To estimate the burden of anemia attributable to malaria, inflammation, and deficiency of iron or vitamin A during low and high malaria seasons among Zambian children.
From a cohort of children ...(n = 820), 4-8 years of age participating in a randomized controlled trial of pro-vitamin A, we estimated attributable fractions for anemia (hemoglobin of <110 or 115 g/L, by age) owing to current malaria or inflammation (C-reactive protein of >5 mg/L, or α-1 acid glycoprotein of >1 g/L, or both), and current or prior iron deficiency (ID; defined as low ferritin <12 or 15 μg/L for age <5 or >5 years or functional ID soluble transferrin receptor of >8.3 mg/L or both) and vitamin A deficiency (retinol of <0.7 μmol/L), during low and high malaria seasons, using multivariate logistic regression. Serum ferritin, soluble transferrin receptor, and retinol were adjusted for inflammation.
The burden of anemia independently associated with current malaria, inflammation, ID, and vitamin A deficiency in the low malaria season were 12% (P < .001), 6% (P = .005), 14% (P = .001), and 2% (P = .07), respectively, and 32% (P < .001), 15% (P < .001), 10% (P = .06), and 2% (P = .06), respectively, in the high malaria season. In both seasons, functional ID was independently associated with more anemia (approximately 11%) than low ferritin (approximately 4%). Anemia and ID in the low malaria season, accounted for 20% (P < .001) and 4% (P = .095) of the anemia in the subsequent high malaria season.
Anemia in this population is strongly linked to malaria, inflammation, and functional ID, and to a lesser extent, low iron stores. Integrated control strategies are needed.
Environmental enteric dysfunction (EED) may be ameliorated by zinc supplementation. The objective of this study was to investigate the impact of different forms of zinc supplementation on biomarkers ...of EED (i.e., plasma citrulline, kynurenine, and tryptophan concentrations and the kynurenine:tryptophan KT ratio) among young Laotian children. In a double-blind randomized controlled trial, 3,407 children aged 6-23 months were randomized into one of four groups: daily preventive zinc dispersible tablets (PZ; 7 mg zinc), daily multiple micronutrient powders (MNP; 10 mg zinc, 6 mg iron, and 13 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/day for 10 days), or daily placebo powder, and followed up for ∼36 weeks. Plasma samples at baseline and endline for 359 children were analyzed for citrulline, kynurenine, and tryptophan concentrations. At baseline, the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively. The mean plasma citrulline, kynurenine, and tryptophan concentrations were 24.6 ± 5.4 µmol/L, 3.27 ± 0.83 µmol/L, and 72.3 ± 12.9 µmol/L, respectively; the mean KT ratio (×1,000) was 45.9 ± 12.0. At endline, neither plasma citrulline, kynurenine, or tryptophan concentrations, nor the KT ratio differed among intervention groups (
> 0.05). In this population, PZ, MNP, and TZ had no overall effect on plasma concentrations of citrulline, kynurenine, and tryptophan, or the KT ratio. The need remains to better understand the etiology of EED, and the development of biomarkers to diagnose EED and evaluate the impact of interventions.
Some studies found that providing micronutrient powder (MNP) causes adverse health outcomes, but modifying factors are unknown. We aimed to investigate whether Fe status and inherited Hb disorders ...(IHbD) modify the impact of MNP on growth and diarrhoea among young Lao children. In a double-blind controlled trial, 1704 children of age 6–23 months were randomised to daily MNP (with 6 mg Fe plus fourteen micronutrients) or placebo for about 36 weeks. IHbD, and baseline and final Hb, Fe status and anthropometrics were assessed. Caregivers provided weekly morbidity reports. At enrolment, 55·6 % were anaemic; only 39·3 % had no sign of clinically significant IHbD. MNP had no overall impact on growth and longitudinal diarrhoea prevalence. Baseline Hb modified the effect of MNP on length-for-age (LAZ) (P for interaction = 0·082). Among children who were initially non-anaemic, the final mean LAZ in the MNP group was slightly lower (–1·93 (95 % CI –1·88, –1·97)) v. placebo (–1·88 (95 % CI –1·83, –1·92)), and the opposite occurred among initially anaemic children (final mean LAZ –1·90 (95 % CI –1·86, –1·94) in MNP v. –1·92 (95 % CI –1·88, –1·96) in placebo). IHbD modified the effect on diarrhoea prevalence (P = 0·095). Among children with IHbD, the MNP group had higher diarrhoea prevalence (1·37 (95 % CI 1·17, 1·59) v. 1·21 (95 % CI 1·04, 1·41)), while it was lower among children without IHbD who received MNP (1·15 (95 % CI 0·95, 1·39) v. 1·37 (95 % CI 1·13, 1·64)). In conclusion, there was a small adverse effect of MNP on growth among non-anaemic children and on diarrhoea prevalence among children with IHbD.
Impairments in visual function have been well characterized in vitamin A deficiency. However, eye function may also be sensitive to other nutrient deficiencies.
We examined associations between ...visual function—characterized by pupillary threshold or pupillary responsiveness—and nutritional status in Zambian children.
We used digital pupillometry to measure visual responses to calibrated light stimuli (−2.9 to 0.1 log cd/m2) among dark-adapted children aged 4–8 y (n = 542). We defined pupillary threshold as the first light stimulus at which pupil diameter decreased by ≥10% and considered a pupillary threshold ≥−0.9 log cd/m2 as impaired. Pupillary responsiveness was defined by absolute percentage of change in pupil diameter from pre- to poststimulus. We tested associations between these measures and serum concentrations of retinol, β-carotene, ferritin, soluble transferrin receptor, and hemoglobin (Hb <11.0 or 11.5 g/dL were used to define anemia, depending on age), as well as anthropometric indexes, with the use multilevel mixed-effects models.
Pupillary threshold was correlated only with serum retinol (r = 0.12, P < 0.05). The strongest correlates of pupillary responsiveness were Hb (r = −0.16, P < 0.01), height-for-age z score (r = 0.14, P < 0.05), weight-for-age z score (r = 0.14, P < 0.05), and soluble transferrin receptor (r = 0.12, P < 0.05). In multivariate models, anemia was positively associated with pupillary responsiveness (β = 2.99; 95% CI: 1.26, 4.72).
In this marginally nourished population, we found positive correlations between vitamin A status, iron status, or anthropometric indexes and visual function. Hb was negatively associated with visual function, with greater pupillary responsiveness among anemic children. We posit that this may signal altered parasympathetic activity, possibly driven by infection. Future studies should consider a broader range of indicators to better characterize the relation between nutrition and visual function. This trial was registered at clinicaltrials.gov as NCT01695148.
Zinc supplementation has been shown to reduce the morbidity burden among young children, and may reduce chronic stress. Hair cortisol has been promoted as an indicator of chronic stress. We assessed ...the impact of different strategies for delivering supplementary zinc on hair cortisol concentrations (HCC) in young Laotian children and examined risk factors associated with HCC. In a randomized double-blind controlled trial (NCT02428647), children aged 6⁻23 mo were randomized to one of four intervention groups and followed for ~36 weeks: daily preventive zinc (PZ) tablets (7 mg/day), daily multiple micronutrient powder (MNP) sachets (containing 10 mg zinc and 14 other micronutrients), therapeutic zinc (TZ) supplements for diarrhea treatment (20 mg/day for 10 days) or daily placebo powder. HCC of 512 children was assessed at baseline and endline. ANCOVA and linear regression models were used to assess group differences in HCC and to examine the risk factors associated with HCC, respectively. At enrollment, mean HCC was 28.8 ± 43.9 pg/mg. In models adjusted for age at enrollment, health district, and baseline HCC there was no overall effect of the interventions on endline HCC and change in HCC. When controlling for additional predetermined covariates, there was a marginally significant effect on change in HCC (
= 0.075) with a slightly lower reduction of HCC in TZ compared to PZ (mean change (95% CI): -4.6 (-7.0; -2.3) vs. -9.4 (-11.7; -7.0) pg/mg;
= 0.053). At baseline, consumption of iron rich foods was negatively associated with HCC, whereas AGP (α1-acid glycoprotein) levels, elevated AGP and C-reactive protein and high soluble transferrin receptor were positively associated with HCC. In young Laotian children, MNP, PZ and TZ had no impact on HCC. The marginal difference in change in HCC between the PZ and TZ groups was too small to be considered of health significance.
Plasma zinc concentrations (PZC) have been shown to significantly increase during zinc supplementation. This study investigated the effects of daily preventive zinc supplementation on hair and nail ...zinc concentrations compared with a control group. In a randomized controlled trial, 6- to 23-month-old children (
n
= 3407) in Lao PDR were randomly assigned to one of four groups and followed for ~ 36 weeks: daily preventive zinc dispersible tablet (7 mg/d; PZ), daily micronutrient powder (10 mg zinc/d; MNP), therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days; TZ), or daily placebo powder (Control). Plasma, hair, and nail zinc concentrations were assessed in a sub-sample of participants (
n
= 457) at baseline and endline. At baseline, 75% of children had low PZC (< 65 μg/dL). At endline, geometric mean (95% CI) PZC were greater in the PZ and MNP groups compared with the TZ and control groups (
P
< 0.01), but hair zinc concentrations did not differ among groups (
P
= 0.99). Nail zinc concentrations were marginally higher in the PZ (115.8 (111.6, 119.9) μg/g) and the MNP (117.8 (113.3, 122.3) μg/g) groups than in the TZ group (110.4 (106.0, 114.8) μg/g;
P
= 0.055) at endline. This study does not support the use of hair zinc as a biomarker of zinc exposure in young children. However, it provides some evidence that zinc concentrations in nails may respond to supplemental zinc interventions and supports the need for collecting additional data on this emerging biomarker.
Higher iron stores, defined by serum ferritin (SF) concentration, may increase malaria risk.
We evaluated the association between SF assessed during low malaria season and the risk of malaria during ...high malaria season, controlling for inflammation.
Data for this prospective study were collected from children aged 4–8 y (n = 745) participating in a biofortified maize efficacy trial in rural Zambia. All malaria cases were treated at baseline (September 2012). We used baseline SF and malaria status indicated by positive microscopy at endline (March 2013) to define exposure and outcome, respectively. Iron status was defined as deficient (corrected or uncorrected SF <12 or <15 μg/L, depending on age <5 or ≥5 y, respectively), moderate (<75 μg/L, excluding deficient), or high (≥75 μg/L). We used a modified Poisson regression to model the risk of malaria in the high transmission seasons (endline) as a function of iron status assessed in the low malaria seasons (baseline).
We observed an age-dependent, positive dose-response association between ferritin in the low malaria season and malaria incidence during the high malaria season in younger children. In children aged <6 y (but not older children), we observed a relative increase in malaria risk in the moderate iron status incidence rate ratio (IRR) with SF: 1.56; 95% CI: 0.64, 3.86; IRR with inflammation-corrected SF: 1.92; 95% CI: 0.75, 4.93 and high iron status (IRR with SF: 2.66; 95% CI: 1.10, 6.43; or IRR with corrected SF: 2.93; 95% CI: 1.17, 7.33) categories compared with the deficient iron status category. The relative increase in malaria risk for children with high iron status was statistically significant only among those with a concurrently normal serum soluble transferrin receptor concentration (<8.3 mg/L; IRR: 1.97; 95% CI: 1.20, 7.37).
Iron adequacy in 4- to 8-y-old children in rural Zambia was associated with increased malaria risk. Our findings underscore the need to integrate iron interventions with malaria control programs. This trial was registered at clinicaltrials.gov as NCT01695148.
Background
Malaria causes anemia by destruction of red blood cells and inhibition of erythropoiesis.
Objective
We assessed whether the magnitude of the malaria‐specific effect on anemia differs by ...age, during low and high malaria seasons.
Method
In rural Zambian children participating in a pro‐vitamin A efficacy trial, we estimated differences in the prevalence of anemia (defined as hemoglobin < 110 g/L for children < 60 months. and < 115 g/L in older children) by malaria status and assessed malaria‐age interactions. Regression models (with anemia as the outcome) were used to model malaria‐age interaction in both the low and high malaria seasons, controlling for potential confounders.
Results
Average age was 68 months at baseline (n = 820 children). In the low malaria season, anemia prevalence was 29% in malaria‐negative children and 54% in malaria‐positive children (p < 0.001), with no malaria‐age interactions (p = 0.44). In the high malaria season, anemia prevalence was 41% in malaria‐negative children and 54% in malaria‐positive children (p < 0.001), with significant malaria‐age interactions (p = 0.02 for anemia). Age‐stratified prevalence of anemia in malaria positive versus negative children was 67.0% versus 37.1% (in children < 60 months); 57.0% versus 37.2% (in 60–69 months.); 46.8% versus 37.2% (in 70–79 months.); 37.0% versus 37.3% (in 80–89 months) and 28.0% versus 37.4% (in 90+ months).
Conclusions
Malarial anemia is most severe in younger children, especially when transmission is intense. Anemia control programs must prioritize this vulnerable group.
Objective
In 4‐ to 8‐year‐old Zambian children (n = 744), we evaluated the effects of adjusting for inflammation (α1‐acid glycoprotein >1 g/l), with or without additional adjustment for malaria, on ...prevalence estimates of iron deficiency (ID) and iron deficiency anaemia (IDA) during low malaria (LowM) and high malaria (HighM) transmission seasons.
Methods
To estimate adjustment factors, children were classified as: (i) reference (malaria negative without inflammation), (ii) inflammation without malaria (I), (iii) malaria without inflammation (M) and (iv) inflammation with malaria (IM). We estimated the unadjusted ID or IDA prevalence, and then adjusted for inflammation alone (IDI or IDAI) or inflammation and malaria (IDIM or IDAIM).
Results
Mean ferritin was 38 (reference), 45 (I), 43 (M) and 54 μg/l (IM) in LowM, increasing to 44, 56, 96 and 167 μg/l, respectively, in HighM. Corresponding mean sTfR was 6.4, 6.9, 7.9 and 8.4 mg/l in LowM, increasing to 8.2, 9.2. 8.7 and 9.7 mg/l in HighM. Ferritin‐based ID, IDI and IDIM were 7.8%, 8.7% or 9.1%, respectively, in LowM and 4.6%, 10.0% or 11.7%, respectively, in HighM. Corresponding soluble transferrin receptor (sTfR)‐based estimates were 27.0%, 24.1% and 19.1%, respectively, in LowM, increasing to 53.6%, 46.5% and 45.3%, respectively, in HighM. Additional adjustment for malaria resulted in a ~1‐ to 2‐percentage point change in IDA, depending on biomarker and season.
Conclusions
In this population, malaria substantially increased ferritin and sTfR concentrations, with modest effects on ID and IDA prevalence estimates.
Objectif
Chez les enfants zambiens de 4 à 8 ans (n = 744), nous avons évalué les effets de l'ajustement pour l'inflammation (α1‐glycoprotéine acide > 1 g/L), avec ou sans ajustement additionnel pour le paludisme, sur les estimations de prévalence de la carence en fer (CF) et l'anémie ferriprive (AF) lors des saisons de transmission faible (LowM) et élevée (HighM) du paludisme.
Méthodes
Pour estimer les facteurs d'ajustement, les enfants ont été classés en: a) référence (paludisme négatif sans inflammation), b) inflammation sans paludisme (I), c) paludisme sans inflammation (M), et d) inflammation avec paludisme (IM). Nous avons estimé la prévalence non ajustée de la CF ou de l’AF, puis avons ajusté pour l'inflammation seule (CFI ou AFI) ou l'inflammation avec le paludisme (CFIM ou AFIM).
Résultats
La ferritine moyenne était de 38 (référence), 45 (I), 43 (M) et 54 (IM) μg/L dans la LowM, augmentant à 44, 56, 96 et 167 μg/L respectivement, dans la HighM. Les valeurs moyennes correspondantes du récepteur soluble de la transferrine (sTfR) étaient de 6,4; 6,9; 7,9 et 8,4 mg/L dans la LowM, augmentant à 8,2; 9,2; 8,7 et 9,7 mg/L dans la HighM. Les CF sur base de la ferritine, de CFI et CFIM étaient respectivement de 7,8%, 8,7% et 9,1% dans la LowM et de 4,6%, 10,0% et 11,7% respectivement, dans la HighM. Les estimations correspondantes du sTfR étaient respectivement de 27,0%, 24,1% et 19,1% dans la LowM, augmentant à 53,6%, 46,5% et 45,3%, respectivement, dans la HighM. Des ajustements supplémentaires pour le paludisme ont entraîné une variation d'environ 1 à 2 points de pourcentage de l’AF selon le biomarqueur et la saison.
Conclusions
Dans cette population, le paludisme a considérablement augmenté les concentrations de ferritine et du sTfR, avec des effets modestes sur les estimations de prévalence la CF et de l'AF.
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