Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial

Soofi, Sajid Bashir; Cousens, Simon; Iqbal, Saleem; Akhund, Tauseef; Khan, Javed; Ahmed, Imran; Zaidi, Anita K. M.; Bhutta, Zulfiqar A

doi:10.1016/s0140-6736(13)60437-7

Cited by 297 publications

(298 citation statements)

References 38 publications

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“…Thus, the Fe in the LNS improved Fe stores but may not have stimulated reticulocytosis, which might explain the lack of adverse effects on malaria morbidity. Our findings are different from the reports of the studies in Pakistan (6) , Kenya (7) , Pemba (8) , Zambia (10) and Cote d'Ivoire (35) . These studies reported increases in malariarelated hospitalizations and deaths, respiratory infections, diarrhoea and intestinal inflammation associated with Fe supplements or Fe-containing MNP provision in children.…”

Section: Discussioncontrasting

confidence: 99%

“…However, there is little evidence regarding the safety of Fe-containing LNS. Safety studies have mainly been reported about MNP, although with conflicting results (3,4,6,10) . A few reports on LNS provision for prevention of child undernutrition suggest that it is safe (11)(12)(13) , but the evidence is not conclusive because those studies had either a relatively short duration (i.e.…”

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confidence: 99%

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The effect of providing lipid-based nutrient supplements on morbidity in rural Malawian infants and young children: a randomized controlled trial

Bendabenda

Alho

Cheung

et al. 2016

Public Health Nutr.

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Objective: Safety of home fortificants in children is uncertain in areas where infections are common. We tested the hypothesis that provision of lipid-based nutrient supplements (LNS) containing Fe does not increase infectious morbidity in children. Design: Randomized controlled trial. Infants were randomised to receive 10, 20 or 40 g LNS/d; or no supplement until age 18 months. All LNS contained 6 mg Fe/d. Morbidity outcomes (serious adverse events, non-scheduled visits and guardian-reported morbidity episodes) were compared between control and intervention groups using a non-inferiority margin of 20 %. Setting: Namwera and Mangochi catchment areas in rural Malawi. Subjects: Infants aged 6 months (n 1932). Results: The enrolled 1932 infants contributed 1306 child-years of follow-up. Baseline characteristics were similar across groups. Compared with the control group, the relative risk (95 % CI) of serious adverse events was 0·71 (0·48, 1·07), 0·67 (0·48, 0·95) and 0·91 (0·66, 1·25) in 10, 20 and 40 g LNS/d groups, respectively. The incidence rate ratio (95 % CI) of non

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Section: Discussioncontrasting

confidence: 99%

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confidence: 99%

The effect of providing lipid-based nutrient supplements on morbidity in rural Malawian infants and young children: a randomized controlled trial

Bendabenda

Alho

Cheung

et al. 2016

Public Health Nutr.

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“…2 ID is known to have a serious impact on child development. 3 However, there is concern that iron supplementation may increase the risk of malaria 4 and other infectious diseases 5 in young children. It is hypothesized that malaria itself might influence iron homeostasis and increase risk of ID.…”

Section: Introductionmentioning

confidence: 99%

Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children

Atkinson

Armitage

Khandwala

et al. 2014

Blood

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Key Points• Iron status, erythropoietic drive, inflammation, and malaria season combine to control dynamic fluctuations of hepcidin in African children.• At the end of the malaria season, hepcidin is low and ID is more prevalent, so iron therapy may be beneficial at this time.Hepcidin is the master regulatory hormone that governs iron homeostasis and has a role in innate immunity. Although hepcidin has been studied extensively in model systems, there is less information on hepcidin regulation in global health contexts where iron deficiency (ID), anemia, and high infectious burdens (including malaria) all coexist but fluctuate over time.We evaluated iron status, hepcidin levels, and determinants of hepcidin in 2 populations of rural children aged £8 years, in the Gambia and Kenya (total n 5 848), at the start and end of a malaria season. Regression analyses and structural equation modeling demonstrated, for both populations, similar combinatorial effects of upregulating stimuli (iron stores and to a lesser extent inflammation) and downregulating stimuli (erythropoietic drive) on hepcidin levels. However, malaria season was also a significant factor and was associated with an altered balance of these opposing factors. Consistent with these changes, hepcidin levels were reduced whereas the prevalence of ID was increased at the end of the malaria season. More prevalent ID and lower hepcidin likely reflect an enhanced requirement for iron and an ability to efficiently absorb it at the end of the malaria season. These results, therefore, have implications for ID and malaria control programs. (Blood. 2014;123(21):3221-3229)

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“…In general terms, low iron status is protective, whereas elevated iron levels promote infection (27,28). The complexity of host-pathogen interactions therefore presents a clinical conundrum; although iron supplements protect against iron deficiency, such measures could negatively impact infectious diseases (29,30). This idea has been extended to suggest that iron deficiency frequently occurs in regions with endemic infectious diseases as a protective adaptation.…”

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confidence: 99%

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Wessling‐Resnick

2015

Journal of Biological Chemistry

110

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During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review.The rationale for host metal withholding against invading pathogens seems intuitive; restriction of any nutrient required for pathogen survival should combat infection. But why metals? The answer to this question becomes crystal clear when one recognizes that iron is required for nearly all life forms, including pathogenic bacteria, with a few rare exceptions that rely on manganese instead (1-7). Iron is essential for ATP production and other metabolic pathways, but its concentration is limited to avoid production of ROS 2 catalyzed by excess levels of this redox-active metal (8). In some organisms, manganese can substitute for redox-active iron to protect against oxidative stress (9, 10). Moreover, most pathogens require manganese to produce their own superoxide dismutase activity to thwart oxidative killing mechanisms exerted by the host (11-13). Iron and manganese have similar ionic radii, have a divalent charge state under physiological conditions, have similar coordination chemistries, and have cellular concentrations in the micromolar range. Consequently, it comes as no surprise that these two metals also share membrane transporters, despite their different cellular functions and distributions. Restriction of iron and/or manganese provides a broad-spectrum metabolic "antidote" against all pathogenic infections, and the common transport pathways used by these metals present selective targets to limit their availability. Although many other immune responses contribute to the fight against infection, metal withholding represents a major force in host defense with combat controlled through transport.The concept of nutritional immunity through metal withholding is largely based on the observations that the iron content of the human diet profoundly affects infectious diseases such as malaria, brucellosis, and tuberculosis (14, 15). Iron overload states such as sickle cell anemia and ␤-thalassemia increase the risk of infection (16 -18). Hereditary hemochromatosis, an inherited disorder of iron metabolism, is also linked to susceptibility to some pathogens (17, 19 -22). Iron deficiency, on the other hand, is associated with decreased survival of individuals infected with HIV and other agents (23). Still, high iron is positively associated with viral load and mortality in HIV (24 -26), suggesting that an optimal balance of iron is necessary. In general terms, low iron status is protective, whereas elevated iron levels promote infection (27, 28). The complexity of host-pathogen interact...

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Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial

Cited by 297 publications

References 38 publications

The effect of providing lipid-based nutrient supplements on morbidity in rural Malawian infants and young children: a randomized controlled trial

The effect of providing lipid-based nutrient supplements on morbidity in rural Malawian infants and young children: a randomized controlled trial

Combinatorial effects of malaria season, iron deficiency, and inflammation determine plasma hepcidin concentration in African children

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

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