Efficacy and safety of Saccharomyces boulardii in the treatment of acute gastroenteritis in the paediatric population: a systematic review

Figures & data

Table 1: Outcome measures and modifiers/confounders

Outcome measures		Confounders
Primary outcomes	Secondary outcomes
• Duration of diarrhoea in days • Mean number of stools passed per day • Mean number of episodes of diarrhoea at follow up • Frequency of diarrhoea at start, mid-point, end of intervention • Stool frequency • Changes in stool consistency post intervention	• Duration of hospital stay in days	• Active ingredients offered concurrently with the intervention (e.g. antibiotics) • The intervention being offered as part of a cocktail of treatment • Differences in dosages offered and method of administration

Figure 1: PRISMA study flow diagram.

Table 2: Characteristics of included studies

Study / Authors	Methods	Participants (n)	Intervention	Control	Sequence generation	Allocation concealment	Outcomes
Billoo et al. (2006)	RCT; 5-day active treatment phase	100 children; 2 months to 12 years; intervention group (50); control group (50)	Sb, 250 mg twice per day x 5 days, WHO-CDD protocol	WHO-CDD protocol only	Only a comment made that ‘100 children were randomized into two groups’	S. boulardii was dissolved in water or semi-solid food, but the control group received nothing; but should have ideally received a placebo powder	Duration of diarrhoea, mean number of stools per day, number of episodes of diarrhoea, percentage weight gain
Burande (2013)	Prospective, parallel, single-blinded RCT	72 participants; Intervention group (35); Control group (35)	Sb, 250 mg x 2 daily for 5 days, ORS and zinc	ORS and zinc supplement only	Patients were assigned a study number corresponding to their entry in the trial. They were randomised by simple randomisation with the help of computer-generated random numbers	As per the allocation, drugs were prescribed to the patients by the paediatrician. It is not clear if parents were aware of the different treatment groups	Days to recovery from loose motions; days to recovery from vomiting
Corrêa et al. (2011)	Double-blinded, placebo-controlled, parallel-group RCT	186 participants; 6–48 months; intervention (90); control (86)	Sb, 200 mg x 2 daily for 5 days	Placebo offered x 2 daily for 5 days	No information on the randomisation of participants into 2 groups	The capsules were randomly coded by computer-generated numbers and distributed to the attending staff	Clinical cure of diarrhoea; frequency of diarrhoea during the first 3 days after start of intervention; frequency of diarrhoea 3 days after start of intervention for patients presenting/not presenting with rotavirus
Dalgic et al. (2011)	Prospective, single-blinded RCT	480 participants; 1–28 months; 8 groups consisting of 60 participants each	• Group 1 (Sb, 250 mg/d x 5 days); • Group 2 (zinc acetate x 20 mg/dx5); • Group 3 (lactose-free formula offered as required); • Group 4 (Sb, 250 mg/d+zinc acetate x 20 mg/d) x 5 days; • Group 5 (Sb, 250 mg/d+lactose-free formula as required) x 5 days; • Group 6 (zinc acetate 20 mg/d+lactose-free formula) x 5 days; • Group 7 (Sb x 250 mg/d+lactose-free formula+zinc acetate x 20 mg/d) x 5 days;  Group 8 (only oral and/or parenteral rehydration solutions)		The patients were randomly assigned from a computerised admissions list to one of the eight different treatment groups described	No information about allocation concealment from participants, caregivers and researchers was achieved	Duration of diarrhoea; duration of hospitalisation; time to resolution of vomiting; Time to resolution of fever
Erdogan et al. (2012)	Prospective RCT	75 participants; 5 months to 5 years; intervention 1 (25); intervention 2 (25); control (5)	• Group 1 (ORS, normal diet, 282.5 mg/d Sb); • Group 2 (ORS, normal diet, 30 mg/d Bifidus.lactis	Group 3 (ORS, rapid refeeding with a normal diet)	A comment with no supporting details was made that participants were divided into 3 groups of 25	No details given on attempts made to conceal allocation. Control group was not offered a placebo and therefore no blinding	Duration time of diarrhoea; vomiting episodes at follow up
Eren et al. (2010)	Randomised, prospective open-label study	55 participants; children aged 5 months to 16 years; intervention 1 (28); intervention 2 (27)	• Group 1 (Sb, 250 mg x 2 daily if >/= 2 years or 125 mg x 2 daily if < 2 years); • Group 2 (Yoghurt fluid containing Lactobacillus bulgaricus and S. thermophiles, 10^7 microorganisms/100 ml; 30 ml x 2 daily if >/= 2 years or 15 ml x 2 daily if < 2 years)		Patients were randomided according to their patient ID number and enrolled in 2 groups. Patients with an odd ID number composed group A and those with an even ID number composed group B	The two interventions differed visibly	Duration of diarrhoea; resolution of diarrhoea at days 3 and 5; days of hospitalisation; duration of vomiting; cost-effectiveness of both interventions
Htwe et al. (2008)	Prospective RCT	100 participants; children aged 3 months to 10 years; intervention (50); control (50)	Group 2 (Sb 250 mg x 2 daily, standard ORS to manage watery AGE, as per WHO guidelines x 5 days)	Group 1 (standard ORS to manage watery AGE, as per WHO guidelines x 5 days)	Patients were alternately assigned to treatment groups	No details given regarding allocation concealment	Duration of diarrhoea; stool frequency per day
Kurugol et al. (2005)	RCT, placebo-controlled	200 participants; aged 3 months to 7 years; intervention (100); control (100)	Group 1 (Sb, 250 mg per day x 5 days)	Group 2 (identical looking placebo diluted in water or juice x 5 days)	A general statement that patients were randomly allocated to treatment groups was made but no further information on how this was done is provided	No information given about allocation concealment	Duration of diarrhoea; duration of watery diarrhoea; duration of fever; duration of vomiting; length of hospital stay
Ozkan et al. (2007)	Double-blinded, placebo-controlled RCT	27 participants; aged 6 months to 10 years; intervention (16); control (11)	Group 1 (Sb 250 mg x 2 daily x 7 days)	Group 2 (identical placebo x 2 daily x 7 days)	A general statement was made that patients were randomly allocated to one of two treatment groups, but no further details on how this was done is described	No details on how allocation concealment was guaranteed are provided	Daily stool frequency
Riaz et al. (2012)	Double-blinded RCT	108 participants; aged 3 months to 59 months; intervention (54); control (54)	Group 1 (Sb mixed with puffed rice powder, 250 mg x 2 daily x 5 days)	Group 2 (placebo mixed with puffed rice powder, 2 daily x 5 days)	A general comment with no further detail is given stating that after informed consent was obtained, the participants were randomly given either a placebo or intervention	A non-departmental colleague not involved in the study randomised these identical packets of placebo or S. boulardii	Duration of post-intervention diarrhoea (time form enrolment to recovery); frequency of stools; time of first semi-formed stool

Notes: RCT: randomized controlled trial; Sb: Saccharomyces boulardii; WHO-CDD: World Health Organization Diarrheal Disease Control Programme; ORS: oral rehydration solution; S. thermophiles: Streptococcus thermophiles; AGE: acute gastroenteritis; WHO: World Health Organization.

Figure 2: Methodological quality graph: judgements on each methodological quality item presented as percentages for all included studies (n = 10).

Table 3: Summary of findings table using GRADE: Saccharomyces boulardii compared with control or placebo for AGE

Outcomes	Illustrative comparative risks * (95% CI)		Relative effect	No. of participants	Quality of the evidence	Comments
			(95% CI)	(studies)	(GRADE)
	Assumed risk	Corresponding risk
	(Control or Placebo)	(Saccharomyces boulardii)
Duration of diarrhoea:		The mean duration of diarrhoea in the intervention groups was		548	⊕⊕⊕⊝
				(5 studies)	moderate^1 ^, ^2
measured in days		0.57 lower
Follow-up: mean 5–7 days		(0.83 to 0.3 lower)
Mean number of stools per day:		The mean number of stools per day in the intervention groups was		133	⊕⊕⊝⊝
				(1 study)	low^3
number of stools per day
		0.97 lower
Follow-up: mean 7 days		(1.56 to 0.39 lower)
Frequency of diarrhoea	Study population		RR 0.66	528	⊕⊕⊕⊕
Evacuation frequency was < 3	775 per 1 000	512 per 1 000	(0.35 to 1.23)	(1 study)	high^4 ^, ^5 ^, ^6
times per day		(271 to 953)
	Moderate
Follow-up: mean 5 days	802 per 1 0	529 per 1 000
	00	(281 to 986)
Number having < 3 stools per day	Study population		RR 1.13	700	⊕⊕⊕⊝
	657 per 1 000	743 per 1 000	(0.97 to 1.31)	(1 study)	moderate^7 ^, ^8
stools passed
		(637 to 861)
	Moderate
Follow-up: mean 7 days	780 per 1 000	881 per 1 000
		(757 to 1000)
Duration of hospital stay (days)		The mean duration of hospital stay (days) in the intervention groups was		320	⊕⊕⊝⊝
				(2 studies)	low^9 ^, ^10 ^, ^11
		0.12 lower
		(1.9 lower to 1.65 higher)

Notes: Patient or population: patients with AGE.

Settings: in paediatric, hospitalised patients.

Intervention: Saccharomyces boulardii.

Comparison: control or placebo.

* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes.

The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence:

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

¹ Selection bias (Kurugol 2005, Erdogan 2012, Burande 2013, Dalgic 2011); reporting bias (Kurugol 2005, Erdogan 2012); blinding (Erdogan 2012, Burande 2013, Dalgic 2011); other bias (Dalgic 2011, Riaz 2013).

² No downgrading for inconsistency as: four of five studies have CIs that overlap meaning that any variation in the size of effect is more likely a result of chance; I2 value of 0% indicating no heterogeneity; non-significant p-value.

³ Downgrading for inconsistency as only Day 0 out of 5 days intercepted the line of no effect meaning that any variation in the size of effect is not due to chance; I2 value is very high 95.3% indicating heterogeneity; very low p-value (< 0.00001).

⁴ Downgrading for inconsistency as the forest plot for this outcome shows that of each of the three days of assessment, only results for Day 1 overlap with the line of no effect; the overall test for heterogeneity showed a high I2 of 96% and a very low p-value (< 0.00001).

⁵ No downgrading as this outcome shows a wide CI with the effect on the side favouring benefit, a large number of events (148+200) and a large sample size (270+258).

⁶ Corrêa 2011: An RR of 0.66 indicating that the Saccharomyces boulardii group was 34% more likely to experience fewer stools per day versus the control group.

⁷ Htwe 2008: not all CIs overlap the line of no effect; I2 value quite high at 95% and accompanied by a very low p-value (< 0.00001).

⁸ Htwe 2008: Overall, this analysis showed a RR (1.13) indicating that the Saccharomyces boulardii group was 1.13 times more likely to experience < 3 stools per day quicker than the control group.

⁹ Only Dalgic 2011 and Kurugol 2005 assessed impact of Saccharomyces boulardii on length of hospital stay.

¹⁰ Dalgic 2011: selection bias was unclear as no information was given on how allocation concealment was achieved. Reporting bias as no mention is made regarding the training of parents for reporting of symptoms like ‘appearance of stools’, ‘watery GE’, ‘GE’. Other bias: 480 participants were recruited and all 480 were reported to have completed the study, with no withdrawals, exclusions or loss to follow-up?

¹¹ Downgrading for inconsistency as neither study truly overlaps with the line of no effect meaning that any variation in the size of effect is not due to chance; I2 value is very high 95% indicating heterogeneity; very low p-value (< 0.0001).

Figure 3: Forest plot of trials comparing Saccharomyces boulardii versus control in children with gastroenteritis: difference in duration of diarrhoea (in days).

Figure 4: Forest plot: duration of hospital stay (in days, Saccharomyces boulardii versus control).