Upload
hugo-simpson
View
220
Download
0
Tags:
Embed Size (px)
Citation preview
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
Why a WAO document on probiotics?
The 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
1990 – 20:1.000.000Tre
nds
in h
ospi
tal a
dmis
sion
rat
es o
f fo
od a
llerg
y by
age
(19
90-2
003)
Gup
ta R
. Tim
e tr
ends
in a
llerg
ic d
isor
ders
in th
e U
K.
Tho
rax
2007
; 62:
91-6
1995 – 60:1.000.000Tre
nds
in h
ospi
tal a
dmis
sion
rat
es o
f fo
od a
llerg
y by
age
(19
90-2
003)
Gup
ta R
. Tim
e tr
ends
in a
llerg
ic d
isor
ders
in th
e U
K.
Tho
rax
2007
; 62:
91-6
2003 – 120:1.000.000Tre
nds
in h
ospi
tal a
dmis
sion
rat
es o
f fo
od a
llerg
y by
age
(19
90-2
003)
Gup
ta R
. Tim
e tr
ends
in a
llerg
ic d
isor
ders
in th
e U
K.
Tho
rax
2007
; 62:
91-6
2010
– ?
?:1.
000.
000
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
Why a WAO document on probiotics?
The roots of food allergyNomenclature
Definitions & objectives Definitions & objectives EpistemologyEpistemology
Human microbiota & hygiene hypothesisHuman microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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.
The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted
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 eczema
sIgEsIgE
SPTSPT
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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclature
Definitions & objectives EpistemologyEpistemology
Human microbiota & hygiene hypothesisHuman microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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
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
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
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
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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclature
Definitions & objectives Epistemology
Human microbiota & hygiene hypothesisHuman microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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
. 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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclature
Definitions & objectives Epistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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
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
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
Human microbiota & hygiene hypothesis
. 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,
.
The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclatureEpistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseProbiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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
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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclatureEpistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseClinical sections Clinical sections
Claims Claims Research Research
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
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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclatureEpistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseClinical sections
Claims Claims Research Research
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
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
The WAO Special Committee on Food Allergy. Clinical Use of Probiotics for Paediatric Allergy (CUPPA) . A WAO position paper, WAO Journal, submitted
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
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
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
Why a WAO document on probiotics?
The roots of food allergyNomenclatureEpistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseClinical sections
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.
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
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
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
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
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
Towards CUPPA
Why a WAO document on probiotics?
The roots of food allergyNomenclatureEpistemology
Human microbiota & hygiene hypothesisProbiotics & Hygiene hypothesis
Probiotics & allergic diseaseClinical sections
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
ilan In
tern
ational M
eeting on Pediatri
c
Allerg
y
Milan, T
hursday 9
th – S
unday 12th Fe
bruary
2012