Intestinal Permeability Is Associated with Mortality and Readmission in Children Hospitalized with Severe Acute Malnutrition.
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BACKGROUND: Severe acute malnutrition (SAM) is the most critical form of undernutrition, associated with high inpatient and postdischarge mortality. It is hypothesized that malnutrition enteropathy contributes to systemic inflammation by allowing translocation of intestinal pathogen-associated molecular patterns across the damaged epithelium. OBJECTIVES: Assess intestinal permeability, markers of bacterial translocation, and correlate these with inflammatory markers in children admitted with SAM and during 1 y after discharge. METHODS: In a substudy of the longitudinal Health Outcomes, Pathogenesis and Epidemiology of Severe Acute Malnutrition observational study, we recruited 264 children with complicated SAM on admission to hospital at 3 centers in Zimbabwe and Zambia. We measured gut permeability by urinary lactulose:mannitol ratio (LMR); plasma lipopolysaccharide (LPS) using the limulus amoebocyte lysate assay; and plasma inflammatory biomarkers by enzyme-linked immunosorbent assay and Luminex, at admission, discharge, 12- and 48-wk postdischarge. Values were compared with 173 adequately nourished community controls. Data were analyzed using mixed effects models for longitudinal data, regression for associations between groups, and Cox proportional hazards models for survival. RESULTS: Gut permeability, as measured by LMR, was 2.5-fold higher in children with SAM compared with community controls [95% confidence interval (CI): 1.4, 4.5], and only resolved by 48-wk postdischarge. Higher inpatient gut permeability was associated with increased risk of death or readmission over the following year [hazard ratio 6.14 (95% CI: 1.03, 36.8) per 10-fold increase in LMR]. Children with high gut permeability had higher levels of the intestinal biomarker glucagon-like peptide-2 and lower L-selectin. Children with higher plasma LPS had independently higher concentrations of circulating inflammatory markers [tumor necrosis factor-α, interleukin (IL)-6, IL-1ra, C-reactive protein, IL-8, chemokine ligand 3, and chemokine ligand 4]. CONCLUSIONS: Collectively, these results highlight the central role of the gut in children with SAM. Malnutrition enteropathy may represent a suitable target for therapeutic interventions to improve clinical outcomes in this high-risk population.