1. Clinical Use of Probiotics for Pediatric Allergy A position paper of the WAO Special Committee on Food Allergy Alessandro Fiocchi, December 5 th, 2011 Chair, the WAO Special Committee on food allergy

2. Learning objectives Introduce “Clinical Use of Probiotics for Paediatric Allergy” (CUPPA) - A WAO position paper. Give an unequivocal definition of what a probiotic is Express the scientific background for possible use of probiotics in clinical allergy Report on studies using probiotics in atopic dermatitis Report on studies using probiotics in food allergy Report on studies on probiotics in GI allergic diseases Report on studies on probiotics in asthma and rhinitis

3. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

4. www.worldallergy.org The world federation of allergy, asthma and clinical immunology societies

5. Why a document on probiotics? medical literature propounding the supplementation of “friendly bacteria” for prevention & treatment of allergic conditions claims and counterclaims patient indication? specificity and reliability of products? biodynamic mechanisms? in vitro immunomodulatory effects! evidence-based clinical applications?

6. Why a document on probiotics? “Despite these problems, the impact of microbial exposure on human allergies is still a worthwhile pursuit”. Gerald Tannock, CUPPA committee; University of Otago, Dunedin, NZ

7. The WAO Food Allergy Special Committee Special Committee on Food Allergy 2010-2011 Alessandro Fiocchi, chairWesley Burks, vice-chair Tari HaathelaLeonard Bielory Ralf HeineDavid A. Osborn Hugh SampsonGerald W Tannock Robert J BoyleGideon Lack Mikael KuitunenSami Bahna Invited experts Sami BahnaACAAI Richard GoodmanAAAAI Sten DreborgAAAAI Bee Wah LeeAPAAI Renata Rodrigues CoccoLASAI EAACI

8. Towards CUPPA Why a WAO document on probiotics? The roots of food allergyNomenclature Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

9. 1990 – 20:1.000.000 Trends in hospital admission rates of food allergy by age (1990-2003) Gupta R. Time trends in allergic disorders in the UK. Thorax 2007; 62:91-6

10. 1995 – 60:1.000.000 Trends in hospital admission rates of food allergy by age (1990-2003) Gupta R. Time trends in allergic disorders in the UK. Thorax 2007; 62:91-6

11. 2003 – 120:1.000.000 Trends in hospital admission rates of food allergy by age (1990-2003) Gupta R. Time trends in allergic disorders in the UK. Thorax 2007; 62:91-6

12. 2010 – ??:1.000.000

13. Hundreds of explanations for the apparent surge in allergic disease in affluent countries over the past 60 years

14. CUPPA rationale. - Changes in life-style impacts exposure to bacteria - Bowel microbiota differ in infants born in countries with low or high prevalence of allergies - Historical differences are not testable - Ethnicity, maternal diet, hygiene standards, obstetric practices, antibiotic use, …. -Unknown connections: composition of the microbiota in early life / immune programming / response to environmental allergens / predisposition to allergies The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

15. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Definitions & objectives Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

16. West CE, D'Vaz N, Prescott SL. Dietary Immunomodulatory Factors in the Development of Immune Tolerance. Curr Allergy Asthma Rep. 2011 May 3

17. Nomenclature Probiotic official definition “live microorganisms which when administered in adequate amounts confer a health benefit on the host”. Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria, October 2001 accessible from http://www.who.int/foodsafety/publications/fs_management/en/probiotics.pdf

18. Nomenclature For the purpose of this document, the following definitions will be used: Probiotics: proprietary formulations of described microorganisms (genus, species and strains) and quantified (in CFU) populations of live bacteria that can be legally prescribed by physicians in recognition of specific, regulated health-related claims to clinical indication. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

19. Atopy. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted A tendency in the infant to become sensitized and produce IgE-antibodies in response to common allergens, sometimes expressed by developing symptoms such as asthma, rhinoconjunctivitis or eczemasIgESPT

20. Allergy. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Hypersensitivity  reaction to a substance tolerated by “normal individuals”. “non-allergic hypersensitivity”  immune system is not involved, “allergic hypersensitivity” or “allergy”  involved

21. A gap between basic research and clinical applications Medical literature propounding “friendly bacteria” Claims and counterclaims Biologists of all disciplines are beginning to realise the implications of mutualism & interrelationship between the various microflorae and their human host “a super-organism in microbiome” Frequency distribution of species? The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Definitions & objectives

22. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Definitions & objectivesEpistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

23. Aim of this overview is the translation from benchside to bedside “Live microorganisms which when administered in adequate amounts confer a health benefit on the host”. Which are these benefits? Allergy health is a precarious concept: Environment? socio-economical factors?... The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Definitions & objectives

24. Exposure to a social stressor alters the structure of the intestinal microbiota Reducing the indigenous microbiota blocks a stressor-induced increase in circulating IL-6 and iNOS mRNA Exposure to stressors significantly affects bacterial populations in the intestines Microbiota are necessary for stressor-induced increases in circulating cytokines M.T. Bailey et al. Brain Behavior Immunity 2011;25:397–407

25. For the purpose of this document, the following definitions will be used: Therapy: intervention targeting secondary or tertiary prevention, temporary relief or cure. Supplementation: intervention targeting add-on, or adjuvant therapy aimed to interfere with allergic mechanisms or homoeostatic processes, for efficient and sufficient therapy (as defined above). Definitions & objectives The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

26. For the purpose of this document, the following definitions will be used: Microbiota: the bowel bacterial community. Commensals (or symbionts): the members of the microbiota. Metagenome: the collective genomes of the microbiota (sometimes this is alluded to as ‘microbiome’, an equivocal term that will not be used in this document). The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Definitions & objectives

27. For the purpose of this document, the following definitions will be used: Microbiota: the bowel bacterial community. Commensals (or symbionts): the members of the microbiota. Metagenome: the collective genomes of the microbiota (sometimes this is alluded to as ‘microbiome’, an equivocal term that will not be used in this document). The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

28. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Definitions & objectives Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

29. Epistemology Probiotics for allergy treatment are a hypothesis based on other hypotheses: 1.The hygiene hypothesis 2.The microbial origin of allergic disease hypothesis 3.That supplementation equals treatment The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

30. . The assumption that efficacy in prevention implies efficacy of supplementation in clinical applications is not borne out by clinical trial evidence Current clinical science does not identify agents able to modify host disease phenotype nor individual host response. Clinical applications via oral supplementation in the context of the super-organism require novel avenues of research before we can claim to have worked out the mechanism of disease and treatment. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Epistemology

31. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Definitions & objectives Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

32. Human microbiota & hygiene hypothesis Humans cloaked with microbes Epidermal surface, upper respiratory tract, vagina Large microbial communities (microbiota) Human infants  genus Bifidobacterium. Microbiota change markedly after weaning Similar changes in other parts of the body The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

33. Human microbiota & hygiene hypothesis Microbiota change markedly after weaning Similar changes in other parts of the body Such changes may be as significant in the possible relationship between microbial exposure and allergies, as events in the bowel. The collapse of immune privilege which allergic disease implies is difficult balancing act between to little and too much immune suppression sensitive to multiple unbalancing stimuli. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

34. The hygiene hypothesis The hygiene hypothesis proposes that as a result of modern public health practices, individuals living in the industrialized world experience a relative deficiency in immune stimulation by microbes, rendering them vulnerable to the development of allergic hypersensitivities and their associated diseases. Prescott S, Fiocchi A. Avoidance or exposure to foods in prevention and treatment of food allergy? Curr Opin Allergy Clin Immunol 2010,10:258–66

35. Noverr & Huffnagle. CEA 2005;35:1511-20 The idea that supplemental probiotic bacteria can be used to manipulate evolutionarily conserved homoeostatic mechanisms remains a hypothesis. In particular, effects beyond the gut remain a working hypothesis only. Hypothesized effects of gut bacteria beyond the gut

36. Human microbiota & hygiene hypothesis. Therefore,  hard to understand 1.how each compartment problem should be addressed 2.by which microorganism 3.at what time in the disease process 4.at what dose 5.for how long,. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

37. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

38. Probiotics and hygiene hypothesis Probiotic administration may provide a tool to probe the relationship between specific microbial exposures and allergies. However, to date microbiota associations have been investigated with different methods, tools and host species, and results are often contradictory. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

39. Probiotics and hygiene hypothesis Probiotics do not sustainably alter the intestinal microbiota They may stimulate some form of evolutionarily conserved homeostatic mechanism of tolerance opening the way towards - prevention - treatment. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted The idea that supplemental probiotic bacteria can be used to manipulate allergy omoeostatic mechanisms remains a hypothesis

40. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections ClaimsResearch

41. Probiotics and allergic disease Progress in the scientific and medical evaluation and validation of probiotics has been slow. Even today, adequate information on retailed probiotics is often lacking. Difficulties: More reviews than experimental reports variable outcomes between trials The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

42. Probiotics and allergic disease Despite these problems, the impact of microbial exposure on human allergies is still a worthwhile pursuit. Tantalizing outcomes particularly from studies concerning probiotics and eczema in at-risk children fuel continuing interest in the field. However, future research must aim to reveal the underlying molecular mechanisms that apparently link microbes and predisposition to allergies. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

43. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sectionsClaimsResearch

44. Probiotics and asthma Murine models: antibiotic administration  allergic airway responses. Humans: - No treatment effect on asthma - sensitization rate for inhalant allergens not reduced - cat allergen sensitization The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

45. Actimel in asthma Giovannini M. A Randomized Prospective Double Blind Controlled Trial on Effects of Long- Term Consumption of Fermented Milk Containing Lactobacillus casei in Pre-School Children With Allergic Asthma and/or Rhinitis. Pediatr Res 2007; 62: 1-4 Objective: does long-term consumption of fermented milk with Lactobacillus casei improve allergic asthma and/or rhinitis in preschoolers? Design: a randomized, prospective, double blind, controlled trial Sample: 187 children 2–5 y of age. Intervention: fermented milk (100 mL) with Lactobacillus casei (108 cfu/mL) or placebo for 12 mo. Outcome measures: time free from- and number of episodes of asthma/rhinitis

46. Cumulative number of episodes of asthma (A) or rhinitis (B) in children with asthma (A) or rhinitis (B) at enrolment. Giovannini M. A Randomized Prospective Double Blind Controlled Trial on Effects of Long- Term Consumption of Fermented Milk Containing Lactobacillus casei in Pre-School Children With Allergic Asthma and/or Rhinitis. Pediatr Res 2007; 62: 1-4 While longterm consumption of fermented milk containing Lactobacillus casei may improve the health status of children with allergic rhinitis, no effect was found in asthmatic children.

47. Probiotics for the treatment of allergic rhinitis and asthma Vliagoftis H. Probiotics for the treatment of allergic rhinitis and asthma: systematic review of randomized controlled trials. Ann Allergy Asthma Immunol. 2008;101:570-9 Probiotics may have a beneficial effect in AR by reducing symptom severity and medication use. Many more good-quality studies are needed to resolve this issue.

48. Probiotics and rhinitis Some strains have been shown to alleviate symptoms and markers of allergic rhinitis: -eosinophil infiltration into nasal mucosa - decreased IL-5 production -increased TNF-alpha, IFN-gamma, IL-10 and IL-12, IL-13 Quality of the clinical studies poor Mechanism yet to be defined The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

49. Probiotics and eczema 14 randomised controlled trials of probiotics or synbiotics for treating eczema 14 for preventing eczema Protagonists are Lactobacillus species, alone or in combination with other probiotics and/or prebiotic, Systematic review and/or meta-analysis of 12 of the 14 published studies undertaken by 3 separate groups The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

50. Probiotics and eczema  there is no evidence currently that probiotics provide clinically meaningful benefits when used to treat established eczema, however the possibility that novel probiotic strains or treatment during adulthood may prove to be effective in the future cannot be discounted. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

51. Lee J. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol. 2008;121:116-21 Probiotics for prevention of pediatric atopic dermatitis

52. Lee J. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis. J Allergy Clin Immunol. 2008;121:116-21 Current evidence is more convincing for probiotics' efficacy in prevention than treatment of PAD Probiotics for treatment of pediatric atopic dermatitis

53. Double-blind, placebo-controlled prospective trial 105 pregnant women from families with >/=1 member (mother, father, or child) with an atopic disease randomly assigned to receive either the probiotic Lactobacillus GG or placebo 94 families (89.5%) completed the trial Supplementation period started 4 to 6 weeks before expected delivery, followed by a postnatal period of 6 months Primary end point: atopic dermatitis at the age of 2 years. Kopp MV. Randomised DBPC trial of probiotics for primary prevention: no clinical effect of lactobacillus GG supplementation. Pediatrics 2008;121:e850-6 GG for prevention of atopic dermatitis.

54. Kopp MV. Randomised DBPC trial of probiotics for primary prevention: no clinical effect of lactobacillus GG supplementation. Pediatrics 2008; 121:e850-6

55. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections Claims & future studiesConclusion

56. Structure & correspondence of claims with the state of the art in allergy research. Intense regulatory efforts dedicated to the possible anti- allergic properties of probiotics 2001: FAO/WHO “Guidelines for the Evaluation of Probiotics in Food”. 2002: FAO/WHO guidelines to the methodology to substantiate health claims. The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted Probiotics could act as immunomodulators in allergy

57. Structure & correspondence of claims with the state of the art in allergy research. The majority of claims for probiotics in allergy medicine have been rejected by EFSA & FDA. 2010: EFSA - “Scientific Opinion on the substantiation of health claims related to various food(s)/food constituent(s) claiming “healthy and balanced digestive system” The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

58. Future studies 1. Hygiene and avoidance of microbes vs. changes in microbial symbioses vs. reduced tolerance? 2. Composition of the ‘normal’ human microbiota in various organ environments - its modifications through different age groups and in allergic disease 3. Which microbial species and varieties are tolerogenic? Does that vary between subjects? The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

59. Future studies 4. What organ, tissues (host), niches (microbiota) and populations of microorganisms (microbiota compartment) are involved in induction of tolerance: oral cavity? small intestine? colon? ….Epithelium, lymphatic tissue, dendritic cells, mast cells, B cells, macrophages, T cells? 5. What is the link between the bacteria, the mucosa of the gut and lungs, the immune system, and the allergic disease states mediated by mucosal bacterial species? 6. Is the same site and mechanism as important for early as to late tolerance or for maintaining tolerance? The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

60. Future studies 7. Do we have enough probiotics? Do we need to focus on certain species such as L. rhamnosus which has produced compelling outcomes with regard to eczema prevention? 8. Is there a role for probiotics in addition to antigen exposure to modulate tolerance in prevention and treatment of food allergy? The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA). A WAO position paper, WAO Journal, submitted

61. Towards CUPPA Why a WAO document on probiotics? The roots of food allergy Nomenclature Epistemology Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections Claims & future studies Conclusion

62. Clinical Use of Probiotic Products for Allergy (CUPPA): a WAO position paper to be published in the WAO Journal. Probiotics: fine for some, but not everybody’s cup of tea

63. Not everybody’s cup of tea! The 6 th Milan International Meeting on Pediatric Allergy Milan, Thursday 9 th – Sunday 12 th February 2012 Not everybody’s cup of tea! The 6 th Milan International Meeting on Pediatric Allergy Milan, Thursday 9 th – Sunday 12 th February 2012