Association between Age, Weight, and Dose and Clinical Response to Probiotics in Children with Acute Gastroenteritis

Abstract

Background: Gastroenteritis is a common and impactful disease in childhood. Probiotics are often used to treat acute gastroenteritis (AGE); however, in a large multicenter randomized controlled trial (RCT) in 971 children, Lactobacillus rhamnosus GG (LGG) was no better than placebo in improving patient outcomes.

Objectives: We sought to determine whether the effect of LGG is associated with age, weight z score and weight percentile adjusted for age and sex, or dose per kilogram administered.

Methods: This was a preplanned secondary analysis of a multicenter double-blind RCT of LGG 1 × 1010 CFU twice daily for 5 d or placebo in children 3-48 mo of age with AGE. Our primary outcome was moderate to severe gastroenteritis. Secondary outcomes included diarrhea and vomiting frequency and duration, chronic diarrhea, and side effects. We used multivariable linear and nonlinear models testing for interaction effects to assess outcomes by age, weight z score and weight percentile adjusted for age and sex, and dose per kilogram of LGG received.

Results: A total of 813 children (84%) were included in the analysis; 413 received placebo and 400 LGG. Baseline characteristics were similar between treatment groups. There were no differential interaction effects across ranges of age (P-interaction = 0.32), adjusted weight z score (P-interaction = 0.43), adjusted weight percentile (P-interaction = 0.45), or dose per kilogram of LGG received (P-interaction = 0.28) for the primary outcome. Whereas we found a statistical association favoring placebo at the extremes of adjusted weight z scores for the number of vomiting episodes (P-interaction = 0.02) and vomiting duration (P-interaction = 0.0475), there were no statistically significant differences in other secondary outcome measures (all P-interactions > 0.05).

Conclusions: LGG does not improve outcomes in children with AGE regardless of the age, adjusted weight z score, and adjusted weight percentile of participants, or the probiotic dose per kilogram received. These results further strengthen the conclusions of low risk of bias clinical trials which demonstrate that LGG provides no clinical benefit in children with AGE.This trial was registered at clinicaltrials.gov as NCT01773967.

Keywords: emergency medicine; gastroenteritis; pediatric; probiotic; randomized controlled trial; secondary analysis.

© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

Participant flow diagram. LGG, Lactobacillus rhamnosus GG.

FIGURE 2

Age, age- and sex-adjusted weight z score, and treatment dose per kilogram had no effect on the outcome at 14-d follow-up. Boxplot graphs of the 14-d MVS score plotted against (A) age, (B) weight z scores adjusted for age and sex, and (C) LGG dose per kilogram (CFU/kg). LGG, n = 400; Placebo, n = 413. LGG, Lactobacillus rhamnosus GG; MVS, Modified Vesikari Scale; +, treatment arm; O, placebo arm.

FIGURE 3

Differential treatment effect of weight and LGG compared with placebo on number of vomiting episodes. A nonlinear relation was identified among weight z scores, treatment, and the number of vomiting episodes. This figure shows the rate-ratio and 95% CI estimated from the best model comparing LGG with placebo across values of weight z scores. The model contained terms for treatment, weight z score, weight z score-squared, and interaction terms between treatment and the age terms along with terms for duration of symptoms, baseline Modified Vesikari Scale score, dehydration score, multiplex PCR (positive compared with negative compared with not tested), season, and enrolling clinical site. LGG, n = 400; Placebo, n = 413. LGG, Lactobacillus rhamnosus GG.