Iron Supplementation in HIV-Infected Malawian Children With Anemia: A Double-Blind, Randomized, Controlled Trial

Esan, Michael; Hensbroek, Michaël Boele van; Nkhoma, Ernest; Musicha, Crispin; White, Sarah; Kuile, Feiko O. ter; Phiri, Kamija S.

doi:10.1093/cid/cit528

Cited by 61 publications

(46 citation statements)

References 20 publications

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“…Haemoglobin at end of treatment was similarly reported in a single study, Giovannini 2006, and was higher with iron and folate, mean difference 0.90 g/dL (95% CI 0.51 to 1.29; 124 children Analysis 2.5). The RR for anaemia at end of treatment was 0.49 (0.25 to 0.99; three trials, 633 children, Analysis 2.6).…”

Section: Resultssupporting

confidence: 69%

“…Eleven trials were multi-armed, which led to 51 comparisons included in the review. We added five new trials in this current review update (Hop 2005; Giovannini 2006; Thi 2006; Esan 2013; Zlotkin 2013 (C)). We excluded 17 trials that assessed iron for the prevention or treatment of anaemia, which were included in the previous review version (Okebe 2011) from the current review update since they were conducted in hypoendemic or mesoendemic areas for malaria or provided an insufficient iron dose.…”

Section: Resultsmentioning

confidence: 99%

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Oral iron supplements for children in malaria-endemic areas

Neuberger

Okebe

Yahav

et al. 2016

Cochrane Database of Systematic Reviews

125

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BackgroundIron-deficiency anaemia is common during childhood. Iron administration has been claimed to increase the risk of malaria.ObjectivesTo evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in areas with hyperendemic or holoendemic malaria transmission.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library, MEDLINE (up to August 2015) and LILACS (up to February 2015). We also checked the metaRegister of Controlled Trials (mRCT) and World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) up to February 2015. We contacted the primary investigators of all included trials, ongoing trials, and those awaiting assessment to ask for unpublished data and further trials. We scanned references of included trials, pertinent reviews, and previous meta-analyses for additional references.Selection criteriaWe included individually randomized controlled trials (RCTs) and cluster RCTs conducted in hyperendemic and holoendemic malaria regions or that reported on any malaria-related outcomes that included children younger than 18 years of age. We included trials that compared orally administered iron, iron with folic acid, and iron with antimalarial treatment versus placebo or no treatment. We included trials of iron supplementation or fortification interventions if they provided at least 80% of the Recommended Dietary Allowance (RDA) for prevention of anaemia by age. Antihelminthics could be administered to either group, and micronutrients had to be administered equally to both groups.Data collection and analysisThe primary outcomes were clinical malaria, severe malaria, and death from any cause. We assessed the risk of bias in included trials with domain-based evaluation and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes, and adjusted analyses for cluster RCTs. We based the subgroup analyses for anaemia at baseline, age, and malaria prevention or management services on trial-level data.Main resultsThirty-five trials (31,955 children) met the inclusion criteria. Overall, iron does not cause an excess of clinical malaria (risk ratio (RR) 0.93, 95% confidence intervals (CI) 0.87 to 1.00; 14 trials, 7168 children, high quality evidence). Iron probably does not cause an excess of clinical malaria in both populations where anaemia is common and those in which anaemia is uncommon. In areas where there are prevention and management services for malaria, iron (with or without folic acid) may reduce clinical malaria (RR 0.91, 95% CI 0.84 to 0.97; seven trials, 5586 participants, low quality evidence), while in areas where such services are unavailable, iron (with or without folic acid) may increase the incidence of malaria, altho...

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Section: Resultssupporting

confidence: 69%

Section: Resultsmentioning

confidence: 99%

Oral iron supplements for children in malaria-endemic areas

Neuberger

Okebe

Yahav

et al. 2016

Cochrane Database of Systematic Reviews

125

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“…A more recent study among HIV-infected children in Malawi found that while iron supplementation improved hematologic indices, the risk of malaria was increased, postulated to be due to the utilization of free iron by Plasmodium species. 47 This theory was supported by another study in Tanzania, in an area of malaria transmission intensity similar to Uganda, in which researchers concluded that the risk of parasitemia was decreased, as was all-cause and malaria-specific mortality, among children with documented iron deficiency. 48 These studies support the role of screening for iron deficiency before supplementation and the relationship between iron metabolism and malaria.…”

Section: Discussionmentioning

confidence: 90%

Prevalence and Factors Associated with Anemia Among Children Under 5 Years of Age—Uganda, 2009

Menon

Yoon

2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Anemia in children under 5 years of age, defined by the World Health Organization as a hemoglobin concentration < 11 g/dL, is a global public health problem. According to the 2006 Demographic Health Survey, the prevalence of anemia among children under five in Uganda was 72% in 2006. The 2009 Uganda Malaria Indicator Survey was conducted in late 2009 and revealed that over 60% of children less than 5 years of age were anemic and that over half of children tested positive for malaria via a rapid diagnostic test. Children with concomitant malaria infection, and in households without any type of mosquito net were more likely to be anemic, confirming that children under 5 years, are vulnerable to both the threat of malaria and anemia and the beneficial effect of malaria prevention tools. However, prevention and treatment of other factors associated with the etiology of anemia (e.g., iron deficiency) are likely necessary to combat the toll of anemia in Uganda.

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“…While iron supplementation in eras with a higher burden of infectious diseases caused detrimental effects toward the risk of malaria or invasive bacterial infections (Sazawal et al, 2006; Soofi et al, 2013), iron supplementation in HIV infected patients resulted in an impaired control of malaria but also in a beneficial or at least neutral course of HIV infection at as reflected by CD4+-cell counts or progression of the disease which was partly dependent on the degree of anemia and base-line iron status (Esan et al, 2013; Prentice et al, 2013; Zlotkin et al, 2013). However, HIV infection is often associated with reactivation of Mycobacterium tuberculosis infection, and iron has been shown to be an essential nutrient for such bacteria which goes along with the observation that iron loading is associated with an increased risk for tuberculosis and an adverse clinical course of this infection (Moyo et al, 1997; Gangaidzo et al, 2001; Schaible and Kaufmann, 2004).…”

Section: Targeting Iron Homeostasis In Infectious Disease-to Walk a Tmentioning

confidence: 99%

Iron at the interface of immunity and infection

et al. 2014

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Both, mammalian cells and microbes have an essential need for iron, which is required for many metabolic processes and for microbial pathogenicity. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. Cytokines and the acute phase protein hepcidin affect iron homeostasis leading to the retention of the metal within macrophages and hypoferremia. This is considered to result from a defense mechanism of the body to limit the availability of iron for extracellular pathogens while on the other hand the reduction of circulating iron results in the development of anemia of inflammation. Opposite, iron and the erythropoiesis inducing hormone erythropoietin affect innate immune responses by influencing interferon-gamma (IFN-γ) mediated (iron) or NF-kB inducible (erythropoietin) immune effector pathways in macrophages. Thus, macrophages loaded with iron lose their ability to kill intracellular pathogens via IFN-γ mediated effector pathways such as nitric oxide (NO) formation. Accordingly, macrophages invaded by the intracellular bacterium Salmonella enterica serovar Typhimurium increase the expression of the iron export protein ferroportin thereby reducing the availability of iron for intramacrophage bacteria while on the other side strengthening anti-microbial macrophage effector pathways via increased formation of NO or TNF-α. In addition, certain innate resistance genes such as natural resistance associated macrophage protein function (Nramp1) or lipocalin-2 exert part of their antimicrobial activity by controlling host and/or microbial iron homeostasis. Consequently, pharmacological or dietary modification of cellular iron trafficking enhances host resistance to intracellular pathogens but may increase susceptibility to microbes in the extracellular compartment and vice versa. Thus, the control over iron homeostasis is a central battlefield in host–pathogen interplay influencing the course of an infectious disease in favor of either the mammalian host or the pathogenic invader.

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Iron Supplementation in HIV-Infected Malawian Children With Anemia: A Double-Blind, Randomized, Controlled Trial

Abstract: ISRCTN-62947977.

Cited by 61 publications

References 20 publications

Oral iron supplements for children in malaria-endemic areas

Oral iron supplements for children in malaria-endemic areas

Prevalence and Factors Associated with Anemia Among Children Under 5 Years of Age—Uganda, 2009

Iron at the interface of immunity and infection

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