Probiotics in alleviating infections in children Prof. Hania Szajewska The Medical University of Warsaw Department of Paediatrics Hierarchy of evidence For questions about the effectiveness of an intervention V A L I D I T Y Systematic review or meta-analysis of RCTs Randomised controlled trial (RCT) Obserwational studies (case-control, cohort) Observational studies (case report, case series) Experimental studies B I A S Randomised controlled trial (RCT) Eligible patients Randomisation Treatment Control Outcome Outcome Systematic review RCT N0 1 Analysis RCT N0 2 Analysis RCT N0 3 Analysis RCT N0 4 Analysis RCT N0 5 Analysis RCT N0 6 Analysis Meta-analysis RCT N0 1 RCT N0 2 RCT N0 3 RCT N0 4 RCT N0 5 RCT N0 6 Statistical techniques Pooled results of all RCTs Meta-analysis • Why to perform a meta-analysis? – To increase power – To improve precision Egger, Smith, Altman (ed.). Systematic review in health care. Meta-analysis in context. BMJ Books 2000. Acute gastroenteritis Acute gastroenteritis • ORS – Despite the proven efficacy of oral rehydration, it remains underused • Why? – ORS dose not reduce frequency of bowel movements, fluid loss, duration of illness • Consequence – Interest in safe, effective, and inexpensive agents as an additional treatment ESPGHAN/ESPID Guidelines JPGN 2008;46:619-21 Rationale for the use of probiotics O'Toole PW, Cooney JC. Interdiscip Perspect Infect Dis. 2008;2008:175285. Acute gastroenteritis Duration of diarrhoea Metaanalysis Szajewska et al. Probiotic Various RCT (n) 8 (773) WMD (95% CI) -20 h (-26 to –14) Various 7 (675) -17 h (-29 to –7) Various 18 (1917) -19 h (-26 to –14) Various 12 (970) -30 h (-42 to –19) J Pediatr Gastr Nutr 2001 Van Niel et al. Pediatrics 2002 Huang et al. Dig Dis Sci 2002 Allen et al. Cochrane Review 2004 Reduced duration of diarrhoea ‘All animals are equal, just some animals are more equal than others’ George Orwell Is a meta-analytical approach appropriate to assess the efficacy of probiotics? Lactobacillus GG Up-date 2009 (12 RCTs, n=2611) Duration of diarrhoea 11 RCTs, n=2483, WMD -1 day (-1.6 to -0.4) Update: Szajewska et al. Aliment Pharmacol Therap 2007;25:257-64 Lactobacillus GG Duration of RV diarrhoea 3 RCTs, n=201, WMD -2.1 day (-3.5 to -0.46 Szajewska et al. Aliment Pharmacol Therap 2007;25:257-64 Saccharomyces boulardii Update 2009 (9 RCTs, n=1117) Duration of diarrhoea 7 RCTs, n=944, WMD -1.1 d (-1.6 to -0.5) Szajewska et al. Aliment Pharmacol Ther 2009 (in press) Would you recommend probiotics to treat acute gastroenteritis in your patients? Guidelines ESPGHAN/ESPID 2008 • A. Guarino • F. Albano • S. Ashkenazi • D. Gendrel • H. Hoekstra • R. Shamir • H. Szajewska NICE 2009 • R. Khanna • M. Lakhanpaul • S. Burman-Roy • S. Murphy ESPGHAN/ESPID Guidelines • Probiotics may be an effective adjunct to the management of AGE • Because there is no evidence of efficacy for many preparations, we suggest the use of probiotic strains with proven efficacy and in appropriate doses Examples • Lactobacillus GG • Saccharomyces boulardii ESPGHAN/ESPID Guidelines JPGN 2008;46:619-21 NICE guidelines • Many studies • High-quality SR suggesting a beneficial effect – Shortening the duration of diarrhoea, reducing the stool frequency – Studies varied in quality, in the specific probiotics studied, in the treatment regimens used • Despite some evidence of possible clinical effect, no recommendation for the use of probiotics at this time • Important field for further research National Institute for Health and Clinical Excellence 2009 Nosocomial diarrhoea Prevention of nosocomial diarrhoea What is known on this topic? Lactobacillus GG RR (95% CI) NNT (95% CI) Szajewska 0.2 (0.06-0.6) 4 (2-10) 0.8 (0.6-1.3) NS B. bifidum+Str. therm RR (95% CI) NNT (95% CI) Saavedra 0.2 (0.06-0.8) 5 (3-20) 0.7 (0.4-1.3) NS J Pediatr 2000 Mastretta JPGN 2002 Lancet 1994 Chouraqui JPGN 2004 What is new of this topic? LGG in the prevention of nosocomial gastrointestinal and respiratory tract infections • Population – N=742 hospitalized children • Intervention – LGG 109 CFU in 100 ml of a fermented milk product • Comparison – Placebo • Outcome – GI & RT infections Hojsak I, Abdovic S, Szajewska H, Kolacek S. J Pediatr Gastroenterol Nutr 2009;48:E85. LGG in the prevention of nosocomial gastrointestinal and respiratory tract infections • Conclusion – LGG administration can be recommended as a valid measure for decreasing the risk of nosocomial gastrointestinal and respiratory tract infections in paediatric facilities Hojsak I, Abdovic S, Szajewska H, Kolacek S. J Pediatr Gastroenterol Nutr 2009;48:E85. Summary of evidence Lactobacillus GG RR (95% CI) NNT (95% CI) Szajewska 0.2 (0.06-0.6) 4 (2-10) 0.8 (0.6-1.3) NS 0.4 (0.25-0.7) 15 (9-34) B. bifidum+Str. therm RR (95% CI) NNT (95% CI) Saavedra 0.2 (0.06-0.8) 5 (3-20) 0.7 (0.4-1.3) NS Mastretta Hojsak J Pediatr 2000 JPGN 2002 2009 Lancet 1994 Chouraqui JPGN 2004 Would you recommend probiotics to prevent nosocomial infections in your patients? Respiratory tract infections Prevention of respiratory tract infections Systematic review Type of studies Types of participants Types of interventions Type of comparisons Types of outcome measures • RCTs • Adults & children • Any probiotic • Placebo or no treatment • Prevention of upper or lower RTI Vouloumanou et al. Int J Antimicrob Agents 2009;34:197.e1-10. What this review found • Prevention – 14 RCTs • 4 RCTs – reduced incidence of RTIs • 10 RCTs – no effect • Severity of subsequent RTIs – Reduction in 5 out of six trials that reported relevant data • Duration of RTI – Reduction reported in 3 of nine trials Vouloumanou et al. Int J Antimicrob Agents 2009;34:197.e1-10. What is new on this topic? Leyer et al. Pediatrics 2009;124:e172-e179 Compares the efficacy of 1-strain (L acidophilus NCFM) and 2-strain preparations (L acidophilus / B animalis subs. lactis Bi-07) Leyer et al. Pediatrics 2009;124:e172-e179 Copyright ©2009 American Academy of Pediatrics Results Leyer et al. Pediatrics 2009;124:e172-e179 Results NS Leyer et al. Pediatrics 2009;124:e172-e179 Conclusion • Summary – Daily dietary probiotic supplementation for 6 months was a safe effective way to reduce fever, rhinorrhoea, and cough incidence and duration and antibiotic prescription incidence, as well as number of missed school days attributable to illness, for children 3 to 5 y of age. Would you recommend probiotics to prevent respiratory tract infections in healthy children 3-5 years of age? Would you recommend L. acidophilus NCFM (alone or in combination with B. animalis Bi-07) to prevent respiratory tract infections in healthy children 3-5 years of age? Probiotics for infections in children To use or not to use? • STEPS – Safety – Tolerability – Effectiveness – Price – Simpilicity Final comment… 'Half of what you are taught as medical students will in ten years have been shown to be wrong, and the trouble is, none of your teachers knows which half…’ S Burwell Dean of Harvard Medical School from 1935 to 1949 Pickering. BMJ 1956 Thank you for your attention Cracow, Poland