Clinical and Biochemical Markers of Risk in Uncomplicated Severe Acute Malnutrition.

BACKGROUND AND OBJECTIVES: Use of mid-upper arm circumference (MUAC) as a single screening tool for severe acute malnutrition (SAM) assumes that children with a low weight-for-height z score (WHZ) and normal MUAC have lower risks of morbidity and mortality. However, the pathophysiology and functional severity associated with different anthropometric phenotypes of SAM have never been well characterized. We compared clinical characteristics, biochemical features, and health and nutrition histories of nonedematous children with SAM who had (1) low WHZ only, (2) both low WHZ and low MUAC, or (3) low MUAC only. METHODS: In Bangladesh, Burkina Faso, and Liberia, we conducted a multicentric cohort study in uncomplicated, nonedematous children with SAM and low MUAC only (n = 161), low WHZ only (n = 138), or a combination of low MUAC and low WHZ (n = 152). Alongside routine anthropometric measurements, we collected a wide range of critical indicators of clinical and nutritional status and viability; these included serum leptin, an adipocytokine negatively associated with mortality risk in SAM. RESULTS: Median leptin levels at diagnosis were lower in children with low WHZ only (215.8 pg/mL; P < .001) and in those with combined WHZ and MUAC deficits (180.1 pg/mL; P < .001) than in children with low MUAC only (331.50 pg/mL). The same pattern emerged on a wide range of clinical indicators, including signs of severe wasting, dehydration, serum ferritin levels, and caretaker-reported health deterioration, and was replicated across study sites. CONCLUSIONS: Illustrative of the likely heterogeneous functional severity of the different anthropometric phenotypes of SAM, our results confirm the need to retain low WHZ as an independent diagnostic criterion.

Plasma proteomics reveals markers of metabolic stress in HIV infected children with severe acute malnutrition.

HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p < 0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p < 0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM.

Vitamin A and iron status of children before and after treatment of uncomplicated severe acute malnutrition.

BACKGROUND & AIMS: Treatment of children with uncomplicated severe acute malnutrition (SAM) is based on ready-to-use therapeutic foods (RUTF) and aims for quick regain of lost body tissues while providing sufficient micronutrients to restore diminished body stores. Little evidence exists on the success of the treatment to establish normal micronutrient status. We aimed to assess the changes in vitamin A and iron status of children treated for SAM with RUTF, and explore the effect of a reduced RUTF dose. METHODS: We collected blood samples from children 6-59 months old with SAM included in a randomised trial at admission to and discharge from treatment and analysed haemoglobin (Hb) and serum concentrations of retinol binding protein (RBP), ferritin (SF), soluble transferrin receptor (sTfR), C-reactive protein (CRP) and α1-acid glycoprotein (AGP). SF, sTfR and RBP were adjusted for inflammation (CRP and AGP) prior to analysis using internal regression coefficients. Vitamin A deficiency (VAD) was defined as RBP < 0.7 µmol/l, anaemia as Hb < 110 g/l, storage iron deficiency (sID) as SF < 12 µg/l, tissue iron deficiency (tID) as sTfR > 8.3 mg/l and iron deficiency anaemia (IDA) as both anaemia and sID. Linear and logistic mixed models were fitted including research team and study site as random effects and adjusting for sex, age and outcome at admission. RESULTS: Children included in the study (n = 801) were on average 13 months of age at admission to treatment and the median treatment duration was 56 days [IQR: 35; 91] in both arms. Vitamin A and iron status markers did not differ between trial arms at admission or at discharge. Only Hb was 1.7 g/l lower (95% CI -0.3, 3.7; p = 0.088) in the reduced dose arm compared to the standard dose, at recovery. Mean concentrations of all biomarkers improved from admission to discharge: Hb increased by 12% or 11.6 g/l (95% CI 10.2, 13.0), RBP increased by 13% or 0.12 µmol/l (95% CI 0.09, 0.15), SF increased by 36% or 4.4 µg/l (95% CI 3.1, 5.7) and sTfR decreased by 16% or 1.5 mg/l (95% CI 1.0, 1.9). However, at discharge, micronutrient deficiencies were still common, as 9% had VAD, 55% had anaemia, 35% had sID, 41% had tID and 21% had IDA. CONCLUSION: Reduced dose of RUTF did not result in poorer vitamin A and iron status of children. Only haemoglobin seemed slightly lower at recovery among children treated with the reduced dose. While improvement was observed, the vitamin A and iron status remained sub-optimal among children treated successfully for SAM with RUTF. There is a need to reconsider RUTF fortification levels or test other potential strategies in order to fully restore the micronutrient status of children treated for SAM.

Metabolomics in plasma of Malawian children 7 years after surviving severe acute malnutrition: "ChroSAM" a cohort study.

BACKGROUND: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM. METHODS: We followed-up children (n = 352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9·6 ±â€¯1·6 years), siblings (n = 44, 10·5 ±â€¯2·7 years), and age and sex-matched community controls (n = 37, 9·4 ±â€¯1·8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index. FINDINGS: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0·3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (ß = 15·2, SE = 3·5, partial R2 = 12%, p < 0·0001) and this relationship could be influenced by early childhood SAM (ß = 17·4, SE = 7·7, partial R2 = 2·8%, p = 0·025). No metabolites were associated with oedema status, duration of hospital stay, anthropometry measured during hospitalization, nor with changes in anthropometry since hospitalization. INTERPRETATION: In this group of survivors, SAM was not associated with longer-term global metabolic changes 7 years after treatment. However, SAM may influence the relationship between current stunting and IGF1. Further risk markers for NCDs in SAM survivors may only be revealed by direct metabolic challenge or later in life.

Soya, maize and sorghum ready-to-use therapeutic foods are more effective in correcting anaemia and iron deficiency than the standard ready-to-use therapeutic food: randomized controlled trial.

BACKGROUND: The prevalence of anaemia and iron deficiency (ID) among children with severe acute malnutrition (SAM) and their correction during nutritional rehabilitation are not well documented. This study assessed anaemia and ID prevalence and their predictors at start of SAM treatment, and the efficacy of their treatment and effect on gut health of two novel Ready-To-Use Therapeutic foods (RUTF) prepared from soybean, maize and sorghum (SMS) with (MSMS-RUTF) or without added milk (FSMS-RUTF) compared to those of the standard formulation prepared from peanut and milk (PM-RUTF). METHODS: This was a 3-arms parallel groups, simple randomised, controlled non-inferiority trial in 6-59 months old Central Malawian children with SAM. Anaemia was defined using altitude- and ethnicity-adjusted haemoglobin. Iron status was defined using soluble transferrin receptor (sTfR) and body iron stores (BIS). We used Pearson's chi-square test, t-test for paired or unpaired data, Kruskal-Wallis test for between-arm differences as appropriate and logistic regression to identify independent predictors of anaemia or iron deficiency anaemia (IDA). RESULTS: The sample size was 389. At admission, the prevalence [%(95%CI)] of anaemia was 48.9(41.4-56.5)% while that of ID and IDA were 55.7(48.6-62.5)% and 34.3(28.2-41.0)% when using sTfR criterion and 29.1(24.4-34.4)% and 28.9(23.7-34.9)% when using BIS criterion, respectively. At discharge, nutrition rehabilitation with SMS-RUTF was associated with the lowest prevalence of anaemia [12.0(6.9-20.3)% for FSMS-RUTF, 18.2(11.9-26.8)% for MSMS-RUTF and 24.5(15.8-35.9)% for PM-RUTF; p = 0.023] and IDA [7.9(3.4-17.3)% for FSMS-RUTF, 10.9(4.8-22.6)% for MSMS-RUTF and 20.5(10.7-35.5)% for PM-RUTF; p = 0.028]. SMS-RUTF was also associated with the highest increase in BIS [Change in BIS (95%CI)] among the iron deplete at admission [6.2 (3.7; 8.6), 3.2 (0.8; 5.6), 2.2 (0.2; 4.3) for the same study arms; Anova p = 0.045]. Compared to P-RUTF, FSMS-RUTF had the highest adjusted recovery rate [OR (95%CI = 0.3 (0.2-0.5) with p < 0.001 for FSMS-RUTF and 0.6 (0.3-1.0) with p = 0.068 for MSMS-RUTF]. No effect of iron content on risk of iron overload or gut inflammation was observed. CONCLUSIONS: Anaemia and ID are common among children with SAM. FSMS-RUTF is more efficacious in treating anaemia and correcting BIS among this group than PM-RUTF. TRIAL REGISTRATION: This study was registered on 15 April 2015 ( PACTR201505001101224 ).

Biomarkers of post-discharge mortality among children with complicated severe acute malnutrition.

High mortality after discharge from hospital following acute illness has been observed among children with Severe Acute Malnutrition (SAM). However, mechanisms that may be amenable to intervention to reduce risk are unknown. We performed a nested case-control study among HIV-uninfected children aged 2-59 months treated for complicated SAM according to WHO recommendations at four Kenyan hospitals. Blood was drawn from 1778 children when clinically judged stable before discharge from hospital. Cases were children who died within 60 days. Controls were randomly selected children who survived for one year without readmission to hospital. Untargeted proteomics, total protein, cytokines and chemokines, and leptin were assayed in plasma and corresponding biological processes determined. Among 121 cases and 120 controls, increased levels of calprotectin, von Willebrand factor, angiotensinogen, IL8, IL15, IP10, TNFα, and decreased levels of leptin, heparin cofactor 2, and serum paraoxonase were associated with mortality after adjusting for possible confounders. Acute phase responses, cellular responses to lipopolysaccharide, neutrophil responses to bacteria, and endothelial responses were enriched among cases. Among apparently clinically stable children with SAM, a sepsis-like profile is associated with subsequent death. This may be due to ongoing bacterial infection, translocated bacterial products or deranged immune response during nutritional recovery.

Amino-acid-enriched cereals ready-to-use therapeutic foods (RUTF) are as effective as milk-based RUTF in recovering essential amino acid during the treatment of severe acute malnutrition in children: An individually randomized control trial in Malawi.

BACKGROUND: Ready-to-use therapeutic food (RUTF) is used to treat children suffering from severe acute malnutrition (SAM). Standard RUTF uses milk as the primary protein source, which makes the product expensive, and given the high worldwide SAM burden, having a less expensive effective alternative is a public health priority. OBJECTIVE: The objective of this study was to evaluate whether newly developed amino acid-enriched milk-free RUTF (FSMS-RUTF) or amino acid-enriched low-milk RUTF (MSMS-RUTF) treatment could replenish plasma amino acids to levels comparable to those following standard peanut-milk RUTF (PM-RUTF) treatment and to improve understanding of the effects of treatment on anthropometric measurements. A secondary analysis was performed to test the noninferiority hypothesis of plasma essential amino acid (EAA) levels. METHODS: Plasma EAA levels were measured in a nonblinded, 3-arm, parallel-group simple randomized controlled trial conducted in Malawi to examine the efficacy of FSMS-RUTF, MSMS-RUTF and PM-RUTF in the treatment of SAM in 2 groups of children aged 6-23 and 24-59 months (mo). Sample size calculations were performed based on the previous our study. A noninferiority margin was set at -25% of the PM-RUTF arm at discharge. RESULTS: The relative values of the differences (95% CI) in plasma EAA levels between PM-RUTF treatment and FSMS-RUTF and MSMS-RUTF treatments at discharge were -7.9% (-18.6, 2.8) and 9.8% (0.2, 19.5), respectively, in children aged 6-23 mo, while in those aged 24-59 mo, the difference values were 17.8% (1.6, 34.1) and 13.6% (-2.8, 29.9), respectively. CONCLUSION: At discharge, the plasma EAA concentrations in 6-59-mo-old SAM children treated with FSMS-RUTF and MSMS-RUTF were not less than those of children treated with PM-RUTF. These findings indicate that treatment with either of the 3 RUTFs was associated with adequate protein synthesis and that all the formulations provided sufficient functional metabolites of plasma amino acids to support nutritional recovery from SAM.

Serum phosphate and magnesium in children recovering from severe acute undernutrition in Ethiopia: an observational study.

BACKGROUND: Children with severe acute malnutrition (SAM) have increased requirements for phosphorus and magnesium during recovery. If requirements are not met, the children may develop refeeding hypophosphatemia and hypomagnesemia. However, little is known about the effect of current therapeutic diets (F-75 and F-100) on serum phosphate (S-phosphate) and magnesium (S-magnesium) in children with SAM. METHODS: Prospective observational study, with measurements of S-phosphate and S-magnesium at admission, prior to rehabilitation phase and at discharge in children aged 6-59 months admitted with SAM to Jimma Hospital, Ethiopia. Due to shortage of F-75, 25 (35 %) children were stabilized with diluted F-100 (75 kcal/100 ml). RESULTS: Of 72 children enrolled, the mean age was 32 ± 14 months, and edema was present in 50 (69 %). At admission, mean S-phosphate was 0.92 ± 0.34 mmol/L, which was low compared to normal values, but increased to 1.38 ± 0.28 mmol/L at discharge, after on average 16 days. Mean S-magnesium, at admission, was 0.95 ± 0.23 mmol/L, and increased to 1.13 ± 0.17 mmol/L at discharge. At discharge, 18 (51 %) children had S-phosphate below the normal range, and 3 (9 %) had S-phosphate above. Most children (83 %) had S-magnesium above normal range for children. Both S-phosphate and S-magnesium at admission were positively associated with serum albumin (S-albumin), but not with anthropometric characteristics or co-diagnoses. Using diluted F-100 for stabilization was not associated with lower S-phosphate or S-magnesium. CONCLUSION: Hypophosphatemia was common among children with SAM at admission, and still subnormal in about half of the children at discharge. This could be problematic for further recovery as phosphorus is needed for catch-up growth and local diets are likely to be low in bioavailable phosphorus. The high S-magnesium levels at discharge does not support that magnesium should be a limiting nutrient for growth in the F-100 diet. Although diluted F-100 (75 kcal/100 mL) is not designed for stabilizing children with SAM, it did not seem to cause lower S-phosphate than in children fed F-75.

Unraveling the Link between Malnutrition and Adverse Clinical Outcomes: Association of Acute and Chronic Malnutrition Measures with Blood Biomarkers from Different Pathophysiological States.

BACKGROUND AND AIMS: Malnutrition is associated with poor clinical outcomes. Whether there is a causal relationship or it merely mirrors a severe patient condition remains unclear. We examined the association of malnutrition with biomarkers characteristic of different pathophysiological states to better understand the underlying etiological mechanisms. METHODS: We prospectively followed consecutive adult medical inpatients. Multivariable regression models were used to investigate the associations between malnutrition - as assessed using the Nutritional Risk Screening (NRS 2002) - and biomarkers linked to inflammation, stress, renal dysfunction, nutritional status and hematologic function. RESULTS: A total of 529 patients were included. In a fully adjusted model, malnutrition was significantly associated with the inflammatory markers procalcitonin (0.20, 95% CI 0.03-0.37), proadrenomedullin (0.28, 95% CI 0.12-0.43) and albumin (-0.39, 95% CI -0.57 to -0.21), the stress marker copeptin (0.34, 95% CI 0.17-0.51), the renal function marker urea (0.23, 95% CI 0.07-0.38), the nutritional markers vitamin D25 (-0.22, 95% CI -0.41 to -0.02) and corrected calcium (0.29, 95% CI 0.10-0.49) and the hematological markers hemoglobin (-0.27, 95% CI -0.43 to -0.10) and red blood cell distribution width (0.26, 95% CI 0.07-0.44). Subgroup analysis suggested that acute malnutrition rather than chronic malnutrition was associated with elevated biomarker levels. CONCLUSION: Acute malnutrition was associated with a pronounced inflammatory response and an alteration in biomarkers associated with different pathophysiological states. Interventional trials are needed to prove causality.

Changes in plasma phosphate during in-patient treatment of children with severe acute malnutrition: an observational study in Uganda.

BACKGROUND: Children treated for severe acute malnutrition (SAM) are at risk of refeeding hypophosphatemia. Therapeutic diets have only recently become fortified with phosphorus to meet United Nations (UN) specifications, but to our knowledge no studies have investigated the effect. OBJECTIVE: The aim was to assess concentrations and correlates of plasma phosphate (P-phosphate) at admission and during treatment and to identify correlates of changes in P-phosphate. DESIGN: This was a prospective observational study in 6- to 59-mo-old children admitted for treatment of SAM to Mulago Hospital, Uganda. P-phosphate was measured at admission, on the second day of treatment with a therapeutic formula containing 75 kcal/100 mL and 560 mg phosphorus/L (F-75, Nutriset), at the start of the transition to a therapeutic formula containing 100 kcal/100 mL and 579 mg phosphorus/L (F-100; Nutriset), at day 2 of transition, and at discharge. RESULTS: Among 120 children, mean ± SD P-phosphate at admission was 1.04 ± 0.31 mmol/L and increased by 0.43 (95% CI: 0.35, 0.52) mmol/L during the first 2 d and more slowly toward discharge. Most (79%) children experienced their lowest P-phosphate concentration at admission, and none developed severe hypophosphatemia. P-phosphate was lowest in children with edema and with elevated C-reactive protein, and a lower increase was seen with increasing caretaker-reported severity of illness. Partially or fully replacing F-75 with rice porridge (i.e., a local practice to reduce diarrhea) during the first 2 d of stabilization was associated with a 0.34-mmol/L (95% CI: 0.18, 0.50 mmol/L) lower increase in P-phosphate during the same first 2 d. CONCLUSIONS: F-75, which complies with UN specifications and provides 73 mg phosphorus · kg(-1) · d(-1) (130 mL · kg(-1) · d(-1)), seems to prevent refeeding hypophosphatemia in children with SAM. Replacing this formula with rice porridge during the first days of treatment to manage diarrhea may have an adverse effect on P-phosphate concentrations. This study was registered at http://www.isrctn.com as ISRCTN55092738.

Essential fatty acid composition and correlates in children with severe acute malnutrition.

BACKGROUND: Severe acute malnutrition (SAM) is a common condition in children living in low-income countries and may be associated with reduced polyunsaturated fatty acids (PUFA) blood levels. The purpose of this study was to describe whole blood fatty acid composition and correlates of PUFA in children admitted with SAM. METHODS: We conducted a cross-sectional study among children admitted with SAM at Mulago National Referral Hospital and healthy controls. Whole blood fatty acid composition was measured and correlated with clinical data such as oedema, levels of haemoglobin, C-reactive protein and HIV-infection status. Multiple linear regression analyses were used to identify correlates of PUFA. RESULTS: The relative contribution of saturated fatty acid to the fatty acids in whole blood (FA%) were lower in 108 children with SAM compared to 24 well-nourished controls whereas most monounsaturated fatty acids were higher in children with SAM. Total and all n-6 PUFA including linoleic (18:2n-6, LA) and arachidonic acid (20:4n-6, AA), as well as total n-3 PUFA and docosahexaenoic acid (22:6n-3, DHA) were lower in children with SAM. The n-6:n-3 PUFA ratio was also lower in the children with SAM. Haemoglobin was a positive correlate of AA, n-3 docosapentaenoic acid (22:5n-3, n-3 DPA), DHA, total n-6 long chain (LC) PUFA and total n-3 LCPUFA. HIV infected children had 0.87 (0.47; 1.58) %-points less n-6 LCPUFA and 0.61 (0.03; 1.19) %-points less AA than the un-infected children. CONCLUSION: Children with SAM presented with lower FA% of LCPUFA. HIV infection and low haemoglobin were also associated with lower FA% of LCPUFA, which may be related to lower numbers of blood cells. Nutrition rehabilitation interventions need to pay more attention to the intake of PUFA.

Assessment of iron, folate and vitamin B12 status in severe acute malnutrition.

OBJECTIVES: To assess iron, folate and vitamin B12 status in hospitalized children aged between 6 mo to 5 y with severe acute malnutrition and its correlation with their clinico-epidemiological profile. METHODS: The study was conducted on 50 children with severe acute malnutrition. Anthropometric measurements were taken to determine their nutritional status. The demographic profile and relevant information of individual patient were collected by using structured proforma and an informed consent was taken for enrolling the children into the study. Serum ferritin, folate and vitamin B12 was estimated using electrochemiluminiscence (ECL) method. RESULTS: Seventy eight percent patients had weight/height (WT/HT) Z score < -3 standard deviation (3SD), 72 % with mid upper arm circumference (MUAC) <11.5 cm and 22 % of them had edematous malnutrition. Anemia was prevalent in 47(94 %) and there was significant correlation between WT/HT < -3SD and vitamin B 12 deficiency (p = 0.015). Significantly higher number of these patients had vitamin B12 deficiency as compared to folate and iron deficiency (p = 0.0006 each). CONCLUSIONS: Vitamin B12 deficiency was more common than iron and folate deficiencies in these patients with severe acute malnutrition.