Malnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial.

Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6-59 months and hospitalised with SAM (using WHO definitions: WLZ <-3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum (n = 25), (ii) N-acetyl glucosamine (n = 24), (iii) subcutaneous teduglutide (n = 26), (iv) budesonide (n = 25) or (v) standard care only (n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α1-antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size -0.89 (90% CI: -1.69,-0.10) P = 0.07), while colostrum (-0.58 (-1.4, 0.23) P = 0.24), N-acetyl glucosamine (-0.20 (-1.01, 0.60) P = 0.67), and budesonide (-0.50 (-1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.

Association between oesophageal cancer and biomass smoke exposure: a case-control study.

Most African populations are regularly exposed to biomass smoke, but knowledge of associated health implications is limited. This study aimed to investigate the association between oesophageal cancer (OC) and exposure to biomass smoke. This case-control study was conducted in Lusaka, Zambia. Cases were patients with endoscopically diagnosed OC, while controls were healthy volunteers. Questionnaires were used to collect lifestyle risk factors. Two sets of data were analysed; one with unmatched cases and controls and the other one with matching by age and sex. We enrolled 366 patients (131 cases and 235 controls). Among the cases, 50 (38%) were female and the median age was 56 years (IQR = 46-65 years). OC was significantly associated with domestic exposure to biomass smoke in univariate analysis (OR: 3.1; 95% CI: 1.7-5.6, p < 0.001) and after adjusting for potential confounders (OR: 2.1; 95% CI: 1.1-3.8, p = 0.017). Matched comparisons showed similar results for this association in univariate analysis (OR: 2.9; 95% CI: 1.5-5.8, p < 0.001) and using conditional logistic regression (OR: 2.8; 95% CI: 1.3-5.9, p = 0.005). Other risk factors found to be associated with OC were rural residence (OR: 2.3; 95% CI: 1.0-5.3, p = 0.004), lack of formal education (OR: 3.9; 95% CI: 1.5-9.9, p = 0.04) and living in poor housing (OR: 2.4; 95% CI: 1.1-5.6, p = 0.034). In conclusion, there is an association between OC and domestic exposure to biomass smoke and other lifestyle factors linked to low socio-economic status.

Adaptation of the small intestine to microbial enteropathogens in Zambian children with stunting.

Environmental enteropathy is a major contributor to growth faltering in millions of children in Africa and South Asia. We carried out a longitudinal, observational and interventional study in Lusaka, Zambia, of 297 children with stunting (aged 2-17 months at recruitment) and 46 control children who had good growth (aged 1-5 months at recruitment). Control children contributed data only at baseline. Children were provided with nutritional supplementation of daily cornmeal-soy blend, an egg and a micronutrient sprinkle, and were followed up to 24 months of age. Children whose growth did not improve over 4-6 months of nutritional supplementation were classified as having non-responsive stunting. We monitored microbial translocation from the gut lumen to the bloodstream in the cohort with non-responsive stunting (n = 108) by measuring circulating lipopolysaccharide (LPS), LPS-binding protein and soluble CD14 at baseline and when non-response was declared. We found that microbial translocation decreased with increasing age, such that LPS declined in 81 (75%) of 108 children with non-responsive stunting, despite sustained pathogen pressure and ongoing intestinal epithelial damage. We used confocal laser endomicroscopy and found that mucosal leakiness also declined with age. However, expression of brush border enzyme, nutrient transporter and mucosal barrier genes in intestinal biopsies did not change with age or correlate with biomarkers of microbial translocation. We propose that environmental enteropathy arises through adaptation to pathogen-mediated epithelial damage. Although environmental enteropathy reduces microbial translocation, it does so at the cost of impaired growth. The reduced epithelial surface area imposed by villus blunting may explain these findings.