Biology of Anemia: A Public Health Perspective.

Our goal is to present recent progress in understanding the biological mechanisms underlying anemia from a public health perspective. We describe important advances in understanding common causes of anemia and their interactions, including iron deficiency (ID), lack of other micronutrients, infection, inflammation, and genetic conditions. ID develops if the iron circulating in the blood cannot provide the amounts required for red blood cell production and tissue needs. ID anemia develops as iron-limited red blood cell production fails to maintain the hemoglobin concentration above the threshold used to define anemia. Globally, absolute ID (absent or reduced body iron stores that do not meet the need for iron of an individual but may respond to iron supplementation) contributes to only a limited proportion of anemia. Functional ID (adequate or increased iron stores that cannot meet the need for iron because of the effects of infection or inflammation and does not respond to iron supplementation) is frequently responsible for anemia in low- and middle-income countries. Absolute and functional ID may coexist. We highlight continued improvement in understanding the roles of infections and inflammation in causing a large proportion of anemia. Deficiencies of nutrients other than iron are less common but important in some settings. The importance of genetic conditions as causes of anemia depends upon the specific inherited red blood cell abnormalities and their prevalence in the settings examined. From a public health perspective, each setting has a distinctive composition of components underlying the common causes of anemia. We emphasize the coincidence between regions with a high prevalence of anemia attributed to ID (both absolute and functional), those with endemic infections, and those with widespread genetic conditions affecting red blood cells, especially in sub-Saharan Africa and regions in Asia and Oceania.

Universal iron supplementation: the best strategy to tackle childhood anaemia in malaria-endemic countries?

Iron deficiency presents a major public health concern in many malaria-endemic regions, and both conditions affect young children most severely. Daily iron supplementation is the standard public health intervention recommended to alleviate rates of iron deficiency in children, but there is controversy over whether universal supplementation could increase the incidence and severity of malaria infection. Current evidence suggests that iron supplementation of deficient individuals is safe and effective in high-transmission settings when accompanied by malaria prevention strategies. However, low-resource settings often struggle to effectively control the spread of malaria, and it remains unclear whether supplementation of iron replete individuals could increase their risk of malaria and other infections. This review explores the evidence for and against universal iron supplementation programmes, and alternative strategies that could be used to alleviate iron deficiency in malaria-endemic areas, while minimising potential harm.

Severe anaemia, iron deficiency, and susceptibility to invasive bacterial infections.

Severe anaemia and invasive bacterial infections remain important causes of hospitalization and death among young African children. The emergence and spread of antimicrobial resistance demand better understanding of bacteraemia risk factors to inform prevention strategies. Epidemiological studies have reported an association between severe anaemia and bacteraemia. In this review, we explore evidence that severe anaemia is associated with increased risk of invasive bacterial infections in young children. We describe mechanisms of iron dysregulation in severe anaemia that might contribute to increased risk and pathogenesis of invasive bacteria, recent advances in knowledge of how iron deficiency and severe anaemia impair immune responses to bacterial infections and vaccines, and the gaps in our understanding of mechanisms underlying severe anaemia, iron deficiency, and the risk of invasive bacterial infections.

Availability of Ferritin-Bound Iron to Enterobacteriaceae.

The sequestration of iron in case of infection, termed nutritional immunity, is an established strategy of host defense. However, the interaction between pathogens and the mammalian iron storage protein ferritin is hitherto not completely understood. To better characterize the function of ferritin in Gram-negative infections, we incubated iron-starved cultures of Salmonella Typhimurium and knockout mutant strains defective for major iron uptake pathways or Escherichia coli with horse spleen ferritin or ionic iron as the sole iron source. Additionally, we added bovine superoxide dismutase and protease inhibitors to the growth medium to assess the effect of superoxide and bacterial proteases, respectively, on Salmonella proliferation and reductive iron release. Compared to free ionic iron, ferritin-bound iron was less available to Salmonella, but was still sufficient to significantly enhance the growth of the bacteria. In the absence of various iron acquisition genes, the availability of ferritin iron further decreased. Supplementation with superoxide dismutase significantly reduced the growth of the ΔentC knockout strain with holoferritin as the sole iron source in comparison with ionic ferrous iron. In contrast, this difference was not observed in the wildtype strain, suggesting that superoxide dismutase undermines bacterial iron uptake from ferritin by siderophore-independent mechanisms. Ferritin seems to diminish iron availability for bacteria in comparison to ionic iron, and its iron sequestering effect could possibly be enhanced by host superoxide dismutase activity.

Vitamin D Deficiency and Its Association with Iron Deficiency in African Children.

Vitamin D regulates the master iron hormone hepcidin, and iron in turn alters vitamin D metabolism. Although vitamin D and iron deficiency are highly prevalent globally, little is known about their interactions in Africa. To evaluate associations between vitamin D and iron status we measured markers of iron status, inflammation, malaria parasitemia, and 25-hydroxyvitamin D (25(OH)D) concentrations in 4509 children aged 0.3 months to 8 years living in Kenya, Uganda, Burkina Faso, The Gambia, and South Africa. Prevalence of iron deficiency was 35.1%, and prevalence of vitamin D deficiency was 0.6% and 7.8% as defined by 25(OH)D concentrations of <30 nmol/L and <50 nmol/L, respectively. Children with 25(OH)D concentrations of <50 nmol/L had a 98% increased risk of iron deficiency (OR 1.98 [95% CI 1.52, 2.58]) compared to those with 25(OH)D concentrations >75 nmol/L. 25(OH)D concentrations variably influenced individual markers of iron status. Inflammation interacted with 25(OH)D concentrations to predict ferritin levels. The link between vitamin D and iron status should be considered in strategies to manage these nutrient deficiencies in African children.

Low Hemoglobin Levels Are Associated with Reduced Psychomotor and Language Abilities in Young Ugandan Children.

Children living in Sub-Saharan Africa are vulnerable to developmental delay, particularly in the critical first five years due to various adverse exposures including disease and nutritional deficiencies. Anemia and iron deficiency (ID) are highly prevalent in pregnant mothers and young children and are implicated in abnormal brain development. However, available evidence on the association between anemia, ID and neurodevelopment in sub-Saharan Africa is limited. Using data from the Entebbe Mother and Baby Study prospective birth cohort, we examined the effect of maternal and child hemoglobin (Hb) levels and child iron status on developmental scores in 933 and 530 pre-school Ugandan children respectively. Associations between Hb levels, iron status and developmental scores were assessed using regression analyses adjusting for potential confounders. Lower maternal and child Hb levels were associated with reduced psychomotor scores at 15 months, while only lower Hb levels in infancy were associated with reduced language scores. We found no evidence that anemia or ID was associated with cognitive or motor scores at five years. This study emphasizes the importance of managing anemia in pregnancy and infancy and highlights the need for further studies on the effects of anemia and ID in children living in Sub-Saharan Africa.

Hepcidin regulation in Kenyan children with severe malaria and non-typhoidal Salmonella bacteremia.

Malaria and invasive non-typhoidal Salmonella (NTS) are life-threatening infections that often co-exist in African children. The iron-regulatory hormone hepcidin is highly upregulated during malaria and controls the availability of iron, a critical nutrient for bacterial growth. We investigated the relationship between Plasmodium falciparum malaria and NTS bacteremia in all pediatric admissions aged <5 years between August 1998 and October 2019 (n=75,034). We then assayed hepcidin and measures of iron status in five groups: (1) children with concomitant severe malarial anemia (SMA) and NTS (SMA+NTS, n=16); and in matched children with (2) SMA (n=33); (3) NTS (n=33); (4) cerebral malaria (CM, n=34); and (5) community-based children. SMA and severe anemia without malaria were associated with a 2-fold or more increased risk of NTS bacteremia, while other malaria phenotypes were not associated with increased NTS risk. Children with SMA had lower hepcidin/ferritin ratios (0.10; interquartile range [IQR]: 0.03-0.19) than those with CM (0.24; IQR: 0.14-0.69; P=0.006) or asymptomatic malaria (0.19; IQR: 0.09-0.46; P=0.01) indicating suppressed hepcidin levels. Children with SMA+NTS had lower hepcidin levels (9.3 ng/mL; IQR: 4.7-49.8) and hepcidin/ferritin ratios (0.03; IQR: 0.01-0.22) than those with NTS alone (105.8 ng/mL; IQR: 17.3-233.3; P=0.02 and 0.31; IQR: 0.06-0.66; P=0.007, respectively). Since hepcidin degrades ferroportin on the Salmonella-containing vacuole, we hypothesize that reduced hepcidin in children with SMA might contribute to NTS growth by modulating iron availability for bacterial growth. Further studies are needed to understand how the hepcidin-ferroportin axis might mediate susceptibility to NTS in severely anemic children.

Prevalence and predictors of vitamin D deficiency in young African children.

BACKGROUND: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children. METHODS: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses. RESULTS: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants. CONCLUSIONS: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.

Malaria is a cause of iron deficiency in African children.

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Effects of iron intake on neurobehavioural outcomes in African children: a systematic review and meta-analysis of randomised controlled trials.

Background: Iron deficiency and developmental delay are common in African children. While experimental studies indicate an important role of iron in brain development, effects of iron on child development remain unclear. We aimed to evaluate the effects of iron supplementation or fortification on neurobehavioural outcomes in African children and further summarise these effects in children living in non-African countries for comparison. Methods: We searched PubMed, EMBASE, PsycINFO, Scopus and Cochrane Library for studies published up to 9 th March 2021. We included randomised controlled trials (RCTs) evaluating effects of iron supplementation or fortification on neurobehavioural outcomes in children. Due to heterogeneity in study methods, we analysed the studies qualitatively and only seven RCTs with 11 arms were meta-analysed. Results: We identified 2155 studies and included 34 studies (n=9808) in the systematic review. Only five studies (n=1294) included African children while 29 (n=8514) included children living in non-African countries. Of the five African studies, two (n=647) reported beneficial effects of iron supplementation on neurobehavioural outcomes in anaemic children while three (n=647) found no beneficial effects. Of 29 studies in children living in non-African countries, nine (n=2925) reported beneficial effects of iron supplementation or fortification on neurobehavioural outcomes, seven (n=786) reported beneficial effects only in children who had iron deficiency, iron deficiency anaemia or anaemia while 13 (n=4803) reported no beneficial effects. Meta-analysis of seven studies (n=775) in non-African countries showed no beneficial effects of iron supplementation on cognitive or motor development in children. Conclusions: There are few studies in African children despite the high burden of iron deficiency and developmental delay in this population. Evidence on the effects of iron supplementation on neurobehavioural outcomes remains unclear and there is need for further well-powered studies evaluating these effects in African populations. PROSPERO registration: CRD42018091278 (20/03/2018).

Iron Deficiency Is Associated With Reduced Levels of Plasmodium falciparum-specific Antibodies in African Children.

BACKGROUND: Iron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria. METHODS: The study included 1794 Kenyan and Ugandan children aged 0-7 years. We measured biomarkers of iron and inflammation, and antibodies to P. falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies. RESULTS: The overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, sex, study site, inflammation, and P. falciparum parasitemia (adjusted mean difference on a log-transformed scale (ß) -0.46; 95 confidence interval [CI], -.66, -.25 P < .0001; ß -0.33; 95 CI, -.50, -.16 P < .0001, respectively). Additional covariates for malaria exposure index, previous malaria episodes, and time since last malaria episode were available for individual cohorts. Meta-analysis was used to allow for these adjustments giving ß -0.34; -0.52, -0.16 for anti-AMA-1 antibodies and ß -0.26; -0.41, -0.11 for anti-MSP-1 antibodies. Low transferrin saturation was similarly associated with reduced anti-AMA-1 antibody levels. Lower AMA-1 and MSP-1-specific antibody levels persisted over time in iron-deficient children. CONCLUSIONS: Reduced levels of P. falciparum-specific antibodies in iron-deficient children might reflect impaired acquisition of immunity to malaria and/or reduced malaria exposure. Strategies to prevent and treat ID may influence antibody responses to malaria for children living in sub-Saharan Africa.

How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children.

Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.

Effects of vitamin D deficiency on neurobehavioural outcomes in children: a systematic review.

Introduction: Vitamin D plays an important role in brain development in experimental studies; however, the effect of vitamin D deficiency on child development remains inadequately characterized. We aimed to estimate the effects of vitamin D deficiency on neurobehavioural outcomes in children up to 18 years of age. Methods: We searched PubMed, EMBASE, PsycINFO, Scopus, Cochrane Library, Web of Science and Open Grey for published studies up to 10th January 2020. We included all studies that assessed the effects of maternal or child vitamin D status or vitamin D supplementation on neurobehavioural outcomes in children. Study findings were synthesized qualitatively as the high level of heterogeneity in study populations and methodologies precluded a quantitative meta-analysis. Results: Our search identified 5,633 studies, of which 31 studies with 31,375 participants from 18 countries were included in the systematic review. Of the studies identified, one was a randomised controlled trial (RCT) of vitamin D supplementation in children, while 30 were observational. The RCT (n=55) reported a beneficial effect of supplementation with lower doses compared to higher doses of vitamin D on motor development. Twelve mother-child studies (n=17,136) and five studies in children (n=1,091) reported an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioural outcomes in children, while 15 mother-child studies (n=20,778) and eight studies in children (n=7,496) reported no association. Conclusions: Although animal studies point to an effect of vitamin D deficiency on brain development, there are few studies on the effects of vitamin D deficiency on neurobehavioural outcomes in children and their findings are inconsistent. There is a need for well-conducted, adequately powered studies to further determine these effects in children. Registration: PROSPERO ID CRD42018087619; registered on 15 February 2018.

Interferon-gamma polymorphisms and risk of iron deficiency and anaemia in Gambian children.

Background: Anaemia is a major public health concern especially in African children living in malaria-endemic regions. Interferon-gamma (IFN-γ) is elevated during malaria infection and is thought to influence erythropoiesis and iron status. Genetic variants in the IFN-γ gene (IFNG) are associated with increased IFN-γ production. We investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes of IFNG in relation to nutritional iron status and anaemia in Gambian children over a malaria season. Methods: We used previously available data from Gambian family trios to determine informative SNPs and then used the Agena Bioscience MassArray platform to type five SNPs from the IFNG gene in a cohort of 780 Gambian children aged 2-6 years. We also measured haemoglobin and biomarkers of iron status and inflammation at the start and end of a malaria season. Results: We identified five IFNG haplotype-tagging SNPs ( IFNG-1616 [rs2069705], IFNG+874 [rs2430561], IFNG+2200 [rs1861493], IFNG+3234 [rs2069718] and IFNG+5612 [rs2069728]). The IFNG+2200C [rs1861493] allele was associated with reduced haemoglobin concentrations (adjusted ß -0.44 [95% CI -0.75, -0.12]; Bonferroni adjusted P = 0.03) and a trend towards iron deficiency compared to wild-type at the end of the malaria season in multivariable models adjusted for potential confounders. A haplotype uniquely identified by IFNG+2200C was similarly associated with reduced haemoglobin levels and trends towards iron deficiency, anaemia and iron deficiency anaemia at the end of the malaria season in models adjusted for age, sex, village, inflammation and malaria parasitaemia. Conclusion: We found limited statistical evidence linking IFNG polymorphisms with a risk of developing iron deficiency and anaemia in Gambian children. More definitive studies are needed to investigate the effects of genetically influenced IFN-γ levels on the risk of iron deficiency and anaemia in children living in malaria-endemic areas.

Vitamin D Status Is Not Associated with Cognitive or Motor Function in Pre-School Ugandan Children.

Vitamin D deficiency is common worldwide and young children are among the most affected groups. Animal studies suggest a key role for vitamin D in brain development. However, studies investigating the effects of vitamin D on neurobehavioural outcomes in children are inconclusive and evidence is limited in sub-Saharan Africa. We evaluated the effect of vitamin D status on cognitive and motor outcomes using prospective data from the Entebbe Mother and Baby Study birth cohort. We analysed data from 302 Ugandan children with 25-hydroxyvitamin D (25(OH)D) measurements below five years and developmental measures at five years of age. We used multivariable linear regression, adjusted for potential confounders, to estimate the effect of 25(OH)D on cognitive and motor outcomes. Of 302 children, eight (2.7%) had 25(OH)D levels <50 nmol/L, 105 (35.8%) had levels 50-75 nmol/L and 189 (62.6%) had levels >75 nmol/L. There was no evidence that earlier vitamin D status was associated with cognitive and motor outcomes in five-year-old Ugandan children. This study adds to the sparse literature and highlights the need for further longitudinal studies on vitamin D and neurobehavioural outcomes in children living in sub-Saharan Africa.

Estimating the burden of iron deficiency among African children.

BACKGROUND: Iron deficiency (ID) is a major public health burden in African children and accurate prevalence estimates are important for effective nutritional interventions. However, ID may be incorrectly estimated in Africa because most measures of iron status are altered by inflammation and infections such as malaria. Through the current study, we have assessed different approaches to the prediction of iron status and estimated the burden of ID in African children. METHODS: We assayed iron and inflammatory biomarkers in 4853 children aged 0-8 years from Kenya, Uganda, Burkina Faso, South Africa, and The Gambia. We described iron status and its relationship with age, sex, inflammation, and malaria parasitemia. We defined ID using the WHO guideline (ferritin < 12 µg/L or < 30 µg/L in the presence of inflammation in children < 5 years old or < 15 µg/L in children ≥ 5 years old). We compared this with a recently proposed gold standard, which uses regression-correction for ferritin levels based on the relationship between ferritin levels, inflammatory markers, and malaria. We further investigated the utility of other iron biomarkers in predicting ID using the inflammation and malaria regression-corrected estimate as a gold standard. RESULTS: The prevalence of ID was highest at 1 year of age and in male infants. Inflammation and malaria parasitemia were associated with all iron biomarkers, although transferrin saturation was least affected. Overall prevalence of WHO-defined ID was 34% compared to 52% using the inflammation and malaria regression-corrected estimate. This unidentified burden of ID increased with age and was highest in countries with high prevalence of inflammation and malaria, where up to a quarter of iron-deficient children were misclassified as iron replete. Transferrin saturation < 11% most closely predicted the prevalence of ID according to the regression-correction gold standard. CONCLUSIONS: The prevalence of ID is underestimated in African children when defined using the WHO guidelines, especially in malaria-endemic populations, and the use of transferrin saturation may provide a more accurate approach. Further research is needed to identify the most accurate measures for determining the prevalence of ID in sub-Saharan Africa.

Prevalence of vitamin D deficiency in Africa: a systematic review and meta-analysis.

BACKGROUND: Vitamin D deficiency is associated with non-communicable and infectious diseases, but the vitamin D status of African populations is not well characterised. We aimed to estimate the prevalence of vitamin D deficiency in children and adults living in Africa. METHODS: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Embase, African Journals Online, and African Index Medicus for studies on vitamin D prevalence, published from database inception to Aug 6, 2019, without language restrictions. We included all studies with measured serum 25-hydroxyvitamin D (25[OH]D) concentrations from healthy participants residing in Africa. We excluded case reports and case series, studies that measured 25(OH)D only after a clinical intervention, and studies with only a meeting abstract or unpublished material available. We used a standardised data extraction form to collect information from eligible studies; if the required information was not available in the published report, we requested raw data from the authors. We did a random-effects meta-analysis to obtain the pooled prevalence of vitamin D deficiency in African populations, with use of established cutoffs and mean 25(OH)D concentrations. We stratified meta-analyses by participant age group, geographical region, and residence in rural or urban areas. The study is registered with PROSPERO, number CRD42018112030. FINDINGS: Our search identified 1692 studies, of which 129 studies with 21 474 participants from 23 African countries were included in the systematic review and 119 studies were included in the meta-analyses. The pooled prevalence of low vitamin D status was 18·46% (95% CI 10·66-27·78) with a cutoff of serum 25(OH)D concentration less than 30 nmol/L; 34·22% (26·22-43·68) for a cutoff of less than 50 nmol/L; and 59·54% (51·32-67·50) for a cutoff of less than 75 nmol/L. The overall mean 25(OH)D concentration was 67·78 nmol/L (95% CI 64·50-71·06). There was no evidence of publication bias, although heterogeneity was high (I2 ranged from 98·26% to 99·82%). Mean serum 25(OH)D concentrations were lower in populations living in northern African countries or South Africa compared with sub-Saharan Africa, in urban areas compared with rural areas, in women compared with men, and in newborn babies compared with their mothers. INTERPRETATION: The prevalence of vitamin D deficiency is high in African populations. Public health strategies in Africa should include efforts to prevent, detect, and treat vitamin D deficiency, especially in newborn babies, women, and urban populations. FUNDING: Wellcome Trust and the DELTAS Africa Initiative.

The ferroportin Q248H mutation protects from anemia, but not malaria or bacteremia.

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.

Iron Status and Associated Malaria Risk Among African Children.

BACKGROUND: It remains unclear whether improving iron status increases malaria risk, and few studies have looked at the effect of host iron status on subsequent malaria infection. We therefore aimed to determine whether a child's iron status influences their subsequent risk of malaria infection in sub-Saharan Africa. METHODS: We assayed iron and inflammatory biomarkers from community-based cohorts of 1309 Kenyan and 1374 Ugandan children aged 0-7 years and conducted prospective surveillance for episodes of malaria. Poisson regression models were fitted to determine the effect of iron status on the incidence rate ratio (IRR) of malaria using longitudinal data covering a period of 6 months. Models were adjusted for age, sex, parasitemia, inflammation, and study site. RESULTS: At baseline, the prevalence of iron deficiency (ID) was 36.9% and 34.6% in Kenyan and Ugandan children, respectively. ID anemia (IDA) affected 23.6% of Kenyan and 17.6% of Ugandan children. Malaria risk was lower in children with ID (IRR, 0.7; 95% confidence interval [CI], 0.6, 0.8; P < .001) and IDA (IRR, 0.7; 95% CI, 0.6, 0.9; P = .006). Low transferrin saturation (<10%) was similarly associated with lower malaria risk (IRR, 0.8; 95% CI, 0.6, 0.9; P = .016). However, variation in hepcidin, soluble transferrin receptors (sTfR), and hemoglobin/anemia was not associated with altered malaria risk. CONCLUSIONS: ID appears to protect against malaria infection in African children when defined using ferritin and transferrin saturation, but not when defined by hepcidin, sTfR, or hemoglobin. Additional research is required to determine causality. CLINICAL TRIALS REGISTRATION: ISRCTN32849447.