Exploratory observational study of therapeutic feeds used to treat intestinal inflammation in Malawian children with severe acute malnutrition (SAM)

Despite interventions to prevent malnutrition, SAM, encompassing both marasmus (severe wasting) and kwashiorkor, occurred in 19m under fives in 2011 and accounted for 7% of all under 5 deaths. Many children with SAM are managed in the community using Ready-to-Use Therapeutic Food (RUTF). However, about 20% requires in-patient care because of inability to take adequate feeds, complications such as infection or diarrhoea or failure to improve under community management.

The in-patient management of children with SAM is extremely challenging. Despite following a well-established WHO protocol, case fatality often exceeds 20% and many of the survivors die following discharge home. Amongst long-term survivors, stunting, the recurrence of wasting and re-admission to hospital are common.

It has long been recognized that children with SAM have intestinal inflammation, termed "environmental" or "tropical" enteropathy. Although of unknown cause, it is thought to result from poor sanitation increasing exposure to microbial pathogens in the gut. Studies of the small intestine have shown that the marked reduction in surface area impairs food digestion and nutrient absorption. Also, the mucosa is "leaky" which likely allows bacteria to enter the tissues and blood stream causing sepsis and exposes the gut immune cells to microbial and food antigens resulting in persistence of the inflammation and consequent gut damage. Children who also have HIV infection may have even more severe enteropathy because HIV itself damages the intestinal mucosa.

After initial stabilisation of the child's condition, the current management of SAM focuses on re-feeding and treating infections. The feeds used (RUTF, F100) contain micronutrients such as vitamin A and zinc that are known to be important for mucosal health. However, these feeds would not be expected to improve the intestinal inflammation and this may underlie the poor response to treatment and poor long-term outcomes in many cases.

The inflammation in the intestine in SAM is very similar to that which occurs in food intolerance and Crohn's disease. In contrast to SAM, the treatment of these conditions targets the gut inflammation. In children, recommended treatments are with an extensively hydrolysed or elemental formula (food intolerance) or polymeric or elemental formula (Crohn's disease). These are complete feeds that promote healing of the intestinal mucosa and nutritional recovery and are free of significant adverse effects. In children with active Crohn's disease, about 60% achieve clinical remission and another 30% improve with these feeds.

The similarity in the gut inflammation across these conditions raises the possibility that treatments that effectively reduce the gut inflammation in food intolerance and Crohn's disease may also be effective in SAM. We aim to undertake a pilot study to see if an extensively hydrolysed, elemental and/or polymeric formula are tolerated by children with SAM and to see if they reduce the intestinal inflammation.

If we find that one or more of these feeds are likely to be effective, they would need to be evaluated in a larger study. If confirmed in a larger study, our findings would establish the necessity of specifically treating the intestinal inflammation in SAM. This could then be included in standard clinical management protocols. Researchers would be encouraged to consider how these alternative therapeutic feeds could be adapted to make them practical and cost-effective in low resource settings perhaps by using local ingredients and formulation as a paste for use at home. Also, it would be important to explore potential alternative approaches to treating the enteropathy - possibly also including children with less severe malnutrition managed in the community.

Objectives: to evaluate the feasibility, tolerability and effect on intestinal inflammation of an extensively hydrolysed, an elemental and a polymeric therapeutic feed in children with SAM.

Children aged 6-23 months with SAM admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi will be invited to join a randomised, open study. Children with HIV infection will be included. Those with a specific cause of malnutrition such as cerebral palsy or other organ disease, where enteropathy may not be a major factor, will be excluded.

Informed consent will be obtained from the parent/guardian. All children will be managed according to WHO guidelines including Formula 75 and broad-spectrum antibiotics during the initial stabilisation phase of management (about 5 days). As children enter the nutritional rehabilitation phase they will be allocated by chance in equal numbers to receive for 2 weeks either standard management (Ready-to-Use Food [RUTF] or Formula 100), an extensively hydrolysed, an elemental or a polymeric therapeutic feed. No other aspects of standard clinical management will be affected. Consumption of feeds would be monitored closely and naso-gastric feeding used according to usual practice to ensure similar nutritional intake in each arm of the study.

Primary outcome: faecal calprotectin concentration, measured by ELISA, at 2 weeks.

In addition, as secondary outcomes, we will measure important clinical parameters (occurrence and duration of diarrhoea; weight gain; occurrence of sepsis) and a number of non-invasive biomarkers in faeces, urine and blood of intestinal and systemic inflammation and the structure and integrity of the small intestine to gain more insights into the phenotypic variability of SAM and also the effects of alternative therapeutic feeds.

The findings of this pilot study may support the conduct of a larger clinical trial to assess the clinical benefits of alternative therapeutic feeds in SAM.

We expect that this trial will directly benefit the participating children. Improved recovery from SAM may reduce the significant long-term burdens of growth faltering and increased susceptibility to infections and, thereby, reduce attendance at health facilities.

All of the children will undergo thorough clinical assessment at baseline and during the intervention phase. The close scrutiny of their clinical progress will ensure that they receive the best care that is available in this setting. We hope that those receiving alternative therapeutic feeds may also benefit through reduce intestinal inflammation and improved gut function. If proven to be effective in subsequent studies and relevant to other settings, improved outcomes as a result of the specific management of intestinal inflammation may benefit many of the estimated 19m under fives with SAM worldwide.

There are several international, national and local companies and non-governmental organisations (NGOs) that produce therapeutic feeds for use in malnutrition. Our findings may ultimately inform the production of more effective feeds. There are multiple government departments and NGOs that provide nutrition interventions at the community level. The effectiveness of their programmes may be enhanced by improved therapeutic feeds.

The environmental enteropathy that occurs in SAM also occurs in milder forms of malnutrition. An effective intervention that could be adapted for use in the community may benefit the millions of undernourished children worldwide that live in low-resource settings. As well as improved nutritional status, responses to oral vaccines and also intestinal absorption of drugs may be improved. Combined, these effects of improved gastrointestinal health may result in an overall improvement in children's survival, growth and cognitive development and their ability to contribute effectively to their societies.