Stool frequency recording in severe acute malnutrition ('StoolSAM'); an agreement study comparing maternal recall versus direct observation using diapers.

BACKGROUND: Approximately 50% of the deaths of children under the age of 5 can be attributed to undernutrition, which also encompasses severe acute malnutrition (SAM). Diarrhoea is strongly associated with these deaths and is commonly diagnosed solely based on stool frequency and consistency obtained through maternal recall. This trial aims to determine whether this approach is equivalent to a 'directly observed method' in which a health care worker directly observed stool frequency using diapers in hospitalised children with complicated SAM. METHODS: This study was conducted at 'Moyo' Nutritional Rehabilitation Unit, Queen Elizabeth Central Hospital, Malawi. Participants were children aged 5-59 months admitted with SAM. We compared 2 days of stool frequency data obtained with next-day maternal-recall versus a 'gold standard' in which a health care worker observed stool frequency every 2 h using diapers. After study completion, guardians were asked their preferred method and their level of education. RESULTS: We found poor agreement between maternal recall and the 'gold standard' of directly observed diapers. The sensitivity to detect diarrhoea based on maternal recall was poor, with only 75 and 56% of diarrhoea cases identified on days 1 and 2, respectively. However, the specificity was higher with more than 80% of children correctly classified as not having diarrhoea. On day 1, the mean stool frequency difference between the two methods was -0.17 (SD; 1.68) with limits of agreement (of stool frequency) of -3.55 and 3.20 and, similarly on day 2, the mean difference was -0.2 (SD; 1.59) with limits of agreement of -3.38 and 2.98. These limits extend beyond the pre-specified 'acceptable' limits of agreement (±1.5 stool per day) and indicate that the 2 methods are non-equivalent. The higher the stool frequency, the more discrepant the two methods were. Most primary care givers strongly preferred using diapers. CONCLUSIONS: This study shows lack of agreement between the assessment of stool frequency in SAM patients using maternal recall and direct observation of diapers. When designing studies, one should consider using diapers to determining diarrhoea incidence/prevalence in SAM patients especially when accuracy is essential. TRIAL REGISTRATION NUMBER: ISRCTN11571116 (registered 29/11/2013)

Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study

Background Tackling severe acute malnutrition (SAM) is a global health priority. Heightened risk of non-communicable diseases (NCD) in children exposed to SAM at around 2 years of age is plausible in view of previously described consequences of other early nutritional insults. By applying developmental origins of health and disease (DOHaD) theory to this group, we aimed to explore the long-term eff ects of SAM. Methods We followed up 352 Malawian children (median age 9·3 years) who were still alive following SAM inpatient treatment between July 12, 2006, and March 7, 2007, (median age 24 months) and compared them with 217 sibling controls and 184 age-and-sex matched community controls. Our outcomes of interest were anthropometry, body composition, lung function, physical capacity (hand grip, step test, and physical activity), and blood markers of NCD risk. For comparisons of all outcomes, we used multivariable linear regression, adjusted for age, sex, HIV status, and socioeconomic status. We also adjusted for puberty in the body composition regression model. Findings Compared with controls, children who had survived SAM had lower height-for-age Z scores (adjusted diff erence vs community controls 0·4, 95% CI 0·6 to 0·2, p=0·001; adjusted diff erence vs sibling controls 0·2, 0·0 to 0·4, p=0·04), although they showed evidence of catch-up growth. These children also had shorter leg length (adjusted diff erence vs community controls 2·0 cm, 1·0 to 3·0, p<0·0001; adjusted diff erence vs sibling controls 1·4 cm, 0·5 to 2·3, p=0·002), smaller mid-upper arm circumference (adjusted diff erence vs community controls 5·6 mm, 1·9 to 9·4, p=0·001; adjusted diff erence vs sibling controls 5·7 mm, 2·3 to 9·1, p=0·02), calf circumference (adjusted diff erence vs community controls 0·49 cm, 0·1 to 0·9, p=0·01; adjusted diff erence vs sibling controls 0·62 cm, 0·2 to 1·0, p=0·001), and hip circumference (adjusted diff erence vs community controls 1·56 cm, 0·5 to 2·7, p=0·01; adjusted diff erence vs sibling controls 1·83 cm, 0·8 to 2·8, p<0·0001), and less lean mass (adjusted diff erence vs community controls –24·5, –43 to –5·5, p=0·01; adjusted diff erence vs sibling controls –11·5, –29 to –6, p=0·19) than did either sibling or community controls. Survivors of SAM had functional defi cits consisting of weaker hand grip (adjusted diff erence vs community controls –1·7 kg, 95% CI –2·4 to –0·9, p<0·0001; adjusted diff erence vs sibling controls 1·01 kg, 0·3 to 1·7, p=0·005,)) and fewer minutes completed of an exercise test (sibling odds ratio [OR] 1·59, 95% CI 1·0 to 2·5, p=0·04; community OR 1·59, 95% CI 1·0 to 2·5, p=0·05). We did not detect signifi cant diff erences between cases and controls in terms of lung function, lipid profi le, glucose tolerance, glycated haemoglobin A1c, salivary cortisol, sitting height, and head circumference. Interpretation Our results suggest that SAM has long-term adverse eff ects. Survivors show patterns of so-called thrifty growth, which is associated with future cardiovascular and metabolic disease. The evidence of catch-up growth and largely preserved cardiometabolic and pulmonary functions suggest the potential for near-full rehabilitation. Future follow-up should try to establish the eff ects of puberty and later dietary or social transitions on these parameters, as well as explore how best to optimise recovery and quality of life for survivors

A quantitative cross-sectional survey of psychosocial stimulation and counselling interventions at nutritional rehabilitation units in Southern Malawi

Background Inpatient treatment at nutritional rehabilitation units (NRUs) is needed for children who have severe acute malnutrition (SAM) and acute illness, loss of appetite, or severe oedema. World Health Organization guidelines state that nutritional counselling should be done with primary caregivers at NRUs. These recommendations also include psychosocial stimulation interventions to improve developmental outcomes in children with SAM. However, there is limited information about the delivery of these types of interventions for caregivers and children in NRU settings. The primary objective of this research was therefore to obtain data about NRU resources, activities, and protocols relevant to psychosocial stimulation and counselling interventions during inpatient treatment of children with SAM. Methods A cross-sectional survey was administered by interview at all 16 NRUs in seven districts in Southern Malawi. Participants were health workers, nurses, and nutritionists employed at the respective NRUs. Results The response rate was 100% across NRUs. Half of participants said that psychosocial stimulation interventions are conducted at their respective NRUs, yet none of the NRUs have protocols for delivery of these interventions. Furthermore, 7/16 (44%) NRUs have no resources for psychosocial stimulation including play materials. Thirteen of 16 (81%) participants said that they feel this type of intervention is very important and 3/16 (19%) participants said that this somewhat important for children with SAM. All NRUs provide counselling to caregivers about breastfeeding and nutrition; 15/16 (94%) also give counselling about water, sanitation and hygiene. Conclusions Ultimately, results from this survey highlighted that there is a need to invest in comprehensive interventions to improve developmental and nutritional outcomes in these vulnerable children requiring admission to NRUs

Urinary Organic Acids Increase After Clinical Stabilization of Hospitalized Children With Severe Acute Malnutrition

Background: Despite a reduction of child mortality in low-income countries, acutely ill undernourished children still have an elevated risk of death. Those at highest risk are children with severe acute malnutrition (SAM) who often show metabolic dysregulations that remains poorly understood. Objective: We performed a pilot study to examine changes in urinary organic acids during nutritional rehabilitation of children with SAM, and to identify metabolites associated with the presence of edema or with mortality. Methods: This study included 76 children aged between 6 and 60 months, hospitalized for SAM at the Moyo Nutritional Rehabilitation and Research Unit in Blantyre, Malawi. Urine was collected at admission and 3 days after clinical stabilization and metabolomics were performed using gas chromatography-mass spectrometry. Metabolite concentrations were evaluated with both uni- and multivariate approaches. Results: Most metabolites increased 3 days after clinical stabilization, and total urinary concentration changed from 1.2 mM (interquartile range [IQR], 0.78-1.7) at admission to 3.8 mM (IQR, 2.1-6.6) after stabilization (P <.0001). In particular, 6 metabolites showed increases: 3-hydroxybutyric, 4-hydroxyhippuric, p-hydroxyphenylacetic, oxoglutaric, succinic, and lactic acids. Urinary creatinine was low at both time points, but levels did increase from 0.63 mM (IQR, 0.2-1.2) to 2.6 mM (IQR,1.6-4.4; P <.0001). No differences in urinary profiles were found between children who died versus those who survived, nor between children with severe wasting or edematous SAM. Conclusions: Total urinary metabolites and creatinine increase after stabilization and may reflect partial recovery of overall metabolism linked to refeeding. The use of urinary metabolites for risk assessment should be furthered explored

Extracellular vesicles isolated from milk can improve gut barrier dysfunction induced by malnutrition

Malnutrition impacts approximately 50 million children worldwide and is linked to 45% of global mortality in children below the age of five. Severe acute malnutrition (SAM) is associated with intestinal barrier breakdown and epithelial atrophy. Extracellular vesicles including exosomes (EVs; 30–150 nm) can travel to distant target cells through biofluids including milk. Since milk-derived EVs are known to induce intestinal stem cell proliferation, this study aimed to examine their potential efficacy in improving malnutrition-induced atrophy of intestinal mucosa and barrier dysfunction. Mice were fed either a control (18%) or a low protein (1%) diet for 14 days to induce malnutrition. From day 10 to 14, they received either bovine milk EVs or control gavage and were sacrificed on day 15, 4 h after a Fluorescein Isothiocyanate (FITC) dose. Tissue and blood were collected for histological and epithelial barrier function analyses. Mice fed low protein diet developed intestinal villus atrophy and barrier dysfunction. Despite continued low protein diet feeding, milk EV treatment improved intestinal permeability, intestinal architecture and cellular proliferation. Our results suggest that EVs enriched from milk should be further explored as a valuable adjuvant therapy to standard clinical management of malnourished children with high risk of morbidity and mortality

The clinical use of longitudinal bio-electrical impedance vector analysis in assessing stabilization of children with severe acute malnutrition

Background & aims: Severe Acute Malnutrition (SAM) in children is determined using anthropometry. However, bio-electrical impedance (BI) analysis could improve the estimation of altered body composition linked to edema and/or loss of lean body mass in children with SAM. We aimed to assess: 1) the changes in BI parameters during clinical stabilization and 2) whether BI parameters add prognostic value for clinical outcome beyond the use of anthropometry. Methods: This prospective observational study enrolled children, aged 6–60 months, that were admitted at Queen Elizabeth Central Hospital in Blantyre, Malawi, for complicated SAM (i.e., having either severe wasting or edematous SAM with a complicating illness). Height, weight, mid-upper arm circumference (MUAC), and BI were measured on admission and after clinical stabilization. BI measures were derived from height-adjusted indices of resistance (R/H), reactance (Xc/H), and phase angle (PA) and considered to reflect body fluids and soft tissue in BI vector analysis (BIVA). Results: We studied 183 children with SAM (55% edematous; age 23.0 ± 12.0 months; 54% male) and 42 community participants (age 20.1 ± 12.3 months; male 62%). Compared to community participants, the BIVA of children with edematous SAM were short with low PA and positioned low on the hydration axis which reflects severe fluid retention. In contrast, children with severe wasting had elongated vectors with a PA that was higher than children with edematous SAM but lower than community participants. Their BIVA position fell within the top right quadrant linked to leanness and dehydration. BIVA from severely wasted and edematous SAM patients differed between groups and from community children both at admission and after stabilization (p < 0.001). Vector position shifted during treatment only in children with edematous SAM (p < 0.001) and showed a upward translation suggestive of fluid loss. While PA was lower in children with SAM, PA did not contribute more than anthropometry alone towards explaining mortality, length of stay, or time-to-discharge or time-to-mortality. The variability and heterogeneity in BI measures was high and their overall added predictive value for prognosis of individual children was low. Conclusions: BIVA did not add prognostic value over using anthropometry alone to predict clinical outcome. Several implementation challenges need to be optimized. Thus, in low-resource settings, the routine use of BI in the management of pediatric malnutrition is questionable without improved implementation

New approaches and technical considerations in detecting outlier measurements and trajectories in longitudinal children growth data

Background Growth studies rely on longitudinal measurements, typically represented as trajectories. However, anthropometry is prone to errors that can generate outliers. While various methods are available for detecting outlier measurements, a gold standard has yet to be identified, and there is no established method for outlying trajectories. Thus, outlier types and their effects on growth pattern detection still need to be investigated. This work aimed to assess the performance of six methods at detecting different types of outliers, propose two novel methods for outlier trajectory detection and evaluate how outliers affect growth pattern detection. Methods We included 393 healthy infants from The Applied Research Group for Kids (TARGet Kids!) cohort and 1651 children with severe malnutrition from the co-trimoxazole prophylaxis clinical trial. We injected outliers of three types and six intensities and applied four outlier detection methods for measurements (model-based and World Health Organization cut-offs-based) and two for trajectories. We also assessed growth pattern detection before and after outlier injection using time series clustering and latent class mixed models. Error type, intensity, and population affected method performance. Results Model-based outlier detection methods performed best for measurements with precision between 5.72-99.89%, especially for low and moderate error intensities. The clustering-based outlier trajectory method had high precision of 14.93-99.12%. Combining methods improved the detection rate to 21.82% in outlier measurements. Finally, when comparing growth groups with and without outliers, the outliers were shown to alter group membership by 57.9 -79.04%. Conclusions World Health Organization cut-off-based techniques were shown to perform well in few very particular cases (extreme errors of high intensity), while model-based techniques performed well, especially for moderate errors of low intensity. Clustering-based outlier trajectory detection performed exceptionally well across all types and intensities of errors, indicating a potential strategic change in how outliers in growth data are viewed. Finally, the importance of detecting outliers was shown, given its impact on children growth studies, as demonstrated by comparing results of growth group detection

Effectiveness of three commonly used transition phase diets in the inpatient management of children with severe acute malnutrition: a pilot randomized controlled trial in Malawi.

BACKGROUND: The case fatality rate of severely malnourished children during inpatient treatment is high and mortality is often associated with diarrhea. As intestinal carbohydrate absorption is impaired in severe acute malnutrition (SAM), differences in dietary formulations during nutritional rehabilitation could lead to the development of osmotic diarrhea and subsequently hypovolemia and death. We compared three dietary strategies commonly used during the transition of severely malnourished children to higher caloric feeds, i.e., F100 milk (F100), Ready-to-Use Therapeutic Food (RUTF) and RUTF supplemented with F75 milk (RUTF + F75). METHODS: In this open-label pilot randomized controlled trial, 74 Malawian children with SAM aged 6-60 months, were assigned to either F100, RUTF or RUTF + F75. Our primary endpoint was the presence of low fecal pH (pH ? 5.5) measured in stool collected 3 days after the transition phase diets were introduced. Secondary outcomes were duration of hospital stay, diarrhea and other clinical outcomes. Chi-square test, two-way analysis of variance and logistic regression were conducted and, when appropriate, age, sex and initial weight for height Z-scores were included as covariates. RESULTS: The proportion of children with acidic stool (pH ?5.5) did not significantly differ between groups before discharge with 30, 33 and 23% for F100, RUTF and RUTF + F75, respectively. Mean duration of stay after transitioning was 7.0 days (SD 3.4) with no differences between the three feeding strategies. Diarrhea was present upon admission in 33% of patients and was significantly higher (48%) during the transition phase (p < 0.05). There was no significant difference in mortality (n = 6) between diets during the transition phase nor were there any differences in other secondary outcomes. CONCLUSIONS: This pilot trial does not demonstrate that a particular transition phase diet is significantly better or worse since biochemical and clinical outcomes in children with SAM did not differ. However, larger and more tightly controlled efficacy studies are needed to confirm these findings. TRIAL REGISTRATION: ISRCTN13916953 Registered: 14 January 2013

Dysglycemia in Children with Severe Acute Malnutrition: A Systematic Review and Meta-Analysis.

Dysglycemia is a common complication of severe acute malnutrition (SAM) in children. Its prevalence and impact on short- and long-term outcomes are not well described. This systematic review was undertaken to review the available evidence on dysglycemia (either hypo- or hyperglycemia) in hospitalized children with SAM. The 2 primary objectives of this systematic review were to understand the prevalence of hypoglycemia and hyperglycemia in children with SAM. A secondary objective was to understand the relation between dysglycemia and clinical outcomes like mortality in children with SAM. MEDLINE was searched with terms related to children, SAM, and dysglycemia. A meta-analysis of proportions was completed to determine the hypoglycemia prevalence and a standard meta-analysis was done to determine the relation between hypoglycemia and mortality. The certainty of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 2148 articles were identified in the database search of which 16 met the inclusion criteria for the systematic review based on screening done by multiple reviewers. The overall prevalence of hypoglycemia in SAM across studies based on the meta-analysis of proportions was 9% (95% CI: 7%, 12%; I2 = 92%). Meta-analysis results showed that hypoglycemia was associated with a higher chance of mortality during hospitalization in children with SAM (OR: 4.29; 95% CI: 3.04, 6.05; I2 = 0%). According to the GRADE evaluation, the certainty of the evidence for the prevalence of hypoglycemia was low and for hyperglycemia was very low. For the relation between hypoglycemia and mortality, the certainty of the evidence was moderate. A meta-analysis was not carried out for the prevalence of hyperglycemia due to the wide range of definitions used for across studies, but the prevalence ranged from 2% to 38% in the literature. This systematic review highlights the need for further work in this area to include serial glucose measurements to understand the clinical importance of dysglycemia during hospitalization in children with SAM