The probiotic Lactobacillus rhamnosus proved no more effective than placebo for treating young children with acute infectious gastroenteritis in two randomized double-blind controlled trials.

Both studies were published online in the New England Journal of Medicine.

In one trial, Stephen B. Freedman, MD, of the University of Calgary in Alberta, and colleagues from the Pediatric Emergency Research Canada Probiotic Regimen for Outpatient Gastroenteritis Utility of Treatment Trial Group, enrolled 886 children ages 3 months to 4 years presenting with a 72-hour history of gastroenteritis symptoms to the emergency departments of six pediatric centers in Canada.

This study, whose results were first presented as an abstract at the 2018 Pediatric Academic Societies (PAS) annual meeting, found that a twice-daily, 5-day course of 4.0 x 109 colony-forming units of a combination of L. rhamnosus and Lactobacillus helveticus failed to prevent the development of moderate-to-severe symptoms as defined by the modified Vesikari scale of symptoms of 9 or more (out of 0 to 20) within 14 days of enrollment any better than placebo.

In those who competed the trial, moderate-to-severe gastroenteritis occurred in 108 of 414 (26.1%) in the probiotic group and 102 of 413 (24.7%) in the placebo arm (odds ratio 1.06, 95% confidence interval 0.77-1.46, P= 0.72). After adjustment for trial site, age, detection of rotavirus in stool, and frequency of diarrhea and vomiting before enrollment, trial-group assignment did not predict moderate-to-severe gastroenteritis (OR 1.06, 95% CI 0.76-t1.49, P = 0.74).

Acute gastroenteritis accounts for about 1.7 million emergency department visits by U.S. children annually, Freedman and co-authors noted.

In other findings from their study, there were no significant inter-arm differences in the median duration of diarrhea of 52.5 hours (interquartile range [IQR] 18.3-95.8) and 55.5 hours (IQR 20.2-102.3, P=0.31), respectively. Duration of vomiting in the two arms was also similar: 17.7 hours (IQR 0-58.6) and 18.7 hours (IQR 0-51.6, P=0.18), respectively.

The percentage of participants having unscheduled visits to a healthcare provider was also comparable in the probiotic and placebo arms: 30.2% and 26.6% (OR 1.19, 95% CI 0.87-1.62, P=0.27), as was the proportion reporting an adverse event (34.8% and 38.7% (OR 0.83, 95% CI 0.62-1.11, P=0.2).

The authors noted several study limitations, including possible recall bias, as well as the potential for inconsistent and selective reporting and post-hoc modifications with the use of composite outcome measures. In addition, results with the specific probiotic used may not be generalizable to other products on the market, and benefit may occur in other populations or for different indications.

Finally, since the study was done in Canadian centers, the local host microbiomes and pathogens may have played a role in the results, and the findings cannot be extrapolated to longer-term use or other outcomes such as stunting in regions where infections are more common.

Same Results for Slightly Different Form of L. Rhamnosus

The second randomized double-blind study, whose results were also first presented at the 2018 PAS meeting, found similarly negative results with a slightly different formulation of L. rhamnosus. Again, the probiotic did not result in fewer patients having moderate-to-severe gastroenteritis and showed no benefit in duration or frequency of vomiting or diarrhea, rate of household transmission, or duration of daycare or work absenteeism.

David Schnadower, MD, MPH, of Cincinnati Children's Hospital Medical Center, and colleagues in the Pediatric Emergency Care Applied Research Network investigated 971 children, also ages 3 months to 4 years, presenting with acute gastroenteritis across 10 U.S. pediatric emergency departments.

The racially and ethnically diverse participants, enrolled during 2014-2017, were randomized to a similar 5-day course of L. rhamnosus GG (minus the L. helveticus) at a dose of 1 x 1010 colony-forming units twice daily or matching placebo. Once again, the primary outcome was moderate-to-severe gastroenteritis, defined as an illness episode with a total score on the modified Vesikari scale of 9 or higher within 14 days of enrollment.

Among the 943 participants (97.1%) completing the trial, the median age was 1.4 years (IQR 0.9- 2.3), and 513 (52.9%) were male. The Vesikari score for the 14-day period after enrollment reached 9 or higher in 55 of 468 participants (11.8%) in the probiotic arm and in 60 of 475 participants (12.6%) in the placebo group, for a relative risk of 0.96 (95% CI 0.68-1.35, P=0.83).

The two groups were comparable in the duration of diarrhea (median 49.7 and 50.9 hours, P=0.26); vomiting (median 0 hours in both groups, P=0.17); and daycare absenteeism (median 2 days in both, P = 0.67). Neither were there differences in the household transmission rate: 10.6% and 14.1%, respectively (P=0.16).

Study limitations, Schnadower and co-authors noted, included that data not collected on children were missed because they presented after hours or on children whose caregivers declined to participate. The study also relied on parental reports of adherence and symptoms, raising the possibility of inaccurate recall bias. In addition, families may have sought subsequent care elsewhere than at the participating sites and although caregivers were instructed to keep the trial medication refrigerated, it could have been exposed to temperature extremes in the home or during transport, which could have affected bacterial viability.

"Taken together, neither of these large, well-done trials provides support for the use of probiotics containing L. rhamnosus to treat moderate-to-severe gastroenteritis in children," wrote J. Thomas Lamont, MD, of Beth Israel Deaconess Medical Center in Boston, in an accompanying commentary about the two studies. "These negative trial data will be valuable to clinicians and professional bodies in making decisions regarding the use of either of these probiotic formulations in children with diarrhea."

Lamont acknowledged, however, that considering the large number of probiotics and their varying properties and mechanisms of action, probiotics other than L. rhamnosus might be effective for infectious diarrhea in children. For example, he pointed to a recent large, placebo-controlled trial in rural India in which prophylaxis with a symbiotic formula containing L. plantarum given to healthy newborns in the first 5 days after birth significantly reduced the rate of sepsis and lower respiratory tract infections in the first 2 months of life.