Incidence and predictors of severe acute malnutrition mortality in children aged 6-59 months admitted at Pawe general hospital, Northwest Ethiopia.

BACKGROUND: Severe acute malnutrition (SAM) is defined as a weight-for-height < -3z scores of the median WHO growth standards, or visible severe wasting or the presence of nutritional edema. SAM related mortality rates in under-five children are well documented in Ethiopia but data on their predictors are limited. We aimed to document factors associated with SAM related mortality to inform better inpatient management. METHODS: A facility-based retrospective cohort study was conducted among children admitted due to SAM at Pawe General Hospital, Northwest Ethiopia, from the 1st of January 2015 to the 31st of December 2019. Data from the records of SAM children were extracted using a standardized checklist. Epi-Data version 3.2 was used for data entry, and Stata version 14 was used for analysis. Bi-variable and multivariable Cox regression analyses were conducted to identify predictors of mortality. Variables with P<0.05 were considered significant predictors of mortality. RESULTS: Five-hundred sixty-eight SAM cases were identified of mean age was 27.4 (SD± 16.5) months. The crude death rate was 91/568 (16.02%) and the mean time to death was determined as 13 (±8) days. Independent risk factors for death were: (i) vomiting AHR = 5.1 (1.35-21.1, p = 0.026), (ii) diarrhea AHR = 2.79 (1.46-5.4, p = 0.002), (iii) needing nasogastric therapy AHR = 3.22 (1.65-6.26, p = 0.001), (iv) anemia AHR = 1.89 (1.15-3.2, p = 0.012), and (v) being readmitted with SAM AHR = 1.7 (1.12-2.8, p = 0.037). CONCLUSION: SAM mortality was high in under-five children in our setting. The identified risk factors should inform treatment and prevention strategies. Improved community health education should focus on healthy nutrition and seeking early treatment. Inpatient mortality may be reduced by stricter adherence to treatment guidelines and recognizing early the key risk factors for death.

Amino acid-enriched plant-based RUTF treatment was not inferior to peanut-milk RUTF treatment in restoring plasma amino acid levels among patients with oedematous or non-oedematous malnutrition.

Ready-to-use therapeutic food (RUTF) with adequate quality protein is used to treat children with oedematous and non-oedematous severe acute malnutrition (SAM). The plasma amino acid (AA) profile reflects the protein nutritional status; hence, its assessment during SAM treatment is useful in evaluating AA delivery from RUTFs. The objective was to evaluate the plasma AAs during the treatment of oedematous and non-oedematous SAM in community-based management of acute malnutrition (CMAM) using amino acid-enriched plant-based RUTFs with 10% milk (MSMS-RUTF) or without milk (FSMS-RUTF) compared to peanut milk RUTF (PM-RUTF). Plasma AA was measured in a non-blinded, 3-arm, parallel-group, simple randomized controlled trial conducted in Malawi. The RUTFs used for SAM were FSMS-RUTF, MSMS-RUTF or PM-RUTF. A non-inferiority hypothesis was tested to compare plasma AA levels from patients treated with FSMS-RUTF or MSMS-RUTF with those from patients treated with PM-RUTF at discharge. For both types of SAM, FSMS-RUTF and MSMS-RUTF treatments were non-inferior to the PM-RUTF treatment in restoration of the EAA and cystine except that for FSMS-RUTF, methionine and tryptophan partially satisfied the non-inferiority criteria in the oedematous group. Amino-acid-enriched milk-free plant-source-protein RUTF has the potential to restore all the EAA, but it is possible that enrichment with amino acids may require more methionine and tryptophan for oedematous children.

Frequency of relapse for severe acute malnutrition and associated factors among under five children admitted to health facilities in Hadiya Zone, South Ethiopia.

BACKGROUND: Severe acute malnutrition is a common cause of morbidity and mortality among under five children in Ethiopia. A child may experience more than one episode of SAM depending on the improvement of the underlying factors. However, there is no study that determined the frequency of relapse of SAM cases after discharge in Ethiopia. OBJECTIVE: To identify the frequency of relapse and associated factors among children discharged after undergoing treatment for SAM in Hadiya Zone, South, Ethiopia. METHODS: An institution based retrospective cohort study was done among children admitted to health posts for treatment of SAM from 2014/2015-2019/2020 under-five children's after discharge in health post for severe acute malnutrition in the last five years in Hadiya zone, SNNPR, Ethiopia. Both first admission data and relapse data were abstracted from the records of the SAM children from Aguste 1-30 /2020 Using a data collection format. Data were coded and edited manually, then doubly entered into Epi-Data statistical software version 3.1 and then exported to SPSS for windows version 26. After checking all the assumptions finally Negative binomial regression for poison has been used. All tests were two sided and P values <0.05 were used to declare statistical significance. RESULTS: In the last five year there were the proportion of relapsed cases were 9.6%, 95% CI: (7.7%, 11.7%) On multivariable negative binomial regression model, after adjusting for background variables relapse of severe acute undernutrition was significantly associated with having edema during admission with (IRR = 2.21, 95% CI:1.303-3.732), being in the age group of 6-11 months (IRR = 4.74,95% CI:1.79-12.53), discharge MUAC for the first admission (P = 0.001, IRR = 0.37, 95% CI:0.270-0.50) increase the risk of incidence rate ratio(IRR) relapse case of severe acute under nutrition. CONCLUSION: Frequency of SAM relapse was positively associated with age, having edema during admission, while it was negatively associated with discharge MUAC. The results imply the need for reviewing the discharge criteria taking into account the recovery of MUAC as a marker for lean tissue accretion, especially in edematous children and those in the younger age.

Treatment outcome of Severe Acute Malnutrition and associated factors among under-five children in outpatient therapeutics unit in Gubalafto Wereda, North Wollo Zone, Ethiopia, 2019.

BACKGROUND: In Ethiopia, uncomplicated severe acute malnutrition is managed through the outpatient therapeutic program at health posts level. This brings the services for the management of Severe Acute Malnutrition closer to the community by making services available at decentralized treatment points within the primary health care settings. So far, evidence of the treatment outcome of the program is limited. OBJECTIVE: The main aim of this study was to determine the magnitude of treatment outcomes of severe acute malnutrition and associated factors among under-five children at outpatient therapeutic feeding units in Gubalafto Wereda, Ethiopia, 2019. METHODS: This was a retrospective cohort study conducted on 600 children who had been managed for Severe Acute Malnutrition (SAM) under Outpatient Therapeutic Program (OTP) in Gubalafto Wereda from April to May/2019. The children were selected using systematic random sampling from 9 health posts. The structured, pre-tested, and adapted questionnaire was used to collect the data. The data was entered by using EPI-data Version 4.2 and exported to SPSS version 24.0 for analysis. Bivariate and Multivariate regression was also carried out to determine the association between dependent and independent variables. RESULTS: A total of 600 records of children with a diagnosis of severe acute malnutrition were reviewed. Of these cases of malnutrition, the recovery rate was found to be 65%. The death rate, default rate, and medical transfer were 2.0, 16.0, and 17.0 respectively. Immunized children had 6.85 times higher odds of recovery than children who were not immunized (AOR = 6.85 at 95% CI (3.68-12.76)). The likelihood of recovery was 3.78 times higher among children with new admission than those with re-admission (AOR = 3.78at 95% CI ((1.77-8.07))). Likewise, children provided with amoxicillin were 3.38 times recovered than their counterparts (AOR = 3.38 at 95% CI ((1.61-7.08))). SAM treatment in OTP is beneficial because of its local access for most severe cases since children reach early before developing complications as a result fatalities will be reduced. CONCLUSIONS: The recovery rate and medical transfer were lower than the sphere standard. Presence of cough, presence of diarrhea admission category, provision of amoxicillin, and immunization status were factors identified as significantly associated with treatment outcome of severe acute malnutrition. The impact on increasing the recovery rates of children treated using the OTP service indicates the potential benefits of increasing the capacity of such services across a target region on child mortality/recovery. Timely intervention is another benefit of a more local service like OTP. Building capacity of OTP service providers and regular monitoring of service provision based on the management protocol was recommended.

Acute malnutrition recovery energy requirements based on mid-upper arm circumference: Secondary analysis of feeding program data from 5 countries, Combined Protocol for Acute Malnutrition Study (ComPAS) Stage 1.

BACKGROUND: Severe and moderate acute malnutrition (SAM and MAM) are currently treated with different food products in separate treatment programs. The development of a unified and simplified treatment protocol using a single food product aims to increase treatment program efficiency and effectiveness. This study, the first stage of the ComPAS trial, sought to assess rate of growth and energy requirements among children recovering from acute malnutrition in order to design a simplified, MUAC-based dosage protocol. METHODS: We obtained secondary data from patient cards of children aged 6-59 months recovering from SAM in outpatient therapeutic feeding programs (TFPs) and from MAM in supplementary feeding programs (SFPs) in five countries in Africa and Asia. We used local polynomial smoothing to assess changes in MUAC and proportional weight gain between clinic visits and assessed their normalized differences for a non-zero linear trend. We estimated energy needs to meet or exceed the growth observed in 95% of visits. RESULTS: This analysis used data from 5518 patients representing 33942 visits. Growth trends in MUAC and proportional weight gain were not significantly different, each lower at higher MUAC values: MUAC growth averaged 2mm/week at lower MUACs (100 to <110mm) and 1mm/week at higher MUACs (120mm to <125mm); and proportional weight gain declined from 3.9g/kg/day to 2.4g/kg/day across the same MUAC values. In 95% of visits by children with a MUAC 100mm to <125mm who were successfully treated, energy needs could be met or exceeded with 1,000 kilocalories a day. CONCLUSION: Two 92g sachets of Ready-to-Use Therapeutic Food (RUTF) (1,000kcal total) is proposed to meet the estimated total energy requirements of children with a MUAC 100mm to <115mm, and one 92g sachet of RUTF (500kcal) is proposed to meet half the energy requirements of children with a MUAC of 115 to <125mm. A simplified, combined protocol may enable a more holistic continuum of care, potentially contributing to increased coverage for children suffering from acute malnutrition.

Risk factors for mortality and management of children with complicated severe acute malnutrition at a tertiary referral hospital in Malawi.

BACKGROUND: Severe acute malnutrition (SAM) is a major cause of childhood mortality in resource-limited settings. The relationship between clinical factors and adherence to the 'WHO 10 Steps' and mortality in children with SAM is not fully understood. METHODS: Data from an ongoing prospective observational cohort study assessing admission characteristics, management patterns and clinical outcome in children aged 6-36 months admitted to a tertiary hospital in Malawi from September 2018 to September 2019 were analysed. Data clerks independently collected data from patients' charts. Demographics, clinical and nutritional status, identification of SAM and adherence to the 'WHO 10 Steps' were summarised. Their relationship to in-hospital mortality was assessed using multivariable logistic regression. RESULTS: Of the 6752 patients admitted, 9.7% had SAM. Mortality was significantly higher in those with SAM (10.1% vs 3.8%, p < 0.001). Compared with independent assessment anthropometrics, clinicians appropriately documented SAM on admission in 39.5%. The following factors were independently associated with mortality: kwashiorkor [adjusted odds ratio (aOR) 5.14, 95% confidence interval (CI) 1.27-20.78], shock (aOR 18.54, 95% CI 3.87-88.90), HIV-positive (aOR 5.32, 95% CI 1.76-16.09), SAM documented on admission (aOR 2.41, 95% CI 1.11-5.22), documentation of blood glucose within 24 hrs (aOR 3.97, 95% CI 1.90-8.33) and IV fluids given without documented shock (aOR 3.13, 95% CI 1.16-8.44). CONCLUSION: HIV infection remains an important predictor of mortality in children with SAM. IV fluids should be avoided in those without shock. Early identification of SAM by the clinical team represents a focus of future quality improvement interventions at this facility.

Nutrition rehabilitation of children with severe acute malnutrition: Revisiting studies undertaken by the National Institute of Nutrition.

Severe acute malnutrition (SAM) in children under five years is an important public health problem due to associated high mortality and long-term health consequences. Research on the dietary causes of SAM, especially the role and relative importance of dietary protein, in the aetiology of oedematous malnutrition, has led to considerable debates and controversies. The present article revisits some of the debates in this field, where the researchers at the National Institute of Nutrition (NIN), Hyderabad, India, with their pioneering work, have contributed to the global literature on the various facets of the disease. Highlighting the importance of energy as a bigger problem than protein malnutrition is a noteworthy contribution of NIN's research. It is, however, important to examine the protein quality of the diets in light of the new information on the lysine requirements. The article argues that the currently dominating hypothesis of free radical theory requires a critical review of the supporting evidence. Over the past few decades, the research has focused on low-cost diets using locally available foods. The article also argues that solutions based on local foods, being acceptable and sustainable, need to be strengthened for their effective delivery through the existing nutrition programmes. Recent evidence shows that the use of ready-to-use therapeutic foods (RUTF) with high micronutrient density may be linked with higher mortality possibly due to the high iron content, which could be counterproductive. There are several unaddressed concerns regarding the potential long-term impact of consumption of RUTF in children with SAM. More evidence and a cautious approach are, therefore, needed before implementing these solutions.

Severe acute malnutrition and mortality in children in the community: Comparison of indicators in a multi-country pooled analysis.

OBJECTIVES: This study aims to describe the mortality risk of children in the community who had severe acute malnutrition (SAM) defined by either a mid-upper arm circumference (MUAC) <115mm, a low weight-for-height Z-score (WHZ) <-3 or both criteria. METHODS: We pooled individual-level data from children aged 6-59 months enrolled in 3 community-based studies in the Democratic Republic of the Congo (DRC), Senegal and Nepal. We estimate the mortality hazard using Cox proportional hazard models in groups defined by either anthropometric indicator. RESULTS: In total, we had 49,001 time points provided by 15,060 children available for analysis, summing to a total of 143,512 person-months. We found an increasing death rate with a deteriorating nutritional status for all anthropometrical indicators. Children identified as SAM only by a low MUAC (<115mm) and those identified only by a low WHZ (Z-score <-3) had a similar mortality hazard which was about 4 times higher than those without an anthropometric deficit. Having both a low MUAC and a low WHZ was associated with an 8 times higher hazard of dying compared to children within the normal range. The 2 indicators identified a different set of children; the proportion of children identified by both indicators independently ranged from 7% in the DRC cohort, to 35% and 37% in the Senegal and the Nepal cohort respectively. CONCLUSION: In the light of an increasing popularity of using MUAC as the sole indicator to identify SAM children, we show that children who have a low WHZ, but a MUAC above the cut-off would be omitted from diagnosis and treatment despite having a similar risk of death.

Transcriptomic analysis of enteropathy in Zambian children with severe acute malnutrition.

BACKGROUND: Children with severe acute malnutrition (SAM), with or without diarrhoea, often have enteropathy, but there are few molecular data to guide development of new therapies. We set out to determine whether SAM enteropathy is characterised by specific transcriptional changes which might improve understanding or help identify new treatments. METHODS: We collected intestinal biopsies from children with SAM and persistent diarrhoea. mRNA was extracted from biopsies, sequenced, and subjected to a progressive set of complementary analytical approaches: NOIseq, Gene Set Enrichment Analysis (GSEA), and correlation analysis of phenotypic data with gene expression. FINDINGS: Transcriptomic profiles were generated for biopsy sets from 27 children of both sexes, under 2 years of age, of whom one-third were HIV-infected. NOIseq analysis, constructed from phenotypic group extremes, revealed 66 differentially expressed genes (DEGs) out of 21,386 mapped to the reference genome. These DEGs include genes for mucins and mucus integrity, antimicrobial defence, nutrient absorption, C-X-C chemokines, proteases and anti-proteases. Phenotype - expression correlation analysis identified 1221 genes related to villus height, including increased cell cycling gene expression in more severe enteropathy. Amino acid transporters and ZIP zinc transporters were specifically increased in severe enteropathy, but transcripts for xenobiotic metabolising enzymes were reduced. INTERPRETATION: Transcriptomic analysis of this rare collection of intestinal biopsies identified multiple novel elements of pathology, including specific alterations in nutrient transporters. Changes in xenobiotic metabolism in the gut may alter drug disposition. Both NOIseq and GSEA identified gene clusters similar to those differentially expressed in pediatric Crohn's disease but to a much lesser degree than those identified in coeliac disease. FUND: Bill & Melinda Gates Foundation OPP1066118. The funding agency had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Brain MRI and cognitive function seven years after surviving an episode of severe acute malnutrition in a cohort of Malawian children.

OBJECTIVE: To assess differences in cognition functions and gross brain structure in children seven years after an episode of severe acute malnutrition (SAM), compared with other Malawian children. DESIGN: Prospective longitudinal cohort assessing school grade achieved and results of five computer-based (CANTAB) tests, covering three cognitive domains. A subset underwent brain MRI scans which were reviewed using a standardized checklist of gross abnormalities and compared with a reference population of Malawian children. SETTING: Blantyre, Malawi.ParticipantsChildren discharged from SAM treatment in 2006 and 2007 (n 320; median age 9·3 years) were compared with controls: siblings closest in age to the SAM survivors and age/sex-matched community children. RESULTS: SAM survivors were significantly more likely to be in a lower grade at school than controls (adjusted OR = 0·4; 95 % CI 0·3, 0·6; P < 0·0001) and had consistently poorer scores in all CANTAB cognitive tests. Adjusting for HIV and socio-economic status diminished statistically significant differences. There were no significant differences in odds of brain abnormalities and sinusitis between SAM survivors (n 49) and reference children (OR = 1·11; 95 % CI 0·61, 2·03; P = 0·73). CONCLUSIONS: Despite apparent preservation in gross brain structure, persistent impaired school achievement is likely to be detrimental to individual attainment and economic well-being. Understanding the multifactorial causes of lower school achievement is therefore needed to design interventions for SAM survivors to thrive in adulthood. The cognitive and potential economic implications of SAM need further emphasis to better advocate for SAM prevention and early treatment.

Thymus gland size during recovery from complicated severe acute malnutrition: a prospective study of the role of probiotics.

Background: Children with severe acute malnutrition (SAM) are prone to infections due to immune dysfunction including severe thymus atrophy which recovers during nutritional rehabilitation. Aim: To investigate predictors of thymus size recovery, including probiotics during nutritional rehabilitation of children admitted with complicated SAM. Methods: In this prospective study nested in a randomized controlled trial, children 6-59 months admitted with SAM received standard care and either probiotics or placebo during hospitalization until 8 weeks post-discharge. Thymus size was measured using ultrasound at admission, discharge, 8 weeks post-discharge and among 27 community controls. Predictors of thymus size recovery were assessed using linear regression. Results: Among 388 children with SAM, mean (SD) thymus size was 1.06 cm2 (0.41), 1.24 cm2 (0.48), 2.85 cm2 (1.07) and 4.2 cm2 (0.93) at admission, discharge, follow-up and in the healthy controls respectively (p < 0.05).Probiotics did not affect thymus recovery. During both inpatient therapeutic care (ITC) and outpatient therapeutic care (OTC), thymus recovery correlated positively with anthropometry but negatively with caregiver-perceived illness severity and Haemoglobin <8 g/dl. Negative predictors of thymus recovery during ITC included grade 3 oedema (ß -0.13, 95%CI -0.25; -0.01), dermatosis (ß -0.21, 95%CI -0.41; -0.01), C-reactive protein (CRP) >15mg/L (ß -0.13, 95%CI -0.25; -0.02) and neutrophils (ß -0.01, 95%CI -0.02; -0.002). During OTC, HIV negatively predicted thymus recovery. Conclusion: Children with SAM failed to regain thymus size at 8 weeks post-discharge. Probiotics did not predict thymus recovery during nutritional rehabilitation. More research is needed to find interventions which can accelerate immune recovery. Abbreviations: ART, Antiretroviral therapy; BB-12, Bifidobacterium animalis subsp. Lactis; CRP, C-reactive protein; ITC, inpatient therapeutic care; LGG, Lactobacillus rhamnosus; MNU, Mwanamugimu Nutrition Unit; MUAC, mid-upper arm circumference; OTC, outpatient therapeutic care; PCR, Polymerised chain reaction; RUTF, ready-to-use therapeutic food; SAM, severe acute malnutrition; VAS, visual analogue score; WHO, World Health Organization; WHZ, weight-for-height score.

Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea.

BACKGROUND: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. METHODS/PRINCIPAL FINDINGS: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). CONCLUSIONS/SIGNIFICANCE: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.

Effectiveness of a Household Water, Sanitation and Hygiene Package on an Outpatient Program for Severe Acute Malnutrition: A Pragmatic Cluster-Randomized Controlled Trial in Chad.

Water, sanitation and hygiene (WASH) interventions have a small but measurable benefit on stunting, but not on wasting. Our objective was to assess the effectiveness of a household WASH package on the performance of an Outpatient Therapeutic feeding Program (OTP) for severe acute malnutrition (SAM). We conducted a cluster-randomized controlled trial embedded in a routine OTP. The study population included 20 health centers (clusters) from Mao and Mondo districts in Chad. Both arms received the OTP. The intervention arm received an additional household WASH package (chlorine, soap, water storage container, and promotion on its use). The primary objective measures were the relapse rates to SAM at 2 and 6 months post-recovery. The secondary objectives included the recovery rate from SAM, the time-to-recovery, the weight gain, and the diarrhea longitudinal prevalence in OTP. The study lasted from April 2015 to May 2016. Among the 1,603 recruited children, 845 were in the intervention arm and 758 in the control arm. No differences in the relapse rates were noticed at 2 (-0.4%; P = 0.911) and 6 (-1.0%; P = 0.532) months. The intervention decreased the time-to-recovery (-4.4 days; P = 0.038), improved the recovery rate (10.5%; P = 0.034), and the absolute weight gain (3.0 g/d; P = 0.014). No statistical differences were noticed for the diarrhea longitudinal prevalence (-1.7%; P = 0.223) and the weight gain velocity (0.4 g/kg/d; P = 0.086). Our results showed that adding a household WASH package did not decrease post-recovery relapse rates but increased the recovery rate among children admitted in OTP. We recommend further robust trials in other settings to confirm our results.

Biochemical and anthropometric correlates of bio-electrical impedance parameters in severely malnourished children: A cross-sectional study.

INTRODUCTION: Despite expanding use of bio-impedance (BI), little is known about its pathophysiologic significance and biological correlates OBJECTIVE: Determine correlations of BI parameters with anthropometry and biomarkers of electrolyte homeostasis, inflammation and liver function in children with severe acute malnutrition (SAM). METHODS: We studied Ethiopian children with SAM (mid-arm circumference <11·0 cm or weight-for-height <70% of the NCHS growth reference median and/or nutritional oedema) at hospitalization. Impedance (Z, Ohm), resistance (R, Ohm), reactance (Xc, Ohm) and phase angle (PA, degree) were measured at 50 kHz. R and Xc were height-indexed. Anthropometric Z-scores were calculated. Serum phosphate, Ca, Na, K, Mg, alkaline phosphatase, bilirubin, α1-acid glycoprotein, albumin and haemoglobin were measured. Healthy children were used for BI comparison. Correlates of BI were established using forward selection after comparing models using likelihood ratio test. RESULTS: The sample comprised 55 children with SAM (age 36 ± 24 months; 60% males; 72.7% oedematous) and 80 healthy control children (age 28 ± 15 months; 47.5% males). Oedematous children had the lowest BI parameters compared with reference and non-oedematous children. Similarly, they had lower serum albumin, K and alkaline phosphatase levels than non-oedematous children. Oedema was independent negative correlate of R, Xc and PA. Serum albumin level and weight-for-height Z-score were positive correlates of R, whereas serum calcium and Cl levels were positive correlates of Xc. MUAC correlated positively with PA. CONCLUSION: Nutritional oedema explained the divergence of BI parameters from normality. Soft tissue mass, serum albumin, Ca and Cl accounted for variability of BI parameters in children with SAM.

Ileus in children presenting with diarrhea and severe acute malnutrition: A chart review.

BACKGROUND: Severely malnourished children aged under five years requiring hospital admission for diarrheal illness frequently develop ileus during hospitalization with often fatal outcomes. However, there is no data on risk factors and outcome of ileus in such children. We intended to evaluate predictive factors for ileus during hospitalization and their outcomes. METHODOLOGY/PRINCIPAL FINDINGS: This was a retrospective chart review that enrolled severely malnourished children under five years old with diarrhea, admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh between April 2011 and August 2012. We used electronic database to have our chart abstraction from previously admitted children in the hospital. The clinical and laboratory characteristics of children with (cases = 45), and without ileus (controls = 261) were compared. Cases were first identified by observation of abnormal bowel sounds on physical examination and confirmed with abdominal radiographs. For this comparison, Chi-square test was used to measure the difference in proportion, Student's t-test to calculate the difference in mean for normally distributed data and Mann-Whitney test for data that were not normally distributed. Finally, in identifying independent risk factors for ileus, logistical regression analysis was performed. Ileus was defined if a child developed abdominal distension and had hyperactive or sluggish or absent bowel sound and a radiologic evidence of abdominal gas-fluid level during hospitalization. Logistic regression analysis adjusting for potential confounders revealed that the independent risk factors for admission for ileus were reluctance to feed (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.24-8.39, p = 0.02), septic shock (OR = 3.62, 95% CI = 1.247-8.95, p<0.01), and hypokalemia (OR = 1.99, 95% CI = 1.03-3.86, p = 0.04). Mortality was significantly higher in cases compared to controls (22% vs. 8%, p<0.01) in univariate analysis; however, in multivariable regression analysis, after adjusting for potential confounders such as septic shock, no association was found between ileus and death (OR = 2.05, 95% CI = 0.68-6.14, p = 0.20). In a separate regression analysis model, after adjusting for potential confounders such as ileus, reluctance to feed, hypokalemia, hypocalcemia, and blood transfusion, septic shock (OR = 168.84, 95% CI = 19.27-1479.17, p<0.01) emerged as the only independent predictor of death in severely malnourished diarrheal children. CONCLUSIONS/SIGNIFICANCE: This study suggests that the identification of simple independent admission risk factors for ileus and risk factors for death in hospitalized severely malnourished diarrheal children may prompt clinicians to be more vigilant in managing these conditions, especially in resource-limited settings in order to decrease ileus and ileus-related fatal outcomes in such children.

Molecular Evidence for Differential Long-term Outcomes of Early Life Severe Acute Malnutrition.

BACKGROUND: Severe acute malnutrition (SAM) in infants may present as one of two distinct syndromic forms: non-edematous (marasmus), with severe wasting and no nutritional edema; or edematous (kwashiorkor) with moderately severe wasting. These differences may be related to developmental changes prior to the exposure to SAM and phenotypic changes appear to persist into adulthood with differences between the two groups. We examined whether the different response to SAM and subsequent trajectories may be explained by developmentally-induced epigenetic differences. METHODS: We extracted genomic DNA from muscle biopsies obtained from adult survivors of kwashiorkor (n=21) or marasmus (n=23) and compared epigenetic profiles (CpG methylation) between the two groups using the Infinium® 450K BeadChip array. FINDINGS: We found significant differences in methylation of CpG sites from 63 genes in skeletal muscle DNA. Gene ontology studies showed significant differential methylation of genes in immune, body composition, metabolic, musculoskeletal growth, neuronal function and cardiovascular pathways, pathways compatible with the differences in the pathophysiology of adult survivors of SAM. INTERPRETATION: These findings suggest persistent developmental influences on adult physiology in survivors of SAM. Since children who develop marasmus have lower birth weights and after rehabilitation have different intermediary metabolism, these studies provide further support for persistent developmentally-induced phenomena mediated by epigenetic processes affecting both the infant response to acute malnutrition and later life consequences. FUNDING: Supported by a Grant from the Bill and Melinda Gates Foundation (Global Health OPP1066846), Grand Challenge "Discover New Ways to Achieve Healthy Growth." EVIDENCE BEFORE THIS STUDY: Previous research has shown that infants who develop either kwashiorkor or marasmus in response to SAM differ in birth weight and subsequently have different metabolic patterns in both infancy and adulthood. ADDED VALUE OF THIS STUDY: This study demonstrates epigenetic differences in the skeletal muscle of adult survivors of marasmus versus kwashiorkor and these differences are in genes that may underlie the longer-term consequences. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: These data are compatible with the different clinical responses to SAM arising from developmentally-induced epigenetic changes laid down largely before birth and provide evidence for the predictive adaptive response model operating in human development.

Correlates of thymus size and changes during treatment of children with severe acute malnutrition: a cohort study.

BACKGROUND: The impairment of immune functions associated with malnutrition may be one reason for the high mortality in children with severe acute malnutrition (SAM), and thymus atrophy has been proposed as a marker of this immunodeficiency. The aim of this study was to identify nutritional and clinical correlates of thymus size in children with SAM, and predictors of change in thymus size with nutritional rehabilitation. METHODS: In an observational study among children aged 6-59 months admitted with SAM in Uganda, we measured thymus area by ultrasound on hospital admission to treatment with F75 and F100, on hospital discharge and after 8 weeks of nutritional rehabilitation with ready-to-use therapeutic food, as well as in well-nourished healthy children. We investigated anthropometric, clinical, biochemical and treatment-related correlates of area and growth of the thymus. RESULTS: Eighty-five children with SAM with a median age of 16.5 months were included. On admission 27% of the children had a thymus undetectable by ultrasound. Median thymus area was 1.3 cm2 in malnourished children, and 3.5 cm2 in healthy children (p < 0.001). Most anthropometric z-scores, hemoglobin and plasma phosphate correlated positively with thymus area. Thymus area correlated negatively with caretaker-reported severity of illness, plasma α-1 acid glycoprotein, and C-reactive protein >5 mg/L. At follow-up after 8 weeks, median thymus area had increased to 2.5 cm2 (p < 0.001). Increase in thymus area during treatment was associated with simultaneous increase in mid-upper-arm circumference, with 0.29 cm2 higher increase in thymus area per cm larger increment in MUAC (p = 0.03). Children whose F-75 had partially been replaced by rice porridge during their hospital admission had less increase in thymus area after 8 weeks. CONCLUSION: Malnutrition and inflammation are associated with thymus atrophy, and thymus area seems positively associated with plasma phosphate. Substituting therapeutic formula with unfortified rice porridge with the aim of alleviating diarrhea may impair regain of thymus size with nutritional rehabilitation. This calls for research into possible effects of phosphate status on thymus size and other immunological markers. TRIAL REGISTRATION: The study is based on data from the FeedSAM study, ISRCTN55092738 .

Impaired Bile Acid Homeostasis in Children with Severe Acute Malnutrition.

OBJECTIVE: Severe acute malnutrition (SAM) is a major cause of mortality in children under 5 years and is associated with hepatic steatosis. Bile acids are synthesized in the liver and participate in dietary fat digestion, regulation of energy expenditure, and immune responses. The aim of this work was to investigate whether SAM is associated with clinically relevant changes in bile acid homeostasis. DESIGN: An initial discovery cohort with 5 healthy controls and 22 SAM-patients was used to identify altered bile acid homeostasis. A follow up cohort of 40 SAM-patients were then studied on admission and 3 days after clinical stabilization to assess recovery in bile acid metabolism. Recruited children were 6-60 months old and admitted for SAM in Malawi. Clinical characteristics, feces and blood were collected on admission and prior to discharge. Bile acids, 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 were quantified. RESULTS: On admission, total serum bile acids were higher in children with SAM than in healthy controls and glycine-conjugates accounted for most of this accumulation with median and interquartile range (IQR) of 24.6 µmol/L [8.6-47.7] compared to 1.9 µmol/L [1.7-3.3] (p = 0.01) in controls. Total serum bile acid concentrations did not decrease prior to discharge. On admission, fecal conjugated bile acids were lower and secondary bile acids higher at admission compared to pre- discharge, suggesting increased bacterial conversion. FGF19 (Fibroblast growth factor 19), a marker of intestinal bile acid signaling, was higher on admission and was associated with decreased C4 concentrations as a marker of bile acid synthesis. Upon recovery, fecal calprotectin, a marker of intestinal inflammation, was lower. CONCLUSION: SAM is associated with increased serum bile acid levels despite reduced synthesis rates. In SAM, there tends to be increased deconjugation of bile acids and conversion from primary to secondary bile acids, which may contribute to the development of liver disease.

Characterization and scoring of skin changes in severe acute malnutrition in children between 6 months and 5 years of age.

BACKGROUND: Severe acute malnutrition is a life-threatening condition. It can be associated with severe skin changes, first properly described by Williams in 1933. The aetiology of these skin changes is still unknown and their character has never been systematically described in dermatological terms. The skin changes have been shown to be a predictor of mortality in hospital care. Systematic investigations on the character of the skin changes that have effect on prognosis, are needed to investigate which of the skin changes that are relevant to improve treatment. OBJECTIVES: Our main objective was to identify the skin changes characteristic of children with severe acute malnutrition and to develop a clinical score that describes the morphology and severity in dermatological terms. We also investigated if any of the different skin changes were connected to prognosis. MATERIALS AND METHODS: At Mulago Hospital, Mwanamugimu (Department of Paediatrics and Child Health), Uganda, 120 children were included over a period of six months and observed when treated for severe acute malnutrition. Skin changes were registered through clinical examination and photo documentation and associated to prognosis using Cox and logistic regression analysis. RESULTS: Skin manifestations were characterized by five objective skin signs: telogenic effluvium, pigmentary changes (hyper- and hypo-pigmentation), ichthyosiform skin changes, lichenoid skin changes and bullae-erosion-desquamation. The skin changes could be registered in a systematic manner using our simple clinical score. Lichenoid skin changes were a significant predictor of death and allowed improved accuracy of prediction of mortality. CONCLUSIONS: The clinical score is simple and practical. A standardized way to register and score the skin changes, will allow a more unified way of reporting results in future studies. The standardization of observations, obtained through the proposed scoring system, will enable comparison of study results in the future.

Comparison of Clinical Characteristics and Treatment Outcomes of Children Selected for Treatment of Severe Acute Malnutrition Using Mid Upper Arm Circumference and/or Weight-for-Height Z-Score.

OBJECTIVES: Debate for a greater role of mid-upper arm circumference (MUAC) measures in nutritional programming continues, but a shift from therapeutic feeding programs admitting children using MUAC and/or weight-for-height Z (WHZ) to a new model admitting children using MUAC only remains complicated by limited information regarding the clinical profile and response to treatment of children selected by MUAC vs. WHZ. To broaden our understanding of how children identified for therapeutic feeding by MUAC and/or WHZ may differ, we aimed to investigate differences between children identified for therapeutic feeding by MUAC and/or WHZ in terms of demographic, anthropometric, clinical, and laboratory and treatment response characteristics. METHODS: Using secondary data from a randomized trial in rural Niger among children with uncomplicated severe acute malnutrition, we compared children that would be admitted to a therapeutic feeding program that used a single anthropometric criterion of MUAC< 115 mm vs. children that are admitted under current admission criteria (WHZ< -3 and/or MUAC< 115 mm) but would be excluded from a program that used a single MUAC< 115 mm admission criterion. We assessed differences between groups using multivariate regression, employing linear regression for continuous outcomes and log-binomial regression for dichotomous outcomes. RESULTS: We found no difference in terms of clinical and laboratory characteristics and discharge outcomes evaluated between children that would be included in a MUAC< 115 mm therapeutic feeding program vs. children that are currently eligible for therapeutic feeding but would be excluded from a MUAC-only program. CONCLUSIONS: A single anthropometric admission criterion of MUAC < 115 mm did not differentiate well between children in terms of clinical or laboratory measures or program outcomes in this context. If nutritional programming is to use a single MUAC-based criterion for admission to treatment, further research and program experience can help to identify the most appropriate criterion in a broad range of contexts to target children in most urgent need of treatment.