Probiotics for treating acute infectious diarrhoea

Shelui Collinson, Andrew Deans, April Padua-Zamora, Germana V Gregorio, Chao Li, Leonila F Dans, Stephen J Allen, Shelui Collinson, Andrew Deans, April Padua-Zamora, Germana V Gregorio, Chao Li, Leonila F Dans, Stephen J Allen

Abstract

Background: Probiotics may be effective in reducing the duration of acute infectious diarrhoea.

Objectives: To assess the effects of probiotics in proven or presumed acute infectious diarrhoea.

Search methods: We searched the trials register of the Cochrane Infectious Diseases Group, MEDLINE, and Embase from inception to 17 December 2019, as well as the Cochrane Controlled Trials Register (Issue 12, 2019), in the Cochrane Library, and reference lists from studies and reviews. We included additional studies identified during external review.

Selection criteria: Randomized controlled trials comparing a specified probiotic agent with a placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent.

Data collection and analysis: Two review authors independently applied inclusion criteria, assessed risk of bias, and extracted data. Primary outcomes were measures of diarrhoea duration (diarrhoea lasting ≥ 48 hours; duration of diarrhoea). Secondary outcomes were number of people hospitalized in community studies, duration of hospitalization in inpatient studies, diarrhoea lasting ≥ 14 days, and adverse events.

Main results: We included 82 studies with a total of 12,127 participants. These studies included 11,526 children (age < 18 years) and 412 adults (three studies recruited 189 adults and children but did not specify numbers in each age group). No cluster-randomized trials were included. Studies varied in the definitions used for "acute diarrhoea" and "end of the diarrhoeal illness" and in the probiotic(s) tested. A total of 53 trials were undertaken in countries where both child and adult mortality was low or very low, and 26 where either child or adult mortality was high. Risk of bias was high or unclear in many studies, and there was marked statistical heterogeneity when findings for the primary outcomes were pooled in meta-analysis. Effect size was similar in the sensitivity analysis and marked heterogeneity persisted. Publication bias was demonstrated from funnel plots for the main outcomes. In our main analysis of the primary outcomes in studies at low risk for all indices of risk of bias, no difference was detected between probiotic and control groups for the risk of diarrhoea lasting ≥ 48 hours (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 2 trials, 1770 participants; moderate-certainty evidence); or for duration of diarrhoea (mean difference (MD) 8.64 hours shorter, 95% CI 29.4 hours shorter to 12.1 hours longer; 6 trials, 3058 participants; very low-certainty evidence). Effect size was similar and marked heterogeneity persisted in pre-specified subgroup analyses of the primary outcomes that included all studies. These included analyses limited to the probiotics Lactobacillus rhamnosus GG and Saccharomyces boulardii. In six trials (433 participants) of Lactobacillus reuteri, there was consistency amongst findings (I² = 0%), but risk of bias was present in all included studies. Heterogeneity also was not explained by types of participants (age, nutritional/socioeconomic status captured by mortality stratum, region of the world where studies were undertaken), diarrhoea in children caused by rotavirus, exposure to antibiotics, and the few studies of children who were also treated with zinc. In addition, there were no clear differences in effect size for the primary outcomes in post hoc analyses according to decade of publication of studies and whether or not trials had been registered. For other outcomes, the duration of hospitalization in inpatient studies on average was shorter in probiotic groups than in control groups but there was marked heterogeneity between studies (I² = 96%; MD -18.03 hours, 95% CI -27.28 to -8.78, random-effects model: 24 trials, 4056 participants). No differences were detected between probiotic and control groups in the number of people with diarrhoea lasting ≥ 14 days (RR 0.49, 95% CI 0.16 to 1.53; 9 studies, 2928 participants) or in risk of hospitalization in community studies (RR 1.26, 95% CI 0.84 to 1.89; 6 studies, 2283 participants). No serious adverse events were attributed to probiotics.

Authors' conclusions: Probiotics probably make little or no difference to the number of people who have diarrhoea lasting 48 hours or longer, and we are uncertain whether probiotics reduce the duration of diarrhoea. This analysis is based on large trials with low risk of bias.

Trial registration: ClinicalTrials.gov NCT03539913 NCT03684538.

Conflict of interest statement

Shelui Collinson has no known conflicts of interest.

Andrew Deans has no known conflicts of interest.

April Padua has no known conflicts of interest.

Germana V Gregorio has no known conflicts of interest.

Chao Li has no known conflicts of interest.

Leonila F Dans has no known conflicts of interest.

Stephen J Allen: travel and accommodation expenses to attend the Nutricia Neocate Syneo Meeting (November 2016) at the Nutricia Utrecht Research Centre were paid.

Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Risk of bias graph: review authors' assessments about each risk of bias item presented as percentages across all included studies.
4
4
Funnel plot of comparison: 1 Primary diarrhoea outcomes, outcome: 1.1 Diarrhoea lasting ≥ 48 hours.
5
5
Funnel plot of comparison: 1 Primary diarrhoea outcomes, outcome: 1.2 Mean duration of diarrhoea.
1.1. Analysis
1.1. Analysis
Comparison 1: Primary diarrhoea outcomes, Outcome 1: Diarrhoea lasting ≥ 48 hours
1.2. Analysis
1.2. Analysis
Comparison 1: Primary diarrhoea outcomes, Outcome 2: Mean duration of diarrhoea
2.1. Analysis
2.1. Analysis
Comparison 2: Secondary diarrhoea outcomes, Outcome 1: Number of people hospitalized in community studies
2.2. Analysis
2.2. Analysis
Comparison 2: Secondary diarrhoea outcomes, Outcome 2: Duration of hospitalization in inpatient studies
2.3. Analysis
2.3. Analysis
Comparison 2: Secondary diarrhoea outcomes, Outcome 3: Diarrhoea lasting ≥ 14 days
3.1. Analysis
3.1. Analysis
Comparison 3: Strain of probiotic organisms, Outcome 1: Diarrhoea lasting ≥ 48 hours
3.2. Analysis
3.2. Analysis
Comparison 3: Strain of probiotic organisms, Outcome 2: Mean duration of diarrhoea
4.1. Analysis
4.1. Analysis
Comparison 4: Diarrhoea pathogen: rotavirus, Outcome 1: Mean duration of diarrhoea
5.1. Analysis
5.1. Analysis
Comparison 5: Age of participants, Outcome 1: Diarrhoea lasting ≥ 48 hours
5.2. Analysis
5.2. Analysis
Comparison 5: Age of participants, Outcome 2: Mean duration of diarrhoea
6.1. Analysis
6.1. Analysis
Comparison 6: Severity of diarrhoea (inpatient vs outpatient), Outcome 1: Diarrhoea lasting ≥ 48 hours
6.2. Analysis
6.2. Analysis
Comparison 6: Severity of diarrhoea (inpatient vs outpatient), Outcome 2: Mean duration of diarrhoea
7.1. Analysis
7.1. Analysis
Comparison 7: Country mortality stratum, Outcome 1: Diarrhoea lasting ≥ 48 hours
7.2. Analysis
7.2. Analysis
Comparison 7: Country mortality stratum, Outcome 2: Mean duration of diarrhoea
8.1. Analysis
8.1. Analysis
Comparison 8: Geographical region, Outcome 1: Diarrhoea lasting ≥ 48 hours
8.2. Analysis
8.2. Analysis
Comparison 8: Geographical region, Outcome 2: Mean duration of diarrhoea
9.1. Analysis
9.1. Analysis
Comparison 9: Exposure to antibiotics, Outcome 1: Diarrhoea lasting ≥ 48 hours
9.2. Analysis
9.2. Analysis
Comparison 9: Exposure to antibiotics, Outcome 2: Duration of diarrhoea
10.1. Analysis
10.1. Analysis
Comparison 10: Use of zinc, Outcome 1: Duration of diarrhoea
11.1. Analysis
11.1. Analysis
Comparison 11: Risk of bias, Outcome 1: Diarrhoea lasting ≥ 48 hours
11.2. Analysis
11.2. Analysis
Comparison 11: Risk of bias, Outcome 2: Mean duration of diarrhoea
12.1. Analysis
12.1. Analysis
Comparison 12: Publication decade, Outcome 1: Diarrhoea lasting ≥ 48 hours
12.2. Analysis
12.2. Analysis
Comparison 12: Publication decade, Outcome 2: Mean duration of diarrhoea
13.1. Analysis
13.1. Analysis
Comparison 13: Prospective trial registration, Outcome 1: Diarrhoea lasting ≥ 48 hours
13.2. Analysis
13.2. Analysis
Comparison 13: Prospective trial registration, Outcome 2: Mean duration of diarrhoea

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Erdogan 2012 {published data only}
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Francavilla 2012 {published data only}
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Guarino 1997 {published data only}
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Hamid 2019 {published data only}
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Hegar 2015 {published data only}
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Henker 2007a {published data only}
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Henker 2008 {published data only}
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Hernandez 1998 {published data only}
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Hochter 1990 {published data only}
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    1. Simadibrata M, Ndraha S, Tedjasaputra R, Syam AF, Santi AFA, Rani A. Revealing the effect of probiotic combination Lactobacillus rhamnosus and Lactobacillus acidophilus (Lacidofil®) on acute diarrhea in adult patients. Journal of Clinical Medicine and Research 2013;5(2):23-8.
Sirsat 2017 {published data only}
    1. Sirsat GM, Sankpal DM. Role of Saccharomyces boulardii in management of acute diarrhoea of children - A randomized controlled trial. MedPulse International Journal of Pediatrics 2017;4(3):68-72.
Sudha 2019 {published data only}
    1. Sudha MR, Jayanthi N, Pandey DC, Verma AK. Bacillus clausii UBBC-07 reduces severity of diarrhoea in children under 5 years of age: a double blind placebo controlled study. Benef Microbes 2019;10(2):149-54.
Szymanski 2006 {published data only}
    1. Szymanski H, Pejcz J, Jawien M, Chmielarczyk A, Strus M, Heczko PB. Treatment of acute infectious diarrhoea in infants and children with a mixture of three Lactobacillus rhamnosus strains -- a randomized, double-blind, placebo-controlled trial. Alimentary Pharmacology and Therapeutics 2006;23(2):247-53.
Szymanski 2019 {published data only}
    1. Szymański H, Szajewska H. Lack of efficacy of Lactobacillus reuteri DSM 17938 for the treatment of acute gastroenteritis: a randomized controlled trial. Pediatric Infectious Disease Journal 2019;38(10):e237-42.
Teran 2009 {published data only}
    1. Teran CG, Teran-Escalera CN, Villarroel P. Nitazoxanide vs. probiotics for the treatment of acute rotavirus diarrhea in children: a randomized, single-blind, controlled trial in Bolivian children. International Journal of Infectiouos Diseases 2009;13(4):518-23.
Urganci 2001 {published data only}
    1. Urganci N, Polat T, Uysalol M, Cetinkaya F. Evaluation of the efficacy of Saccharomyces boulardii in children with acute diarrhoea. Archives of Gastroenterohepatology 2001;20(3-4):81-3.
Vidjeadevan 2018 {published data only}
    1. Vidjeadevan D, Vinoth S, Ramesh S. Role of Saccharomyces boulardii and Bacillus clausii in reducing the duration of diarrhea: a three-armed randomised controlled trial. International Journal of Contemporary Pediatrics 2018;5(5):1811-4.
Villarruel 2007 {published data only}
    1. Villarruel G, Rubio DM, Lopez F, Cintioni J, Gurevech R, Romero G, et al. Saccharomyces boulardii in acute childhood diarrhea: a randomised placebo controlled study. Acta Paediatrica 2007;96(4):538-41.
Vivatvakin 2006 {published data only}
    1. Vivatvakin B, Kowitdamrong E. Randomized control trial of live Lactobacillus acidophilus plus Bifidobacterium infantis in treatment of infantile acute watery diarrhea. Journal of the Medical Association of Thailand 2006;89:Suppl 3:S126-33.
Wunderlich 1989 {published data only}
    1. Wunderlich PF, Braun L, Fumagalli I, D'Apuzzo V, Heim F, Karly M, et al. Double-blind report of the efficacy of lactic acid-producing Enterococcus SF68 in the prevention of antibiotic-associated diarrhoea and in the treatment of acute diarrhoea. Journal of International Medical Research 1989;17(4):333-8.
Xie 2013 {published data only}
    1. Xie YM, Gao S, Wang LY, Wang ZL. Therapeutic effect of probiotics and oral IgY as supplementary drugs in the treatment of pediatric rotavirus enteritis: a comparative study. Chinese Journal of Contemporary Pediatrics 2013;15(11):1000-5.
References to studies excluded from this review Agarwal 2001 {published data only}
    1. Agarwal KN, Bhasin SK, Faridi MMA, Mathur M, Gupta S. Lactobacillus casei in the control of acute diarrhoea - a pilot study. Indian Pediatrics 2001;38(8):905-10.
Agarwal 2002 {published data only}
    1. Agarwal KN, Bhasin SK. Feasibility studies to control acute diarrhoea in children by feeding fermented milk preparations Actimel and Indian Dahi. European Journal of Clinical Nutrition 2002;56(Suppl. 4):S56-9.
Ahmadipour 2018 {published data only (unpublished sought but not used)}
    1. Ahmadipour S, Motamed F, Mohsenzadeh A, Esfandiarpour B. Probiotic or zinc, which is more effective in treatment of diarrhea in children? Journal of Pediatric Gastroenterology and Nutrition Conference: 51st Annual Meeting European Society for Paediatric Gastroenterology, Hepatology and Nutrition 2018;66:332.
Alexander 1971 {published data only}
    1. Alexander JG. Lactobacillus casei tablets in the treatment of intestinal infection. Journal of the Royal College of General Practitioners 1971;21(111):623-4.
Alvisi 1982 {published data only}
    1. Alvisi V, Tralli M, Loponte A, Pavani F, Massari M. Double-blind study of treatment with SF 68 or with antibiotics in acute enteritis in adults [Studio in doppio cieco sul trattamento con SF68 o con antibiotici nelle enteritis acute dell'adulto]. La Clinica Terapeutica 1982;101(6):581-6.
Asmat 2018 {published data only (unpublished sought but not used)}
    1. Asmat S, Shaukat F, Asmat R, Bakhat H, Asmat TM. Clinical efficacy comparison of Saccharomyces boulardii and lactic acid as probiotics in acute pediatric diarrhea. Journal of the College of Physicians and Surgeons - Pakistan 2018;28:214-7.
Barone 2000 {published data only}
    1. Barone C, Pettinato R, Avola E, Alberti A, Greco D, Failla P, et al. Comparison of three probiotics in the treatment of acute diarrhea in mentally retarded children. Minerva Pediatrica 2000;52(3):161-5.
Beck 1961 {published data only}
    1. Beck C, Necheles H. Beneficial effects of administration of Lactobacillus acidophilus in diarrheal and other intestinal disorders. American Journal of Gastroenterology 1961;35:522-30.
Bellomo 1979 {published data only}
    1. Bellomo G, Finocchiaro C, Frigerio G. A new approach for the treatment of enteritides in paediatrics [Une novelle approche pour le traitement des entérites en pédiatrie]. Médecine et Hygiène 1979;37:3781-4.
Bellomo 1980 {published data only}
    1. Bellomo G, Mangiagle A, Nicastro L, Frigeria G. A controlled double-blind study of SF68 strain as a new biological preparation for the treatment of diarrhoea in pediatrics. Current Therapeutic Research: Clinical and Experimental 1980;28(6):927-35.
Bellomo 1982 {published data only}
    1. Bellomo G, Finocchiaro C, Frigerio G, Mangiagli A, Nicastro L. Controlled study of Enterococcus LAB strain SF68 in acute enteritis in children with concomitant respiratory infection [Studio controllato sull'enterococco L.A.B. ceppo SF 68 nelle enteriti acute del bambino concomitanti ad infezioni delle vie respiratorie]. Clinica Pediatrica 1982;64:219-27.
Bin Li Xie 1995 {published data only}
    1. Bin Li Xie. Controlled clinical trial of Lacteol Fort Sachet versus furazolidone or berberine in treatment of acute diarrhoea in children [Étude contrôlée du Lactéol Fort sachets versus furazolidone ou berbérine dans le traitement des diarrhées aiguës de l'enfant]. Annales de Pediatrie 1995;42(6):396-401.
Boulloche 1994 {published data only}
    1. Boulloche J, Mouterde O, Mallet E. Management of acute diarrhoea in infants and young children. Controlled study of the anti-diarrheal efficacy of killed L. acidophilus (LB strain) versus a placebo and a reference drug (loperamide). Annales de Pediatrie 1994;41(7):457-63.
Brewster 2004 {published data only}
    1. Brewster DR, Ritchie B, McNeil Y, Davidson G, Butler R. Efficacy of probiotic therapy in Aboriginal children with acute diarrheal disease. Journal of Pediatric Gastroenterology and Nutrition 2004;39:S404.
Camarri 1981 {published data only}
    1. Camarri E, Belvisi A, Guidoni G, Marini G, Frigerio G. A double-blind comparison of two different treatments for acute enteritis in adults. Chemotherapy 1981;27(6):466-70.
Cetina Sauri 1990 {published data only}
    1. Cetina-Sauri G, Basto GS. Therapeutic evaluation of children with acute diarrhea. Tribuna Medica 1990;81(3):141-4.
Chandra 2002 {published data only}
    1. Chandra RK. Effect of Lactobacillus on the incidence and severity of acute rotavirus diarrhoea in infants. A prospective placebo-controlled double-blind study. Nutrition Research 2002;22(1):65-9.
Chapoy 1985 {published data only}
    1. Chapoy P. Treatment of acute infantile diarrhea: controlled trial of Saccharomyces boulardii [Traitement des diarrhées aiguës infantiles]. Annales de Pediatrie 1985;32(6):561-3.
Chicoine 1973 {published data only}
    1. Chicoine L, Joncas JH. Use of lactic enzymes in non-bacterial gastroenteritis [Emploi des ferments lactiques dans la gastro-entérite non bactérienne]. L'Union Médicale du Canada 1973;102(5):1114-5.
Costa‐Ribeiro 2000a {published data only}
    1. Costa-Ribeiro H, Ribeiro TCM, Mattos AP, Almeida PS, Valois SS, Vanderhoof JA. Use of Lactobacillus GG in the treatment of severe, acute diarrhoea in adverse environmental conditions. Journal of Pediatric Gastroenterology and Nutrition 2000;31 Suppl 2:251-2.
Costa‐Ribeiro 2000b {published data only}
    1. Costa-Ribeiro H, Ribeiro TCM, Mattos AP, Lins EV, Neri DA, Valois SS, Vanderhoof JA. Prophylactic administration of Lactobacillus GG to children in a daycare center. Journal of Pediatric Gastroenterology and Nutrition 2000;31 Suppl 2:252.
Cui 2004 {published data only}
    1. Cui Y-L, Wan F-C, Tang D-L, Wu S-H. Efficacy of Bacillus coagulans tablets in the treatment of acute and chronic diarrhoea. International Journal of Immunotherapy 2004;20(1):17-22.
Czerwionka 2009 {published data only}
    1. Czerwionka-Szaflarska M, Murawska S, Swincow G. Evaluation of influence of oral treatment with probiotic and/or oral rehydration solution on course of acute diarrhoea in children. Przeglad Gastroenterologiczny 2009;4(3):166-72.
Dash 2016 {published data only}
    1. Dash DK, Dash M, Mohanty MD, Acharya N. Efficacy of probiotic Saccharomyces boulardii as an adjuvant therapy in acute childhood diarrhoea. Journal of Nepal Paediatric Society 2016;36(3):250-5.
de dios Pozo‐O 1978 {published data only}
    1. dios Pozo-Olano J, Warram JH Jr, Gomez RG, Cavazos MG. Effect of a lactobacilli preparation on traveler's diarrhoea. A randomised, double blind clinical trial. Gastroenterology 1978;74(5 Pt 1):829-30.
Eren 2010 {published data only}
    1. Eren M, Dinleyici EC, Vandenplas Y. Clinical efficacy comparison of Saccharomyces boulardii and yogurt fluid in acute non-bloody diarrhea in children: a randomized, controlled, open label study. American Journal of Tropical Hygiene 2010;82(3):488-91.
Escribano 2018 {published data only (unpublished sought but not used)}
    1. Escribano J, Ferre N, Gispert-Llaurado M, Luque V, Rubio-Torrents C, Zaragoza-Jordana M, et al. Bifidobacterium longum subsp infantis CECT7210-supplemented formula reduces diarrhea in healthy infants: a randomized controlled trial. Pediatric Research 2018;83:1120-8.
Fang 2009 {published data only}
    1. Fang SB, Lee H-C, Hu J-J, Hou S-Y, Liu H-L, Fang H-W. Dose-dependent effect of Lactobacillus rhamnosus on quantitative reduction of faecal rotavirus shedding in children. Journal of Tropical Pediatrics 2009;55(5):297-301.
Fourrier 1968 {published data only}
    1. Fourrier A, Lequien P. The treatment of infantile gastroenteritis by the use solely of a combination of colibacillus and lactobacillus. Apropos of 56 cases. Annales de Pediatrie 1968;15:491-5.
Freedman 2018b {published data only}
    1. Freedman S, Williamson-Urquharta S, Farionb K, Gouinc S, Willand A, Poonaie N, et al. "Probiotics in acute gastroenteritis-benefit or harm?: a multicenter, randomized, double-blind, placebo-controlled clinical trial" in North American Congress of Clinical Toxicology (NACCT) Abstracts 2018. Clinical Toxicology 2018;56(10):912-1092.
Frigerio 1986 {published data only}
    1. Frigerio G. A lactic acid producer enterococcus in the prevention of antibiotic-associated diarrhoea and in the treatment of acute diarrhoeal disorders: a double-blind multicentre placebo-controlled clinical trial (Abstract). Digestive Diseases and Sciences 1986;31 Suppl:496.
Girola 1995 {published data only}
    1. Girola M, Ventura P. Efficacy of probiotic preparation with living, freeze-dried lactic acid bacteria and yeast on child diarrhoea [Efficacia di un prodotto probiotico a base di fermenti lattici e lievito vitali liofilizzati nel trattamento della diarrea del bambino]. Archivio di Medicina Interna 1995;47(2-3):61-72.
Gracheva 1996 {published data only}
    1. Gracheva NM, Gavrilov AF, Solov'eva AI, Smirnov VV, Sorokulova IB, Reznik SR, et al. The efficacy of the new bacterial preparation biosporin in treating acute intestinal infections. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 1996;1(1):75-7.
Grandi 2009 {published data only}
    1. Grandi G, Medina M, Soria R, Teran C, Araya M. Probiotics in the management of acute rotavirus diarrhea in Bolivian children: a randomized, double-blind, controlled trial of two different preparations. In: Pediatric Research. Vol. 67. 2010:447 (abstract 10).
Grandy 2010 {published data only}
    1. Grandy G, Medina M, Soria R, Terán CG, Araya M. Probiotics in the treatment of acute rotavirus diarrhoea. A randomized, double-blind, controlled trial using two different probiotic preparations in Bolivian children. BMC Infectious Diseases 2010;10:253.
Hafeez 2002 {published data only}
    1. Hafeez A, Tariq P, Ali S, Kundi ZU, Khan A, Hassan M. The efficacy of Saccharomyces boulardii in the treatment of acute watery diarrhoea in children: a multicentre randomized controlled trial. Journal of College of Physicians and Surgeons Pakistan 2002;12(7):432-4.
Henker 2007b {published data only}
    1. Henker J, Blokhin BM, Bolbot YK, Maydannik VG. Acute diarrhoea in infants and small children. Successful adjuvant therapy with the probiotic Mutaflor [Akute diarrhő bei säuglingen und kleinkindern. Erfolgreiche adjuvante therapie mit dem probiotikum Mutaflor]. Pädiat. Prax 2007;71:605-10.
Heydarian 2010 {published data only}
    1. Heydarian F, Kianifar HR, Ahanchian H, Khakshure A, Seyedi J, Moshirian D. A comparison between traditional yogurt and probiotic yogurt in non-inflammatory acute gastroenteritis. Saudi Medical Journal 2010;31(3):280-3.
Htwe 2008 {published data only}
    1. Htwe K, Yee KS, Tin M, Vandenplas Y. Effect of Saccharomyces boulardii in the treatment of acute watery diarrhea in Myanmar children: a randomized control study. American Journal of Tropical Medicine and Hygiene 2008;78(2):214-6.
Isolauri 1991 {published data only}
    1. Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei GG) promotes recovery from acute diarrhea in children. Pediatrics 1991;88(1):90-7.
Jimenez‐Rodriguez 2018 {published data only}
    1. Jimenez-Rodriguez C, Jimenez-Diaz J, Hernandez-Martinez F, Rodriguez-De-vera B. Efficacy of probiotics against acute diarrhoea in warm areas. In: Annals of Nutrition and Metabolism Conference: 9th workshop probiotics and prebiotics. Vol. 72. 2018.
Kaila 1992 {published data only}
    1. Kaila M, Isolauri E, Soppi E, Virtanen E, Laine S, Arvilommi H. Enhancement of the circulating antibody secreting cell response in human diarrhea by a human Lactobacillus strain. Pediatric Research 1992;32(2):141-4.
Kaila 1995 {published data only}
    1. Kaila M, Isolauri E, Saxelin M, Arvilommi H, Vesikari T. Viable versus inactivated Lactobacillus strain GG in acute rotavirus diarrhoea. Archives of Disease in Childhood 1995;72(1):51-3.
Khan 2012 {published data only}
    1. Khan A, Javed T, Chishti AL. Clinical efficacy of use of probiotic “Saccharomyces boulardii” in children with acute watery diarrhea. Pakistan Pediatric Journal 2012;36(3):122-7.
Khanna 2005 {published data only}
    1. Khanna V, Seema A, Ashraf M, Abida M. Efficacy of tyndalized Lactobacillus acidophilus in acute diarrhoea. Indian Journal of Pediatrics 2005;72(11):935-8.
Khoshdel 2018 {published data only}
    1. Khoshdel A, Kasiri KA, Salehi S, Sedehi M. Effect of probiotics in the treatment of acute noninflammatory diarrhea in hospitalized children aged 2–10 years. International Journal of Pharmaceutical Investigation 2018;8:200-4.
Korviakova 2000 {published data only}
    1. Korviakova EP. Use of loading doses of Bifidumbacterin forte for the treatment of patients with acute enteric infections. Zhurnal Mikrobiologii, Epidemiologii, i Immunobiologii 2000;6:58-61.
Lahiri 2015a {published data only}
    1. Lahiri K, D'Souza J, Gahlowt P. Beneficial role of probiotic in acute childhood diarrhoea. Journal of Harmonized Research in Medical and Health Science 2015;2(2):26-30.
Lahiri 2015b {published data only}
    1. Lahiri K, Jadhav K, Gahlowt P, Najmuddin F. Bacillus clausii as an adjuvant therapy In acute childhood diarrhoea. IOSR Journal of Dental and Medical Sciences 2015;14(5):74-6.
Lei 2006 {published data only}
    1. Lei V, Friis H, Michaelsen KF. Spontaneously fermented millet product as a natural probiotic treatment for diarrhea in young children: an intervention study Northern Ghana. International Journal of Food Microbiology 2006;110(3):246-53.
Le Leyur 2010 {published data only}
    1. Le Luyer B, Makhoul G, Duhamel JF. A multicentric study of a lactose free formula supplemented with Saccharomyces boulardii in children with acute diarrhea. Archives de Pédiatrie 2010;17(5):459-65.
Lievin Le‐Maol 2007 {published data only}
    1. Lievin-Le Maol V, Sarrazin-Davilla LE, Servin AL. An experimental study and a randomized, double-blind, placebo-controlled clinical trial to evaluate the antisecretory activity of Lactobacillus acidophilus strain LB against non-rotavirus diarrhea. Pediatrics 2007;120(4):795-803.
Lin 2009 {published data only}
    1. Lin JS, Chiu YH, Lin NT, Chu CH, Huang KC, Liao KW, et al. Different effects of probiotic species/strains on infections in preschool children: a double-blind, randomized, controlled study. Vaccine 2009;27(7):1073-9.
Magreiter 2006 {published data only}
    1. Margreiter M, Ludl K, Phleps W, Kaehler ST. Therapeutic value of a Lactobacillus gasseri and Bifdobacterium longum fixed bacterium combination in acute diarrhea: a randomized, double-blind, controlled clinical trial. International Journal of Clinical Pharmacology and Therapeutics 2006;44(5):207-15.
Majamaa 1995 {published data only}
    1. Majamaa H, Isolauri E, Saxelin M, Vesikari T. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. Journal of Pediatric Gastroenterology and Nutrition 1995;20(3):333-8.
Maragkoudaki 2018 {published data only (unpublished sought but not used)}
    1. Maragkoudaki M, Chouliaras G, Moutafi A, Thomas A, Orfanakou A, Papadopoulou A. Efficacy of an oral rehydration solution enriched with Lactobacillus reuteri DSM 17938 and zinc in the management of acute diarrhoea in infants: a randomized, double-blind, placebo-controlled trial. Nutrients 2018;10(9):pii: E1189.
Maugo 2012 {published data only}
    1. Maugo BM. Effectiveness of Bacillus clausii in reducing duration of illness in acute diarrhoea in children 6–59 months of age admitted with severe dehydration. University of Nairobi, Kenya 2012.
Mazo 2006 {published data only}
    1. Mazo SA, Arias SA. Efficacy and safety of milk fermented by lactobacillus (kumis) in nutritional recovery of undernourished children and control of their diarrhoea episodes. Revista Facultad Nacional de Salud Pública 2006;24(2):83-97.
Michielutti 1995 {published data only}
    1. Michielutti F, Bertini M, Presciuttini B, Andreotti G. Clinical assessment of a new oral bacterial treatment for children with acute diarrhea [Valutazione clinica di un nuovo batterioterapico orale in pazienti di eta pediatrica con diarrea acuta]. Minerva Medica 1996;87(11):545-50.
Misra 2009 {published data only}
    1. Misra S, Sabui TK, Pal NK. A randomized controlled trial to evaluate the efficacy of Lactobacillus GG in infantile diarrhea. Journal of Pediatrics 2009;155(1):129-32.
Mitra 1990 {published data only}
    1. Mitra AK, Rabbini GH. A double-blind, controlled trial of bioflorin (Streptococcus faecium SF68) in adults with acute diarrhea due to Vibrio chlolerae and entertoxigenic Escherichia coli. Gastroenterology 1990;99(4):1149-52.
Moraes 2001 {published data only}
    1. Moraes E, Chinzon D, Coelho LG, Fernandes TF, Haddad MT, et al. A multicentric, randomised, investigator-blind, parallel group study to assess the efficacy, safety and tolerability of Racecadotril versus Saccharomyces boulardii in the treatment of acute diarrhoea in adults [Estudo multicêntrico de grupos paralelos, randomizado, cego para o investigador, para avaliar a eficácia, segurança e tolerabilidade do racecadotril versus Saccharomyces boulardii no tratamento da diarréia aguda em adultos]. Revista Brasileira de Medicina 2001;58(1-2):65-74.
Niv 1963 {published data only}
    1. Niv M, Levy W, Greenstein NM. Yogurt in the treatment of infantile diarrhea. Clinical Pediatrics 1963;2(7):407-11.
Ortlieb 1974 {published data only}
    1. Ortlieb R. Randomized comparative testing of a new drug in intestinal disorders in a child. Therapie der Gegenwart 1974;113(1):76-8.
Pashapour 2006 {published and unpublished data}
    1. Pashapour N, Iou SG. Evaluation of yogurt effect on acute diarrhea in 6-24-month-old hospitalized infants. Turkish Journal of Pediatrics 2006;48(2):115-8.
Pearce 1974 {published data only}
    1. Pearce JL, Hamilton JR. Controlled trial of orally administered lactobacilli in acute infantile diarrhea. Journal of Pediatrics 1974;84(2):261-2.
Pedone 1999 {published data only}
    1. Pedone CA, Bernabeu AO, Postaire ER, Bouley CF, Reinert P. The effect of supplementation with milk fermented by Lactobacillus casei (strain DN-114 001) on acute diarrhoea in children attending day care centres. International Journal of Clinical Practice 1999;53(3):179-84.
Pedone 2000 {published data only}
    1. Pedone CA, Arnaud CC, Postaire ER, Bouley CF, Reinert P. Multicentric study of the effect of milk fermented by Lactobacillus casei on the incidence of diarrhoea. International Journal of Clinical Practice 2000;54(9):568-71.
Pene 1966 {published data only}
    1. Pene P, Linhard J, Bernou JC. The colibacillus-lactobacillus combination in the treatment of diarrhea in adults, children and infants [L'association colibacilles-lactobacilles dans le traitement des diarrhées de l'adulte, de l'enfant et du nourrisson]. La Semaine Des Hopitaux 1966;42(4):241-4.
Perez 2019 {published data only}
    1. Perez M, De Castro J-A, Guno MJ. Coddle study: Bacillus clausii as an adjunctive treatment of acute community-acquired diarrhoea in Filipino children. Journal of Pediatric Gastroenterology and Nutrition 2019;68(S1):477.
Pernica 2017 {published data only}
    1. Pernica JM, Steenhoff AP, Mokomane M, Moorad B, Lechiile K, Smieja M, et al. Rapid enteric testing to permit targeted antimicrobial therapy, with and without Lactobacillus reuteri probiotics, for paediatric acute diarrhoeal disease in Botswana: a pilot, randomized, factorial, controlled trial. PLoS ONE 2017;12(10):e0185177.
Rafeey 2008b {published data only}
    1. Rafeey M, Ghojazadeh M, Hadari V. Probiotics in children with acute diarrhea. In: WCPGHAN 3: World Congress of Pediatric Gastroenterology, Hepatology and Nutrition. 2008:129-35.
Rautanen 1998 {published data only}
    1. Rautanen T, Isolauri E, Salo E, Vesikari T. Management of acute diarrhoea with low osmolarity oral rehydration solutions and Lactobacillus strain GG. Archives of Disease in Childhood 1998;79(2):157-60.
Saint‐Marc 1991 {published data only}
    1. Saint-Marc T, Rossello-Prats L, Touraine JL. Efficacy of Saccharomyces boulardii in the treatment of diarrhea in AIDS [Efficacite de Saccharomyces boulardii dans le traitement des diarrhees du SIDA]. Annales de Médecine Interne 1991;142(1):64-5.
Salazar‐Lindo 2004 {published data only}
    1. Salazar-Lindo E, Miranda-Langschwager P, Campos-Sanchez M, Chea-Woo E, Bradley Sack R. Lactobacillus casei strain GG in the treatment of infants with acute watery diarrhoea: a randomised, double-blind, placebo controlled clinical trial. BMC Pediatrics 2004;4(18). []
Salazar‐Lindo 2007 {published data only}
    1. Salazar-Lindo E, Figueroa-Quintanilla D, Caciano MI, Reto-Valiente V, Chauviere G, Colin P, et al. Effectiveness and safety of Lactobacillus LB in the treatment of mild acute diarrhea in children. Journal of Paediatric Gastroenterology and Nutrition 2006;44(5):571-6.
Satoh 1984 {published data only}
    1. Satoh Y, Iwata S, Iwata Y, Yamashita N, Oikawa T, Osano M, et al. Effect of Bifidobacterium breve administration on clinical course and intestinal flora in children with acute diarrhea [Abstract]. Nippon Shonikagakkai Zasshi 1984;88:2178-9.
Savas‐Erdeve 2009 {published data only}
    1. Savas-Erdeve S, Gökay S, Dallar Y. Efficacy and safety of Saccharomyces boulardii in amebiasis-associated diarrhea in children. Turkish Journal of Pediatrics 2009;51(3):220-4.
Schrezenmeir 2004 {published data only}
    1. Schrezenmeir J, Heller K, McCue M, Llamas C, Lam W, Burrow H, et al. Benefits of oral supplementation with and without synbiotics in young children. Clinical Paediatrics 2004;43:239-49.
Sepp 1995 {published data only}
    1. Sepp E, Tamm E, Torm S, Lutsar I, Mikelsaar M, Salminen S. Impact of a Lactobacillus probiotic on the faecal microflora in children with shigellosis. Microecology and Therapy 1995;23(1):74-80.
Sharif 2017 {published data only}
    1. Sharif A, Kashani HH, Nasri E, Soleimani Z, Sharif MR. The role of probiotics in the treatment of dysentery: a randomized double-blind clinical trial. Probiotics and Antomicrobial Proteins 2017;9(4):380-5.
Simakachorn 2000 {published data only}
    1. Simakachorn N, Pichaipat V, Rithipornpaisarn P, Kongkaew C, Tongpradit P, Varavithya W. Clinical evaluation of the addition of lyophilized, heat-killed Lactobacillus acidophilus LB to oral rehydration therapy in the treatment of acute diarrhoea in children. Journal of Pediatric Gastroenterology and Nutrition 2000;30(1):68-72.
    1. Simakachorn N, Pichaipat V, Rithipornpaisarn P, Kongkaew C, Tongpradit P, Varavithya W. Erratum. Journal of Pediatric Gastroenterology 2000;30(2):228.
Sindhu 2014 {published data only}
    1. Sindhu KNC, Sowmyanarayanan TV, Paul A, Babji S, Ajjampur SSR, Priyadarshini S, et al. Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clinical Infectious Diseases 2014;58(8):1107–15.
Singh 1987 {published data only}
    1. Singh T. Yoghurt feeding during acute diarrhea. Indian Pediatrics 1987;24(6):530.
Singh 2018 {published data only}
    1. Singh M, Alam MS, Iqbal SMJ. Comparison of clinical efficacy of Saccharomyces boulardii with yogurt in acute watery diarrhea in children. Pakistan Paediatric Journal 2018;42(3):167-71.
Sudarmo 2003 {published data only}
    1. Sudarmo SM, Ranuh RG, Rochim A, Soeparto P. Management of infant diarrhea with high-lactose probiotic-containing formula. Southeast Asian Journal of Tropical Medicine and Public Health 2003;34(4):845-8.
Sugita 1994 {published data only}
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