Nutritional rehabilitation of persistent diarrhea in childhood : factors determining recovery and the relationship of systemic infections with intestinal function

Abstract: Nutritional rehabilitation of persistent diarrhea (PD), a major killer of children in the third world, poses an enormous challenge. We validated the efficacy of a traditional local weaning diet based on rice-lentils (Khitchri) and yogurt (K-Y diet) for nutritional rehabilitation of PD. The K-Y diet was well tolerated, and led to significant improvement in stool output and weight gain with adequate absorption of macronutrients on metabolic balance studies. However, approximately 16% of children failed nutritional therapy with persistence of diarrhea and inadequate weight gain. Analysis of risk factors for therapeutic failure among children receiving dietary therapy for PD suggested a possible relationship with young age, high purging rate, vomiting and associated pyrexia. The presence of systemic infection was associated with significantly delayed "time-to-recovery" on survival analysis. A prospective study evaluating the serum IGF-I response in children recovering from PD also confirmed a close association of treatment failure and poor IGF-I response with the presence of systemic infection. An inverse correlation was demonstrable between baseline CRP levels and corresponding IGF-I response. A subsequent case-control study of diarrheal deaths among hospitalized children in Karachi also identified concomitant bacteremia as an important risk-factor for mortality. Our data thus indicated that in children with PD, concomitant infections were an important determinant of outcome, with a significant impact on diarrheal and nutritional recovery. In order to elucidate the relationship of systemic infections with intestinal function, we developed an in-vivo secretory gut model in young Sprague-Dawley rats by luminal injection of Escherichia coli heat stable toxin (STa) into closed ileal loops. Concomitant i.v. administration of 100 myg/kg of lipopolysaccharide (LPS) not only led to a significant increase in loop fluid output, but also increased the intestinal permeability, as quantitated by Evans Blue permeation. Evaluation of intestinal myoelectric activity indicated that i.v. LPS administration completely abolished the migrating myoelectric complexes in the small intestine, along with development of diarrhea. The intestinal fluid secretion correlated closely with luminal nitrite content. Bioassay of intestinal tissue cytokine activity revealed markedly increased activity of IL- I and IL-6 in LPS treated loops. Assessment of tissue homogenates by RT-PCR using specific primers revealed that systemic LPS administration, but not local STa, led to production of local IL-6, TNFalpha, lL-1alpha and lL-lbeta within 60 minutes. These experiments showed that systemic endotoxin administration resulted in increased intestinal permeability and a secretory state. These effects appeared to be mediated by increased local cytokine and nitric oxide activity. Our clinical and experimental data suggests that systemic infections play a major contributory role in determining the outcome during nutritional rehabilitation of malnourished children with PD. This effect seems to be independent of energy intake, and is related to both induction and perpetuation of a secretory state in the intestine as well as altered mucosal integrity. A closer attention to prompt and effective treatment of systemic infections or measures reducing inflammatory mediators, may further improve clinical outcome.