clinical use of probiotics for pediatric allergy a position paper of the wao special committee on...

Clinical Use of Probiotics for Pediatric Allergy

A position paper of the WAO Special Committee on Food Allergy

Alessandro Fiocchi, December 5th, 2011Chair, the WAO Special Committee on food allergy

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

Towards CUPPA

Why a WAO document on probiotics?

The roots of food allergyThe roots of food allergyNomenclatureNomenclature

Human microbiota & hygiene hypothesisHuman microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis

Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections

Claims Claims Research Research

www.worldallergy.org

The world federation of allergy, asthma and clinical immunology societies

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?

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

The WAO Food Allergy Special Committee

Special Committee on Food Allergy 2010-2011

Alessandro Fiocchi, chair Wesley Burks, vice-chair

Tari Haathela Leonard Bielory

Ralf Heine David A. Osborn

Hugh Sampson Gerald W Tannock

Robert J Boyle Gideon Lack

Mikael Kuitunen Sami Bahna

Invited experts

Sami Bahna ACAAI

Richard Goodman AAAAI

Sten Dreborg AAAAI

Bee Wah Lee APAAI

Renata Rodrigues Cocco LASAI

EAACI

Towards CUPPA


The roots of food allergyNomenclatureNomenclature




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

years

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

Towards CUPPA


The roots of food allergyNomenclature

Definitions & objectives Definitions & objectives EpistemologyEpistemology




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

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.


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

sIgEsIgE

SPTSPT

Allergy

.


Hypersensitivity reaction to a substance tolerated by

“normal individuals”.

“non-allergic hypersensitivity” immune system is not involved,

“allergic hypersensitivity” or “allergy” involved

Towards CUPPA



Definitions & objectives EpistemologyEpistemology




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?...


Definitions & objectives

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



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).





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).



Towards CUPPA



Definitions & objectives Epistemology




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 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.


Epistemology

Towards CUPPA



Definitions & objectives Epistemology

Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis



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



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 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

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


. Therefore, hard to understand

1.how each compartment problem should be addressed2.by which microorganism

3.at what time in the disease process4.at what dose 5.for how long,

.


Towards CUPPA


The roots of food allergyNomenclatureEpistemology

Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis



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.


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 idea that supplemental probiotic bacteria can be used

to manipulate allergy omoeostatic mechanisms

remains a hypothesis

Towards CUPPA




Probiotics & allergic diseaseClinical sections Clinical sections


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


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.


Towards CUPPA




Probiotics & allergic diseaseClinical sections


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


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

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, noeffect was found in asthmatic children.

Probiotics for the treatment of allergic rhinitisand 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 moregood-quality studies are needed to

resolve this issue.

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 poorMechanism yet to be defined


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


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.


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

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

• 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.

Kopp MV. Randomised DBPC trial of probiotics for

primary prevention: no clinical effect of

lactobacillus GG supplementation.

Pediatrics 2008; 121:e850-6

Towards CUPPA





Claims & future studies Conclusion Conclusion

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.


Probiotics could act as immunomodulators in

allergy

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”


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?


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?


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?


Towards CUPPA





Claims & future studies Conclusion

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

Not eve

rybody’s

cup of t

ea!

The 6th M

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Allerg

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Milan, T

hursday 9

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unday 12th Fe

bruary

2012

clinical use of probiotics for pediatric allergy a position paper of the wao special committee on...

Documents

food allergy slide

food allergy report

clinical use of probiotics

clinical allergy report

nz slide

rhinitis slide

pediatric allergy

possible use of probiotics