Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial

Abstract

BackgroundEnvironmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy.MethodsIn this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention.ResultsTreatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone – insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth.ConclusionsIntestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust.Trial registrationRegistered at Clinicaltrials.gov NCT01841099.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0133-2) contains supplementary material, which is available to authorized users.

Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study

“…This suggests that children with SAM have high degrees of intestinal inflammation, which is consistent with a previous report (29). Interestingly, Hestvik et al (30) described heightened concentrations of fecal calprotectin in healthy Ugandan infants with a median of 249 mg/kg feces, yet they did not find differences linked to pathogens in stool.…”

“…These similarities should be interpreted with caution but do warrant further investigation. Several authors have paralleled the symptoms of SAM and IBD, and this has led to the experimental use of established IBD treatments such as the anti-inflammatory agent mesalazine in patients with SAM (29, 48). …”

Environmental enteropathy

“…There was nonsustained decrease in the markers of inflammation (erythrocyte sedimentation rate, fecal calprotectin, and immunoglobulin levels) but no difference in the nutritional outcomes [35].…”

“…Extrapolating from experience in inflammatory bowel disease, Jones and colleagues [35] used mesalazine along with nutritional rehabilitation for the treatment of environmental enteropathy but they failed Environmental enteropathy Ali et al…”

New insights into environmental enteric dysfunction

“…These have been previously reviewed elsewhere9 10 and more recent trials have not fundamentally changed this conclusion,23–25 although a small recent trial of the anti-inflammatory medication mesalazine shows some promise 26. This general lack of demonstrated benefit may be due to the ongoing challenge of not yet having a perfect biomarker or case definition for EED.…”