1. תזונה בינקות כהתחלה טובה לחיים הכינוס המדעי השני יום רביעי 14 במאי 2008, ט " ז באייר תשס " ח

2. Probiotics in paediatrics. Where are we now? Hania Szajewska The Medical University of Warsaw, Poland

3. Objectives To discuss the hierarchy of evidence to guide clinical decision making To review the evidence on the use of probiotics in paediatrics

4. VALIDITYVALIDITY BIASBIAS Meta-analysis of RCTs Randomised controlled trial (RCT) Obserwational studies (case-control, cohort) Observational studies (case report, case series) Experimental studies Hierarchy of evidence For questions about the effectiveness of an intervention

5. Randomised controlled trial (RCT) Eligible patients Treatment Randomisation Control Outcome

6. RCT N 0 1 RCT N 0 2 RCT N 0 3 RCT N 0 4 RCT N 0 5RCT N 0 6 Pooled results of all RCTs Statistical methods Meta-analysis

7. Why to perform a meta-analysis? –To increase power –To improve precision When to pool the results? –If the studies are considered sufficiently homogenous in terms of the question and methods Egger, Smith, Altman (ed.). Systematic review in health care. Meta-analysis in context. BMJ Books 2000.

8. Objectives To discuss the hierarchy of evidence to guide clinical decision making To review the evidence on the use of probiotics in paediatrics

9. Documented…

10. 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

11. Duration of diarrhoea MetaanalysisProbioticRCT (n)WMD (95% CI) Szajewska et al. J Pediatr Gastr Nutr 2001 Various8 (773)-20 h (-26 to –14) Van Niel et al. Pediatrics 2002 Various7 (675)-17 h (-29 to –7) Huang et al. Dig Dis Sci 2002 Various18 (1917)-19 h (-26 to –14) Allen et al. Cochrane Review 2004 Various12 (970)-30 h (-42 to –19) Reduced duration of diarrhoea

12. Criticism Beneficial effects of probiotics are strain specific Pooling data on different strains may result in misleading conclusions

13. Lactobacillus GG Duration of diarrhoea Up-date 2008 (2 new RCTs) 9 RCTs, n=1714, WMD -23 h (-38 to -7) Szajewska et al. Aliment Pharmacol Therap 2007;25:871-81

14. Saccharomyces boulardii Duration of diarrhoea Update 2008 (1 new RCT) 5 RCTs, n=656, WMD -17 h (-23 to -13) Szajewska et al. Aliment Pharmacol Therap 2007;25:257-64

15. Not all probiotics are created equal

16. RCT, open Children, age 3-36 mo, AGE, out-patients, Italy 5 probiotic preparations vs placebo –LGG –S boulardii –B clausii –Mix of 4 –E faecium SF68 Canani et al. BMJ 2007

17. Probiotic(s) Difference (95% CI) LGG-32 (-41 to -23) S. boulardii-5 (-13 to 5) B. clausii1 (-7 to 8) Mix-37 (-47 to -25) E. faecium SF682 (-5 to 11). Duration of diarrhea Mean difference in hours (compared with ORS only) Canani et al. BMJ 2007 -30-20-100102030....

18. Would you recommend probiotics to treat acute gastroenteritis in your patients?

19. ESPGHAN/ESPID Evidence-based Guidelines for the Management of Acute Gastroenteritis in Children in Europe A Guarino F Albano S Ashkenazi D Gendrel H Hoekstra R Shamir H Szajewska ESPGHAN/ESPID Guidelines JPGN 2008;46:619-21

20. 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 ESPGHAN/ESPID Guidelines JPGN 2008;46:619-21

21. Unanswered question How would a rotavirus vaccine impact the need for probiotics?

22. Antibiotic associated-diarrhoea Definition –Acute inflammation of the intestinal mucosa caused by the administration of broad-spectrum antibiotics Etiology –Most commonly Clostridium difficile Incidence in children receiving broad- spectrum antibiotics –11-40%

23. Probiotic(s)NRR (95% CI)NNT LGG1880.3 (0.1-0.6) LGG1490.3 (0.1-1.1) 3070.3 (0.2-0.6)7 (5-13) L. acid/B. infantis180.5 (0.2-1.2) L. acid/L. bulg381.0 (0.6-1.5) B. lactis/Str. ther1570.5 (0.3-0.9)7 (4-62) S. boulardii2460.2 (0.1-0.6)8 (5-15) Total (6 RCTs)7660.4 (0.3-0.8)7 (5-10)...... Favours probiotics Favours control Probiotics for prevention of AAD in children Szajewska et al. J Pediatr 2006;149:367-72

24. L. rhamnosus (E/N, Oxy, Pen) RCT, double-blind N=240, 3 mo to 14 y ITT analysis Ruszczynski M, Radzikowski A, Szajewska H. Aliment Pharmacol Ther 2008 (in press) Diarrhea RR 0.4 (0.2 to 0.9) NNT 11 (6 to 106)

25. MetaanalysisRR (95% CI)NNT (95% CI) D’Souza Br Med J 2002 0.4 (0.3-0.5)11 (8-18) Cremonini Aliment Pharm Ther 2002 0.4 (0.3-0.6)9 (7-14) Szajewska Aliment Pharm Ther 2005 0.4 (0.2-0.8)10 (7-16) Szajewska J Pediatr 2006 0.4 (0.3-0.8)7 (5-10) Johnston CMAJ 2006 0.4 (0.3-0.8)6 (5-8) Prevention of AAD in adults and children

26. Diarrhea RR 0.4 (0.2 to 0.8) NNT 5 (3 to 15) C difficile diarrhea NNT 6 (4 to 14) Lactobacillus preparation to prevent AAD L casei DN 114 001, L bulgaricus, Str thermophilus (Actimel) RCT, adults, n=135 Hickson et al. BMJ 2007;335:80-5.

27. 60% reduction in the risk of AAD Would you recommend probiotics to prevent AAD in your patients?

28. Probiotics in the prevention of AAD Conclusions The use of probiotic strains with proven efficacy is reasonable whenever the physician feels that preventing this usually self-limited complication is important In children (in alphabetical order): –B. lactis Bb12/Str. thermophilus –Lactobacillus GG –L. rhamnosus (E/N, Oxy, Pen) –Saccharomyces boulardii Szajewska, Setty, Mrukowicz, Guandalini. J Pediatr Gastroenterol Nutr 2006;42:454-75

29. Promising…

30. Necrotizing enterocolitis Background –Incidence 2.6-2.8% of VLBW –Low colonisation with bifidobacteria and lactobacilli Rationale –Increased barrier to translocation of bacteria across mucosa –Exclusion of pathogens –Modification of host response

31. Effect of probiotics on NEC stage 2 or greater Deshpande et al. Lancet 2007;369:1614–20

32. Effect of probiotics on NEC stage 2 or greater Effective combinations B. infantis. Str therm. B bifidum L. acidophilus. B. infantis Effective combinations NNT 9 (5-30) NNT 24 (12-24) Deshpande et al. Lancet 2007;369:1614–20

33. Effect of probiotics on blood-culture- positive sepsis NS Deshpande et al. Lancet 2007;369:1614–20

34. Probiotics for prevention of NEC Probiotics might reduce the risk of NEC However, the short- term and long-term safety of probiotics needs to be assessed in large trials Probiotics reduces the occurence of NEC and death in infants <1500 g Insufficient data for infants <1000 g Deshpande et al. Lancet 2007;369:1614–20AlFaleh, Bassler. Cochrane Review 2008

35. Would you recommend probiotics to prevent NEC in your preterm patients?

36. Questionable…

37. Probiotics for allergy prevention What is already known on this topic? –Insufficient evidence to recommend the addition of probiotics 1 –Current evidence is more convincing for probiotics’ efficacy in prevention than treatment of pediatric atopic dermatitis 2 What is new on this topic? 1. Osborn & Sinn. Cochrane Review 2006 2. Lee et al. JACI 2008;121:116-21.

38. Lactobacillus GG Kalliomaki et al. Lancet 2001 & 2003; JACI 2007 Design –RCT Participants –159 pregnant women (atopic disease or  1 first degree relative or partner with atopic disease) Intervention –LGG 1x10 10 CFU or placebo –2-4 weeks before delivery + 6 months postnatally

39. Lactobacillus GG Kalliomaki et al. Lancet 2001 & 2003; JACI 2007 2 y 132/159 (83%) RR 0.5 (0.3-0.8) NNT 5 (3-16) 4 y 107/159 (67%) RR 0.6 (0.3-0.9) NNT 6 (3-64) 7 y 116/159 (73%) RR 0.6 (0.5-0.9) NNT 5 (3-18)

40. 7 y 116/159 (73%) RR 3 (0.98-12) NS 4 y 107/159 (67%) RR 2 (0.8-5) NS 7 y 116/159 (73%) RR 2 (0.9-6) NS 4 y 107/159 (67%) RR 3 (0.5-2) NS Lactobacillus GG Kalliomaki et al. Lancet 2001 & 2003; JACI 2007

41. Lactobacillus GG Kalliomaki 2001Kopp 2008 N132/15994/105 Population Atopic disease or  1 first degree relative or partner with atopic disease InterventionLGG 1x10 10 CFU, once daily LGG 5x10 9 CFU, twice daily, 2-4 w before delivery + 6 m postnatally 4-6 wk before delivery + 6 m postnatally ComparisonPlacebo StudyRCT

42. RR 1 (0.5-2) NS RR 2.9 (1.1-8) NNH 6 (4-75) Kopp et al. Pediatrics 2008;121:e850-6 Lactobacillus GG

43. Why conflicting results?

44. Minor deviations in the protocol? –Highly unlikely Differences in confounding variables –Number of atopic family members per individual –Recruitment of more infants with older siblings Different genetic backgound? –Susceptibility to probiotics might differ between individuals because of different genetic background Kopp et al. Pediatrics 2008;121:e850-6

45. Would you recommend LGG to prevent allergic disorders in your patients?

46. Would I recommend LGG to prevent allergic disorders? LGG cannot be generally recommended for primary prevention Future research to determine if probiotics may nonetheless be beneficial in certain subgroups of infants

47. Intriguing…

48. Gut microbiota and obesity … when one of bacteria is dominant, this may impact on how many calories we extract from our diet… Ley et al. Nature 2006;444:1022-3 Turnbaugh et al. Nature 2006;444:1027-31

49. Safety

50. Are probiotics safe? Safe for use in generally healthy population Recent report PROPATRIA Study –RCT, severe acute pancreatitis (adults) –Probiotic mix vs placebo –Death 16% vs 6% (RI 2.5, 95% CI 1.2 to 5.3) Lancet 2008;371:651-9 4 lactobacilli: L acidophilus, L casei, L salivarius, L lactis, 2 bifidobacteria: B bifidum and B lactis Total daily dose 10 10 CFU

51. Are probiotics safe? Probiotic prevention study –LGG group significantly more likely to experience at least 5 episodes of wheezing bronchitis (26% vs 9%)

52. Safety … it is no longer tenable to regard probiotics as risk-free… Editorial. Lancet 2008;371:624.

53. Safety Caution in –Immunocompromised subjects –Recovering from surgery –Individuals who have compromised gut integrity –At increased risk for infection from any source Douglas & Sanders. JADA 2008;108:510-21

54. Safety Caution is needed –Some probiotic preparations contain cow’s milk protein (France – two out of three preparations) –Case report – anaphylaxis after taking a probiotic containing cow’s milk protein Lee et al. J Allergy Clin Immunol 2007;119:746-7

55. STEPS –Safety –Tolerability –Effectiveness –Price –Simpilicity Probiotics in pediatrics To use or not to use?

56. 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’ Sidney Burwell Dean of Harvard Medical School from 1935 to 1949 Pickering. BMJ 1956

57. Thank you for your attention Cracow, Poland

58. Unanswered questions Population –Can we further identify populations at high risk of disease that would benefit most from probiotics? Probiotic strains –Have we exausted the choice of probiotics or are there more promising strains? –What about strain combinations? –What about genetically modified probiotic bacteria?

59. Unanswered questions Delivery vehicles –What are the best delivery vehicles? –Do we need food or pharmaceutical based preparations? Dosing –What are the most effective dosing schedules and how to verify viability?

60. Unanswered questions Cost-effectiveness –Have we addressed properly the cost- effectiveness of using probiotics to prevent/treat infections? Study design –What are the best study desings for future trials? –Head to head comparisons or placebo controlled trials?

61. Take-home messages Not all probiotics are created equal Well documented indications –AGE, AAD Promising data –NEC Questionable –Prevention of allergy Safe in otherwise healthy children