Impact of Emergency Department Probiotic Treatment of Pediatric Gastroenteritis

描述（由申请人提供）：急性胃肠炎（AGE）是全球营养不良和死亡的主要原因。在美国，每年有近4800万人感染AGE， 12.8万人住院。年龄的发作可导致儿童及其家庭的严重发病率。此外，护理人员、卫生保健系统和社会的成本也很大。目前，治疗选择是有限的，并且针对症状管理而不是疾病改变。益生菌是一种活的微生物培养物，当摄入足够的量时，可以带来有记载的健康益处，可能是一种理想的解决方案。假设它们通过直接微生物和免疫机制的结合起作用。益生菌在发展中国家住院儿童的早期临床研究中显示出前景。这些早期的努力受到样本小、结果与门诊患者缺乏相关性、方法差和缺乏副作用报告的限制；因此，益生菌的潜在作用仍然不明确，实践指南不支持它们的使用。然而，目前的趋势要求对这些药物进行紧急评估。首先，益生菌制造商已经开始采取激进的公共营销策略，其健康声明可能没有严格的研究支持，并且益生菌产品的全球市场正在稳步增长（预计2009-2014年增长12.6%，总额为326亿美元/年）。其次，政府机构（美国食品药品监督管理局和欧洲食品安全局）仍然关注它们的价值和安全性。第三，一些机构现在基于可能存在缺陷或有限的证据推荐使用益生菌。第四，老年患者的父母经常在没有医疗专业人员指导的情况下给孩子用药。因此，我们担心益生菌的消费量在没有确凿证据支持其使用的情况下不断增加，这强调了立即进行明确试验的必要性。目的-这项多国随机临床试验的总体目标是确定一种特定的益生菌制剂，鼠李糖乳杆菌GG(LGG)，美国最广泛使用，研究和监管的益生菌，是否应该常规用于门诊患有AGE的儿童。本提案的具体目的是：(1)确定LGG的临床有效性；(2)确定LGG在急诊科（ED）患有age的3-48月龄儿童中的安全性和副作用。研究设置与设计-本研究将在联邦资助的儿科急诊应用研究网络（PECARN）内的8个美国儿科急诊科进行。我们将随机选择900名儿童接受5天的益生菌制剂（LGG 1 x 1010 CFU，每天两次）或安慰剂。主要结果是根据修订的Vesikari评分（一种经过验证的临床严重程度评分）定义的中重度疾病的发生情况，该评分包括腹泻的频率和持续时间、呕吐的频率和持续时间、发烧的高度、未来就诊的需要以及提供的医疗干预措施。我们还将评估与使用LGG相关的不良事件和副作用的发生情况。我们将收集粪便样本进行行动机制研究，并收集经济数据进行成本效益分析。影响-本研究将通过提供第一个明确的证据来支持或反对在儿童AGE治疗中常规使用益生菌的建议，从而直接告知临床实践。此外，它将为卫生保健从业人员和政策制定者提供(a)关于使用益生菌潜在副作用的清晰图景，以及收集到的数据(b)关于作用机制的知识和(c)益生菌使用对卫生保健系统和社会的潜在经济影响。因此，拟议研究的潜在临床和社会影响是巨大的，其结果将指导护理标准：如果是积极的，指南将能够支持益生菌管理，每年对数百万美国儿童的健康产生重要的积极影响。此外，如果有益，对卫生保健系统和社会的成本节约可能是巨大的。如果结果是否定的，一个坚定的建议反对常规使用益生菌将是合理的。合作者-这项工作是在联邦资助的多中心网络（PECARN）内著名儿童医院的多中心和AGE研究领导者（Schnadower, Freedman, Tarr, Gorelick, Mahajan, Stanley, Roskind, Powell， O' connell, Ruddy Chun， Levine和Casper）之间的合作，在进行高质量，高影响的临床试验方面有着良好的记录。

DESCRIPTION (provided by applicant): Acute gastroenteritis (AGE) is a leading cause of malnutrition and death worldwide. In the US, close to 48 million people contract AGE and 128,000 are hospitalized each year . Episodes of AGE can result in substantial morbidity to children and their families. In addition, the costs to caregivers, the health-care system, and society are significant. At present, treatment options are limited and targeted at symptom management rather than disease modification. Probiotics - live microbial cultures which, when consumed in adequate amounts, confer documented health benefits - may be an ideal solution. They are hypothesized to work via a combination of direct microbiologic and immunologic mechanisms. Probiotics have shown promise in early clinical research in hospitalized children in developing countries. These early efforts are limited by small samples, outcomes lacking relevance to outpatients, poor methodology and absence of side effect reporting; thus, the potential role of probiotics remains poorly defined and practice guidelines do not endorse their use. There are current trends, however, that obligate an urgent assessment of these agents. First, probiotic manufacturers have embarked in aggressive public marketing strategies that make health claims that may not be supported by rigorous research, and the world-wide market for probiotic products is growing steadily (projected growth 2009-2014 12.6% for a total of US $32.6 billion/year). Second, government agencies (US FDA and European Food safety Authority (EFSA)) remain concerned about their value and safety. Third, some institutions are now recommending the use of probiotics based on potentially flawed or limited evidence. Fourth, parents of patients with AGE are often medicating their children without guidance from medical professionals. We are therefore concerned that probiotic consumption is increasing without solid evidence to support its use, which underscores the necessity to conduct a definitive trial without delay. Objectives - The overall objective of this multi-national randomized clinical trial is to determine if a specific probiotic agent, Lactobacillus rhamnosus GG(LGG), the most widely available, studied and regulated probiotic in the US, should routinely be administered to outpatient children who are suffering from AGE. The specific aims of this proposal are: (1) to determine the clinical effectiveness of LGG and (2) to determine the safety and side effect profile of LGG in children 3-48 months of age presenting to the Emergency Department (ED) with AGE. Study Setting & Design - The study will be conducted in 8 US pediatric emergency departments within the federally funded Pediatric Emergency Care Applied Research Network (PECARN). We will randomize 900 children to receive 5 days of a probiotic agent (LGG 1 x 1010 CFU twice a day) or placebo. The main outcome is the occurrence of moderate-severe disease as defined by the Modified Vesikari Score, a validated clinical severity score, which incorporates the frequency and duration of diarrhea, frequency and duration of vomiting, height of fever, need for future health-care visits and medical interventions provided. We will also assess the occurrence of adverse events and side effects related to the use of LGG. We will collect stool samples to conduct mechanism of action studies as well as economic data to conduct cost effectiveness analyses in the future. Impact - This study will directly inform clinica practice by providing the first definitive evidence to support recommendations for or against the routine use of probiotics in the treatment of pediatric AGE. In addition it will provide health-car practitioners and policy makers with (a) a clear picture on the potential side effects from probiotic use, and with the data collected (b) knowledge on the mechanism of action and (c) of the potential economic impact of probiotic use on health-care systems and society. Thus, the potential clinical and societal impacts of the proposed study are substantial and the results will guide the standard of care: if positive, guidelines will be able to endorse probiotic administratio with important positive consequences for the health of several million US children annually. Moreover, if beneficial the cost savings to the health-care system and society may be substantial. If the results are negative, a firm recommendation against the routine use of probiotics would be justified. Collaborators - This work is collaboration between leaders in multicenter and AGE research (Schnadower, Freedman, Tarr, Gorelick, Mahajan, Stanley, Roskind, Powell, O'Connel, Ruddy Chun, Levine and Casper) in prestigious Children's Hospitals within a federally funded multicenter network (PECARN) with a strong record in conducting high quality, high impact clinical trials.