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The role of routine antibiotic use in the treatment of severe acute malnutrition is unclear. In this randomized, placebo-controlled trial in Niger, amoxicillin did not significantly improve nutritional recovery in children with severe acute malnutrition. Severe acute malnutrition affects approximately 19 million children under 5 years of age worldwide and contributes substantially to mortality and the disease burden among children. 1 To reduce the risk of death from severe acute malnutrition, specialized nutritional and medical intervention is required. Bacterial infection can complicate advanced cases of severe acute malnutrition, 2 – 9 and the risk of nosocomial infection in inpatient settings can be high. Therefore, in 1999, when all children with severe acute malnutrition were treated as inpatients, the World Health Organization (WHO) recommended routine use of broad-spectrum antibiotics for the management of severe acute malnutrition, irrespective of clinical . . .

International recommendations advise against the use of intravenous rehydration therapy in children with severe acute malnutrition because of the concern about fluid overload, but evidence to support this concern is lacking. Given the high mortality associated with the current recommendations, the adoption of intravenous rehydration strategies might improve outcomes. We conducted a factorial, open-label superiority trial in four countries in Africa. Children 6 months to 12 years of age with severe acute malnutrition with gastroenteritis and dehydration underwent randomization in a 2:1:1 ratio to one of three rehydration strategies: oral rehydration, plus intravenous boluses for shock; a rapid intravenous strategy that consisted of lactated Ringer's solution (100 ml per kilogram of body weight) administered over a period of 3 to 6 hours, with boluses for shock; or a slow intravenous strategy that consisted of the same solution administered over a period of 8 hours, with no boluses. The primary end point was death at 96 hours. A total of 272 children underwent randomization; 138 were assigned to the oral strategy, 67 to the rapid intravenous strategy, and 67 to the slow intravenous strategy. Participants were followed for 28 days. A nasogastric tube was used for oral rehydration in 126 of 135 participants (93%) in the oral group and in 82 of 126 (65%) in the intravenous groups. Intravenous boluses were administered at admission in 12 participants (9%) in the oral group, 7 (10%) in the rapid intravenous group, and none in the slow intravenous group. At 96 hours, 11 participants (8%) in the oral group and 9 (7%) in the intravenous groups (5 in the rapid group and 4 in the slow group) had died (risk ratio, 1.02; 95% confidence interval [CI], 0.41 to 2.52; P = 0.69). At 28 days, 17 participants (12%) in the oral group and 14 (10%) in the intravenous groups had died (hazard ratio, 0.85; 95% CI, 0.41 to 1.78). Serious adverse events occurred in 32 participants (23%) in the oral group, 14 (21%) in the rapid intravenous group, and 10 (15%) in the slow intravenous group. No evidence of pulmonary edema, heart failure, or fluid overload was noted. Among children with severe acute malnutrition and gastroenteritis, no evidence of a difference in mortality at 96 hours was noted between oral and intravenous rehydration strategies. (Funded by the Joint Global Health Trials scheme and others; GASTROSAM Current Controlled Trials number, ISRCTN76149273.).

Malnutrition underlies 3 million child deaths worldwide. Current treatments differentiate severe acute malnutrition (SAM) from moderate acute malnutrition (MAM) with different products and programs. This differentiation is complex and costly. The Combined Protocol for Acute Malnutrition Study (ComPAS) assessed the effectiveness of a simplified, unified SAM/MAM protocol for children aged 6-59 months. Eliminating the need for separate products and protocols could improve the impact of programs by treating children more easily and cost-effectively, reaching more children globally. A cluster-randomized non-inferiority trial compared a combined protocol against standard care in Kenya and South Sudan. Randomization was stratified by country. Combined protocol clinics treated children using 2 sachets of ready-to-use therapeutic food (RUTF) per day for those with mid-upper arm circumference (MUAC) < 11.5 cm and/or edema, and 1 sachet of RUTF per day for those with MUAC 11.5 to <12.5 cm. Standard care clinics treated SAM with weight-based RUTF rations, and MAM with ready-to-use supplementary food (RUSF). The primary outcome was nutritional recovery. Secondary outcomes included cost-effectiveness, coverage, defaulting, death, length of stay, and average daily weight and MUAC gains. Main analyses were per-protocol, with intention-to-treat analyses also conducted. The non-inferiority margin was 10%. From 8 May 2017 to 31 March 2018, 2,071 children were enrolled in 12 combined protocol clinics (mean age 17.4 months, 41% male), and 2,039 in 12 standard care clinics (mean age 16.7 months, 41% male). In total, 1,286 (62.1%) and 1,202 (59.0%), respectively, completed treatment; 981 (76.3%) on the combined protocol and 884 (73.5%) on the standard protocol recovered, yielding a risk difference of 0.03 (95% CI -0.05 to 0.10, p = 0.52; per-protocol analysis, adjusted for country, age, and sex). The amount of ready-to-use food (RUTF or RUSF) required for a child with SAM to reach full recovery was less in the combined protocol (122 versus 193 sachets), and the combined protocol cost US$123 less per child recovered (US$918 versus US$1,041). There were 23 (1.8%) deaths in the combined protocol arm and 21 (1.8%) deaths in the standard protocol arm (adjusted risk difference 95% CI -0.01 to 0.01, p = 0.87). There was no evidence of a difference between the protocols for any of the other secondary outcomes. Study limitations included contextual factors leading to defaulting, a combined multi-country power estimate, and operational constraints. Combined treatment for SAM and MAM is non-inferior to standard care. Further research should focus on operational implications, cost-effectiveness, and context (Asia versus Africa; emergency versus food-secure settings). This trial is complete and registered at ISRCTN (ISRCTN30393230). The trial is registered at ISRCTN, trial number ISRCTN30393230.

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.

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.

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 ).

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.

Little is known about the outcomes of subjects with a history of severe acute malnutrition (SAM). We therefore sought to explore the long-term effects of SAM during childhood on human capital in adulthood in terms of education, cognition, self-esteem and health-related disabilities in daily living. We traced 524 adults (median age of 22) in the eastern Democratic Republic of the Congo, who were treated for SAM during childhood at Lwiro hospital between 1988 and 2007 (median age 41 months). We compared them with 407 community controls of comparable age and sex. Our outcomes of interest were education, cognitive function [assessed using the Mini Mental State Examination (MMSE) for literate participants, or its modified version created by Ertan et al. (MMSE-I) for uneducated participants], self-esteem (measured using the Rosenberg Self-Esteem Scale) and health-related social and functional disabilities measured using the World Health Organization Disability Assessment Schedule (WHODAS). For comparison, we used the Chi-squared test along with the Student's t-test for the proportions and means respectively. Compared with the community controls, malnutrition survivors had a lower probability of attaining a high level of education (p < 0.001), of reporting a high academic performance (p = 0.014) or of having high self-esteem (p = 0.003). In addition, malnutrition survivors had an overall mean score in the cognitive test that was lower compared with the community controls [25.6 compared with 27.8, p = 0.001 (MMSE) and 22.8 compared with 26.3, p < 0.001(MMSE-I)] and a lower proportion of subjects with a normal result in this test (78.0% compared with 90.1%, p < 0.001). Lastly, in terms of health-related disabilities, unlike the community controls, malnutrition survivors had less social disability (p = 0.034), but no difference was observed as regards activities of daily living (p = 0.322). SAM during childhood exposes survivors to low human capital as regards education, cognition and behaviour in adulthood. Policy-deciders seeking to promote economic growth and to address various psychological and medico-social disorders must take into consideration the fact that appropriate investment in child health as regards SAM is an essential means to achieve this.

Mid‐upper arm circumference (MUAC) < 11.5 cm and weight‐for‐height Z‐score (WHZ) < −3 are used for screening for severe acute malnutrition (SAM). Underweight and concurrent wasting and stunting may better target those at the highest risk of mortality. We compared anthropometric outcomes in children enrolled in a trial of antibiotics for SAM based on categories of baseline anthropometry, including indicators for programme admission (WHZ < −3, MUAC < 11.5) and alternative indicators (weight‐for‐age Z‐score [WAZ] < −3, concurrent wasting and stunting [WHZ < −3 and height‐for‐age Z‐score < −3]). Participants were followed weekly until nutritional recovery and at 8 weeks. We evaluated changes in weight gain (g/kg/day), MUAC, and WHZ in children admitted by admissions criteria (MUAC only, WHZ only, or MUAC and WHZ) and by underweight or concurrent wasting and stunting. Of 301 admitted children, 100 (33%) were admitted based on MUAC only, 41 (14%) WHZ only, and 160 (53%) both MUAC and WHZ, 210 (68%) were underweight and 67 (22%) were concurrently wasted/stunted. Low MUAC and low WHZ children had the lowest probability of nutritional recovery (17% vs. 50% for MUAC‐only and 34% for WHZ‐only). There was no difference in weight gain velocity or WHZ by admissions criteria (WHZ and/or MUAC). Underweight and concurrently wasted/stunted children had lower MUAC and WHZ at 8 weeks compared with those who were not underweight or concurrently wasted and stunted. Children with both low MUAC and low WHZ had the worst outcomes. Relying on MUAC alone may miss children who have poor outcomes. Other indicators, such as WAZ, may be useful for identifying vulnerable children. Weight‐for‐height Z‐score (WHZ) and mid‐upper arm circumference (MUAC) are used for screening for severe acute malnutrition, but alternative indicators such as weight‐for‐age Z‐score (WAZ) may identify children at high risk of mortality. We evaluated anthropometric outcomes in children with severe acute malnutrition by baseline anthropometric status. Children with both low WHZ and MUAC had the worst outcomes, and low WAZ additionally identified children with poor outcomes Key messages Mid‐upper arm circumference (MUAC) and weight‐for‐height Z‐score (WHZ) are currently used for severe acute malnutrition (SAM) screening, but alternative indicators such as weight‐for‐age Z‐score (WAZ) may be additional options. Children admitted to the nutritional program based on both low MUAC and low WHZ had the worst outcomes, including the lowest probability of nutritional recovery and the worst anthropometric outcomes. While MUAC identified most children with SAM, WHZ may provide additional information about poor outcomes beyond MUAC alone. WAZ may be a useful alternative indicator to identify children who would benefit from a therapeutic feeding program without requiring height measurement.

ObjectiveWe hypothesised that an alternative RUTF (ready-to-use therapeutic food) made with oats (oat-RUTF) would be non-inferior to standard RUTF (s-RUTF).DesignThis was a randomised, triple-blind, controlled, clinical non-inferiority trial comparing oat-RUTF to s-RUTF in rural Sierra Leone. Children aged 6–59 months with severe acute malnutrition (SAM) were randomised to oat-RUTF or s-RUTF. s-RUTF was composed of milk powder, sugar, peanut paste and vegetable oil, with a hydrogenated vegetable oil additive. Oat-RUTF contained oats and no hydrogenated vegetable oil additives. The primary outcome was graduation, an increase in anthropometric measurements such that the child was not acutely malnourished. Secondary outcomes were rates of growth, time to graduation and presence of adverse events. Intention to treat analyses was used.ResultsOf the 1406 children were enrolled, graduation was attained in 404/721 (56%) children receiving oat-RUTF and 311/685 (45%) receiving s-RUTF (difference 10.6%, 95% CI 5.4% to 15.8%). Death, hospitalisation or remaining with SAM was seen in 87/721 (12%) receiving oat-RUTF and in 125/685 (18%) receiving s-RUTF (difference 6.2%, 95% CI 2.3 to 10.0, p=0.001). Time to graduation was less for children receiving oat RUTF; 3.9±1.8 versus 4.5±1.8 visits, respectively (p<0.001). Rates of weight in the oat-RUTF group were greater than in the s-RUTF group; 3.4±2.7 versus 2.5±2.3 g/kg/d, p<0.001.ConclusionOat-RUTF is superior to s-RUTF in the treatment of SAM in Sierra Leone. We speculate that might be because of beneficial bioactive components or the absence of hydrogenated vegetable oil in oat-RUTF.Trial registration number NCT03407326.