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

尽管采取了预防营养不良的干预措施，但2011年，包括消瘦（严重消瘦）和营养不良在内的急性营养不良仍在1900万5岁以下儿童中发生，占5岁以下儿童死亡总数的7%。许多患有急性口疮的儿童在社区中使用即食治疗食品（RUTF）进行管理。然而，约有20%的儿童由于无法摄入足够的食物、感染或腹泻等并发症或未能在社区管理下得到改善而需要住院治疗。儿童SAM的住院治疗极具挑战性。尽管遵循了世卫组织完善的规程，但病死率往往超过20%，许多幸存者在出院后死亡。在长期幸存者中，发育迟缓、消瘦复发和再次住院是常见的。长期以来，人们认识到患有SAM的儿童有肠道炎症，称为“环境”或“热带”肠病。虽然原因不明，但人们认为这是由于卫生条件差导致肠道中微生物病原体的暴露增加。对小肠的研究表明，表面积的显著减少会影响食物的消化和营养的吸收。此外，粘膜是“渗漏的”，这可能使细菌进入组织和血液，导致败血症，并使肠道免疫细胞暴露于微生物和食物抗原，导致炎症持续存在，从而导致肠道损伤。感染艾滋病毒的儿童可能会有更严重的肠病，因为艾滋病毒本身会损害肠黏膜。在儿童病情初步稳定后，目前对急性呼吸道感染的管理侧重于重新喂养和治疗感染。所使用的饲料（RUTF, F100）含有微量营养素，如维生素A和锌，已知对粘膜健康很重要。然而，预计这些饲料不会改善肠道炎症，这可能是许多病例对治疗反应不佳和长期预后不佳的原因。SAM的肠道炎症与食物不耐受和克罗恩病非常相似。与SAM相反，这些疾病的治疗目标是肠道炎症。对于儿童，推荐的治疗方法是广泛水解或单质配方（食物不耐受）或聚合或单质配方（克罗恩病）。这些是促进肠黏膜愈合和营养恢复的完整饲料，没有明显的不良反应。在患有活动性克罗恩病的儿童中，大约60%的人通过这些饲料获得临床缓解，另外30%的人得到改善。这些情况下肠道炎症的相似性提出了一种可能性，即有效减少食物不耐受和克罗恩病肠道炎症的治疗方法也可能对SAM有效。我们的目标是开展一项试点研究，以了解广泛水解，元素和/或聚合物配方是否对患有SAM的儿童耐受，并了解它们是否减轻肠道炎症。如果我们发现其中一种或多种饲料可能有效，则需要在更大的研究中进行评估。如果在更大规模的研究中得到证实，我们的研究结果将确定特异性治疗SAM肠道炎症的必要性。这可以纳入标准的临床管理方案。将鼓励研究人员考虑如何对这些替代性治疗性饲料进行调整，使其在资源匮乏的环境中具有实用性和成本效益，或许可以通过使用当地成分和配方作为膏状在家中使用。此外，探索治疗肠病的潜在替代方法也很重要——可能还包括在社区管理营养不良程度较轻的儿童。

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.