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Clinical Use of Probiotics for Pediatric Allergy
A position paper of the WAO Special Committee on Food Allergy
Alessandro Fiocchi, December 5th, 2011
Chair, 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 allergy
Nomenclature
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims
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 allergy
Nomenclature
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims
Research
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
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
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
2003 – 120:1.000.000
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 allergy
Nomenclature
Definitions & objectives
Epistemology
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims
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
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
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
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
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
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
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
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
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 allergy
Nomenclature
Definitions & objectives
Epistemology
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims
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
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
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
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
Hypothesized effects of gut bacteria beyond the gut
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.
Noverr & Huffnagle . CEA 2005;35:1511-20
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
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
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
The idea that supplemental
bacteriaalter
canthebeintestinal
used microbiota
Probiotics probiotic
do not sustainably
to manipulate allergy
They may stimulate
some form
of evolutionarily conserved
omoeostatic
mechanisms
homeostatic mechanism of tolerance opening the way
remains a hypothesis
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
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
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 allergy
Nomenclature
Epistemology
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims
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
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 LongTerm Consumption of Fermented Milk Containing Lactobacillus casei in Pre-School
Children With Allergic Asthma and/or Rhinitis. Pediatr Res 2007; 62: 1-4
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 LongTerm Consumption of Fermented Milk Containing Lactobacillus casei in Pre-School
Children With Allergic Asthma and/or Rhinitis. Pediatr Res 2007; 62: 1-4
Probiotics for the treatment of allergic rhinitis
and 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
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
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
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
Probiotics for treatment of pediatric atopic
dermatitis
Current evidence is more convincing for
probiotics' efficacy in prevention than
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
GG for prevention of 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
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 allergy
Nomenclature
Epistemology
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical sections
Claims & future studies
Conclusion
Structure & correspondence of claims
with the state of the art in allergy
research.
Probiotics could act as
immunomodulators in allergy
Intense regulatory efforts dedicated to the possible antiallergic 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
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 allergy
Nomenclature
Epistemology
Human microbiota & hygiene hypothesis
Probiotics & Hygiene hypothesis
Probiotics & allergic disease
Clinical 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