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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.

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 (sT f R) 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 sT f R 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 ).

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.

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. 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. 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. 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. 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.

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.

We have previously shown that high-dose vitamin D 3 improved weight gain and neurodevelopmental indices in children receiving standard therapy for uncomplicated severe acute malnutrition (SAM). Here we present results of a randomised placebo-controlled trial in Lahore, Pakistan, to determine whether two oral doses of 200,000 international units (IU) vitamin D 3 (the first administered on or before the day of hospital discharge and the second administered 14 days later) would benefit children aged 6-59 months during the convalescent phase of complicated SAM. Eligible participants were individually randomised to intervention vs. control arms with a one-to-one allocation ratio and stratification by hospital of recruitment using computer-generated random sequences. Double-blinding to treatment allocation was maintained by concealing allocation from participants’ parents or guardians, their medical care providers, and all trial staff. The primary outcome was mean weight-for-height or -length z-score (WHZ) at 2-month follow-up. Secondary efficacy outcomes included mean WHZ at 6-month follow-up and mean lean mass index, Malawi Development Assessment Tool (MDAT) scores and serum 25-hydroxyvitamin D (25[OH]D) concentrations at 2- and 6-month follow-up. The trial has now completed. 259 children were randomised (128 to vitamin D, 131 to placebo), of whom 251 (96.9%) contributed data to analysis of the primary outcome (123 allocated to vitamin D, 128 to placebo). At 2-month follow-up, participants allocated to vitamin D had significantly higher mean serum 25(OH)D concentrations than those allocated to placebo (adjusted mean difference [aMD] 100.0 nmol/L, 95% confidence interval [CI] 72.2–127.8 nmol/L). This was not associated with an inter-arm difference in mean WHZ at 2-month follow-up (aMD 0.02, 95% CI −0.20 to 0.23), or in any anthropometric or neurodevelopmental secondary outcome assessed at 2- or 6-month follow-up. The intervention was safe. In conclusion, high-dose vitamin D 3 elevated mean serum 25(OH)D concentrations in children receiving standard therapy for complicated SAM in Pakistan, but did not influence any anthropometric or neurodevelopmental outcome studied. The trial was registered at ClinicalTrials.gov with the identifier NCT04270643. High-dose oral vitamin D 3 supplements have previously been shown to be beneficial in children receiving standard therapy for uncomplicated severe acute malnutrition. This randomised controlled trial shows that the same intervention, given in addition to standard therapy, did not improve anthropometric or neurodevelopmental outcomes in children with complicated severe acute malnutrition in Pakistan.

Objectives To determine the proportion of children with severe acute malnutrition (SAM) having vitamin B12 deficiency, its clinical predictors, and its association with development. Methods In this cross-sectional study, 100 children between 1 mo to 59 mo [mean (SD) age 17 (12.75) mo; 55 males], with diagnosis of SAM as per WHO criteria, were included. Serum vitamin B12, serum folate, and serum ferritin levels were measured by chemiluminescence immunometric assay method, while serum Homocysteine (Hcy) level was measured by enzymatic cycling method. Development assessment was done by Denver Development Screening Tool (DDST-II). Results The mean (SD) serum vitamin B12 (cobalamin) levels were 296.52 (246.95) pg/mL; 45% children were vitamin B12 deficient (<203 pg/mL). Hyperhomocysteinemia (>14 µmol/L) was present in 39 (39%), and among these 69% (27/39) children had concomitant low serum vitamin B12 levels. Severe anemia and hypoproteinemia were significantly and independently associated with vitamin B12 deficiency [aOR (95% CI) 3.22 (1.13, 10) and 10 (1.66, 58.82), respectively]. Out of 45 children who were vitamin B12 deficient, 93%, 87%, 62% and 80% had gross motor, fine-motor, language and adaptive-cognitive delay, respectively. Vitamin B12 level was significantly associated ( P  <0.001) with developmental delay. Conclusions There is a high prevalence of vitamin B12 deficiency in children with SAM, which is also associated with development delay across all domains (except language) in these children.

Severe acute malnutrition (SAM) is a major contributor to under-five mortality in developing countries such as India, where SAM children are susceptible to infections. However, there is inconsistent literature on the derangement of immune mechanisms and subsequent infection-related mounting of inflammatory responses in SAM cases compared to nutritionally-normal controls with infections. To address this, authors conducted a case–control study comparing serum inflammatory markers in 60 SAM children with systemic infections to nutritionally-normal children with infection. Cases had a lower mean serum C-reactive protein (CRP) on admission compared to controls ( p -value <0.001), which continued during the follow-up ( p -value <0.001). Cases also had a lower mean serum interleukin-6 (IL-6) on admission ( p -value = 0.04). Baseline CRP, procalcitonin, and follow-up procalcitonin were positively correlated with antibiotic therapy duration ( p -value = 0.018, 0.025, and 0.007, respectively). This study suggests that SAM children had some ability to mount an inflammatory response during a systemic infection, but it was weaker compared to nutritionally normal children with a systemic infection.

We have previously shown that high-dose vitamin D improved weight gain and neurodevelopmental indices in children receiving standard therapy for uncomplicated severe acute malnutrition (SAM). Here we present results of a randomised placebo-controlled trial in Lahore, Pakistan, to determine whether two oral doses of 200,000 international units (IU) vitamin D (the first administered on or before the day of hospital discharge and the second administered 14 days later) would benefit children aged 6-59 months during the convalescent phase of complicated SAM. Eligible participants were individually randomised to intervention vs. control arms with a one-to-one allocation ratio and stratification by hospital of recruitment using computer-generated random sequences. Double-blinding to treatment allocation was maintained by concealing allocation from participants' parents or guardians, their medical care providers, and all trial staff. The primary outcome was mean weight-for-height or -length z-score (WHZ) at 2-month follow-up. Secondary efficacy outcomes included mean WHZ at 6-month follow-up and mean lean mass index, Malawi Development Assessment Tool (MDAT) scores and serum 25-hydroxyvitamin D (25[OH]D) concentrations at 2- and 6-month follow-up. The trial has now completed. 259 children were randomised (128 to vitamin D, 131 to placebo), of whom 251 (96.9%) contributed data to analysis of the primary outcome (123 allocated to vitamin D, 128 to placebo). At 2-month follow-up, participants allocated to vitamin D had significantly higher mean serum 25(OH)D concentrations than those allocated to placebo (adjusted mean difference [aMD] 100.0 nmol/L, 95% confidence interval [CI] 72.2-127.8 nmol/L). This was not associated with an inter-arm difference in mean WHZ at 2-month follow-up (aMD 0.02, 95% CI -0.20 to 0.23), or in any anthropometric or neurodevelopmental secondary outcome assessed at 2- or 6-month follow-up. The intervention was safe. In conclusion, high-dose vitamin D elevated mean serum 25(OH)D concentrations in children receiving standard therapy for complicated SAM in Pakistan, but did not influence any anthropometric or neurodevelopmental outcome studied. The trial was registered at ClinicalTrials.gov with the identifier NCT04270643.

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.