Association Between Diarrhea Duration and Severity and Probiotic Efficacy in Children With Acute Gastroenteritis

Background: Despite the popular belief that probiotics are most efficacious when treating acute childhood diarrhea if started early and when symptoms are more severe, the data supporting these assumptions are unclear.  We sought to evaluate whether the efficacy of probiotics depends on the duration and severity of diarrhea prior to treatment. Methods: This was a pre-planned secondary analysis of two randomized placebo-controlled trials in children 3-48 months of age with acute gastroenteritis, conducted in sixteen emergency departments in North America evaluating the efficacy of two probiotic products. Participants were categorized in severity groups according to the duration (< 24h, 24 – < 72h, and ≥ 72h) and the frequency of diarrhea episodes in the 24 hours (≤ 3, 4 – 5 and ≥ 6) prior to presentation. We used regression models to assess the interaction between pre-treatment diarrhea severity groups and treatment arm (probiotic or placebo) on the presence of moderate-to-severe gastroenteritis defined by a Modified Vesikari Scale score ≥9. Secondary outcomes included diarrhea frequency and duration, unscheduled healthcare provider visits and hospitalization. Findings: 1,770 children were included, 882 (50%) received a probiotic. The development of moderate-to-severe gastroenteritis symptoms following the initiation of treatment did not differ between groups [probiotic - 18.4% (162/882) vs. placebo - 18.3% (162/888); RR 1.00; 95%CI: 0.87, 1.16; P=0.95]. There was no evidence of interaction between baseline severity and treatment (P=0.61) for the primary or any of the secondary outcomes: diarrhea duration (P=0.88), maximum diarrheal episodes in a 24 hour period (P=0.87), unscheduled health care visits (P=0.21) and hospitalization (P=0.87). Interpretation: In children 3 to 48 months with acute gastroenteritis the lack of effect of probiotics is not explained by the duration of symptoms or frequency of diarrheal episodes prior to presentation. Trial Registration: Clinicaltrials.gov # NCT01773967 and # NCT01853124. Funding Statement: This work is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD071915) and by the Canadian Institutes of Health Research (grants 286384 and 325412). Declaration of Interests: Dr. David Schnadower received in-kind study drug and placebo from iHeath Inc., however the company did not contribute financially to the study or to the investigators, and their employees do not have access study data. I-Health personnel had no role in study design, collection management, analysis and interpretation of data; nor did they have any role or authority in writing the report nor the decision to submit the trial for publication. Dr. Stephen Freedman has received in-kind (study drug and placebo) from Lallemand Health Solutions. He provides consulting services to Takeda Pharmaceutical Company, RedHill Biopharma Ltd and Eligo Bioscience S.A.S. on childhood intestinal disorders and is supported by the Alberta Children’s Hospital Foundation Professorship in Child Health and Wellness. All other authors report no relevant conflicts. Ethics Approval Statement: The studies were approved by all local Institutional Review Boards. Written informed consent was obtained from the legal guardians of all participants.