Abstract
Acute diarrhea is one of the most frequent causes of doctor visits and hospital admissions for children. Our objective was to evaluate the association between probiotics administration and reduction of acute infectious diarrhea duration in children dwelling in developed countries. Bibliographic databases, gray literature, and reference lists were searched up to September 29, 2019. Double-blind, randomized controlled trials that examined probiotics efficacy in children with acute infectious diarrhea residing in developed countries were included. Data were synthesized by generic inverse variance method using fixed- and random-effects model. Twenty trials met the eligibility criteria (n = 3469 patients) and were included in the qualitative synthesis, and 19 studies in meta-analysis. Twelve trials (n = 840) were assessed as high/unclear risk of bias and eight (n = 2629) as low risk of bias. Comparisons revealed a moderate effectiveness of probiotics in low risk of bias studies (MD = − 13.45 h; 95% CI − 24.26, − 2.62; p = 0.02, Bayesian meta-analysis pooled effect MD = − 0.38, 95% CrI − 2.3, 1.58) and a notable effect in studies with high/unclear risk for bias (MD = − 19.70 h; 95% CI − 28.09, − 11.31; p = 0.0004). In trials of optimal methodological quality (n = 1989), probiotics effect was absent (MD = − 3.32 h; 95% CI − 8.78, 2.13, p = 0.23).
Conclusion: Outcomes suggest that probiotics do not demonstrate sufficient clinical impact in reducing diarrhea duration in children in the developed countries.
Systematic Review Registration: This review is registered at PROSPERO (ID: CRD42020152966).
What is Known: • Probiotics, due to the conflicting study results, are administered without adequate evidence as an adjuvant therapeutic agent for eliminating duration of acute infectious diarrhea in pediatric patients. | |
What is New: • In developed countries, probiotics are demonstrated as ineffective in reducing the duration of acute infectious diarrhea in children. |
Similar content being viewed by others
Data availability
The data are available on request.
Code availability
n/a
All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
References
Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME (2014) The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the. Nature. 11:506–514. https://doi.org/10.1038/nrgastro.2014.66
Toropov V, Demyanova E, Shalaeva O, Sitkin S (2020) Whole-genome sequencing of Lactobacillus helveticus D75 and D76 confirms safety and probiotic potential. Microorganisms. 8(329). https://doi.org/10.3390/microorganisms8030329
Chondrou P, Karapetsas A, Kiousi DE, Tsela D, Anestopoulos I, Kotsianidis I (2018) Lactobacillus paracasei K5 displays adhesion, anti-proliferative activity and apoptotic effects in human colon cancer cells. Benefic Microbes 9(6):975–983. https://doi.org/10.3920/BM2017.0183
Pagnini C, Corleto VD, Martorelli M, Lanini C, D’Ambra G, Giulio ED, Fave GD (2018) Mucosal adhesion and anti-inflammatory effects of Lactobacillus rhamnosus GG in the human colonic mucosa: a proof-of-concept study. World J Gastroenterol 24(41):4652–4662. https://doi.org/10.3748/wjg.v24.i41.4652
Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A (2019) Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health. Appl Microbiol Biotechnol 103:6463–6472
Guarino A, Ashkenazi S, Gendrel D, Vecchio A (2014) Lo, Shamir R, Szajewska H. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases Evidence-Based Guidelines for the Management of Acute Gastroenteritis in Children in Europe: Update 2014. JPGN. 59(1):132–152. https://doi.org/10.1097/MPG.0000000000000375
Freedman SB, Eltorky M, Gorelick M (2010) Pediatric Emergency Research Canada Gastroenteritis Study Group T. Evaluation of a gastroenteritis severity score for use in outpatient settings. Pediatrics. 125(6):e1278–e1285. https://doi.org/10.1542/peds.2009-3270
Szajewska H, Guarino A, Hojsak I, Indrio F, Kolacek S, Shamir R, Vandenplas Y, Weizman Z (2014) Use of probiotics for management of acute gastroenteritis: a position paper by the ESPGHAN Working Group for Probiotics and Prebiotics. JPGN. 58(4):531–539. https://doi.org/10.1097/MPG.0000000000000320
Lo Vecchio A, Vandenplas Y, Benninga M, Broekaert I, Falconer J, Gottrand F, Lifschitz C, Lionetti P, Orel R, Papadopoulou A, Ribes-Koninckx C, Salvatore S, Shamir R, Schäppi M, Staiano A, Szajewska H, Thapar N, Wilschanski M, Guarino A (2016) An international consensus report on a new algorithm for the management of infant diarrhoea. Acta Paediatr 105(8):e384–e389. https://doi.org/10.1111/apa.13432
Higgins P, Green S (2011) Cochrane handbook for systematic reviews of interventions version 5.1.0 [Updated March 2011], The Cochrane Collaboration
Moher D, Liberati A, Tetzlaff J, Altman DG, Group TP (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA Statement. PLoS Med 6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097
IMF. International Monetary Fund. 2019. World Economic Outlook: Global Manufacturing Downturn, Rising Trade Barriers. Washington, DC, October; 2019.
UNDP. Human Development Report 2019. Beyond income, beyond averages, beyond today: inequalities in human development in the 21st century; 2019.
Kovacevic M, Assa J, Bonini A, et al. (2018) Human Development Indices and Indicators: 2018 Statistical Update, Published for the United Nations Development Programme (UNDP)
Subnational Human Development Index (3.0), Institute for Management Research Radboud University, https://globaldatalab.org/shdi/shdi/ Accessed: 13 November 2019.
Flores-Maltos DA, Mussatto SI, Contreras-Esquivel JC, Rodriguez-Herrera R, Teixeira J, Aguilar C (2014) Biotechnological production and application of fructooligosaccharides. Crit Rev Biotechnol 8551:1–9. https://doi.org/10.3109/07388551.2014.953443
Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
RStudio Team (2019). RStudio: Integrated Development for R. RStudio, Inc., Boston, MA URL http://www.rstudio.com/.
Harrer M, Cuijpers P, Furukawa T, Ebert DD (2019) Doing meta-analysis in R: a hands-on guide. https://doi.org/10.5281/zenodo.2551803
Inthout J, Ioannidis JPA, Rovers MM, Goeman JJ (2016) Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open 6:e010247. https://doi.org/10.1136/bmjopen-2015-010247
Viechtbauer W, Cheung MW (2010) Outlier and influence diagnostics for meta-analysis. Res Synth Methods 1:112–115. https://doi.org/10.1002/jrsm.11
Baujat B, Mahe C, Pignon J, Hill C (2002) A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials. Stat Med 2652:2641–2652. https://doi.org/10.1002/sim.1221
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2010) A basic introduction to fixed-effect and random-effects models for meta-analysis. Res Synth Methods 1:97–111. https://doi.org/10.1002/jrsm.12
Hartung J, Knapp G (2001) On tests of the overall treatment effect in meta-analysis with normally distributed responses. Stat Med 20:1771–1782. https://doi.org/10.1002/sim.791
Sidik K, Jonkman JN (2002) A simple confidence interval for meta-analysis. Stat Med 21:3153–3159. https://doi.org/10.1002/sim.1262
Sidik K, Jonkman JN (2006) Robust variance estimation for random effects meta-analysis. Comput Stat Data Anal 50:3681–3701. https://doi.org/10.1016/j.csda.2005.07.019
Inthout J, Ioannidis JP, Borm GF (2014) The Hartung–Knapp–Sidik–Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian–Laird method. BMC Med Res Methodol 14:25
Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JPT, Langan D, Salanti G (2016) Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods 7:55–79. https://doi.org/10.1002/jrsm.1164
McNeish D (2016) On using Bayesian methods to address small sample problems. Struct Equ Model A Multidiscip J 23(5):750–773. https://doi.org/10.1080/10705511.2016.1186549
Higgins JPT, Altman DG, Sterne JAC. Chapter 8: assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane Collaboration (2011). Available online at: https://training.cochrane.org/handb.
Cochrane Handbook for Systematic Reviews of Interventions – studies assessed as at unclear risk of bias. https://handbook-5-1.cochrane.org/chapter_8/8_8_2_2_studies_asses sed_as_at_unclear_risk_of_bias.htm Accessed December 29, 2019.
Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T (1991) A human Lactobacillus strain (Lactobacillus strain casei sp strain GG) promotes recovery from acute diarrhea in children. Pediatrics. 88(1):90–97
Isolauri E, Kaila M, Mykkänen H, Ling W, Salminen S (1994) Oral bacteriotherapy for viral gastroenteritis. Dig Dis Sci 39(12):2595–2600
Shornikova A, Casas I, Isolauri E, Mykkanen H, Vesikari T (1997) Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children. J Pediatr Gastroenterol Nutr 24(4):399–404
Shornikova A, Casas I, Mykkänen H, Salo E, Vesikari T (1997) Bacteriotherapy with Lactobacillus reuteri in rotavirus gastroenteritis. Pediatr Infect Dis J 16:1103–1107
Guarino A, Canani RB, Spagnuolo MI, Albano F, Di Benedetto L (1997) Oral bacterial therapy reduces the duration of symptoms and of viral excretion in children with mild diarrhea. J Pediatr Gastroenterol Nutr 25(July 2019):516–519. https://doi.org/10.1097/00005176-199711000-00005
Guandalini S, Pensabene L, Zikri M et al (2000) Lactobacillus GG administered in oral dehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gastroenterol Nutr 30(1):54–60
Rosenfeldt V, Fleischer Michaelsen K, Jakobsen M et al (2002) Effect of probiotic Lactobacillus strains in young children hospitalized with acute diarrhea. Pediatr Infect Dis J 21(5):411–416. https://doi.org/10.1097/01.inf.0000014470.82881.25
Rosenfeldt V, Fleischer Michaelsen K, Jakobsen M et al (2002) Effect of probiotic Lactobacillus strains on acute diarrhea in a cohort of nonhospitalized children attending day-care centers. Pediatr Infect Dis J 21(5):417–419. https://doi.org/10.1097/01.inf.0000014471.82190.59
Szymański H, Pejcz J, Jawien M, Chmielarczyk A, Strus M, Heczko PH (2006) Treatment of acute infectious diarrhoea in infants and children with a mixture of three Lactobacillus rhamnosus strains – a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 23(2):247–253. https://doi.org/10.1111/j.1365-2036.2006.02740.x
Chen C, Kong M, Lai M, Chao H (2010) Probiotics have clinical, microbiologic, and immunologic efficacy in acute infectious diarrhea. Pediatr Infect Dis J 29(2):135–138. https://doi.org/10.1097/INF.0b013e3181b530bf
Nixon A, Cunningham S, Cohen H, Crain E (2012) The effect of Lactobacillus GG (LGG) on acute diarrheal illness in the pediatric emergency department (ED). Pediatr Emerg Care 28(10):1048–1051. https://doi.org/10.1097/PEC.0b013e31826cad9f
Lee D, Park J, Kim M, Seo J, Lee J, Ha N (2015) Probiotic bacteria, B. longum and L. acidophilus inhibit infection by rotavirus in vitro and decrease the duration of diarrhea in pediatric patients. Clin Res Hepatol Gastroenterol 39(2):237–244. https://doi.org/10.1016/j.clinre.2014.09.006
Freedman SB, Sherman PM, Willan A, Johnson D, Gouin S, Schuh S (2015) Emergency department treatment of children with diarrhea who attend day care: a randomized multidose trial of a Lactobacillus helveticus and Lactobacillus rhamnosus combination probiotic. Clin Pediatr (Phila) 1-9. https://doi.org/10.1177/0009922815569200.
Park MS, Kwon B, Ku S, Ji GE. The efficacy of Bifidobacterium longu BORI and Lactobacillus acidophilus AD031 probiotic treatment in infants with rotavirus infection. Nutrients. 2017;9(887). https://doi.org/10.3390/nu9080887.
Freedman S, Williamson-Urquhart S, Farion K et al (2018) Multicenter trial of a combination probiotic for children with gastroenteritis. N Engl J Med 379(21):2015–2026. https://doi.org/10.1056/NEJMoa1802597
Schnadower D, Tarr P, Casper T et al (2018) Lactobacillus rhamnosus GG versus placebo for acute gastroenteritis in children. N Engl J Med 379(21):2002–2014. https://doi.org/10.1056/NEJMoa1802598
Pearce J, Hamilton J (1974) Controlled trial of orally administered lactobacilli in acute infantile diarrhea. Br Clin Lab Obs 84(2):261–262
Vandenplas Y, Hert SGD, PROBIOTICAL-study group (2011) Randomised clinical trial: the synbiotic food supplement probiotical vs. placebo for acute gastroenteritis in children. Aliment Pharmacol Ther 34:862–867. https://doi.org/10.1111/j.1365-2036.2011.04835.x
Passariello A, Terrin G, Cecere G, Micillo M, Marco G, di Costanzo M, Cosenza L, Leone L, Nocerino R, Berni Canani R (2012) Randomised clinical trial: efficacy of a new synbiotic formulation containing Lactobacillus paracasei B21060 plus arabinogalactan and xilooligosaccharides in children with acute diarrhoea. Aliment Pharmacol Ther 35:782–788. https://doi.org/10.1111/j.1365-2036.2012.05015.x
Francavilla R, Lionetti E, Castellaneta S, et al. (2012) Randomised clinical trial: Lactobacillus reuteri DSM 17938 vs. placebo in children with acute diarrhoea – a double-blind study. Aliment Pharmacol Ther. :1-7 https://doi.org/10.1111/j.1365-2036.2012.05180.x.
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135
Dehui L, Xiang W, Jiming L, Tiejun T (2018) Optimally estimating the sample mean from the sample size, median, mid-range and/or mid-quartile range. Stat Methods Med Res 27:1785–1805
Weir CJ, Butcher I, Assi V, Lewis SC, Murray GD, Langhorne P, Brady MC (2018) Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review. BMC Med Res Methodol 18(1):25
Sindhu KNC, Sowmyanarayanan TV, Paul A, Babji S, Ajjampur SSR, Priyadarshini S, Sarkar R, Balasubramanian KA, Wanke CA, Ward HD, Kang G (2014) Immune response and intestinal permeability in children with acute gastroenteritis treated with Lactobacillus rhamnosus GG: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis 58(8):1107–1115. https://doi.org/10.1093/cid/ciu065
Urbanska M, Gieruszczak-Bialek D, Szajewska H (2016) Systematic review with meta-analysis: Lactobacillus reuteri DSM 17938 for diarrhoeal diseases in children. Aliment Pharmacol Ther 43:1025–1034. https://doi.org/10.1111/apt.13590
Ianiro G, Rizzatti G, Plomer M, Lopetuso L, Scaldaferri F, Franceschi F, Cammarota G, Gasbarrini A (2018) Bacillus clausii for the treatment of acute diarrhea in children: a systematic review and meta-analysis of randomized controlled trials. Nutrients. 10:1074. https://doi.org/10.3390/nu10081074
Cruchet S, Furnes R, Maruy A, Hebel E, Palacios J, Medina F, Ramirez N, Orsi M, Rondon L, Sdepanian V, Xóchihua L, Ybarra M, Zablah RA (2015) The use of probiotics in pediatric gastroenterology: a review of the literature and recommendations by Latin-American experts. Pediatr Drugs 17:199–216. https://doi.org/10.1007/s40272-015-0124-6
Van Niel CW Van, Feudtner C, Garrison MM, Dimitri A. Lactobacillus therapy for acute infectious diarrhea in children: a meta-analysis. Pediatrics. 2002;109(4):678-684. doi:https://doi.org/10.1542/peds.109.4.678
Schnadower D, Finkelstein Y, Freedman SB (2015) Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries. Curr Opin Gastroenterol 31(1):1–6. https://doi.org/10.1097/MOG.0000000000000132
Liu D, Wang J (2017) Effect of immunoglobulin assisted probiotics on course of disease, bacterial infection rate, and secretory IgA levels in infants with rotavirus enteritis. WCJD 25(27):2486–2490. https://doi.org/10.11569/wcjd.v25.i27.2486
Maragkoudaki M, Chouliaras G, Moutafi A, Thomas A, Orfanakou A, Papadopoulou A (2018) 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. 10:1189. https://doi.org/10.3390/nu10091189
Bruzzese E, Fedele MC, Bruzzese D, Viscovo S, Giannattasio A, Mandato C, Siani P, Guarino A (2016) Randomised clinical trial: a Lactobacillus GG and micronutrient-containing mixture is effective in reducing nosocomial infections in children, vs. placebo. Aliment Pharmacol Ther 44(6):568–575. https://doi.org/10.1111/apt.13740
Szymanski H, Szajewska H (2019) Lack of efficacy of Lactobacillus reuteri DSM 17938 for the treatment of acute gastroenteritis: a randomized controlled trial. Pediatr Infect Dis J 38(10):237–242. https://doi.org/10.1097/INF.0000000000002355
Suez J, Zmora N, Segal E, Elinav E (2019) The pros, cons, and many unknowns of probiotics. Nat Med 25:716–729. https://doi.org/10.1038/s41591-019-0439-x
Bafeta A, Koh M, Riveros C, Ravaud P (2018) Harms reporting in randomized controlled trials of interventions aimed at modifying microbiota. Ann Intern Med 169(4):240–247. https://doi.org/10.7326/M18-0343
Lerner A, Shoenfeld Y, Matthias T (2019) Probiotics: if it does not help it does not do any harm. Really? Microorganisms 7(4):104.
Cohen P (2018) Probiotic safety — no guarantees (opinion). JAMA Intern Med 178(12):1577–1578. https://doi.org/10.7326/M18-0343
Morelli L, Callegari ML, Patrone V (2018) Prebiotics, probiotics, and synbiotics: a bifidobacterial view. Elsevier Inc. https://doi.org/10.1016/B978-0-12-805060-6/00017-X
Freedman S, Schnadower D, Tarr P (2020) The probiotic conundrum: regulatory confusion, conflicting studies, and safety concerns (opinion). JAMA. 323:823–824. https://doi.org/10.7326/M18-0343
Allen S, Martinez E, Gregorio G, Dans L (2010) Probiotics for treating acute infectious diarrhoea (review). Cochrane Database Syst Rev 11:CD003048. https://doi.org/10.1002/14651858.CD003048.pub3
Freedman SB, Ali S, Oleszczuk M, Gouin S, Hartling L, Freedman SB (2013) Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries. Evid-Based Child Heal 8:1123–1137. https://doi.org/10.1002/ebch.1932
Freedman SB, Pasichnyk D, Black KJL, Fitzpatrick E, Gouin S, Milne A, Hartling L, Pediatric Emergency Research Canada Gastroenteritis Study Group (2015) Gastroenteritis therapies in developed countries: systematic review and meta-analysis. PLoS One 10(6):e0128754. https://doi.org/10.1371/journal.pone.0128754
Fletcher SM, Mclaws M, Ellis JT (2013) Prevalence of gastrointestinal pathogens in developed and developing countries: systematic review and meta-analysis. J Public Ηealth Res 2(e9):42–53
do Carmo M, Santos C, Araújo M, Girón J, Fernandes E, Monteiro-Neto V (2018) Probiotics, mechanisms of action, and clinical perspectives for diarrhea management in children. Food Funct 9(10):5074–5095. https://doi.org/10.1039/c8fo00376a
Bero LA (2013) Why the Cochrane Risk of Bias tool should include funding source as a standard item. Cochrane Database Syst Rev 12:ED000075. https://doi.org/10.1002/14651858.ED000075
Sterne JAC (2013) Why the Cochrane Risk of Bias tool should not include funding source as a standard item. Cochrane Database Syst Rev 12:ED000076. https://doi.org/10.1002/14651858.ED000076
Sansotta N, Peroni DG, Romano S, Rugiano A (2019) The good bugs: the use of probiotics in pediatrics. Curr Opin Pediatr 31:661–669. https://doi.org/10.1097/MOP.0000000000000808
Author information
Authors and Affiliations
Contributions
L.V. and P.S.X. drafted the article, collected data, carried out analyses, and interpreted data. F.L. conceptualized the study topic and design, contributed in analyses and data interpretation, and reviewed the manuscript critically for important intellectual content.
Corresponding author
Ethics declarations
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Consent to participate
n/a
Consent for publication
n/a
Conflict of Interest
The authors declare that they have no conflict of interest.
Additional information
Communicated by Nicole Ritz
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(PDF 1.95 mb)
Rights and permissions
About this article
Cite this article
Vassilopoulou, L., Spyromitrou-Xioufi, P. & Ladomenou, F. Effectiveness of probiotics and synbiotics in reducing duration of acute infectious diarrhea in pediatric patients in developed countries: a systematic review and meta-analysis. Eur J Pediatr 180, 2907–2920 (2021). https://doi.org/10.1007/s00431-021-04046-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-021-04046-7