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

Abstract

Background: Environmental 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.

Methods: In 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.

Results: Treatment 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.

Conclusions: Intestinal 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 registration: Registered at Clinicaltrials.gov NCT01841099.

Figure 1

Trial flow diagram: *Some children had multiple reasons for being ineligible.

Figure 2

Safety and toxicity. Cumulative timing of adverse events between the arms (A). Stool consistency (Bristol Stool Form Scale) and frequency in the 24 hours preceding clinical review (B,C). Hepatic enzymes, aspartate aminotransferase (AST), alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT), for all participants in the study (D). Change in hepatic enzymes from baseline to day 7 (E). Creatinine and hemoglobin for all participants (F,G). Differences between arms at baseline are highlighted if P <0.1, upper limit of normal (alongside lower limit for creatinine) illustrated where appropriate.

Figure 3

IGF-1 and growth. Insulin-like growth factor-1 (IGF-1) increases during follow-up (A). Enrollment IGF-1 had negative correlations with several inflammatory markers (B, color indicates statistical significance level, + or – indicates a positive or negative correlation). This effect reduced between IGF-1 and concurrent inflammatory markers at later time points. Concentrations of IGF-1 and endotoxin correlated positively and negatively (respectively) with linear growth over the course of the study (C).

Figure 4

Impact on inflammatory activation. Key clinically important and gut-specific inflammatory markers between arms. Differences at baseline are highlighted if P <0.1. Upper limit of normal illustrated where appropriate.