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Clinical Use of Probiotics for Pediatric Allergy

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. Learning objectives.

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Clinical Use of Probiotics for Pediatric Allergy

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  1. Clinical Use of Probiotics for Pediatric Allergy A position paper of the WAO Special Committee on FoodAllergy Alessandro Fiocchi, December 5th, 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 rootsoffoodallergy Nomenclature Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections Claims Research

  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

  8. Towards CUPPA Why a WAO document on probiotics? The rootsoffoodallergy Nomenclature Human microbiota & hygiene hypothesis Probiotics & Hygiene hypothesis Probiotics & allergic disease Clinical sections Claims Research

  9. Trends in hospital admissionratesoffoodallergybyage (1990-2003) Gupta R. Time trends in allergic disorders in the UK.Thorax 2007; 62:91-6 1990 – 20:1.000.000

  10. Trends in hospital admissionratesoffoodallergybyage (1990-2003) Gupta R. Time trends in allergic disorders in the UK.Thorax 2007; 62:91-6 1995 – 60:1.000.000

  11. Trends in hospital admissionratesoffoodallergybyage (1990-2003) Gupta R. Time trends in allergic disorders in the UK.Thorax 2007; 62:91-6 2003 – 120:1.000.000

  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 Claims Research

  16. Nomenclature Probioticofficialdefinition “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

  17. 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

  18. Atopy 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 eczema sIgE SPT . The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted

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

  20. 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 Claims Research

  21. Definitions & objectives 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

  22. 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

  23. Definitions & objectives 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). The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted

  24. Definitions & objectives 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

  25. Definitions & objectives 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

  26. 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 Claims Research

  27. Epistemology • Probiotics forallergy treatment are a hypothesisbased on otherhypotheses: • The hygienehypothesis • The microbialoriginofallergicdiseasehypothesis • Thatsupplementationequals treatment The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted

  28. Epistemology . 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

  29. 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 Claims Research

  30. 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

  31. 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

  32. 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

  33. Hypothesized effects of gut bacteria beyond the gut The idea thatsupplemental probiotic bacteria can beusedtomanipulateevolutionarilyconservedhomoeostaticmechanismsremains a hypothesis. In particular, effectsbeyond the gutremain a workinghypothesisonly. Noverr & Huffnagle . CEA 2005;35:1511-20

  34. Human microbiota & hygiene hypothesis • . • Therefore,  hard to understand • how each compartment problem should be addressed • by which microorganism • at what time in the disease process • at what dose • 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

  35. 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 Research

  36. 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

  37. The idea thatsupplementalprobioticbacteria can beusedtomanipulateallergyomoeostaticmechanismsremains a hypothesis 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

  38. 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 Research

  39. 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

  40. 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

  41. 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 Research

  42. 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

  43. Actimel in asthma 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 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

  44. Cumulative number of episodes of asthma (A) or rhinitis (B) in children with asthma (A) or rhinitis (B) at enrolment. 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. 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

  45. Probiotics for the treatment of allergic rhinitisand asthma 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. 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

  46. 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

  47. 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

  48. 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

  49. Probiotics for prevention of pediatric atopic dermatitis Lee J. Meta-analysisofclinicaltrialsof probiotics forprevention and treatment ofpediatricatopicdermatitis. J Allergy Clin Immunol. 2008;121:116-21

  50. Probiotics for treatment ofpediatricatopicdermatitis Currentevidenceis more convincingforprobiotics' efficacy in preventionthan treatment of PAD 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

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