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

תזונה בינקות כהתחלה טובה לחיים הכינוס המדעי השני יום רביעי 14 במאי 2008 , ט"ז באייר תשס"ח. Probiotics in paediatrics. Where are we now?. Hania Szajewska The Medical University of Warsaw, Poland. Objectives. To discuss the hierarchy of evidence to guide clinical decision making

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

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  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. Hierarchy of evidenceFor questions about the effectiveness of an intervention V A L I D I T Y B I A S Meta-analysis of RCTs Randomised controlled trial (RCT) Obserwational studies (case-control, cohort) Observational studies (case report, case series) Experimental studies

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

  6. Meta-analysis RCT N0 3 RCT N0 2 RCT N0 5 RCT N0 6 RCT N0 1 RCT N0 4 Statistical methods Pooled results of all RCTs

  7. Meta-analysis • 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 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 diarrhoeaUp-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 boulardiiDuration of diarrhoeaUpdate 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. Not all probiotics are created equal • 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. Duration of diarrhea Mean difference in hours (compared with ORS only) . . . . . -30 -20 -10 0 10 20 30 Canani et al. BMJ 2007

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

  19. AGuarino FAlbano SAshkenazi DGendrel H Hoekstra RShamir HSzajewska ESPGHAN/ESPID Evidence-based Guidelines for the Management of Acute Gastroenteritis in Children in Europe ESPGHAN/ESPID Guidelines JPGN 2008;46:619-21

  20. 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

  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. Probiotics for prevention of AAD in children Szajewska et al. J Pediatr 2006;149:367-72 . . . . . . Favours probiotics Favours control

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

  25. Prevention of AAD in adults and children

  26. Lactobacillus preparation to prevent AADL casei DN 114 001, L bulgaricus, Str thermophilus (Actimel)RCT, adults, n=135 Diarrhea RR 0.4 (0.2 to 0.8) NNT 5 (3 to 15) C difficile diarrhea NNT 6 (4 to 14) 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 AADConclusions • 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 NNT 9 (5-30) NNT 24 (12-24) • Effective combinations • B. infantis. Str therm. B bifidum • L. acidophilus. B. infantis Deshpande et al. Lancet 2007;369:1614–20

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

  34. 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 Probiotics for prevention of NEC Deshpande et al. Lancet 2007;369:1614–20 AlFaleh, 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 probiotics1 • Current evidence is more convincing for probiotics’ efficacy in prevention than treatment of pediatric atopic dermatitis2 • 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 1x1010 CFU or placebo • 2-4 weeks before delivery + 6 months postnatally

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

  40. Lactobacillus GGKalliomaki et al. Lancet 2001 & 2003; JACI 2007 4 y 107/159 (67%) RR 3 (0.5-2) NS 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

  41. Lactobacillus GG

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

  43. Why conflicting results?

  44. Why conflicting results? • 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) • 4 lactobacilli: • L acidophilus, L casei, L salivarius, L lactis, • 2 bifidobacteria: • B bifidum and B lactis • Total daily dose 1010 CFU Lancet 2008;371:651-9

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