Frank T. Wieringa

Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis

BACKGROUNDnThe World Health Organization recommends serum ferritin concentrations as the best indicator of iron deficiency (ID). Unfortunately, ferritin increases with infections; hence, the prevalence of ID is underestimated.nnnOBJECTIVEnThe objective was to estimate the increase in ferritin in 32 studies of apparently healthy persons by using 2 acute-phase proteins (APPs), C-reactive protein (CRP) and alpha(1)-acid glycoprotein (AGP), individually and in combination, and to calculate factors to remove the influence of inflammation from ferritin concentrations.nnnDESIGNnWe estimated the increase in ferritin associated with inflammation (ie, CRP gt 5 mg/L and/or AGP gt 1 g/L). The 32 studies comprised infants (5 studies), children (7 studies), men (4 studies), and women (16 studies) (n = 8796 subjects). In 2-group analyses (either CRP or AGP), we compared the ratios of log ferritin with or without inflammation in 30 studies. In addition, in 22 studies, the data allowed a comparison of ratios of log ferritin between 4 subgroups: reference (no elevated APP), incubation (elevated CRP only), early convalescence (both APP and CRP elevated), and late convalescence (elevated AGP only).nnnRESULTSnIn the 2-group analysis, inflammation increased ferritin by 49.6% (CRP) or 38.2% (AGP; both P lt 0.001). Elevated AGP was more common than CRP in young persons than in adults. In the 4-group analysis, ferritin was 30%, 90%, and 36% (all P lt 0.001) higher in the incubation, early convalescence, and late convalescence subgroups, respectively, with corresponding correction factors of 0.77, 0.53, and 0.75. Overall, inflammation increased ferritin by ap 30% and was associated with a 14% (CI: 7%, 21%) underestimation of ID.nnnCONCLUSIONSnMeasures of both APP and CRP are needed to estimate the full effect of inflammation and can be used to correct ferritin concentrations. Few differences were observed between age and sex subgroups.

Micronutrient Deficits Are Still Public Health Issues among Women and Young Children in Vietnam

Background The 2000 Vietnamese National Nutrition Survey showed that the populations dietary intake had improved since 1987. However, inequalities were found in food consumption between socioeconomic groups. As no national data exist on the prevalence of micronutrient deficiencies, a survey was conducted in 2010 to assess the micronutrient status of randomly selected 1526 women of reproductive age and 586 children aged 6–75 mo. Principal Findings In women, according to international thresholds, prevalence of zinc deficiency (ZnD, 67.2±2.6%) and vitamin B12 deficiency (11.7±1.7%) represented public health problems, whereas prevalence of anemia (11.6±1.0%) and iron deficiency (ID, 13.7±1.1%) were considered low, and folate (<3%) and vitamin A (VAD, <2%) deficiencies were considered negligible. However, many women had marginal folate (25.1%) and vitamin A status (13.6%). Moreover, overweight (BMI≥23 kg/m2 for Asian population) or underweight occurred in 20% of women respectively highlighting the double burden of malnutrition. In children, a similar pattern was observed for ZnD (51.9±3.5%), anemia (9.1±1.4%) and ID (12.9±1.5%) whereas prevalence of marginal vitamin A status was also high (47.3±2.2%). There was a significant effect of age on anemia and ID prevalence, with the youngest age group (6–17 mo) having the highest risk for anemia, ID, ZnD and marginal vitamin A status as compared to other groups. Moreover, the poorest groups of population had a higher risk for zinc, anemia and ID. Conclusion The prevalence of anemia and ID in Vietnam has been markedly reduced over the last decade, but a large part of the population is still at risk for other deficiencies such as zinc, vitamin A, folate and vitamin B12 especially the youngest children aged 6–17 mo. Consequently specific interventions to improve food diversity and quality should be implemented, among them food fortification of staple foods and condiments and improvement of complementary feeding.

Multi-Micronutrient–Fortified Biscuits Decreased Prevalence of Anemia and Improved Micronutrient Status and Effectiveness of Deworming in Rural Vietnamese School Children

Concurrent micronutrient deficiencies are prevalent among Vietnamese school children. A school-based program providing food fortified with multiple micronutrients could be a cost-effective and sustainable strategy to improve health and cognitive function of school children. However, the efficacy of such an intervention may be compromised by the high prevalence of parasitic infestation. To evaluate the efficacy of school-based intervention using multi-micronutrient-fortified biscuits with or without deworming on anemia and micronutrient status in Vietnamese schoolchildren, a randomized, double-blind, placebo-controlled trial was conducted among 510 primary schoolchildren, aged 6-8 y, in rural Vietnam. Albendazole (Alb) (400 mg) or placebo was given at baseline. Nonfortified or multi-micronutrient-fortified biscuits including iron (6 mg), zinc (5.6 mg), iodine (35 microg), and vitamin A (300 microg retinol equivalents) were given 5 d/wk for 4 mo. Multi-micronutrient fortification significantly improved the concentrations of hemoglobin (+1.87 g/L; 95% CI: 0.78, 2.96), plasma ferritin (+7.5 microg/L; 95% CI: 2.8, 12.6), body iron (+0.56 mg/kg body weight; 95% CI: 0.29, 0.84), plasma zinc (+0.61 micromol/L; 95% CI: 0.26, 0.95), plasma retinol (+0.041 micromol/L; 95% CI: 0.001, 0.08), and urinary iodine (+22.49 micromol/L; 95% CI: 7.68, 37.31). Fortification reduced the risk of anemia and deficiencies of zinc and iodine by >40%. Parasitic infestation did not affect fortification efficacy, whereas fortification significantly enhanced deworming efficacy, with the lowest reinfection rates in children receiving both micronutrients and Alb. Multi-micronutrient fortification of biscuits is an effective strategy to improve the micronutrient status of Vietnamese schoolchildren and enhances effectiveness of deworming.

Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi.

Background:Although anemia is common among adults with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection in sub-Saharan Africa, the factors contributing to its pathogenesis have not been well characterized.Objective:To characterize the antioxidant micronutrient status, interleukin-6 (IL-6) concentrations, and HIV load in relationship with anemia in adults with pulmonary tuberculosis.Setting:Zomba district, Malawi.Methods:Erythropoietin, IL-6, plasma HIV load, and markers of micronutrient status (hemoglobin (Hb), plasma concentrations of retinol, α-tocopherol, carotenoids, ferritin, zinc, and selenium) were measured in 500 adults who presented with pulmonary tuberculosis in Zomba Central Hospital, Malawi.Results:Among 370 HIV-positive and 130 HIV-negative adults, the prevalence of anemia was 88 and 77%, respectively (P=0.002), and moderate to severe anemia (Hb<80u2009g/l) occurred in 30 and 15%, respectively (P=0.001). Geometric mean IL-6 concentration was 21.1u2009pg/ml, with no difference between HIV-positive and -negative adults. The erythropoietin response to anemia was not different between adults with elevated IL-6 and those with lower IL-6 concentrations. In a multivariate logistic regression model, HIV load, and lower plasma selenium concentrations were associated with moderate to severe anemia. In a final multivariate linear regression model, IL-6, plasma HIV load, and plasma selenium concentrations were associated with Hb concentrations.Conclusion:This study suggests that low selenium concentrations, high HIV load, and high IL-6 concentrations are associated with anemia in adults with pulmonary tuberculosis in sub-Saharan Africa.

Sex differences in prevalence of anaemia and iron deficiency in infancy in a large multi-country trial in South-East Asia.

To evaluate effects of Fe supplementation and sex on the prevalence of anaemia and Fe status in infants in South-East Asia, biochemical data from four parallel, randomized, double-blind trials with Fe and/or Zn supplementation in infants (n 2452) in Indonesia, Thailand and Vietnam was pooled. At recruitment (5 months of age), Hb concentrations were slightly but significantly lower in boy infants compared with girl infants (108.7 g/l v. 111.4 g/l, P = 0.04). At 11 months of age, boy infants not receiving Fe had significantly lower Hb (106.2 g/l v. 111.0 g/l, P < 0.001) and lower serum ferritin concentrations (14.3 microg/l v. 21.1 g/l, P < 0.001) than girl infants not receiving Fe. Consequently, boy infants had a relative risk of 1.6 (95% CI 1.3, 2.1) to be anaemic, and of 3.3 (95% CI 2.1, 5.0) for having Fe deficiency anaemia compared with girl infants. Fe supplementation significantly increased Hb concentrations in both boys and girls. There was no sex difference in Fe status in infants receiving Fe for 6 months. This study shows that the markedly higher risk for anaemia and Fe deficiency indicates higher Fe requirements in boy than in girl infants. In South-East Asia, standard infant feeding practices do not provide sufficient Fe to meet requirements of infants, especially boys. Current daily recommended intake for Fe in infancy is the same for boy and girl infants however. Our findings suggest that in especially the second half of infancy, Fe requirements for boy infants are approximately 0.9 mg/d higher than for girl infants.

Optimal Screening of Children with Acute Malnutrition Requires a Change in Current WHO Guidelines as MUAC and WHZ Identify Different Patient Groups

Background Timely treatment of acute malnutrition in children <5 years of age could prevent >500,000 deaths annually. Screening at community level is essential to identify children with malnutrition. Current WHO guidelines for community screening for malnutrition recommend a Mid Upper Arm Circumference (MUAC) of <115 mm to identify severe acute malnutrition (SAM). However, it is currently unclear how MUAC relates to the other indicator used to define acute malnutrition: weight-for-height Z-score (WHZ). Methods Secondary data from >11,000 Cambodian children, obtained by different surveys between 2010 and 2012, was used to calculate sensitivity and ROC curves for MUAC and WHZ. Findings The secondary analysis showed that using the current WHO cut-off of 115 mm for screening for severe acute malnutrition over 90% of children with a weight-for-height z-score (WHZ) <−3 would have been missed. Reversely, WHZ<−3 missed 80% of the children with a MUAC<115 mm. Conclusions The current WHO cut-off for screening for SAM should be changed upwards from the current 115 mm. In the Cambodian data-set, a cut-off of 133 mm would allow inclusion of >65% of children with a WHZ<−3. Importantly, MUAC and WHZ identified different sub-groups of children with acute malnutrition, therefore these 2 indicators should be regarded as independent from each other. We suggest a 2-step model with MUAC used a screening at community level, followed by MUAC and WHZ measured at a primary health care unit, with both indicators used independently to diagnose severe acute malnutrition. Current guidelines should be changed to reflect this, with treatment initiated when either MUAC <115 mm or WHZ<−3.

The use of linear programming to determine whether a formulated complementary food product can ensure adequate nutrients for 6- to 11-month-old Cambodian infants

BACKGROUNDnA new software tool, Optifood, developed by the WHO and based on linear programming (LP) analysis, has been developed to formulate food-based recommendations.nnnOBJECTIVEnThis study discusses the use of Optifood for predicting whether formulated complementary food (CF) products can ensure dietary adequacy for target populations in Cambodia.nnnDESIGNnDietary data were collected by 24-h recall in a cross-sectional survey of 6- to 11-mo-old infants (n = 78). LP model parameters were derived from these data, including a list of foods, median serving sizes, and dietary patterns. Five series of LP analyses were carried out to model the target populations baseline diet and 4 formulated CF products [WinFood (WF), WinFood-Lite (WF-L), Corn-Soy-Blend Plus (CSB+), and Corn-Soy-Blend Plus Plus (CSB++)], which were added to the diet in portions of 33 g/d dry weight (DW) for infants aged 6-8 mo and 40 g/d DW for infants aged 9-11 mo. In each series of analyses, the nutritionally optimal diet and theoretical range, in diet nutrient contents, were determined.nnnRESULTSnThe LP analysis showed that baseline diets could not achieve the Recommended Nutrient Intake (RNI) for thiamin, riboflavin, niacin, folate, vitamin B-12, calcium, iron, and zinc (range: 14-91% of RNI in the optimal diets) and that none of the formulated CF products could cover the nutrient gaps for thiamin, niacin, iron, and folate (range: 22-86% of the RNI). Iron was the key limiting nutrient, for all modeled diets, achieving a maximum of only 48% of the RNI when CSB++ was included in the diet. Only WF and WF-L filled the nutrient gap for calcium. WF-L, CSB+, and CSB++ filled the nutrient gap for zinc (9- to 11-mo-olds).nnnCONCLUSIONSnThe formulated CF products improved the nutrient adequacy of complementary feeding diets but could not entirely cover the nutrient gaps. These results emphasize the value of using LP to evaluate special CF products during the intervention planning phase. The WF study was registered at controlled-trials.com as ISRCTN19918531.

Decreased parasite load and improved cognitive outcomes caused by deworming and consumption of multi-micronutrient fortified biscuits in rural Vietnamese schoolchildren.

Micronutrient deficiencies are associated with impaired growth and cognitive function. A school-based fortification program might benefit schoolchildren but a high prevalence of parasite infestation might affect effectiveness. A randomized, double-blind, placebo-controlled 2 × 2 factorial trial was conducted to assess the efficacy of multi-micronutrient fortified biscuits with or without de-worming on growth, cognitive function, and parasite load in Vietnamese schoolchildren. Schoolchildren (n = 510), 6-8 years of age were randomly allocated to receive albendazole or placebo at baseline and four months of multi-micronutrient fortified biscuits (FB) or non-fortified biscuits. Children receiving FB for four months scored higher on two cognitive tests: Ravens Colored Progressive Matrices and the Digit Span Forward test. Children receiving albendazole plus FB had the lowest parasite load after four months. In children receiving FB, mid-upper arm circumference was slightly improved (+0.082 cm) but there were no differences in other indexes of anthropometry. Combining multi-micronutrient fortified biscuits with de-worming is an effective strategy.

Effects of animal source food and micronutrient fortification in complementary food products on body composition, iron status, and linear growth: a randomized trial in Cambodia

BACKGROUNDnPoor nutritional quality of complementary foods often limits growth. Animal source foods, such as milk or meat, are often unaffordable. Local affordable alternatives are needed.nnnOBJECTIVEnWe evaluate the efficacy of 2 newly developed, rice-based complementary food products: WinFood (WF) with small fish and edible spiders and WinFood-Lite (WF-L) fortified with small fish, against 2 existing fortified corn-soy blend products, CSB+ (purely plant based) and CSB++ (8% dried skimmed milk).nnnDESIGNnIn total, 419 infants aged 6 mo were enrolled in this randomized, single-blinded study for 9 mo, designed primarily to assess increments in fat-free mass by a deuterium dilution technique and change in plasma ferritin and soluble transferrin receptor. Secondary endpoints were changes in anthropometric variables, including knee-heel length. Data were analyzed by the intention-to-treat approach.nnnRESULTSnThere was no difference in fat-free mass increment in WF or WF-L compared with CSB+ [WF: +0.04 kg (95% CI: -0.20, 0.28 kg); WF-L: +0.14 kg (95% CI: -0.10, 0.38 kg)] or CSB++ [WF: -0.03 kg (95% CI: -0.27, 0.21 kg); WF-L: +0.07 kg (95% CI: -0.18, 0.31 kg)] and no effect on iron status. The 1.7-mm (95% CI: -0.1, 3.5 mm) greater increase in knee-heel length in WF-L than in CSB+ was not significant.nnnCONCLUSIONSnNo difference was found between the locally produced products (WF and WF-L) and the CSBs. Micronutrient fortification may be necessary, and small fish may be an affordable alternative to milk to improve complementary foods. The dietary role of edible spiders needs to be further explored. This trial was registered at controlled-trials.com as ISRCTN19918531.

Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population.

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case-control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63.2 % of active TB compared with 6.8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.