Nutritional disorders are glaring examples of health inequalities between high- and low-income countries, and within low-income countries. Malnutrition underlies almost half of all child deaths globally and therefore contributes enormously to the unacceptably high under-5 mortality rates in these regions. Chronic undernutrition is usually manifest as stunting (poor linear growth), affects 40% and 27% of children in Zambia and Zimbabwe, respectively. Acute malnutrition is usually manifest as wasting (loss of tissue), with or without oedema, and is the most conspicuous of all nutritional disorders. Severe acute malnutrition (SAM) carries the highest mortality, particularly if associated 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. In our experience, 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.
We 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 we now have substantial evidence that this plays a central role in the genesis of systemic inflammation, bacterial translocation and sepsis with all its adverse nutritional consequences.
The need for new approaches: We postulate that the central lesion in malnutrition enteropathy is epithelial leakiness through tight junction damage and microerosions, and so we propose therapy directed at restoration of the mucosal barrier which will permit reversal of the cascade of downstream inflammatory derangements. Without novel approaches we cannot hope to achieve a radical improvement in outcome and reduce current unacceptably high mortality rates. We therefore propose 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, we may open up novel therapeutic approaches which could have an impact on our world’s most disadvantaged children. We may also identify where current management strategies are failing.
Study Location: Harare Central Hospital and Parirenyatwa Hospital.
Sample Size: 225 children (half in Zimbabwe, half in Zambia) hospitalized with SAM, randomized to one of 5 treatment arms (including Standard of Care).