[Show abstract][Hide abstract] ABSTRACT: Kwashiorkor, an enigmatic form of severe acute malnutrition, is the consequence of inadequate nutrient intake plus additional environmental insults. To investigate the role of the gut microbiome, we studied 317 Malawian twin pairs during the first 3 years of life. During this time, half of the twin pairs remained well nourished, whereas 43% became discordant, and 7% manifested concordance for acute malnutrition. Both children in twin pairs discordant for kwashiorkor were treated with a peanut-based, ready-to-use therapeutic food (RUTF). Time-series metagenomic studies revealed that RUTF produced a transient maturation of metabolic functions in kwashiorkor gut microbiomes that regressed when administration of RUTF was stopped. Previously frozen fecal communities from several discordant pairs were each transplanted into gnotobiotic mice. The combination of Malawian diet and kwashiorkor microbiome produced marked weight loss in recipient mice, accompanied by perturbations in amino acid, carbohydrate, and intermediary metabolism that were only transiently ameliorated with RUTF. These findings implicate the gut microbiome as a causal factor in kwashiorkor.
[Show abstract][Hide abstract] ABSTRACT: The family Polyomaviridae is comprised of circular double-stranded DNA viruses, several of which are associated with diseases, including cancer, in immunocompromised patients. Here we describe a novel polyomavirus recovered from the fecal microbiota of a child in Malawi, provisionally named STL polyomavirus (STLPyV). We detected STLPyV in clinical stool specimens from USA and The Gambia at up to 1% frequency. Complete genome comparisons of two STLPyV strains demonstrated 5.2% nucleotide divergence. Alternative splicing of the STLPyV early region yielded a unique form of T antigen, which we named 229T, in addition to the expected large and small T antigens. STLPyV has a mosaic genome and shares an ancestral recombinant origin with MWPyV. The discovery of STLPyV highlights a novel alternative splicing strategy and advances our understanding of the complex evolutionary history of polyomaviruses.
[Show abstract][Hide abstract] ABSTRACT: We have discovered a novel polyomavirus present in multiple human stool samples. The virus was initially identified by shotgun pyrosequencing of DNA purified from virus-like particles isolated from a stool sample collected from a healthy child from Malawi. We subsequently sequenced the virus' 4,927-bp genome, which has been provisionally named MW polyomavirus (MWPyV). The virus has genomic features characteristic of the family Polyomaviridae but is highly divergent from other members of this family. It is predicted to encode the large T antigen and small T antigen early proteins and the VP1, VP2, and VP3 structural proteins. A real-time PCR assay was designed and used to screen 514 stool samples from children with diarrhea in St. Louis, MO; 12 specimens were positive for MWPyV. Comparison of the whole-genome sequences of the index Malawi case and one St. Louis case demonstrated that the two strains of MWPyV varied by 5.3% at the nucleotide level. The number of polyomaviruses found in the human body continues to grow, raising the question of how many more species have yet to be identified and what roles they play in humans with and without manifest disease.
Journal of Virology 06/2012; 86(19):10321-6. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.
[Show abstract][Hide abstract] ABSTRACT: Typical treatment of moderate acute malnutrition, simple wasting, in sub-Saharan Africa consists of dietary counselling and/or general or targeted distribution of corn/soy-blended flour (CSB). A randomised clinical effectiveness trial in 2007 showed CSB to be less effective than ready-to-use supplementary food (RUSF).
To determine the operational effectiveness of treating moderate acute malnutrition with RUSF.
Children aged 6-59 months were recruited in rural southern Malawi. Each child received 65 kcal/kg/d of locally produced soy/peanut RUSF, a product that provided about 1 RDA of each micronutrient. Anthropometric measurements were taken every 2 weeks and additional rations of RUSF were distributed at this time if the child remained wasted. Study participation lasted up to 8 weeks.
Of the 2417 children enrolled, 80% recovered, 4% defaulted, 0.4% died, 12% remained moderately wasted and 3% developed severe acute malnutrition. Weight, length and MUAC gain were 2.6 g/kg/d, 0.2 mm/d and 0.1 mm/d respectively. Cost per child treated was $5.39.
This intervention proved to be robust, maintaining high recovery rates and low default rates when instituted without the additional supervision and beneficiary incentives of a research setting.
Annals of Tropical Paediatrics International Child Health 01/2010; 30(2):103-8. · 0.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine if home-based nutritional therapy will benefit a significant fraction of malnourished, HIV-infected Malawian children, and to determine if ready-to-use therapeutic food (RUTF) is more effective in home-based nutritional therapy than traditional foods.
93 HIV-positive children >1 y old discharged from the nutrition unit in Blantyre, Malawi were systematically allocated to one of three dietary regimens: RUTF, RUTF supplement or blended maize/soy flour. RUTF and maize/soy flour provided 730 kJ x kg(-1) x d(-1), while the RUTF supplement provided a fixed amount of energy, 2100 kJ/d. These children did not receive antiretroviral chemotherapy. Children were followed fortnightly. Children completed the study when they reached 100% weight-for-height, relapsed or died. Outcomes were compared using regression modeling to account for differences in the severity of malnutrition between the dietary groups.
52/93 (56%) of all children reached 100% weight-for-height. Regression modeling found that the children receiving RUTF gained weight more rapidly and were more likely to reach 100% weight-for-height than the other two dietary groups (p < 0.05).
More than half of malnourished, HIV-infected children not receiving antiretroviral chemotherapy benefit from home-based nutritional rehabilitation. Home-based therapy RUTF is associated with more rapid weight gain and a higher likelihood of reaching 100% weight-for-height.
[Show abstract][Hide abstract] ABSTRACT: The present study compared leucine kinetics and acute-phase-protein concentrations in three groups of marasmic, acutely infected Malawian children fed one of three isoenergetic diets. These were: an enhanced-protein-quality diet (egg-white+tryptophan, providing 1.2 g protein/kg per d; n 14); an increased-protein-content diet (egg-white+tryptophan, providing 1.8 g protein/kg per d; n 14); a standard-protein diet (1.2 g milk protein/kg per d; n 25). The hypotheses tested were that children receiving a diet with more protein would have greater rates of non-oxidative leucine disposal and that children receiving an isonitrogenous diet with a higher protein quality would have lower rates of leucine oxidation. The children were studied after 24 h of therapy using standard [(13)C]leucine stable-isotope tracer techniques. The children receiving the higher-protein-content diet had greater leucine kinetic rates than those receiving the standard-protein-content diet; non-oxidative leucine disposal was 170 (sd 52) v. 122 (sd 30) mumol leucine/kg per h (P<0.01). Leucine oxidation was less in the children receiving the enhanced-protein-quality diet than in those receiving the standard-protein-quality diet; 34 (sd 12) v. 45 (sd 13) mumol leucine/kg per h (P<0.05). The children receiving the high-protein-content diet increased their serum concentration for five of six acute-phase proteins 24 h after starting therapy, while those receiving the standard-protein-content diet did not. These data suggest that there was greater whole-body protein synthesis, and a more vigorous acute-phase response associated with the higher-protein-content diet. The clinical benefits associated with a higher protein intake in marasmic, acutely infected children need further study.
British Journal Of Nutrition 10/2004; 92(4):589-95. · 3.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The standard treatment of severe malnutrition in Malawi often utilises prolonged inpatient care, and after discharge results in high rates of relapse.
To test the hypothesis that the recovery rate, defined as catch-up growth such that weight-for-height z score >0 (WHZ, based on initial height) for ready-to-use food (RTUF) is greater than two other home based dietary regimens in the treatment of malnutrition.
HIV negative children >1 year old discharged from the nutrition unit in Blantyre, Malawi were systematically allocated to one of three dietary regimens: RTUF, RTUF supplement, or blended maize/soy flour. RTUF and maize/soy flour provided 730 kJ/kg/day, while the RTUF supplement provided a fixed amount of energy, 2100 kJ/day. Children were followed fortnightly. Children completed the study when they reached WHZ >0, relapsed, or died. Outcomes were compared using a time-event model.
A total of 282 children were enrolled. Children receiving RTUF were more likely to reach WHZ >0 than those receiving RTUF supplement or maize/soy flour (95% v 78%, RR 1.2, 95% CI 1.1 to 1.3). The average weight gain was 5.2 g/kg/day in the RTUF group compared to 3.1 g/kg/day for the maize/soy and RTUF supplement groups. Six months later, 96% of all children that reached WHZ >0 were not wasted.
Home based therapy of malnutrition with RTUF was successful; further operational work is needed to implement this promising therapy.
Archives of Disease in Childhood 07/2004; 89(6):557-61. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypotheses that the rate of CO2 production is less in marasmic children with acute infection when compared to well-nourished children, but greater when compared to uninfected marasmic children.
A descriptive comparison of children aged 12-60 months who had their rates of CO2 production measured using a stable isotope tracer dilution method while receiving feedings. Body mass index (BMI) was the best measure of lean body mass available in this study.
Queen Elizabeth Central Hospital, Blantyre, Malawi.
A total of 56 children were studied, 28 with marasmus and acute infection, 16 with marasmus, and 12 well nourished with acute infection. Those with acute infection had malaria, pneumonia, or sepsis.
Well-nourished children with acute infection produced more CO2 than marasmic children (344+/-60 vs 225+/-65 mmol CO2/h, mean+/-s.d., P<0.001; 24.2+/-4.6 vs 18.4+/-5.4 mmol CO2/BMI h, P=0.001). However, the rate of CO2 production in marasmic children with acute infection was not greater than in uninfected marasmic children (225+/-65 vs 228+/-61 mmol CO2/h). The observed rate of CO2 production was greater than that which could be produced from the dietary intake alone (29.6 vs. 25.8 mmol CO2/kg h).
Marasmic children do not increase energy expenditure in response to acute infection, as well-nourished children do. Dietary energy provided to marasmic children should be at least 420 kJ/kg day.
European Journal of Clinical Nutrition 01/2004; 58(1):116-20. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To test the hypothesis that kwashiorkor is associated with increased oxidative stress, urinary concentrations of 2 oxidized amino acids, o,o '-dityrosine and ortho -tyrosine, were measured by gas chromatography-mass spectrometry. Children with kwashiorkor, with or without infection, had a 3- to 7-fold increase in urinary o,o '-dityrosine and a 1.5- to 2-fold increase in ortho -tyrosine when compared with well-nourished children. This observation raises the possibility that oxidative damage to proteins and other biologic targets plays a role in the clinical manifestations of kwashiorkor.
Journal of Pediatrics 10/2000; 137(3):421-4. · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The case fatality rate for children with kwashiorkor in central hospitals in Malawi was 30.5% (275/901) in 1995. The purpose of this study was to determine whether improved case management with intensive nursing care could lower this case fatality rate. A total of 75 children admitted with kwashiorkor in Blantyre, Malawi, received intensive nursing care. This included nursing in individual clean beds with blankets, a nurse:child ratio of 1:3, supervised feedings every 2 h, a paediatrician with expertise in treating kwashiorkor always available for consultation, laboratory evaluation for systemic infection and empiric use of ceftriaxone. Nineteen of these children died (25%). The causes of death were life threatening electrolyte abnormalities (hypokalaemia, hyponatraemia, hypophosphataemia) in nine cases, overwhelming infection in eight cases and congestive heart failure in two children. Children infected with the human immunodeficiency virus were more likely to die (9/20), as were children with life threatening electrolyte abnormalities (9/15) and children with more severe wasting. When compared with 225 children treated in the same year at the same institution, who were carefully matched for severity of kwashiorkor, intensive nursing did not improve overall survival.
[Show abstract][Hide abstract] ABSTRACT: In kwashiorkor, there is less endogenous proteolysis in response to acute infection than in a well-nourished state. Thus the amino acid composition of dietary protein may be more important in facilitating the acute phase response in kwashiorkor. This study tested the hypothesis that during the treatment of kwashiorkor with infection, there is a lower rate of urea appearance when the dietary intake of amino acids more closely resembles the amino acid composition of acute phase proteins. Thirty children in Malawi with kwashiorkor and acute infection were fed isoenergetic, isonitrogenous meals containing either egg white-tryptophan or milk as a protein source. After 24 h, the rates of urea appearance and whole-body protein breakdown and synthesis were measured with the use of 1-13C-leucine and 15N2-urea tracers. Plasma concentrations of seven acute phase proteins, interleukin 6 and tumor necrosis factor-alpha were measured on admission, and at 24 and 48 h. The 16 children who received egg white-tryptophan had lower rates of urea appearance than those who received milk [57+/-30 vs. 87+/-36 micromol/(kg x h), mean +/- SD, P<0.02]. No significant differences were found in the rates of whole-body protein turnover or in the concentration of any of the acute phase proteins or cytokines. The concentration of interleukin 6 was consistent with an appropriate proinflammatory response and correlated directly with the concentrations of C-reactive protein (r = 0.67, P<0.01) and alpha1-antitrypsin (r = 0.40, P<0.05). The findings suggest that egg white-tryptophan is associated with less amino acid oxidation in kwashiorkor and acute infection than is milk.
Journal of Nutrition 02/2000; 130(2):183-8. · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe hypophosphatemia, serum phosphate concentration <0.32 mmol/L (<1.0 mg/dL), occurred in 8 of 68 (12%) of children with kwashiorkor within 48 hours of admission; 5 of 8 (63%) of these children died, compared with 13 of 60 (22%) children without severe hypophosphatemia (P <.02). Dermatosis and dehydration were significantly correlated with severe hypophosphatemia, but these clinical signs could not reliably predict fatal cases. Severe hypophosphatemia seems to be common and life-threatening in children with kwashiorkor in Malawi.
Journal of Pediatrics 12/1998; 133(6):789-91. · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Marasmus and kwashiorkor are clinically distinct manifestations of severe malnutrition. This study tested the hypothesis that rates of whole-body protein synthesis and breakdown are higher in marasmus than in kwashiorkor during acute infection. We measured whole-body protein kinetics using stable isotope tracers in eight children with marasmus and acute infection (pneumonia or malaria) to determine the rate of appearance of urea and leucine in plasma. Serum concentrations of total protein, albumin, and C-reactive protein were also measured. These findings were compared with those reported previously for 13 children with kwashiorkor (including marasmic kwashiorkor) and acute infection who were studied with the same methods. HIV infection was present in 10 of 21 children. Rates of protein breakdown and synthesis were higher in marasmus than in kwashiorkor (227 +/- 59 compared with 103 +/- 30 micromol leucine x kg(-1) x h(-1) and 216 +/- 60 compared with 97 +/- 30 micromol leucine x kg(-1) x h(-1), P < 0.001). The concentration of globulin (total protein minus albumin) was higher in marasmus than kwashiorkor (40 +/- 17 compared with 25 +/- 7 g/L, P < or = 0.01), but C-reactive protein was not different (73 +/- 79 compared with 83 +/- 89 mg/L). HIV infection and body composition did not explain the differences between marasmus and kwashiorkor. The accelerated rate of protein turnover in children with marasmus and acute infection requires further investigation.
American Journal of Clinical Nutrition 07/1998; 67(6):1205-9. · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study tested the hypothesis that during treatment of kwashiorkor (including marasmic kwashiorkor) with infection there is a lower rate of amino acid oxidation when the dietary intake of amino acids resembles the amino acid composition of acute phase proteins (APPs). Twenty-two children in Blantyre, Malawi, with kwashiorkor and acute infection were fed an isoenergetic, isonitrogenous diet with either egg white or milk as a protein source. The whole-body amino acid oxidation rate was measured after 24 h by determining the plasma urea rate of appearance, and whole-body protein breakdown and synthesis rates were determined from the plasma leucine rate of appearance. Plasma concentrations of C-reactive protein, alpha1-antitrypsin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) were determined on admission and at 24 and 48 h. The 11 children who received milk had a lower rate of amino acid oxidation than the children who received egg white (x +/- SD: 137 +/- 65 compared with 195 +/- 66 micromol urea x kg body wt(-1) x h(-1), P < 0.05). No significant differences were found between the two groups in the rate of whole-body protein breakdown or protein synthesis. The TNF-alpha concentration correlated inversely with whole-body protein breakdown and synthesis rates, and the IL-6 concentration correlated directly with C-reactive protein. We conclude that by making the amino acid composition of the diet resemble that of APPs in the treatment of acute kwashiorkor, the rate of amino acid oxidation can be decreased.
American Journal of Clinical Nutrition 09/1997; 66(3):643-8. · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: (1) To improve case management of kwashiorkor at seven Nutritional Rehabilitation Centres (NRCs) through 2-4 weekly paediatric supervisory visits. (2) To evaluate the impact of the use of routine tube-feeding and a micronutrient supplement (Nutriset).
An intervention project with descriptive clinical data in which Nutriset was introduced halfway through the project, and routine tube-feeding at one NRC was compared to no tube-feeding at a similar one.
NRCs located at two central hospitals, two district hospitals and three rural clinics in southern Malawi.
1625 consecutive kwashiorkor admissions from January-December 1995.
The overall case-fatality rate was 24.2% (393/1625), varying by facility level (central 30.5%, district 25.8% and rural 7.5%), reflecting different severity of cases. From ELISA testing and a clinical protocol, we estimate that 21.7% (353/1625) of these kwashiorkor cases were HIV-infected, including 121 breastfed children. Routine tube-feeding was associated with better weight gain (8.24 g/kg/d) than no tube-feeding (4.51 g/kg/d) at central NRCs, but with no reduction in mortality (31.4% vs 30.3%). The introduction of Nutriset was associated with improved weight gain (6.06 vs 4.66 g/kg/d) and a lower mortality (20.8 vs 25.8%), but was confounded by seasonal factors.
From a clinical perspective, HIV infection has transformed kwashiorkor in this part of Africa. Routine tube-feeding was associated with improved body weight gain in the treatment of kwashiorkor. The benefit of paediatric supervision was limited by the infrequency of visits, by constraints of health worker motivation, by a lack of resources and by the severity of disease. Efforts need to focus-not just on case management protocols-but on how to actually improve clinical practice in this setting.
European Journal of Clinical Nutrition 04/1997; 51(3):139-47. · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intestinal permeability can be assessed non-invasively using the lactulose-rhamnose (L-R) test, which is a reliable measure of small intestinal integrity.
To determine risk factors for abnormal intestinal permeability in kwashiorkor, and to measure changes in L-R ratios with inpatient rehabilitation.
A case-control study of 149 kwashiorkor cases and 45 hospital controls. The L-R test was adapted to study kwashiorkor in Malawi, with testing at weekly intervals during nutritional rehabilitation. Urine sugars were measured by thin layer chromatography in London.
The initial geometric mean L-R ratios (x100) (with 95% confidence interval) in kwashiorkor were 17.3 (15.0 to 19.8) compared with 7.0 (5.6 to 8.7) for controls. Normal ratios are < 5, so the high ratios in controls indicate tropical enteropathy syndrome. Abnormal permeability in kwashiorkor was associated with death, oliguria, sepsis, diarrhoea, wasting and young age. Diarrhoea and death were associated with both decreased L-rhamnose absorption (diminished absorptive surface area) and increased lactulose permeation (impaired barrier function) whereas nutritional wasting affected only L-rhamnose absorption. Despite, clinical recovery, mean L-R ratios improved little on treatment, with mean weekly ratios of 16.3 (14.0 to 19.0), 13.3 (11.1 to 15.9) and 14.4 (11.0 to 18.8).
Abnormal intestinal permeability in kwashiorkor correlates with disease severity, and improves only slowly with nutritional rehabilitation.
Archives of Disease in Childhood 04/1997; 76(3):236-41. · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The dual sugar test of intestinal permeability is a reliable non-invasive way of assessing the response of the small intestinal mucosa to nutritional rehabilitation.
To compare a local mix of maize-soya-egg to the standard milk diet in the treatment of kwashiorkor.
The diets were alternated three monthly in the sequence milk-maize-milk. There were a total of 533 kwashiorkor admissions of at least five days during the study who received either milk or maize. Intestinal permeability was assessed at weekly intervals by the lactulose-rhamnose test in 100 kwashiorkor cases, including 55 on milk and 45 on the maize diet.
Permeability ratios (95% confidence interval) on the milk diet improved by a mean of 6.4 (1.7 to 11.1) compared with -6.8 (-16.8 to 5.0) in the maize group. The improved permeability on milk occurred despite more diarrhoea, which constituted 34.8% of hospital days (29.8 to 39.8) compared with 24.3% (17.8 to 30.8) in the maize group. Case fatality rates for all 533 kwashiorkor admissions were 13.6% v 20.9%, respectively, giving a relative risk of death in the maize group of 1.54 (1.04 to 2.28). The maize group also had more clinical sepsis (60% v 31%) and less weight gain (2.9 v 4.4 g/kg/day) than the milk group.
Milk is superior to a local maize based diet in the treatment of kwashiorkor in terms of mortality, weight gain, clinical sepsis, and improvement in intestinal permeability.
Archives of Disease in Childhood 04/1997; 76(3):242-8. · 3.05 Impact Factor