Therapeutic Approaches to Malnutrition Enteropathy

Over the last two decades, three key developments in the approach to treatment have improved the outcome of SAM: standardised management protocols, ready to use therapeutic food (RUTF), and community management of acute malnutrition (CMAM). CMAM has four components, namely, community mobilization and community identification of cases of acute malnutrition, supplementary feeding programme (SFP) for children with moderate acute malnutrition (MAM), outpatient therapeutic programme (OTP) of SAM with no medical complications and inpatient management of SAM with medical complications However, severely malnourished children with medical complications requiring hospitalisation often fail to respond to treatment, and continue to experience high inpatient mortality of up to 35%. Even after discharge, children have a poor prognosis, with 42% mortality over the subsequent year. It is a subgroup of children with SAM and acute or persistent diarrhoea who pose the most difficult management challenges, although the vast majority of children with SAM have substantial degree of enteropathy. Current treatment guidelines for SAM are not well supported by an evidence base, and there is a dearth of clinical trial data; in particular, there are no specific interventions to target enteropathy in SAM. In a systematic review, only three trials were found which inform management of SAM and persistent diarrhoea, and no trials dealing with the HIV-infected child. The investigators therefore believe that novel therapeutic approaches are urgently needed, and that a series of small phase 2 trials could guide development of a new generation of treatments. These trials should focus on repairing damage to the small intestinal mucosa, as there is now substantial evidence that this plays a central role in the genesis of systemic inflammation, bacterial translocation and sepsis with all its adverse nutritional consequences.

Evidence of malnutrition enteropathy: Recent studies have been highly informative about the infectious contribution to dysfunction of the small intestine in malnourished children. A high pathogen burden causes damage to the mucosa which exacerbates nutritional impairment and leads to further susceptibility to infection and impaired epithelial regeneration, in a cyclical process first described in Central America in the 1970s. This mucosal damage in SAM is here referred to as malnutrition enteropathy. In previous studies, markers of microbial translocation and systemic inflammation were dramatically increased in children with SAM compared to healthy controls. Enteropathy is characterised by multiple epithelial breaches, microbial translocation from the gut lumen to the systemic circulation, and systemic inflammation. Epithelial breaches were present in histological (haematoxylin/eosin-stained) sections and sections studies using immunofluorescence for claudin 4 and E-cadherin. In adults, these lesions were shown to occur in vivo using confocal laser endomicroscopy. There was also a consistent pattern of blunted epithelial repair, with reduced glucagon-like peptide 2 (GLP2) in serum, reduced trefoil factor 3 in duodenal aspirates, and a strong transcriptomic signature of impaired mucosal defence. Two further immunological abnormalities were identified in children with malnutrition enteropathy: low-level false positive coeliac-like autoantibodies, and upregulation of SMAD7 similar to the pattern seen in Crohn's disease. Together, these abnormalities indicate there is substantial structural and functional damage to the small intestine, and that this primary gut pathology is associated with systemic sequelae.

WHO guidelines clearly state that antibiotic treatment should be part of the initial management of all cases of SAM, whether associated with overt features of infection ('complicated' SAM) or not ('uncomplicated' SAM). Antibiotic use was associated with reduced short term mortality and improved nutritional rehabilitation in SAM with no medical complications in Malawi but post-discharge prophylaxis with cotrimoxazole did not reduce long-term mortality following complicated SAM in Kenya, and in Niger antibiotics conferred no benefit. Even in the best outcome group in the Malawi antibiotic trial, mortality was not reduced below 4% over 12 weeks in children managed as outpatients in OTP. This seems to be a glass floor below which it has never been possible to reduce mortality in SAM, even in uncomplicated cases in the community or in clinical trials. In SAM with medical complications who are managed as inpatients, mortality is much higher, and when combined with HIV infection can reach 35% in hospital and 62% over one year post-discharge.

If optimal antibiotics are insufficient to reduce mortality below 4% in uncomplicated cases treated in the community, and mortality is much higher in complicated cases, there must be other factors which lead inexorably to adverse outcomes in a subgroup of children with complicated SAM. It seems that a major contributor to the residual mortality observed after current optimal therapies have been implemented is failure of restitution in the gut. This means that in a subset of children with SAM, largely but not exclusively those with persistent diarrhoea, the intestinal mucosa is damaged and leaky, permitting efflux of plasma proteins and influx of luminal microbial products, and fails to repair following the infective insult. The evidence leading to this interpretation is:

i. In children with SAM and persistent diarrhoea, there are epithelial gaps visualised in haematoxylin/eosin-stained sections and using immunohistochemistry for claudin-4 and E-cadherin; ii. These are morphologically similar to lesions seen in environmental enteropathy in adults, though more severe and more numerous; iii. Plasma proteins are easily detected in western blots of duodenal aspirates, suggesting leakage from blood to gut lumen; iv. Biomarkers of microbial products (bacterial DNA and lipopolysaccharide) are found in very high concentrations in peripheral blood, direct evidence of microbial translocation from lumen to blood; v. Children with persistent diarrhoea and malnutrition have reduced circulating concentrations of glucagon-like peptide-2 (GLP2) and reduced trefoil factor 3 in intestinal secretions, suggesting a failure of homeostatic repair mechanisms. Circulating LPS was inversely proportional to circulating GLP2, and this remained true in multivariate analysis.

In a recent study of children with complicated SAM in Malawi, children who died were more likely to have diarrhoea and higher levels of faecal calprotectin (a marker of intestinal inflammation), and levels of systemic inflammation were directly related to mortality. There is now clear evidence that enteropathy is associated with systemic inflammation and mortality in SAM and a new treatment paradigm is required to improve outcomes.

There is a need for new approaches. The investigators postulate that the central lesion in malnutrition enteropathy is epithelial leakiness through tight junction damage and microerosions, and so propose therapy directed at restoration of the mucosal barrier which will permit reversal of the cascade of downstream inflammatory derangements. Novel approaches are required in order to achieve a radical improvement in outcome, and reduce current unacceptably high mortality rates. The TAME trial will investigate four potential therapeutic approaches to achieving mucosal restoration. Colostrum, teduglutide and N-acetyl glucosamine are all intended to achieve mucosal healing. Budesonide, a corticosteroid with limited absorption, is targeted at the downstream inflammatory changes; in inflammatory conditions such as coeliac disease or Crohn's disease, steroids produce rapid clinical response. If any of these interventions impact on malnutrition enteropathy, it will become possible to trial these novel therapeutic approaches in phase 3 trials to detect an impact on our world's most disadvantaged children. The trial will also generate useful information about pathophysiology.

The novel therapeutic approaches to be tested in the TAME trial are:

- Colostrum: high-protein bovine colostrum powder (Neovite) orally 1.5 g every 8 hours for 14 days, reconstituted with water and given through a nasogastric (NG) tube or orally. Colostrum reduces the increased epithelial permeability seen in heat shock. Colostrum contains nutrients, immunoglobulins and growth factors, including epidermal growth factor (EGF) and insulin-like growth factor 1 (IGF-1).

- N-acetyl glucosamine (GlcNAc) will be given orally or via NG tube for 14 days, gradually increased from a starting dose of 0.5g, to 1g three times daily to avoid osmotic diarrhoea. Impaired glycosylation of glycosaminoglycans has been noted in oedematous malnutrition, with reduced concentrations of glycosaminoglycans found in blood, urine, kidney, brain and small intestine. Specific consequences of reduced heparan sulphate expression include gut epithelial leakiness with hypoalbuminaemia. GlcNAc administration has been demonstrated to restore the intestinal epithelial charged barrier in Crohn's disease. GlcNAc may theoretically induce osmotic diarrhoea if not absorbed in the small intestine. Although this has not been observed clinically in animals or in older children we will use a dose escalation schedule to minimise the chance of this.

- Teduglutide by subcutaneous injection (0.05mg/kg/day) daily for 14 days. Teduglutide is a long-acting form of GLP2 which has proven efficacy in intestinal failure, improving absorption and reducing the need for parenteral support. GLP2 is a hormone secreted by L cells in the terminal ileum, which drives epithelial repair and mediates intestinal adaptation by increased cellular proliferation and villus hypertrophy.

- Budesonide 3mg orally daily for 7 days, then 2mg for 4 days then 1mg for 3 days. Budesonide is standard therapy for Crohn's disease, and can be used for refractory coeliac disease. Since malnutrition enteropathy is characterized by intestinal inflammation, with infiltration of activated T cells, an anti-inflammatory approach is rational. A prior trial of mesalazine in Kenya confirmed an immuno-modulatory approach is safe in the setting of SAM, but targeting the small, rather than large, intestine with a more potent agent is likely to be more effective.