Introduction

In developing countries, acute gastroenteritis is a leading cause of death in children < 5 years of age. Moreover, acute gastroenteritis results in a high rate of hospitalization. According to the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, 2014 guidelines, acute gastroenteritis in children can be managed by using probiotics such as Lactobacillus rhamnosus GG and Saccharomyces boulardii.

Aim

To review randomized controlled trials (RCT) assessing the effectiveness of L rhamnosus GG in treating acute gastroenteritis in children

Methods

Study Design

• A systematic review of Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE, and EMBASE databases from May 2013 (end of last search) to January 2019

Primary Outcome

• Stool volume and duration of diarrhea
• Subgroup analyses based on factors that could potentially influence the magnitude of the treatment response were planned for the following:

(a) Dose of L rhamnosus GG (high dose [≥1010 CFU/day] vs lower dose [<1010CFU/day]);

(b) Setting (studies carried out in geographical Europe vs non?European countries);

(c) Type of treatment (outpatient vs inpatient);

(d) Aetiology of diarrhoea

Results

• The meta-analysis included 18 randomized control trials which enrolled 4208 participants (2201 in the experimental group and 2007 in the control group) who ranged in age from 1 month to 7 years.
• The daily doses of L rhamnosus GG ranged from 1.2 x 10⁸ CFU to 2 x 10¹² CFU.

Primary outcome

Effect on Duration of Diarrhoea

• Reduction in the duration of diarrhoea was seen for those treated with L rhamnosus GG compared with placebo or no treatment (meta-analysis of 15 RCTs, MD −0.85 days, 95% CI −1.15 to −0.56) (Figure 1).
• Children presenting with >2 days of diarrhoea, the L rhamnosus GG group returned to normal stool earlier (51 hours [32?78] vs 74 hours [45?120], respectively, P = 0.02).

Effect on Stool Volume

• Compared with controls, L rhamnosus GG had no effect on the total stool volume (2 RCTs, n = 303)

Subgroup analysis

Effect based on Dose

• L rhamnosus GG was effective when used at a daily dose ≥10¹⁰ CFU (meta-analysis of 11 RCTs, n = 2764, MD −0.83, 95% CI −1.17 to −0.49) and <10¹⁰ CFU (meta-analysis of 4 RCTs, n = 1056, MD −0.92, 95% CI −1.83 to −0.02); however, the latter dose produced results of borderline significance.

Effect based on Setting

• Reduction in the duration of diarrhoea was noted in children treated both in Europe (meta-analysis of 6 RCTs, n = 844, MD −1.22 d, 95% CI −1.73, −0.71) and in non?European settings (meta-analysis of 9 RCTs, n = 2976; MD −0.61 days, 95% CI −0.98, −0.25); however, the latter effect was smaller.

Inpatient vs Outpatient

• Reduction in the duration of diarrhoea in both in inpatients (8 RCTs, n = 1868, MD −0.66 days, 95% CI −1.27 to −0.05) and outpatients (meta-analysis of 4 RCTs, n = 1368, MD −0.95, 95% CI −1.72 to −0.17) was observed.

Etiology

• L rhamnosus GG was effective in treating diarrhoea due to rotavirus (5 RCTs, n = 324; MD −1.38, 95% CI −2.14 to −0.63) and of unknown cause (meta-analysis of 3 RCTs, n = 253; MD −1.10, 95% CI −1.87 to −0.33).

Duration of Hospitalization

• Reduction in the duration of hospitalization was observed for those treated with L rhamnosus GG compared with the control group (meta-analysis of 5 RCTs, MD −1.22 days, 95% CI −2.33 to −0.10)

Discussion

• The study demonstrated that compared to placebo or no treatment, addition of L rhamnosus GG to standard rehydration therapy was associated with a reduced duration of diarrhoea by approximately 20 hours.
• It was also observed that patients treated with daily high dose of L rhamnosus GG (≥10¹⁰ CFU/day) were likely to benefit more, however, the effect was also evident when L rhamnosus GG at a daily dose of <10¹⁰ CFU/day was used.
• In hospitalized patients, L rhamnosus GG use reduced the duration of hospitalization by approximately 29 hours.
• Evidence also suggests that L rhamnosus GG is more effective in treating diarrhea due to rotavirus.
• Subgroup analyses were conducted to investigate whether factors such as dose, geographical location, in/outpatient settings, or aetiology modify the treatment effect. Some revealed a significant subgroup effect (P < 0.1 indicating a statistically significant subgroup effect), while in others there was high heterogeneity between group and/or the small number of trials and participants.
• The exact mechanisms by which L rhamnosus GG might exert its actions are unclear. However, the possible mechanisms may include:
  • interference with pathogen attachment,
  • interaction with normal microbiota, and
  • stimulation or modulation of immune responses, both within the lumen and systemically.
• It was observed that adverse events were similar in both study groups.
• The findings from 2013 meta-analysis of RCTs demonstrated that administration of L rhamnosus GG during acute gastroenteritis, at a dose of ≥10¹⁰ colony-forming units (CFU)/day, reduced the duration of diarrhoea in all patients (ambulatory and hospitalized).
• The current meta-analysis confirms the results of 2013 meta-analysis, providing answer to the question as to whether current evidence on L rhamnosus GG should change clinical practice.

Conclusion

• These findings imply that, irrespective of recent RCT demonstrating no effect of L rhamnosus GG in acute gastritis, the current systematic review showed that L rhamnosus GG reduced the duration of diarrhoea and hospitalization in inpatients.
• These findings should be viewed in the context of the high heterogeneity and methodological limitations of the included trials.

Reference

Szajewska H, Ko?odziej M, Gieruszczak-Bia?ek D, Sk?rka A, Ruszczy?ski M, Shamir R. Systematic Review With Meta-Analysis: Lactobacillus Rhamnosus GG for Treating Acute Gastroenteritis in Children - A 2019 Update. Aliment Pharmacol Ther. 2019 Jun;49(11):1376-1384.