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.

Public Health Relevance

Gastroenteritis, or intestinal infection, which usually manifests as vomiting and diarrhea, is one of the most common illnesses of childhood. It causes over 1.7 million deaths per year worldwide. In the United States, it is rarely fatal, however it results in .4 million doctor visits and 128,000 hospitalizations per year and constitutes a significant burden for patients, their families and society. Currently, available treatments for this condition are aimed only at the symptoms and complications (e.g. dehydration) and not at modifying the disease process. We propose to study the effectiveness and side effects of a probiotic, LGG, in treating children with gastroenteritis. If successful, this therapeutic intervention would be the frst treatment that actually changes the disease process and would represent an enormous public health advance both in the US, and potentially, globally.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Study Section
Biobehavioral and Behavioral Sciences Subcommittee (CHHD)
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Grave, Gilman D
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Washington University
Schools of Medicine
Saint Louis
United States
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Schnadower, David; Tarr, Phillip I; Casper, T Charles et al. (2018) Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. N Engl J Med 379:2002-2014
Schnadower, David; Tarr, Phillip I; Casper, T Charles et al. (2017) Randomised controlled trial of Lactobacillus rhamnosus (LGG) versus placebo in children presenting to the emergency department with acute gastroenteritis: the PECARN probiotic study protocol. BMJ Open 7:e018115
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