erythropoiesis after surgery. Br J Surg. 1998;85:41–5.PubMed van Iperen CE, Kraaijenhagen RJ, Biesma DH, Beguin Y, Marx JJ, van de Wiel A. Iron metabolism and erythropoiesis after surgery. Br J Surg. 1998;85:41–5.PubMed
33.
go back to reference Birgegård G, Hällgren R, Killander A, Strömberg A, Venge P, Wide L. Serum ferritin during infection. A longitudinal study. Scand J Haematol. 1978;21:333–40.PubMed Birgegård G, Hällgren R, Killander A, Strömberg A, Venge P, Wide L. Serum ferritin during infection. A longitudinal study. Scand J Haematol. 1978;21:333–40.PubMed
34.
go back to reference Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens. 2014;23:411–9.PubMedPubMedCentral Wolf M, White KE. Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease. Curr Opin Nephrol Hypertens. 2014;23:411–9.PubMedPubMedCentral
35.
go back to reference David V, Francis C, Babitt JL. Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol. 2017;312:F1–8.PubMed David V, Francis C, Babitt JL. Ironing out the cross talk between FGF23 and inflammation. Am J Physiol Renal Physiol. 2017;312:F1–8.PubMed
36.
go back to reference Castberg FC, Maretty L, Staalsoe T, Hempel C, Clasen-Linde E, Hviid L, Kurtzhals JAL. Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation. Malar J. 2018;17:34.PubMedPubMedCentral Castberg FC, Maretty L, Staalsoe T, Hempel C, Clasen-Linde E, Hviid L, Kurtzhals JAL. Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation. Malar J. 2018;17:34.PubMedPubMedCentral
37.
go back to reference Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta. 2003;329:9–22.PubMed Beguin Y. Soluble transferrin receptor for the evaluation of erythropoiesis and iron status. Clin Chim Acta. 2003;329:9–22.PubMed
38.
go back to reference Skikne BS. Serum transferrin receptor. Am J Hematol. 2008;83:872–5.PubMed Skikne BS. Serum transferrin receptor. Am J Hematol. 2008;83:872–5.PubMed
39.
go back to reference Menendez C, Quinto LL, Kahigwa E, Alvarez L, Fernandez R, Gimenez N, et al. Effect of malaria on soluble transferrin receptor levels in Tanzanian infants. Am J Trop Med Hyg. 2001;65:138–42.PubMed Menendez C, Quinto LL, Kahigwa E, Alvarez L, Fernandez R, Gimenez N, et al. Effect of malaria on soluble transferrin receptor levels in Tanzanian infants. Am J Trop Med Hyg. 2001;65:138–42.PubMed
40.
go back to reference Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052–7.PubMed Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052–7.PubMed
41.
go back to reference Rehman K, Lötsch F, Kremsner PG, Ramharter M. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis. 2014;29:268–73.PubMed Rehman K, Lötsch F, Kremsner PG, Ramharter M. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis. 2014;29:268–73.PubMed
42.
go back to reference Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel J, et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat Commun. 2014;5:4446.PubMed Clark MA, Goheen MM, Fulford A, Prentice AM, Elnagheeb MA, Patel J, et al. Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum. Nat Commun. 2014;5:4446.PubMed
43.
go back to reference Maretty L, Sharp RE, Andersson M, Kurtzhals JAL. Intravenous ferric carboxymaltose accelerates erythropoietic recovery from experimental malarial anemia. J Infect Dis. 2012;205:1173–7.PubMed Maretty L, Sharp RE, Andersson M, Kurtzhals JAL. Intravenous ferric carboxymaltose accelerates erythropoietic recovery from experimental malarial anemia. J Infect Dis. 2012;205:1173–7.PubMed
44.
go back to reference Atkinson SH, Armitage AE, Khandwala S, Mwangi TW, Uyoga S, Bejon PA, et al. Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children. Blood. 2014;123:3221–9.PubMedPubMedCentral Atkinson SH, Armitage AE, Khandwala S, Mwangi TW, Uyoga S, Bejon PA, et al. Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children. Blood. 2014;123:3221–9.PubMedPubMedCentral
45.
go back to reference Glinz D, Kamiyango M, Phiri KS, Munthali F, Zeder C, Zimmermann MB, et al. The effect of timing of iron supplementation on iron absorption and haemoglobin in post-malaria anaemia: a longitudinal stable isotope study in Malawian toddlers. Malar J. 2014;13:397.PubMedPubMedCentral Glinz D, Kamiyango M, Phiri KS, Munthali F, Zeder C, Zimmermann MB, et al. The effect of timing of iron supplementation on iron absorption and haemoglobin in post-malaria anaemia: a longitudinal stable isotope study in Malawian toddlers. Malar J. 2014;13:397.PubMedPubMedCentral
46.
go back to reference WHO Multicentre Growth Reference Study Group. WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization; 2006. WHO Multicentre Growth Reference Study Group. WHO child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development. Geneva: World Health Organization; 2006.
Metadata
Title
Malaria causes long-term effects on markers of iron status in children: a critical assessment of existing clinical and epidemiological tools
Publication date
01-12-2018
Published in
Malaria Journal / Issue 1/2018
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-018-2609-6

Other articles of this Issue 1/2018

Malaria Journal 1/2018 Go to the issue