To accurately assess micronutrient status, it is necessary to characterize the effects of inflammation and the acute-phase response on nutrient biomarkers.
Within a norovirus human challenge study, ...we aimed to model the inflammatory response of C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) by infection status, model kinetics of micronutrient biomarkers by inflammation status, and evaluate associations between inflammation and micronutrient biomarkers from 0 to 35 d post–norovirus exposure.
Fifty-two healthy adults were enrolled into challenge studies in a hospital setting and followed longitudinally; all were exposed to norovirus, half were infected. Post hoc analysis of inflammatory and nutritional biomarkers was performed. Subjects were stratified by inflammation resulting from norovirus exposure. Smoothed regression models analyzed the kinetics of CRP and AGP by infection status, and nutritional biomarkers by inflammation. Linear mixed-effects models were used to analyze the independent relations between CRP, AGP, and biomarkers for iron, vitamin A, vitamin D, vitamin B-12, and folate from 0 to 35 d post–norovirus exposure.
Norovirus-infected subjects had median (IQR) peak concentrations for CRP 16.0 (7.9–29.5) mg/L and AGP 0.9 (0.8–1.2) g/L on day 3 and day 4 postexposure, respectively. Nutritional biomarkers that differed (P < 0.05) from baseline within the inflamed group were ferritin (elevated day 3), hepcidin (elevated days 2, 3), serum iron (depressed days 2–4), transferrin saturation (depressed days 2–4), and retinol (depressed days 3, 4, and 7). Nutritional biomarker concentrations did not differ over time within the uninflamed group. In mixed models, CRP was associated with ferritin (positive) and serum iron and retinol (negative, P < 0.05).
Using an experimental infectious challenge model in healthy adults, norovirus infection elicited a time-limited inflammatory response associated with altered serum concentrations of certain iron and vitamin A biomarkers, confirming the need to consider adjustments of these biomarkers to account for inflammation when assessing nutritional status. These trials were registered at clinicaltrials.gov as NCT00313404 and NCT00674336.
IntroductionAnaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa and 49% in Asia. Oral iron therapy requires extended adherence to achieve ...correction of anaemia and replenishment of iron stores. Ferric carboxymaltose (FCM) is a recently established intravenous iron formulation associated with substantial advantages in safety, speed of delivery and total dose deliverable in a single infusion. We aim to determine whether FCM given once during the second trimester of pregnancy compared with standard oral iron distributed through routine antenatal services is effective and safe for treatment of moderate to severe maternal anaemia in sub-Saharan Africa.Methods and analysisThe randomized controlled trial of the effect of intravenous iron on anaemia in Malawian pregnant women (REVAMP) is a two-arm confirmatory individually randomised trial set in Blantyre and Zomba districts in Malawi. The trial will randomise 862 women in the second trimester of pregnancy with a capillary haemoglobin concentration below 100.0 g/L. The study comprises two arms: (a) intravenous FCM (20 mg/kg up to 1000 mg) given once at randomisation, and (b) standard of care oral iron (65 mg elemental iron two times per day) for 90 days (or the duration of pregnancy, whichever is shorter) provided according to local healthcare practices. Both arms receive sulfadoxine-pyrimethamine as intermittent preventive treatment in pregnancy. The primary outcome is the prevalence of anaemia (Hb <110.0 g/L) at 36 weeks’ gestation. Secondary outcomes include birth weight, gestation duration and safety outcomes, including clinical malaria, serious perinatal events and postpartum haematologic and health-related outcomes in the mother and child.Ethics and disseminationEthical approval was granted by the Research Ethics Committee (COMREC P.02/18/2357) in Malawi and the Human Research Ethics Committee (WEHI: 18/02), Melbourne, Australia. The protocol is registered with the Australian and New Zealand Clinical Trials Registry. The results will be shared with the local community that enabled the research, and also to the international fora.Trial registration numberACTRN12618001268235; Pre-results.
Undernutrition remains a major public health problem among children living in Asia. Although the burden is maximal among poorer, rural and Indigenous communities, the problem affects the majority in ...many Asian countries, especially in South Asia. In order to prevent the pervasive consequences of undernutrition, strategies that address this burden are required. Successful implementation of strategies may be limited by the complex aetiology of undernutrition, including the political setting. Rising food insecurity because of climate change, land use for biofuel production and the recent global financial crisis threaten to exacerbate childhood malnutrition. In this review, we describe the burden of undernutrition among Asian children and discuss contributing factors and potential solutions.
Childhood anemia is a major global health problem resulting from multiple causes. Iron supplementation addresses iron deficiency anemia but is undesirable for other types of anemia and may exacerbate ...infections. The peptide hormone hepcidin governs iron absorption; hepcidin transcription is mediated by iron, inflammation, and erythropoietic signals. However, the behavior of hepcidin in populations where anemia is prevalent is not well established. We show that hepcidin measurements in 1313 African children from The Gambia and Tanzania (samples taken in 2001 and 2008, respectively) could be used to identify iron deficiency anemia. A retrospective secondary analysis of published data from 25 Gambian children with either postmalarial or nonmalarial anemia demonstrated that hepcidin measurements identified individuals who incorporated >20% oral iron into their erythrocytes. Modeling showed that this sensitivity of hepcidin expression at the population level could potentially enable simple groupings of individuals with anemia into iron-responsive and non-iron-responsive subtypes and hence could guide iron supplementation for those who would most benefit.
Anemia and iron deficiency have been associated with poor child cognitive development. A key rationale for the prevention of anemia using supplementation with iron has been the benefits to ...neurodevelopment. However, little causal evidence exists for these gains.
We aimed to examine effects of supplementation with iron or multiple micronutrient powders (MNPs) on brain activity measures using resting electroencephalography (EEG).
Children included in this neurocognitive substudy were randomly selected from the Benefits and Risks of Iron Supplementation in Children study, a double-blind, double-dummy, individually randomized, parallel-group trial in Bangladesh, in which children, starting at 8 mo of age, received 3 mo of daily iron syrup, MNPs, or placebo. Resting brain activity was recorded using EEG immediately after intervention (month 3) and after a further 9-month follow-up (month 12). We derived EEG band power measures for delta, theta, alpha, and beta frequency bands. Linear regression models were used to compare the effect of each intervention with that of placebo on the outcomes.
Data from 412 children at month 3 and 374 at month 12 were analyzed. At baseline, 43.9% were anemic and 26.7% were iron deficient. Immediately after intervention, iron syrup, but not MNPs, increased the mu alpha-band power, a measure that is associated with maturity and the production of motor actions (iron vs. placebo: mean difference = 0.30; 95% CI: 0.11, 0.50 μV
; P = 0.003; false discovery rate adjusted P = 0.015). Despite effects on hemoglobin and iron status, effects were not observed on the posterior alpha, beta, delta, and theta bands, nor were effects sustained at the 9-month follow-up.
The effect size for immediate effects on the mu alpha-band power is comparable in magnitude with psychosocial stimulation interventions and poverty reduction strategies. However, overall, we did not find evidence for long-lasting changes in resting EEG power spectra from iron interventions in young Bangladeshi children. This trial was registered at www.anzctr.org.au as ACTRN12617000660381.
IntroductionApproximately 40% of children aged 6–59 months worldwide are anaemic. Iron-containing multiple micronutrient powders (MNPs) and iron supplements (syrup/drops) are used to combat anaemia ...in children in different parts of the world. However, evidence for functional benefits of iron supplementation in children is scarce, and potential risks remain poorly defined, particularly concerning diarrhoea and malaria. This trial aims to determine if: (1) the efficacy of iron supplements or MNPs (containing iron) given with malaria chemoprevention is superior to malaria chemoprevention alone, or (2) if the efficacy of malaria chemoprevention alone is superior to placebo on child cognitive development.Methods and analysisIRMA is a four-arm, parallel-group, double-blinded, placebo-controlled, triple-dummy, randomised trial in Southern Malawi. The study recruits 2168 infants aged 6 months, with an intervention period of 6 months and a post-intervention period of a further 6 months. Children are randomised into four arms: (1) No intervention (placebo); (2) malaria chemoprevention only; (3) MNPs and malaria chemoprevention; and (4) iron syrup and malaria chemoprevention. The primary outcome, cognitive development (Cognitive Composite Score (CogCS)), is measured at the end of the 6 months intervention. Secondary outcomes include CogCS at a further 6 months post-intervention, motor, language and behavioural development, physical growth and prevalence of anaemia and iron deficiency. Safety outcomes include incidence of malaria and other infections, and prevalence of malaria parasitaemia during and post-intervention period.Ethics and disseminationThe trial is approved by the National Health Sciences Research Committee (#19/01/2213) (Malawi) and the Human Research Ethics Committee (WEHI: 19/012) (Australia). Written informed consent in the local language is obtained from each participant before conducting any study-related procedure. Results will be shared with the local community and internationally with academic and policy stakeholders.Trial registration numberACTRN12620000386932.
Anemia affects over 800 million women and children globally. Measurement of hepcidin as an index of iron status shows promise, but its diagnostic performance where hemoglobinopathies are prevalent is ...unclear. We evaluated the performance of hepcidin as a diagnostic test of iron deficiency in adolescents across Sri Lanka.
We selected 2273 samples from a nationally representative cross‐sectional study of 7526 secondary schoolchildren across Sri Lanka and analyzed associations between hepcidin and participant characteristics, iron indices, inflammatory markers, and hemoglobinopathy states. We evaluated the diagnostic accuracy of hepcidin as a test for iron deficiency with estimation of the AUCROC, sensitivity/specificity at each hepcidin cutoff, and calculation of the Youden Index to find the optimal threshold.
Hepcidin was associated with ferritin, sTfR, and hemoglobin. The AUCROC for hepcidin as a test of iron deficiency was 0.78; hepcidin outperformed Hb and sTfR. The Youden index‐predicted cutoff to detect iron deficiency (3.2 ng/mL) was similar to thresholds previously identified to predict iron utilization and identify deficiency in African populations. Neither age, sex, nor α‐ or β‐thalassemia trait affected diagnostic properties of hepcidin. Hepcidin pre‐screening would prevent most iron‐replete thalassemia carriers from receiving iron whilst still ensuring most iron deficient children were supplemented. Our data indicate that the physiological relationship between hepcidin and iron status transcends specific populations. Measurement of hepcidin in individuals or populations could establish the need for iron interventions.
Absolute plasma hepcidin concentrations measured by various procedures differ substantially, complicating interpretation of results and rendering reference intervals method dependent. We investigated ...the degree of equivalence achievable by harmonization and the identification of a commutable secondary reference material to accomplish this goal.
We applied technical procedures to achieve harmonization developed by the Consortium for Harmonization of Clinical Laboratory Results. Eleven plasma hepcidin measurement procedures (5 mass spectrometry based and 6 immunochemical based) quantified native individual plasma samples (n = 32) and native plasma pools (n = 8) to assess analytical performance and current and achievable equivalence. In addition, 8 types of candidate reference materials (3 concentrations each, n = 24) were assessed for their suitability, most notably in terms of commutability, to serve as secondary reference material.
Absolute hepcidin values and reproducibility (intrameasurement procedure CVs 2.9%-8.7%) differed substantially between measurement procedures, but all were linear and correlated well. The current equivalence (intermeasurement procedure CV 28.6%) between the methods was mainly attributable to differences in calibration and could thus be improved by harmonization with a common calibrator. Linear regression analysis and standardized residuals showed that a candidate reference material consisting of native lyophilized plasma with cryolyoprotectant was commutable for all measurement procedures. Mathematically simulated harmonization with this calibrator resulted in a maximum achievable equivalence of 7.7%.
The secondary reference material identified in this study has the potential to substantially improve equivalence between hepcidin measurement procedures and contributes to the establishment of a traceability chain that will ultimately allow standardization of hepcidin measurement results.
Vaccines are the most effective measure to prevent deaths and illness from infectious diseases. Nevertheless, the efficacy of several paediatric vaccines is lower in low-income and middle-income ...countries (LMICs), where mortality from vaccine-preventable infections remains high. Vaccine efficacy can also be decreased in adults in the context of some common comorbidities. Identifying and correcting the specific causes of impaired vaccine efficacy is of substantial value to global health. Iron deficiency is the most common micronutrient deficiency worldwide, affecting more than 2 billion people, and its prevalence in LMICs could increase as food security is threatened by the COVID-19 pandemic. In this Viewpoint, we highlight evidence showing that iron deficiency limits adaptive immunity and responses to vaccines, representing an under-appreciated additional disadvantage to iron deficient populations. We propose a framework for urgent detailed studies of iron-vaccine interactions to investigate and clarify the issue. This framework includes retrospective analysis of newly available datasets derived from trials of COVID-19 and other vaccines, and prospective testing of whether nutritional iron interventions, commonly used worldwide to combat anaemia, improve vaccine performance.
•Homozygous HFE mutations are overrepresented in patients with PV.•Hepcidin levels govern severity of, and can be manipulated to modify, the erythroid phenotype in PV.
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Polycythemia ...vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients’ hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
It is well established that iron deficiency alters the polycythemia vera (PV) phenotype, but whether regulation of iron homeostasis modulates the pathophysiology of JAK2 V617F PV has been unclear. Bennett and colleagues use unbiased genome-wide analyses to establish and validate an association between disordered iron homeostasis and PV diagnosis. The authors then go on to show how hepcidin levels govern the severity of the erythroid phenotype in a murine model of PV. These data may inform future use of emerging drugs that mimic hepcidin action.
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