Kenneth Maleta

Antibiotics as part of the management of severe acute malnutrition.

BACKGROUND Severe acute malnutrition contributes to 1 million deaths among children annually. Adding routine antibiotic agents to nutritional therapy may increase recovery rates and decrease mortality among children with severe acute malnutrition treated in the community. METHODS In this randomized, double-blind, placebo-controlled trial, we randomly assigned Malawian children, 6 to 59 months of age, with severe acute malnutrition to receive amoxicillin, cefdinir, or placebo for 7 days in addition to ready-to-use therapeutic food for the outpatient treatment of uncomplicated severe acute malnutrition. The primary outcomes were the rate of nutritional recovery and the mortality rate. RESULTS A total of 2767 children with severe acute malnutrition were enrolled. In the amoxicillin, cefdinir, and placebo groups, 88.7%, 90.9%, and 85.1% of the children recovered, respectively (relative risk of treatment failure with placebo vs. amoxicillin, 1.32; 95% confidence interval [CI], 1.04 to 1.68; relative risk with placebo vs. cefdinir, 1.64; 95% CI, 1.27 to 2.11). The mortality rates for the three groups were 4.8%, 4.1%, and 7.4%, respectively (relative risk of death with placebo vs. amoxicillin, 1.55; 95% CI, 1.07 to 2.24; relative risk with placebo vs. cefdinir, 1.80; 95% CI, 1.22 to 2.64). Among children who recovered, the rate of weight gain was increased among those who received antibiotics. No interaction between type of severe acute malnutrition and intervention group was observed for either the rate of nutritional recovery or the mortality rate. CONCLUSIONS The addition of antibiotics to therapeutic regimens for uncomplicated severe acute malnutrition was associated with a significant improvement in recovery and mortality rates. (Funded by the Hickey Family Foundation and others; ClinicalTrials.gov number, NCT01000298.).

Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children

Microbiota and infant development Malnutrition in children is a persistent challenge that is not always remedied by improvements in nutrition. This is because a characteristic community of gut microbes seems to mediate some of the pathology. Human gut microbes can be transplanted effectively into germ-free mice to recapitulate their associated phenotypes. Using this model, Blanton et al. found that the microbiota of healthy children relieved the harmful effects on growth caused by the microbiota of malnourished children. In infant mammals, chronic undernutrition results in growth hormone resistance and stunting. In mice, Schwarzer et al. showed that strains of Lactobacillus plantarum in the gut microbiota sustained growth hormone activity via signaling pathways in the liver, thus overcoming growth hormone resistance. Together these studies reveal that specific beneficial microbes could potentially be exploited to resolve undernutrition syndromes. Science, this issue p. 10.1126/science.aad3311, p. 854 Microbes from healthy children protect mice from the detrimental effects of the microbiota of malnourished infants. INTRODUCTION As we come to appreciate how our microbial communities (microbiota) assemble following birth, there is an opportunity to determine how this facet of our developmental biology relates to the healthy or impaired growth of infants and children. Childhood undernutrition is a devastating global health problem whose long-term sequelae, including stunting, neurodevelopmental abnormalities, and immune dysfunction, remain largely refractory to current therapeutic interventions. RATIONALE To test the hypothesis that perturbations in the normal development of the gut microbiota are causally related to undernutrition, we first applied random forests (RF), a machine learning method, to bacterial 16S ribosomal RNA data sets generated from fecal samples that were collected serially from healthy Malawian infants and children during their first 3 postnatal years. Age-discriminatory bacterial taxa were identified with distinctive time-dependent changes in their relative abundances; they were used to construct a sparse RF-derived model describing a program of normal postnatal gut microbiota development that is shared across biologically unrelated individuals. A metric based on this model (microbiota-for-age Z-score) was used to define the state of development (maturation) of fecal microbiota from infants and children with varying degrees of undernutrition. Fecal samples obtained from 6- and 18-month-old children with healthy growth patterns or with varying degrees of undernutrition were transplanted into young germ-free mice that were fed a representative Malawian diet. The recipient animals’ rate of lean body mass gain was characterized by serial quantitative magnetic resonance, their metabolic phenotypes were determined by targeted mass spectrometry, and their femoral bone morphologic features were delineated by microcomputed tomography. RESULTS Undernourished children in the Malawian birth cohort that we studied have immature gut microbiota. Unlike microbiota from healthy children, immature microbiota transmit impaired growth, altered bone morphology, and metabolic abnormalities in the muscle, liver, and brain to recipient gnotobiotic mice. The representation of several age-discriminatory taxa in the transplanted microbiota harbored by recipient animals correlated with their growth rates. Microbiota from 6-month-old infants produced greater effects on growth than did microbiota from 18-month-old children, although in each age bin, the growth effects produced by a healthy donor’s community were greater than those produced by an undernourished donor’s community. Cohousing coprophagic mice shortly after they received microbiota from healthy or severely stunted and underweight 6-month-old infants resulted in the invasion of age- and growth-discriminatory taxa from the former into the latter microbiota in the recipient animals, with associated prevention of growth impairments. Introducing cultured members from this group of invasive species ameliorated growth and metabolic abnormalities in recipients of microbiota from undernourished donors. CONCLUSION These preclinical findings provide evidence that gut microbiota immaturity is causally related to childhood undernutrition. The age- and growth-discriminatory taxa that we identified should help direct studies of the effects of host and environmental factors on gut microbial community development, and they represent therapeutic targets for repairing or preventing gut microbiota immaturity. Preclinical evidence that gut microbiota immaturity is causally related to childhood undernutrition. (A) A model of normal gut microbial community development in Malawian infants and children, based on the relative abundances of 25 bacterial taxa that provide a microbial signature defining the “age,” or state of maturation, of an individual’s (fecal) microbiota. (Hierarchical clusterings of operational taxonomic units are indicated on the left.) (B) Fecal samples from healthy (H) or stunted and underweight (Un) infants and children were transplanted into separate groups of young germ-free mice that were fed a Malawian diet. The immature microbiota of Un donors transmitted impaired growth phenotypes to the mice

Sialylated Milk Oligosaccharides Promote Microbiota-Dependent Growth in Models of Infant Undernutrition

Identifying interventions that more effectively promote healthy growth of children with undernutrition is a pressing global health goal. Analysis of human milk oligosaccharides (HMOs) from 6-month-postpartum mothers in two Malawian birth cohorts revealed that sialylated HMOs are significantly less abundant in those with severely stunted infants. To explore this association, we colonized young germ-free mice with a consortium of bacterial strains cultured from the fecal microbiota of a 6-month-old stunted Malawian infant and fed recipient animals a prototypic Malawian diet with or without purified sialylated bovine milk oligosaccharides (S-BMO). S-BMO produced a microbiota-dependent augmentation of lean body mass gain, changed bone morphology, and altered liver, muscle, and brain metabolism in ways indicative of a greater ability to utilize nutrients for anabolism. These effects were also documented in gnotobiotic piglets using the same consortium and Malawian diet. These preclinical models indicate a causal, microbiota-dependent relationship between S-BMO and growth promotion.

Complementary feeding with fortified spread and incidence of severe stunting in 6- to 18-month-old rural Malawians.

OBJECTIVE To compare growth and incidence of malnutrition in infants receiving long-term dietary supplementation with ready-to-use fortified spread (FS) or micronutrient-fortified maize-soy flour (likuni phala [LP]). DESIGN Randomized, controlled, single-blind trial. SETTING Rural Malawi. PARTICIPANTS A total of 182 six-month-old infants. INTERVENTION Participants were randomized to receive 1 year of daily supplementation with 71 g of LP (282 kcal), 50 g of FS (FS50) (256 kcal), or 25 g of FS (FS25) (130 [corrected] kcal). OUTCOME MEASURES Weight and length gains and the incidences of severe stunting, underweight, and wasting. RESULTS Mean weight and length gains in the LP, FS50, and FS25 groups were 2.37, 2.47, and 2.37 kg (P = .66) and 12.7, 13.5, and 13.2 cm (P = .23), respectively. In the same groups, the cumulative 12-month incidence of severe stunting was 13.3%, 0.0%, and 3.5% (P = .01), of severe underweight was 15.0%, 22.5%, and 16.9% (P = .71), and of severe wasting was 1.8%, 1.9%, and 1.8% (P > .99). Compared with LP-supplemented infants, those given FS50 gained a mean of 100 g more weight and 0.8 cm more length. There was a significant interaction between baseline length and intervention (P = .04); in children with below-median length at enrollment, those given FS50 gained a mean of 1.9 cm more than individuals receiving LP. CONCLUSION One-year-long complementary feeding with FS does not have a significantly larger effect than LP on mean weight gain in all infants, but it is likely to boost linear growth in the most disadvantaged individuals and, hence, decrease the incidence of severe stunting.

Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy

Gut bacterial strains targeted by IgA in undernourished Malawian children produce severe enteropathy in gnotobiotic mice and correlate with health status. BugFACS Inc. In a new study, Kau et al. show that bacterial targets of gut immunoglobulin A (IgA) responses have diagnostic and therapeutic implications for childhood undernutrition. Purifying IgA-targeted microbes from fecal samples collected during the first 2 years of life from Malawian children using a method called BugFACS, these authors demonstrate that IgA responses to several types of bacteria, including Enterobacteriaceae, correlate with undernutrition. Transplanting IgA-bound bacteria from undernourished children to germ-free mice led to disruption of the gut lining (epithelium), weight loss, and sepsis in animals consuming a nutrient-deficient Malawian diet. This was prevented by a nutrient-sufficient diet or two IgA-targeted bacterial species from a healthy donor’s microbiota. Dissecting a collection of cultured IgA-targeted bacterial strains from an undernourished donor revealed that Enterobacteriaceae interacted with other community members to produce pathology. These findings have implications for the diagnosis and treatment of childhood undernutrition. To gain insights into the interrelationships among childhood undernutrition, the gut microbiota, and gut mucosal immune/barrier function, we purified bacterial strains targeted by immunoglobulin A (IgA) from the fecal microbiota of two cohorts of Malawian infants and children. IgA responses to several bacterial taxa, including Enterobacteriaceae, correlated with anthropometric measurements of nutritional status in longitudinal studies. The relationship between IgA responses and growth was further explained by enteropathogen burden. Gnotobiotic mouse recipients of an IgA+ bacterial consortium purified from the gut microbiota of undernourished children exhibited a diet-dependent enteropathy characterized by rapid disruption of the small intestinal and colonic epithelial barrier, weight loss, and sepsis that could be prevented by administering two IgA-targeted bacterial species from a healthy microbiota. Dissection of a culture collection of 11 IgA-targeted strains from an undernourished donor, sufficient to transmit these phenotypes, disclosed that Enterobacteriaceae interacted with other consortium members to produce enteropathy. These findings indicate that bacterial targets of IgA responses have etiologic, diagnostic, and therapeutic implications for childhood undernutrition.

Supplementary Feeding with Fortified Spreads Results in Higher Recovery Rates Than with a Corn/Soy Blend in Moderately Wasted Children

Moderate childhood wasting is defined as having a weight-for-height Z-score (WHZ) < -2, but > or = -3. These children are typically given fortified corn/soy blended flour (CSB), but this intervention has shown limited effectiveness. Fortified spreads (FS) can be used as supplementary foods instead; they are energy-dense, lipid-based pastes with added powdered micronutrients. In this randomized clinical effectiveness trial, the recovery rates were compared among children with moderate wasting who received either milk/peanut FS, soy/peanut FS, or CSB. Children received isoenergetic quantities of food, 314 kJ x kg(-1) x d(-1), for up to 8 wk with biweekly follow-up. The primary outcome was recovery, defined as having a WHZ > -2. Time-event analysis was used to compare the recovery rate. A total of 1362 children were enrolled in the study. Children receiving soy/peanut FS had a similar recovery rate to those receiving milk/peanut FS and children in either FS group were more likely to recover than those receiving CSB (80% in both FS groups vs. 72% in the CSB group; P < 0.01). The rate of weight gain in the first 2 wk was greater among children receiving milk/peanut FS (2.6 g x kg(-1) x d(-1), n = 465) or children receiving soy/peanut FS (2.4 g x kg(-1) x d(-1), n = 450) than among children receiving CSB (2.0 g x kg(-1) x d(-1), n = 447; P < 0.05). Rates of length gain did not differ among the 3 groups. A total of 8% of children in each feeding group developed edema, indicative of severe malnutrition, while receiving supplemental feeding. We conclude that FS are superior supplementary foods to CSB for moderately wasted Malawian children.

Comparison of real-time PCR and microscopy for malaria parasite detection in Malawian pregnant women

BackgroundNew diagnostic tools for malaria are required owing to the changing epidemiology of malaria, particularly among pregnant women in sub-Saharan Africa. Real-time PCR assays targeting Plasmodium falciparum lactate dehydrogenase (pfldh) gene may facilitate the identification of a high proportion of pregnant women with a P. falciparum parasitaemia below the threshold of microscopy. These molecular methods will enable further studies on the effects of these submicroscopic infections on maternal health and birth outcomes.MethodsThe pfldh real-time PCR assay and conventional microscopy were compared for the detection of P. falciparum from dried blood spots and blood smears collected from the peripheral blood of 475 Malawian women at delivery. A cycle threshold (Ct) of the real-time PCR was determined optimizing the sensitivity and specificity of the pfldh PCR assay compared to microscopy. A real-time PCR species-specific assay was applied to identify the contribution to malaria infections of three Plasmodium species (P. falciparum P. ovale and P. malariae) in 44 discordant smear and pfldh PCR assay results.ResultsOf the 475 women, P. falciparum was detected in 11 (2.3%) by microscopy and in 51 (10.7%) by real-time PCR; compared to microscopy, the sensitivity of real-time PCR was 90.9% and the specificity 91.2%. If a Ct value of 38 was used as a cut-off, specificity improved to 94.6% with no change in sensitivity. The real-time PCR species-specific assay detected P. falciparum alone in all but four samples: two samples were mixed infections with P. falciparum and P. malariae, one was a pure P. malariae infection and one was a pfldh PCR assay-positive/species-specific assay-negative sample. Of three P. malariae infections detected by microscopy, only one was confirmed by the species-specific assay.ConclusionsAlthough microscopy remains the most appropriate method for clinical malaria diagnosis in field settings, molecular diagnostics such as real-time PCR offer a more reliable means to detect malaria parasites, particularly at low levels. Determination of the possible contribution of these submicroscopic infections to poor birth outcomes and maternal health is critical. For future studies to investigate these effects, this pfldh real-time PCR assay offers a reliable detection method.

Growth and change in blood haemoglobin concentration among underweight Malawian infants receiving fortified spreads for 12 weeks: a preliminary trial.

Objective: Fortified spreads (FSs) have proven effective in the rehabilitation of severely malnourished children. We examined acceptability, growth and change in blood haemoglobin (Hb) concentration among moderately underweight ambulatory infants given FS. Methods: This was a randomised, controlled, parallel-group, investigator-blind clinical trial in rural Malawi. Six- to 17-month-old underweight infants (weight for age <−2), whose weight was greater than 5.5 kg and weight-for-height z score greater than −3 received for 12 weeks at home 1 of 8 food supplementation schemes: nothing, 5, 25, 50, or 75 g/day milk-based FS or 25, 50, or 75 g/day soy-based FS. Outcome measures included change in weight, length and blood Hb concentration. Results: A total of 126 infants started and 125 completed the intervention. All infants accepted the spread well, and no intolerance was recorded. Average weight and length gains were higher among infants receiving daily 25 to 75 g FS than among those receiving only 0 to 5 g FS. Mean Hb concentration remained unchanged among unsupplemented controls but increased by 10 to 17 g/L among infants receiving any FS. All average gains were largest among infants receiving 50 g of FS daily: mean difference (95% confidence interval) in the 12-week gain between infants in 50 g milk-based FS group and the unsupplemented group was 290 g (range, −130 to 700 g), 0.9 cm (range, −0.3 to 2.2 cm), and 17 g/L (range, 0 to 34 g/L) for weight, length and blood Hb concentration, respectively. In soy- vs milk-based FS groups, average outcomes were comparable. Conclusions: Supplementation with 25 to 75 g/day of highly fortified spread is feasible and may promote growth and alleviate anaemia among moderately malnourished infants. Further trials should test this hypothesis.

Supplementary feeding of underweight, stunted malawian children with a ready-to-use food

Objective Maize and soy flour mixes are often used in the treatment of moderate malnutrition in Malawi. Their efficacy has not been formally evaluated. A recently developed ready-to-use food (RTUF) effectively promotes growth among severely malnourished children. The authors compared the effect of maize and soy flour with that of RTUF in the home treatment of moderately malnourished children. Methods Sixty-one underweight, stunted children 42 to 60 months of age were recruited in rural Malawi, in southeastern Africa. They received either RTUF or maize and soy flour for 12 weeks. Both supplements provided 2 MJ (500Kcal) of energy daily but had different energy and nutrient densities. Outcome variables were weight and height gain and dietary intake. Results Before intervention, the mean dietary intake and weight and height gain were similar in the two groups. During the supplementation phase, the consumption of staple food fell among children receiving maize and soy flour but not among those receiving RTUF. There was thus higher intake of energy, fat, iron, and zinc in the RTUF group. Both supplements resulted in modest weight gain, but the effect lasted longer after RTUF supplementation. Height gain was not affected in either group. Periodic 24-hour dietary recalls suggested that the children received only 30% and 43%, respectively, of the supplementary RTUF and maize and soy flour provided. Conclusions RTUF is an acceptable alternative to maize and soy flour for dietary supplementation of moderately malnourished children. Approaches aimed at increasing the consumption of supplementary food by the selected recipients are needed.

The impact of lipid-based nutrient supplement provision to pregnant women on newborn size in rural Malawi: a randomized controlled trial

BACKGROUND Small birth size, often associated with insufficient maternal nutrition, contributes to a large share of global child undernutrition, morbidity, and mortality. We developed a small-quantity lipid-based nutrient supplement (SQ-LNS) to enrich the diets of pregnant women. OBJECTIVE The objective was to test a hypothesis that home fortification of pregnant womens diets with SQ-LNS would increase birth size in an African community. DESIGN We enrolled 1391 women with uncomplicated pregnancies (<20 gestational weeks) in a randomized controlled trial in Malawi. The women were provided with one daily iron-folic acid (IFA) capsule, one capsule containing multiple micronutrients (MMNs), or one 20-g sachet of SQ-LNS (LNS, containing 118 kcal, protein, carbohydrates, essential fatty acids, and 21 micronutrients). Primary outcomes were birth weight and newborn length. Secondary outcomes included newborn weight, head and arm circumference, and pregnancy duration. Analysis was by intention to treat. RESULTS The mean ± SD birth weight and newborn length were 2948 ± 432, 2964 ± 460, and 3000 ± 447 g (P = 0.258) and 49.5 ± 2.4, 49.7 ± 2.2, and 49.9 ± 2.1 cm (P = 0.104) in the IFA, MMN, and LNS groups, respectively. For newborn weight-for-age, head circumference, and arm circumference, the point estimate for the mean was also highest in the LNS group, intermediate in the MMN group, and lowest in the IFA group, but except for midupper arm circumference (P = 0.024), the differences were not statistically significant. The prevalence of low birth weight (<2500 g) was 12.7%, 13.5%, and 12.1% (P = 0.856), respectively; newborn stunting (length-for-age z score < -2) was 19.2%, 14.0%, and 14.9% (P = 0.130), respectively; and newborn small head circumference (head circumference-for-age z score < -2) was 5.8%, 3.0%, and 3.1% (P = 0.099), respectively. The associations between the intervention and the outcomes were not modified by maternal parity, age, or nutritional status (P > 0.100). CONCLUSION The study findings do not support a hypothesis that provision of SQ-LNS to all pregnant women would increase the mean birth size in rural Malawi. The trial was registered at clinicaltrials.gov as NCT01239693.