CLINICAL GUIDELINES: NUTRITION

Use of Probiotics for the Management of Acute

Gastroenteritis in Children: An Update

Hania Szajewska, yAlfredo Guarino, zIva Hojsak, §Flavia Indrio, zSanja Kolacek, jjRok Orel,
ô
Silvia Salvatore, #Raanan Shamir, Johannes B. van Goudoever, yyYvan Vandenplas, zz
Zvi Weizman, and Bartłomiej M. Zalewski, on behalf of the Working Group on
Probiotics and Prebiotics of the European Society for Paediatric Gastroenterology,
Hepatology and Nutrition

See ‘‘Evidence-based Usage of Probiotics for Pediatric Acute What Is Known

Gastroenteritis’’ by Merenstein on page 146.
 Acute gastroenteritis has a high prevalence
in children.
Downloaded from http://journals.lww.com/jpgn by BhDMf5ePHKbH4TTImqenVAPwFBsBoeDVFNdnOa/9xnCXpiB67bjyfG6v5VbH/gpy on 07/25/2020

ABSTRACT
 Oral rehydration is the key treatment and should be
Since the publication of the 2014 European Society for Paediatric Gastro- applied as soon as possible.
enterology, Hepatology, and Nutrition Working Group (WG) on Probiotics  Many guidelines recommend the use of probiotics
and Prebiotics guidelines for the management of acute gastroenteritis with documented efficacy in the management of
(AGE), new evidence concerning the efficacy of probiotics has become acute gastroenteritis.
available. This document provides updated recommendations on the use of  Recent evidence has questioned the efficacy and
probiotics for the treatment of AGE in previously presumed healthy infants safety of probiotics.
and children. A systematic literature search was performed. All pooled
analyses were explicitly performed for the current report. The WG graded What Is New
the recommendations and assessed the certainty of the supporting evidence
using the Grading of Recommendations, Assessment Development, and  These updated recommendations replace the 2014
Evaluations tool. The recommendations were formulated if at least 2 European Society for Paediatric Gastroenterology,
randomized controlled trials that used a given probiotic were available. Hepatology, and Nutrition document.
Despite the large number of identified trials, the WG could not identify 2  Despite the large number of identified trials, we could
randomized controlled trial of high quality for any strain that provided not identify 2 randomized controlled trials of high
benefit when used for treating AGE. The WG made weak recommendations quality for any strain that provided benefit when used
for (in descending order in terms of the number of trials evaluating any given for treating acute gastroenteritis.
strain): Saccharomyces boulardii (low to very low certainty of evidence);  Weak recommendations for some new specific strains
Lactobacillus rhamnosus GG (very low certainty of evidence); L reuteri are made, whereas the use of other (combinations of)
DSM 17938 (low to very low certainty of evidence); and L rhamnosus strains is discouraged.
19070-2 and L reuteri DSM 12246 (very low certainty of evidence). The WG
made a strong recommendation against L helveticus R0052 and L rhamnosus
R0011 (moderate certainty of evidence) and a weak recommendation against
Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of
evidence).
Key Words: children, diarrhea, guideline, infants, microbiota, probiotics
I n 2014, the Working Group (WG) on Probiotics and Prebiotics of
the European Society for Paediatric Gastroenterology, Hepatol-
ogy, and Nutrition (ESPGHAN) published its guidelines for the
management of acute gastroenteritis (AGE) in children. The guide-
(JPGN 2020;71: 261–269) lines concluded that the use of the following probiotics may be

Received March 21, 2020; accepted April 4, 2020.

From the Department of Paediatrics, The Medical University of Warsaw, and the #Institute for Gastroenterology, Nutrition and Liver Diseases,
Warsaw, Poland, the yDepartment of Translational Medical Science, Schneider Children’s Medical Center, Sackler Faculty of Medicine, Tel
Section of Paediatrics, University Federico II, Naples, Italy, zChildren’s Aviv University, Tel Aviv, Israel, Amsterdam UMC, University of
Hospital Zagreb, University of Zagreb School of Medicine, University Amsterdam and Vrije Universiteit Amsterdam, Emma Children’s Hospi-
J.J. Strossmayer School of Medicine, Osijek, Croatia, the §Department of tal, Paediatrics, Amsterdam, The Netherlands,yyKidZ Health Castle, UZ
Paediatric Gastroenterology, Ospedale Pediatrico Giovanni XXIII, Uni- Brussel, Vrije Universiteit Brussel, Brussels, Belgium, and the zzFaculty
versity of Bari, Bari, Italy, the jjDepartment of Gastroenterology, Hepa- of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
tology and Nutrition, University Medical Centre Ljubljana, University Address correspondence and reprint requests to Hania Szajewska, MD,
Children’s Hospital Ljubljana, Ljubljana, Slovenia, the ôDepartment of Department of Paediatrics, The Medical University of Warsaw, Żwirki
Pediatrics, ‘‘F. Del Ponte’’ Hospital, University of Insubria, Varese, Italy, i Wigury 63A, 02-091 Warsaw, Poland (e-mail: [email protected]).

JPGN  Volume 71, Number 2, August 2020 261

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Szajewska et al JPGN  Volume 71, Number 2, August 2020

considered in the management of children with AGE, in addition to the WG, however, decided to focus on outcomes for therapeutic
rehydration therapy: Lactobacillus rhamnosus GG (LGG) (low studies suggested in the literature (6).
quality of evidence, strong recommendation) and Saccharomyces The WG decided to evaluate strain(s) only, rather than brand
boulardii (low quality of evidence, strong recommendation). or trade names, because the same brands may change composition
Less compelling evidence was available for L reuteri DSM and/or manufacturing practices over time and may have a different
17938 (very low quality of evidence, weak recommendation). composition in different locations. Even when avoiding brand
Other strains or combinations of strains were evaluated, but names, the WG is aware that different manufacturers may supply
evidence on their efficacy was weak (1). Since 2014, new taxonomically equivalent probiotic microorganisms. Depending on
evidence concerning the efficacy of probiotics has become the country, the same probiotic microorganism(s) may be available
available, including a high impact publication showing that as food supplements, as registered pharmaceutical products, or
LGG, a probiotic with a positive recommendation, is not effica- incorporated into foods, which is linked with different regulatory
cious in the treatment of AGE (2). The efficacy of other processes and quality control. The matrix, as well as the production
probiotics also has been questioned (3,4). processes and conditions, may potentially affect the characteristics
The purpose of this document developed by the ESPGHAN and functionality of the probiotic microorganism. It is likely that
WG on Probiotics and Prebiotics, working within the ESPGHAN effect of a specific strain may depend on the matrix. Consequently,
Special Interest Group on Gut Microbiota and Modifications, is the taxonomically equivalent probiotics are presented jointly,
intended to provide updated recommendations for the use of regardless of the manufacturer. In this document, the effectiveness
probiotics for the treatment of AGE in previously healthy infants of well-specified probiotics was analyzed regardless of the regula-
and children. Children with underlying diseases such as chronic tory status. Nonviable microorganisms, that is, those not meeting
disorders or immunodeficiency are not covered. the definition of a probiotic (5), were not considered.
The WG followed the approach developed earlier (1) and did
METHODOLOGY not provide a recommendation on the use of probiotics in general.
The methods used for the development of this document are Instead, the WG is reporting evidence and recommendations related
described in Table S1 (Supplemental Digital Content, http://links.lww.- to a specific probiotic strain or their combinations. As previously,
com/MPG/B830). In brief, all systematic reviews and/or meta-analy- the WG adopted the position that at least 2 adequate and well-
ses, and subsequently published randomized controlled trials (RCTs) controlled studies, each convincing on its own, are needed to
that compared the use of probiotics, as a single ingredient, in all establish the effectiveness of an intervention. Consequently, the
delivery vehicles and formulations, at any dose, with no probiotic (ie, recommendations were formulated if at least 2 RCTs that used a
placebo or no treatment), were eligible for inclusion. Probiotics were given probiotic were available. If there was only 1 RCT, regardless
defined as ‘‘live microorganisms that, when administered in adequate of whether or not it showed a benefit, no recommendation was
amounts, confer a health benefit on the host’’ (5). formulated. Moreover, if any outcome of interest was reported in
Participants were children with clinically diagnosed AGE one RCT only, it was not considered for the recommendations.
(regardless of the definition used by the investigators), including in- Probiotics have to be described by genus, species, and strain
and outpatients. The focus of the WG was on young children, designations. Consequently, if the strain designation (used by the
preferably living in geographic Europe. Studies were, however, not depositor for the strain) was not given or the probiotic product was
excluded if the above criteria were not met. not otherwise identifiable, no recommendation was made.
The outcome measures of interest were the duration of diarrhea The WG graded the recommendations and assessed the certainty
(regardless of the definition used by the investigators); the need for of the supporting evidence using the GRADEpro software (https://
hospitalization for outpatients (or the duration of hospitalization for gdt.gradepro.org), developed by the Grading of Recommendations,
inpatients); and the percentage of children recovered by 48 hours Assessment Development, and Evaluations Working Group (7).
(also defined as the absence of diarrhea on day 2). The authors of the The certainty of evidence (also called quality of the evi-
original trials often evaluated other outcomes. For pragmatic reasons, dence) is categorized as high, moderate, low, or very low based on

Supplemental digital content is available for this article. Direct URL Douxmatok, Else, Frutarum, Nestlé Nutrition Institute, Nestle Health
citations appear in the printed text, and links to the digital files are Sicience, NGS, Teva, Ukko, and YMINI. J.B.G. has participated as a
provided in the HTML text of this article on the journal’s Web site clinical investigator, and/or speaker for, Nestlé Nutrition Institute and
(www.jpgn.org). Danone, without receiving any numeration. He is the director of the
H.S. has participated as a clinical investigator, and/or advisory board National Human Milk Bank and a member of the National Health
member, and/or consultant, and/or speaker for Arla, BioGaia, Biocodex, Council. Y.V. has participated as a clinical investigator, and/or advisory
Chr. Hansen, Danone, Nestlé, Nestlé Nutrition Institute, Nutricia, and board member, and/or consultant, and/or speaker for Abbott Nutrition,
Merck. A.G. has participated as a clinical investigator, and/or advisory Biocodex, BioGaia, Danone, Chr. Hansen, Nestlé Health Science, Nestlé
board member, and/or consultant, and/or speaker for Dicofarm and Nutrition Institute, Nutricia, Mead Johnson Nutrition, United Pharma-
Biocodex. I.H. received payment/honorarium for lectures/consultation ceuticals (Novalac), and Wyeth. Z.W. has participated as a clinical
form BioGaia, Nutricia, Oktal Pharma, Nestlé, Biocodex, Abela Pharm, investigator, and/or advisory board member, and/or consultant, and/or
and Chr. Hansen. F.I. reports receipt of payment/honorarium for lectures speaker for BioGaia, Biocodex, HiPP, Mead Johnson, Nestlé, Sensus,
BioGaia, Nestlé, Danone, and Abbot and as consultant for BioGaia. S.K. and Materna. B.M.Z. reports research funding from Nutricia Foundation
received speakers fee, support for travelling, and nonrestricted grants for (not related to this document).
the hospital from Abbott, AbbVie, Abela Pharm, BioGaia, Fresenius, Disclaimer: Although this paper is produced by the ESPGHAN Working
GM Pharma, Mead Johnson, Nestlé, Nutricia, Oktal Pharma, and Shire. Group on Probiotics and Prebiotics, working within the ESPGHAN
R.O. has participated as a clinical investigator, and/or advisory board Special Interest Group on Gut Microbiota and Modifications, it does not
member, and/or consultant, and/or speaker for Abbott, AbbVie, necessarily represent ESPGHAN policy and is not endorsed by
BioGaia, Dr. Falk, Ewopharma, J.G.L., Lek, Medis, Nestlé, Nutricia, ESPGHAN.
Sandoz, and Takeda. S.S. has participated as advisory board member, Copyright # 2020 by European Society for Pediatric Gastroenterology,
and/or consultant, and/or speaker for Bioproject, Danone, Nestlé, and Hepatology, and Nutrition and North American Society for Pediatric
Novalac. R.S. has participated as a clinical investigator, and/or advisory Gastroenterology, Hepatology, and Nutrition
board member, and/or consultant, and/or speaker for Abbott, Danone, DOI: 10.1097/MPG.0000000000002751

262 www.jpgn.org

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JPGN  Volume 71, Number 2, August 2020 Probiotics for Acute Gastroenteritis

consideration of the risk of bias, the directness of evidence, within 10 days. The WG intends to revise the recommendations not
consistency, and precision of the estimates. Low and very low- later than in 5 years and produce an updated document.
certainty of evidence indicates that the estimated effects of inter-
ventions are very uncertain, and further research is very likely to SUMMARY OF EVIDENCE
influence resulting recommendations. The strength of recommen- Table S4 summarizes the characteristics of 16 systematic
dations is expressed as either strong or weak (conditional). For reviews and meta-analyses published since 2010, including 9
interpretation of strong and weak (conditional recommendation), reviews focusing on all probiotics (8–16), and 7 strain-specific
see Table S2 (Supplemental Digital Content, http://links.lww.com/ systematic reviews (LGG only (17); S boulardii only (18–21);
MPG/B830). Final recommendations were based on combined Bacillus clausii O/C, SIN, N/R, and T only (22); L reuteri DSM
evidence on outcomes of interest, together with the assessment 17938 (23)). Overall, more than 150 RCTs were identified (see
of the certainty of the evidence (depicted in Grading of Recom- Table S5 for the references). Only a few RCTs included in the
mendations, Assessment Development, and Evaluations tables, see systematic reviews overlap.
Table S2, Supplemental Digital Content, http://links.lww.com/ Three systematic reviews and meta-analyses were performed
MPG/B830). The wording of recommendations was specified prior specifically for the purposes of this document (17,21,23). All pooled
to formulating the recommendations (Table S3, Supplemental analyses reported in this document were taken from the above meta-
Digital Content, http://links.lww.com/MPG/B830). analyses or were explicitly performed for the current report.
A draft of the guidelines was evaluated by all of the WG
members. All critical feedback was discussed during a meeting held GENERAL STATEMENT
in Rome (September 8, 2019), and changes and a second draft were Despite the large number of identified trials, the WG could
evaluated by all WG members until 30 January 2020. The prefinal not identify 2 RCTs of high quality for any strain that provided
draft of this document was submitted for public consultation on benefit when used for treating AGE.
February 28, 2020 via the ESPGHAN Web site. ESPGHAN members Table 1 summarizes the WG recommendations, and
and all interested parties were invited to submit written comments Table S6 summarizes Grading of Recommendations, Assessment

TABLE 1. Probiotics for the management of acute gastroenteritis

Weak recommendations for

(In descending order in terms of the number of trials evaluating any given strain)
S boulardii (250–750 mg/day, for 5–7 days) (low to very low certainty of evidence)
L rhamnosus GG (1010 CFU/day, typically 5–7 day) (very low certainty of evidence)
L reuteri DSM 17938 (1  108 to 2  108 to 4  108 CFU/day, for 5 days) (low to very low certainty of evidence)
L rhamnosus 19070–2 and L reuteri DSM 12246 (2  1010 CFU of each strain/d, for 5 days) (very low certainty of evidence)
Strong recommendation against
L helveticus R0052 and L rhamnosus R0011 (moderate certainty of evidence)
Weak recommendation against
Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of evidence)
No recommendation
No strain specification L acidophilus (24)
B longum, B lactis, L acidophilus, L rhamnosus, L plantarum, Pediococcus pentosaceus (25)
Only 1 RCT available, strain Bacillus clausii UBBC-07 (26)
identification available L acidophilus rhamnosus 573L/1, 573L/2, 573L/3 (27)
L delbrueckii var bulgaricus, L acidophilus, S thermophilus, B bifidum (strains LMG-P17550, LMG-P 17549, LMG-P 17503,
and LMG-P 17500) (28)
L paracasei strain ST11 (29)
Only 1 RCT available, no B lactis, Lactobacillus, and B bifidum, and L rhamnosus (30)
strain identification B longum, B lactis, L acidophilus, L rhamnosus, L plantarum, and Pediococcus pentosaceus (25)
L acidophilus, B bifidum, L bulgaricus (31)
L acidophilus, L paracasei, L bulgaricus, L plantarum, B breve, B infantis, B longum, S thermophilus (32)
L casei (33)
L sporogenes (Bacillus coagulans) (34)
L sporogenes (35)
LGG, L acidophilus, L casei, L plantarum, B infantis (36)
Two or more RCTs available, Bacillus clausii (37–39)
no strain identification Bacillus mesentericus and Clostridium butyricum and E faecalis (40,41)—(further specified by the manufacturer by email
communication) as Bacillus subtilis TO-A (FERM BP-07462), Enterococcus faecium T-110 (FERM BP-10867), and C
butyricum TO-A (FERM BP-10866), respectively. However, not deposited in any culture collection.
L acidophilus and L rhamnosus and B longum and S boulardii (42,43).
L acidophilus and B bifidum (44–46)
L acidophilus and B bifidum at 4-C and L acidophilus and B bifidum at room temp (47)
L acidophilus and B infantis (48,49)
Safety concerns (50,51) E faecium SF68 (28,52)
Methodological issues (1) Escherichia coli Nissle 1917 (53,54)

LGG U Lactobacillus rhamnosus GG; RCT U randomized controlled trial.

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Szajewska et al JPGN  Volume 71, Number 2, August 2020

Development, and Evaluations analyses for probiotics with recom- placebo or no intervention groups, the use of S boulardii signifi-
mendations (selected outcomes). cantly reduced the risk of diarrhea on day 2 (2 RCTs, n ¼ 463, RR
0.75, 95% CI 0.67 to 0.84, I2 ¼ 0%) (low certainty of evidence)
PROBIOTIC WITH RECOMMENDATIONS (Fig. S3, Supplemental Digital Content, http://links.lww.com/
The following probiotics were evaluated in 2 or more RCTs, MPG/B830).
and the formulation of a recommendation was possible: LGG; In 13 trials (1599 participants), the S boulardii CNCM I-745
L reuteri DSM 17938; S boulardii; B clausii O/C; SIN, N/R, and strain was used. In the remaining 10 trials (1851 participants), there
T, L helveticus R0052 and L rhamnosus R0011; and L rhamnosus was no information on the strain designation. Regardless of the
19070-2 and L reuteri DSM 12246. strain designation, the duration of diarrhea was reduced (MD 0.99
d [1.27 to 0.70], I2 ¼ 85% vs 1.12 d [1.68 to 0.57],
 Weak recommendations for I2 ¼ 91%, respectively). The test for subgroup differences suggested
that there is no significant difference (P ¼ 0.66).
Below, probiotics with weak recommendations for use in Only 1 RCT (57) was considered to be at low risk of bias with
clinical practice are discussed in descending order in terms of the regard to adequate randomization, allocation concealment, blind-
number of trials evaluating any given strain (or strains). If any one ing, and follow-up. This study confirmed the efficacy of S boulardii
of these probiotics will be considered for the management of (retrospectively identified as S boulardii CMCM I-745) in reducing
AGE, it should be used as an adjunct to oral rehydration the duration of diarrhea if administered within 72 hours after the
therapy (55), and should not replace any fluid and dietary recom- onset of the disease.
mendations.

S boulardii
Recommendation Healthcare professionals (HCPs) may recommend
S boulardii (at a dose of 250–750 mg/day, for
Effect, MD Doses used in Certainty of 5–7 days) for the management of AGE in
or RR (95% CI) clinical trials evidence children
Certainty of evidence Low to very low
Duration of 23 RCTs, n ¼ 3450, MD 250–750 mg/day Very low
Grade of recommendation Weak
diarrhea 1.06 d (1.32 to 0.79), (typically 5–7 days)
I2 ¼ 90%
Duration of 8 RCTs, Very low
hospitalization n ¼ 999, MD 0.85 d
L rhamnosus GG (LGG)
(1.35 to 0.34), I2 ¼ 91%
Need for 2 RCTs, n ¼ 233, RR 1.08 Very low
hospitalization (0.62 to 1.87), I2 ¼ 0% Effect, MD or RR Certainty of
(for outpatients) (95% CI) Doses used in clinical trials evidence
Diarrhea on day 2 2 RCTs, Low
n ¼ 463, RR 0.75 (0.67 to Duration of 16 RCTs, n ¼ 3949 Daily doses 1010 CFU or
0.84), I2 ¼ 0%. diarrhea MD 0.83 d <1010 CFU were
(1.13 to effective; however, the
0.53), latter produced results of
I2 ¼ 98% borderline significance
In addition to the previously identified meta-analysis (56), . Various Very low

2 new meta-analyses (19,20) were identified. The meta-analyses 5 RCTs , n ¼ 2409, Daily doses 1.2  108 to Very low
differed concerning the search dates and inclusion/exclusion MD 0.68 1  1010 to 2  1010 to
criteria. For this document, the most recent meta-analysis was (1.82 to 0.45), 2  1012 CFU
I2 ¼ 98%
considered (21). In this meta-analysis, 29 RCTs that randomized
Duration of 5 RCTs, n ¼ 1790 Daily doses 1.2  108 to Very low
4217 participants (2152 in the experimental group and 2065 in the hospitalization MD 1.22 d 1  1010 to 2  1010 to
control group) were included. Only 38% of trials adequately (for inpatients) (2.33 to 0.1); 2  1012 CFU.
generated their randomization sequence, only 17% of trials ade- I2 ¼ 99%
quately concealed allocation, and only 1 trial adequately blinded Need for Not reported Not reported –
participants, study personnel, and outcome assessors. However, hospitalization
83% provided complete outcome data. The pooled results dem- (for outpatients)
onstrated that, compared with placebo or no intervention, the Diarrhea on day 2 1 RCTy, n ¼ 36, RR 1  1010 CFU Very low
administration of S boulardii reduced the duration of diarrhea by 0.37 (0.17 to
0.84).
1 day (23 RCTs, n ¼ 3450, mean difference [MD] 1.06 day, 95%
confidence interval [CI] 1.32 to 0.79; high heterogeneity 
Studies considered to be at low risk of bias.
[I2 ¼ 90%]) (very low certainty of evidence) (Fig. S1, Supple- y
As this outcome was reported in 1 trial only, it was not considered for the
mental Digital Content, http://links.lww.com/MPG/B830). S bou- recommendations.
lardii use was also associated with a reduced duration of
hospitalization (8 RCTs, n ¼ 999, MD 0.85 d, 95% CI 1.35
to 0.34; I2 ¼ 91%) (very low certainty of evidence) (Fig. S1, Since 2014, 1 systematic review focusing exclusively on
Supplemental Digital Content, http://links.lww.com/MPG/B830). LGG was identified (17) with later published comments (58,59).
Two RCTs reported the need for hospitalization and found no The Cochrane Library, MEDLINE, and EMBASE databases were
difference between the S boulardii and control groups (2 RCTs, searched from May 2013 (end of the last search) to January 2019.
n ¼ 233, relative risk [RR] 1.08, 95% CI 0.62 to 1.87, I2 ¼ 0%) Eighteen RCTs (n ¼ 4208) were included.
(very low certainty of evidence) (Fig. S2, Supplemental Digital Concerning outcomes of interest for this document, com-
Content, http://links.lww.com/MPG/B830). Compared with the pared with placebo or no treatment, LGG use was associated with a

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JPGN  Volume 71, Number 2, August 2020 Probiotics for Acute Gastroenteritis

reduced duration of diarrhea (16 RCTs, n ¼ 3949, mean difference, 17938 significantly reduced the duration of hospitalization; how-
MD 0.83 d, 95% CI 1.13 to 0.53, high heterogeneity, ever, the difference was of a borderline statistical significance
I2 ¼ 98%) (Fig. S4, Supplemental Digital Content, http://links.lww. (3 RCTs, n ¼ 284, MD 0.54 d, 95% CI 1.09 to 0.0; high
com/MPG/B830). LGG was effective when used at a daily dose of heterogeneity, I2 83%) (Fig. S6, Supplemental Digital Content,
1010 CFU or <1010 CFU; however, the latter produced results of http://links.lww.com/MPG/B830). Compared with the placebo or no
borderline significance. LGG was more effective when used in intervention groups, the use of L reuteri DSM 17938 significantly
European countries compared with non-European countries, mainly increased the cure rate on day 2 (3 RCTs, n ¼ 256, RR 4.54, 95% CI
when considered by region. 2.02–10.18, I2 ¼ 53%) (Fig. S7, Supplemental Digital Content,
Of note, the analysis of 5 RCTs (2409 participants) consid- http://links.lww.com/MPG/B830).
ered to be at low risk of bias with regard to adequate randomization,
allocation concealment, blinding, and follow-up found that, com-
pared with controls, LGG had no effect on the duration of diarrhea
Recommendation HCPs may recommend L reuteri DSM 17938 (daily
(MD 0.68 d, 95% CI 1.82 to 0.45; high heterogeneity, I2 ¼ 98%) doses 1  108 to 2  108 to 4  108 CFU, for 5 d) for
(Fig. S4, Supplemental Digital Content, http://links.lww.com/ the management of AGE in children
MPG/B830). Certainty of evidence Low to very low
A meta-analysis of 5 RCTs (n ¼ 1790) showed a reduction in Grade of recommendation Weak
the duration of hospitalization for those treated with LGG com-
pared with the control group (MD 1.22 d, 95% CI 2.33 to
0.10; high heterogeneity, I2 ¼ 99%) (Fig. S5, Supplemental L rhamnosus 19070-2 and L reuteri DSM 12246
Digital Content, http://links.lww.com/MPG/B830). The analysis
of 3 RCTs (1328 participants), however, considered to be at Effect, MD or RR (95% CI) Doses used in Certainty of
low risk of bias found no effect on the duration of hospitalization clinical trials evidence
(MD 1.68 d, 95% CI 4.62 to 1.26; high heterogeneity, I2 ¼ 99%)
(Fig. S5). Duration of 2 RCTs, n ¼ 112, MD 0.97 d 2  1010 CFU of Very low
diarrhea (1.72, 0.22), I2 ¼ 0% each strain, for 5
Limited data showed that, compared with placebo, LGG days
reduced the risk of diarrhea on day 2 (1 RCT, n ¼ 36, RR 0.37, 95% Duration of 1 RCT, n ¼ 69, MD 1.10 d Very low
CI 0.17 to 0.84). This outcome was, however, not considered for the hospitalization

(1.82, 0.38)
recommendations. (for inpatients)
Need for Not reported – –
hospitalization
(for outpatients)
Percentage of Not reported – –
Recommendation HCPs may recommend LGG [at a dose of 1010 children
CFU/day, typically 5–7 days] for the recovered by 48 h
management of AGE in children

Certainty of evidence Very low As this outcome was reported in one trial only, it was not considered for
Grade of recommendation Weak the recommendations

L reuteri DSM 17938 The WG formulated a weak recommendation on use of L

rhamnosus 19070-2 and L reuteri DSM 12246. It is, however,
based on the findings from only 2 RCTs with a very limited
Effect, MD or RR (95% CI) Doses used in clini- Certainty of
number of subjects; thus, compared to other strains, this recom-
cal trials evidence
mendation is more prone to changes when further studies
Duration of 4 RCTs, n ¼ 347, Daily doses 1  108 Very low are accomplished.
diarrhea MD 0.87 d (1.43 to to 2  108 to Two Danish double-blind RCTs assessed the efficacy of L
0.31); I2 ¼ 72% 4  108 CFU, for
rhamnosus 19070-2 and L reuteri DSM 12246 for the treatment of
5 days
Duration of 3 RCTs, n ¼ 284, Very low AGE, both in hospitalized children (n ¼ 69, mean age 17.6 months)
hospitalization MD 0.54 d (1.09 to 0.0); (64) and in nonhospitalized children attending day care (n ¼ 43,
(for inpatients) I2 ¼ 83% mean age 22 months) (65). The pooled results from these 2 RCTs
Need for Not reported
(n ¼ 112) showed that, compared with the placebo, the administra-
hospitalization
(for outpatients) tion of L rhamnosus 19070-2 and L reuteri DSM 12246 at a daily
Percentage of 3 RCTs, n ¼ 256, Low dose 2  1010 CFU of each strain, for 5 days, reduced the duration of
children RR 4.54 (2.02 to 10.18); diarrhea (MD 0.97 d, 95% CI 1.72 to 0.22, I2 ¼ 0%) (Fig. S8).
recovered by 48 h I2 ¼ 53%
In hospitalized children, the duration of hospitalization was 1 day
(cure on day 2)
shorter in the probiotic group (1 RCT, n ¼ 69, MD 1.10 d, 95% CI
1.82 to 0.38) (Fig. S8). This outcome was, however, not
In addition to 2 RCTs identified previously (60,61), 2 new considered for the recommendations.
RCTs (62,63) that evaluated L reuteri DSM 17938 were published.
All of these trials were included in a recent meta-analysis (23). The
pooled results of 4 RCTs (347 participants) showed a reduction in Recommendation HCPs may recommend L rhamnosus 19070-2 and L
the duration of diarrhea of 0.87 d (95% CI 1.43 to 0.31) for reuteri DSM 12246 (at a dose of 2  1010 CFU of
those treated with L reuteri DSM 17938 compared with placebo. each strain, for 5 days) for the management of AGE
High heterogeneity was found (I2 ¼ 72%) (Fig. S6, Supplemental in children.
Digital Content, http://links.lww.com/MPG/B830). Compared with Certainty of evidence Very low
Grade of recommendation Weak
the placebo or no intervention groups, the use of L reuteri DSM

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Szajewska et al JPGN  Volume 71, Number 2, August 2020

 Strong recommendation against  Weak recommendation against

L helveticus R0052 and L rhamnosus R0011 B clausii strains O/C, SIN, N/R, and T
Effect, MD or RR Doses used in clinical Certainty of Effect, MD or RR Doses used in clinical Certainty of
(95% CI) trials evidence (95% CI) trials evidence

Duration of diarrhea 4 RCTs, n ¼ 1133, 2  109 to 8  109 CFU/ Moderate Duration of 7 RCTs, n ¼ 1107, 2–4  109 CFU for 3–5 Very low
MD 0.15 d, day for 5–10 days diarrhea MD 0.40 d days
(0.67 to 0.36), (0.82 to 0.02);
I2 ¼ 67% I2 ¼ 92%
Duration of hospitalization Not reported – Duration of 3 RCTs, n ¼ 291, Very low
(for inpatients) hospitalization MD 0.8 d
Need for hospitalization (for 2 RCTs, n ¼ 950, 4–8  109 CFU/d Moderate (for inpatients) (1.45 to
outpatients) RR 1.52 (0.91 to 0.15); I2 ¼ 61%
2.55) I2 ¼ 0%. Need for Not reported
Percentage of children Not reported – hospitalization
recovered by 48 h (for outpatients)
Diarrhea on day 2 Not reported

Four RCTs were identified. A 2005 RCT conducted in Czech

children ages 12 to 72 months with AGE treated as outpatients was The probiotic currently available on the market contains
found. Children receiving L helveticus R0052 and L rhamnosus different B clausii strains, most including the strains intrinsically
R0011 (previously known as L acidophilus Rosell-11 and L rham- resistant to chloramphenicol (O/C), novobiocin, and rifampicin (N/
nosus Rosell-11 (66) (n ¼ 38), compared with placebo (n ¼ 33), had R), tetracycline (T), or neomycin, and streptomycin (SIN). The
a significantly shorter duration of diarrhea (4.0  2.0 vs 5.45  2.2 molecular characterization of other B clausii strains has been
days, MD 1.45 days, 95% CI 2.5 to 0.4) (67). In contrast, 3 reviewed by Senesi et al (70).
more recent RCTs produced negative results. A 2014 RCT assessed A 2018 meta-analysis (22) identified 6 RCTs evaluating B
112 Indonesian children aged 6 to 36 months with acute infectious clausii strains O/C, SIN, N/R, and T (28,71–75). In addition, the
diarrhea and moderate dehydration treated as outpatients. Com- WG identified 1 RCT evaluating B clausii strains O/C, SIN, N/R,
pared with placebo, the addition to standard therapy (oral rehydra- and T (76). The pooled analysis performed for this review found
tion solution and zinc) of L rhamnosus R0011 (1.9  109 CFU) and that, compared with the placebo or no intervention, the use of B
L acidophilus R0052 (0.1  109 CFU/day) for 7 days had no effect clausii strains O/C, SIN, N/R, and T reduced the duration of
on the duration of diarrhea (median [IQR] 61.5 hours [range 21– diarrhea; however, the difference was of borderline significance
166] vs 68.5 h [range 13–165], respectively, P ¼ 0.596) (68). A (7 RCTs, n ¼ 1107, MD 0.40 d, 95% CI 0.82 to 0.02; I2 ¼ 92%
2015 Canadian RCT performed in the Emergency Department, (Fig. S11, Supplemental Digital Content, http://links.lww.com/
involving children aged 4 to 48 months receiving L helveticus- MPG/B830). Moreover, the WG noted issues related to 2 of the
52 (5%) and L rhamnosus Rosell-11 (95%) at 2 doses (4  109 CFU/ included RCTs. One was a clinical study report available only via
day or 8  109 CFU/day), or placebo, over 5 days, found no the company’s Web site (73). The other one was only available as an
difference in the duration of diarrhea (59.1  55.2 vs 84.0  96.4 abstract (75). Both were published in 2008; however, to the best of
vs 63.5  64.3 days, respectively). There was no difference in the our knowledge, neither was later published in a peer-reviewed
need for hospitalization in the probiotic groups as well as in the journal. The exclusion of these 2 RCTs confirmed no significant
placebo group (1 vs 0, respectively) (69). A 2018 RCT performed in difference between the study groups (5 RCTs, n ¼ 773, MD 0.38
Canada in which 886 children aged 3 to 48 months received a d, 95% CI 0.95 to 0.19, heterogeneity I2 ¼ 94%).
combination probiotic product containing L rhamnosus R0011 and Of note, the analysis of 2 RCTs (28) (74) (ref. 74—published
L helveticus R0052, at a dose of 4.0  109 CFU twice daily, or as thesis) considered to be at lower risk of bias with regard to
placebo, over 5 days, found no difference between groups in the adequate randomization, allocation concealment, blinding of out-
duration of diarrhea (median duration of diarrhea: 52.5 hours come assessment, and follow-up found that, compared with con-
[interquartile range, 18.3–95.8] and 55.5 hours [interquartile range, trols, B clausii strains O/C, SIN, N/R, and T had no effect on the
20.2–102.3], respectively; P ¼ 0.31) (4). duration of diarrhea (MD 0.06 d, 95% CI 0.45 to 0.32; hetero-
The pooled results of these 4 RCTs (n ¼ 1133) performed geneity, I2 ¼ 34%) (Fig. S11, Supplemental Digital Content, http://
for this review demonstrated that, compared with placebo or no links.lww.com/MPG/B830).
intervention, the administration of L helveticus R0052 and L In hospitalized children, the use of B clausii O/C, SIN, N/R,
rhamnosus R0011 had no significant effect on the duration of and T reduced the duration of hospitalization (3 RCTs, n ¼ 291, MD
diarrhea (MD 0.15 d, 95% CI 0.67 to 0.36), heterogeneity 0.8 d, 95% CI 1.45 to 0.15, heterogeneity I2 ¼ 61%) (Fig. S12,
I2 ¼ 67%) (Fig. S9). Supplemental Digital Content, http://links.lww.com/MPG/B830).
The duration of hospitalization was not reported in any of the
trials. The pooled results of 2 RCTs (n ¼ 950) showed no significant
difference in the need for hospitalization in outpatients (RR 1.52, Recommendation HCPs may not recommend B clausii
95% CI 0.91–2.55, no heterogeneity I2 ¼ 0%] (Fig. S10, Supple- strains O/C, SIN, N/R, and T for the
mental Digital Content, http://links.lww.com/MPG/B830). management of AGE in children.
Certainty of evidence Very low
Grade of recommendation Weak
Recommendation HCPs should not recommend L helveticus
R0052 and L rhamnosus R0011 for the
management of AGE. PROBIOTICS WITH NO RECOMMENDATION
Certainty of evidence Moderate Several studies were identified with insufficient evidence to
Grade of recommendation Strong make a recommendation for or against use for reasons such as

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JPGN  Volume 71, Number 2, August 2020 Probiotics for Acute Gastroenteritis

methodological limitations, no strain specification, or the availabil- were genetically identical (with the exception of a few point
ity of only 1 RCT (Table 1). The WG has decided not to make any mutations) to the LGG present in the administered probiotic (86).
recommendation with regard to use of these probiotics. In countries The effects of long-term administration of probiotics remain
in which probiotics with positive recommendations are not avail- largely unknown. With regard to the management of AGE, pro-
able, or because of their lower cost, healthcare professionals may biotics are, however used for a short time. Overall, more research is
consider selecting a probiotic based on the findings from 1 trial needed before absolute statements on the safety of probiotics, in
only, provided there is some evidence, even if limited, that docu- general, or for individual probiotic strains, can be made.
ments its safety and efficacy for the management of acute diarrhea
in children. It is essential to understand that such lack of evidence is SUMMARY OF THE RECOMMENDATIONS
not the same as evidence of no efficacy (‘‘evidence of no efficacy’’ For the use of probiotics in the management of children with
6¼ ‘‘no evidence of efficacy’’). AGE, the WG made the following weak recommendations for (in
descending order in terms of the number of trials evaluating any
FACTORS AFFECTING THE EFFICACY OF given strain):
PROBIOTICS  S boulardii (at a dose of 250–750 mg/day, for 5–7 days) (low to
The efficacy of probiotics depends on many variables. very low certainty of evidence).
Registration as a ‘‘drug’’ or ‘‘medication’’ does not always guar-  L rhamnosus GG (at a dose 1010 CFU/day, typically 5–7 days)
antee the quality of the product. First, some products have a (very low certainty of evidence).
historical registration and would no longer qualify if a new appli-  L reuteri DSM 17938 (daily doses 1  10[8] to 2  10[8] to 4 
cation was done. Second, requirements for registration differ from 10[8] CFU, for 5 days) (low to very low certainty of evidence).
country to country.  L rhamnosus 19070-2 and L reuteri DSM 12246 (at a dose of 2 
The strains with which a study has been performed need to be 1010 CFU of each strain, for 5 days) (low to very low certainty of
appropriately identified at the genus, species, and strain level. There evidence).
is an ongoing debate as to what level of evidence is deemed
sufficient to support health claims. In the opinion of the WG, such The WG made the following strong recommendation
studies should, however, be performed with the commercialized against:
product, and obviously, the claim that is aimed at should be the
primary endpoint of the clinical trials. At least 2 similar trials with  L helveticus R0052 and L rhamnosus R0011 (moderate certainty
the same primary endpoint should be independently performed by 2 of evidence).
different centers or 2 multicenter trials should be carried out before
a claim can be considered. The dosage and matrix used in the The WG made the following weak recommendation against:
clinical trials should be identical to those of the commercialized
product. Except for antibiotic-associated diarrhea, a clear dose-  B clausii strains O/C, SIN, N/R, and T (very low certainty of
response effect of probiotics has not been documented (77). The evidence).
matrix in which the probiotic is administered may also affect the
efficacy. Carrier matrices have a significant impact on the quality of
probiotic products. Matrix components, such as proteins, carbohy- For other probiotics, the WG made no recommendation for or
drates, and flavoring agents, are shown to alter probiotic efficacy against use. In countries in which probiotics with positive recom-
and viability (78,79). Furthermore, in vivo studies have revealed mendations are not available, or because of their lower cost, HCPs
strain-dependent matrix effects on the gastrointestinal tract survival may consider selecting a probiotic based on the findings from 1 trial
of probiotic bacteria (78,79). Therefore, although unnecessary in only, provided there is some evidence, even if limited, that docu-
clinical settings, data on the pathogens causing AGE are important ments its safety and efficacy for the management of AGE
in study design and study report. By preference, the quality of each in children.
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