Infant Food Allergies
Where Are We Now?
Janice Joneja Ph.D., RD
Food Allergy in the Past 7 Years

Nearly 4% of North Americans have food
allergies, many more than recorded in the
past


Incidence of food allergy much higher in
children (>8%) than adults (<2%)
Prevalence of peanut allergy doubled in
American children younger than 5 years of
age in the years 2002 - 2007
2
Food Allergy in the Past 7 Years


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Prevalence of food allergy highest in infants and
toddlers
Cow’s milk allergy incidence: 2.5% of infants
Up to 8% of children under 3 years have allergy to a
limited number of foods:

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Cow’s milk
Egg
Soy
Peanut

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Wheat
Shellfish
Fish
Tree nuts
For every child who actually had a food allergy, over three
more children were believed wrongly by their parents to suffer
from the condition
______________
Venter et al 2008
3
Age Relationship Between Food Allergy and Atopy
Effect of Food Allergens
Effect of Air-borne Allergens
Asthma
Relative Incidence
Rhinitis
Eczema
Food Allergy
Anaphylaxis
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16
Age (in years)
4
Historical Perspective

Sensitization to food allergens was thought to
be the start of the “allergic march”
Food allergy
Atopic dermatitis/eczema
Asthma
Rhinitis

Reducing sensitization to foods was therefore
considered the essential first step in allergy
prevention
5
Historical Perspective

Measures of prevention were all designed to avoid
sensitization to allergens during what were
considered the most vulnerable periods:



This meant reduction in exposure to highly allergenic
foods:


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Intra-uterine life
From birth to 2-3 years
Mother’s diet during pregnancy and lactation
Delay in introduction of highly allergenic foods during
weaning
In spite of these stringent measures to prevent allergy,
incidence of all types of allergies have increased
significantly
6
Change in Direction During the Past
Five Years




Understanding of the importance of immunological
sensitization and tolerance
Recognition that tolerance not sensitization is the
critical step in allergy prevention
Finding that exposure to the allergenic food at an
optimum stage is probably a critical step in allergy
prevention
Recognition that tolerance can be induced after
allergy has been established – leading to important
measures for allergy management
7
Allergy is a Response of the Immune System


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Our immune systems are designed to protect
the body from invasion by foreign materials
All foods contain proteins – derived from
plants and animals – all of which are foreign to
the human body
In order for food to be absorbed, metabolized,
and utilized by the body, the immune system
needs to be “educated” that the foreign
material is safe
________
Herz 2008
8
Education of the Immune System



Involves a complex series of immunological
reactions controlled by T cell lymphocytes (T
cells)
T helper (Th) cells detect foreign proteins
(antigens) in any form
T cells then trigger a series of immunological
reactions, mediated by cytokines (the “control
chemicals” of the immune system)
_________
Joneja 2007
9
T-helper Cell Subclasses

There are two subclasses of T-helper cells

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Th1
Th2
Each Th cell type produces its own specific
set of cytokines
The types of cytokines generated determine
the resulting immune response


Th1 principally INF-
Th2 principally IL-4
10
Role of T-helper Cell Subtypes

Th1 triggers the protective response to a
pathogen such as a virus or bacterium
 IgM, IgG, IgA antibodies are produced

Th2 is responsible for the allergic
(hypersensitivity) reaction
 IgE antibodies are produced
11
T cells involved in Oral Tolerance


T cell response depends on the type of T helper cell
that is activated
Latest research indicates that T cells that produce a
cytokine called TGF- are important in inducing oral
tolerance



Sometimes called Th3 cells
T cells that produce IL-10 and IL-13 may also be
involved in tolerance
These also regulate immune response to resident
microflora, preventing the usual immune
inflammatory response to microorganisms
___________________
Strobel and Mowat 2006
12
Oral Tolerance



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“Education” of the T cells to not respond to that food
protein when it enters via the oral route – called oral
tolerance
Contrasts with the active immune responses needed to
protect the gut against continual bombardment by
invading pathogens and their products (toxins, etc)
Also contrasts with the reduced responsiveness to the
millions of microorganisms that are permanent
residents of the large bowel
T cells involved in these processes are called
regulator T cells (Treg)
13
Prevention of Food Allergy in Clinical
Practice
Significant change in directives within the past 5
years:
 Previously:
Avoidance of allergen to prevent
sensitization (allergen-specific IgE)
 Current:
Active stimulation of the immature
immune system to induce tolerance of the
antigens in food
________________
Rautava et al 2005
14
Factors Predictive of Allergy:
High and Low risk Groups


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Many factors investigated as possible
predictive markers for allergy
Only significant variable in studies:
Family history of allergy (all types)
High risk for allergy:


One first degree relative with diagnosed
allergy (IgE-mediated) of any type
First-degree relative: parent or sibling
15
Does Atopic Disease Start in Fetal
Life?


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Fetal cytokines are skewed to the Th2 type
of response
Suggested that this may guard against
rejection of the “foreign” fetus by the
mother’s immune system
IgE occurs from as early as 11 weeks
gestation and can be detected in cord blood
_____________
Jones et al 2000
16
Does Atopic Disease Start in Fetal Life?
(continued)


At birth neonates have low INF- and tend
to produce the cytokines associated with
Th2 response, especially IL-4
So why do all neonates not have allergy?
17
Does Atopic Disease Start in Fetal Life?
(continued)



New research indicates that the immune
system of the mother may play a very
important role in expression of allergy in
the neonate and infant
IgG crosses the placenta; IgE does not
Certain sub-types of IgG (IgG1; IgG3) can
inhibit IgE response
18
Significance in Practice


Food proteins demonstrated to cross the
placenta and can be detected in amniotic
fluid
Exposure to small quantities of food
antigens from mother’s diet thought to
tolerize the fetus, by means of IgG1 and
IgG3, within a “protected environment”
19
Immune Response of the Allergic Mother

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Atopic mother’s immune system may
dictate the response of the fetus to antigens
in utero
The allergic mother may be incapable of
providing sufficient IgG1 and IgG3 to
downregulate (depress) fetal IgE
There is no convincing evidence that
sensitization to specific food allergens is
initiated prenatally
20
Diet During Pregnancy
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Current directive: the atopic mother should strictly
avoid her own allergens and replace the foods with
nutritionally equivalent substitutes
There are no indications for mother to avoid other
foods during pregnancy
A nutritionally complete, well-balanced diet is
essential
Authorities recommend avoidance of excessive intake
of highly allergenic foods such as peanuts and nuts to
prevent “allergen overload”, but there is no scientific
data to support this
_______________
Kramer et al 2006
21
Breast-feeding and Allergy
Studies indicating that breast-feeding is
protective against allergy report:
A definite improvement in infant eczema and
associated gastrointestinal complaints when
baby is exclusively breast-fed
 Reduced risk of asthma in the first 24 months
of life

__________________
Kirjavainen et al 2002
22
Breast-feeding and Allergy

Other studies are in conflict with these
conclusions:
Some report no improvement in symptoms
 Some suggest symptoms get worse with breastfeeding and improve with feeding of
hydrolysate formulae
 Japanese study suggests that breast-feeding
increases the risk of asthma at adolescence

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Why the conflicting results?
_______________
Miyake et al 2003
23
Immunological Factors in Human Milk that
may be Associated with Allergy:
Cytokines and Chemokines

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Atopic mothers tend to have a higher level of the
cytokines and chemokines associated with allergy in
their breast milk
Those identified include:
IL-4
IL-5
IL-8
IL-13
Some chemokines (e.g. RANTES)

Atopic infants do not seem to be protected from
allergy by the breast milk of atopic mothers
___________________________
Snijders et al 2007 KOALA study
24
Immunological Factors in Human Milk
that may be Associated with Allergy:
TGF-1
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Cytokine, transforming growth factor-1 (TGF1) promotes tolerance to food components in the
intestinal immune response
TGF-1 in mother’s colostrum may influence the
type and intensity of the infant’s response to food
allergens
A normal level of TGF-1 is likely to facilitate
tolerance to food encountered by the infant in
mother’s breast milk and later to formulae and
solids
______________
Rigotti et al 2006
25
Implications of Research Data

Exclusive breast-feeding with exclusion of
mother’s and baby’s allergens will reduce signs of
allergy in the first 1-2 years; specifically:



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Cow’s milk allergy
Eczema
Reduction or prevention of early food allergy by
breast-feeding does not seem to have long-term
effects on the development of asthma and allergic
rhinitis
Other benefits of breast-feeding far outweigh any
possible negative effects on allergy: exclusive
breast-feeding for 4-6 months is strongly
encouraged
26
Summary of 2008 AAP Guidelines for Allergy
Management [Greer et al 2008]


There is no convincing evidence that women
who avoid highly allergenic foods, or other
foods during pregnancy and breast-feeding
lower their child’s risk of allergies
For high-risk for allergy infants (one firstdegree relative with established allergy),
exclusive breast-feeding for at least 4 months
prevents or delays the occurrence of atopic
dermatitis (eczema), cow’s milk allergy, and
wheezing in early childhood
_____________
Greer et al 2008
____________________
Sicherer and Burks 2008
27
Preventive Effect of Breast-feeding:
KOALA Study
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Longer duration of breastfeeding is associated with
lower risk for eczema in non-atopic mothers
Slightly lower risk for mothers with allergy but no
asthma
Longer duration of breastfeeding reduced risk for
wheezing in infants: possibly due to reduction in
respiratory infections
There is a lack of evidence that exclusive or
prolonged breast-feeding has any positive effect on
the development of asthma in older children
___________________________
Snijders et al 2007 KOALA study
28
Summary of 2008 AAP Guidelines
continued


In infants at high risk for allergy who are not
exclusively breast-fed for 4-6 months there is
modest evidence that the onset of atopic
disease (allergy), especially eczema, may be
delayed or prevented by the use of hydrolyzed
formulas
There is no good evidence that soy-based
infant formulas have any preventive effect on
the development of allergy
29
Preventive Effect of Hydrolyzed Infant
Formulae

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No evidence of any reduction in allergy with
hydrolyzed formula compared to breastfeeding
Limited evidence that prolonged feeding with
hydrolyzed formula compared to cow’s milk reduces
incidence of CMA and eczema
No evidence that hydrolyzed formulas have any effect
on the development of rhinitis and asthma later
Extensively hydrolyzed cow’s milk (Ehf) formulas
marginally better than partially hydrolyzed whey
(Phf) in prevention
_________________________________
Osborn and Sinn 2009 Cochrane Review
__________________________
Von Berg et al GINI Study 2009
30
Infant Formulae for the Allergic Baby
Current Recommendations


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Cow’s milk based formula if there are no signs
of milk allergy
Partially hydrolysed (phf) whey-based formula
if there are no signs of milk allergy in high risk
for allergy group
Extensively hydrolysed (ehf) casein based
formula if milk allergy is proven
_________________
Greer et al AAP 2008
Von Berg et al 2007
31
Recommendations for Introduction of Solids
to High Risk for Allergy Infants
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Little evidence that delaying the introduction of
complementary foods beyond 4-6 months of age
prevents allergy
Introduction of solid foods should be individualized
Foods should be introduced one at a time in small
amounts
Mixed foods containing various potential food
allergens should not be given unless tolerance to each
ingredient has been assessed
____________________
Greer et al AAP 2008
_____________________
Thygaran and Burks 2008
32
Introduction of Solid Foods in
Relationship to Celiac Disease

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Results suggest that in high risk for celiac disease
infants introduction of gluten-containing grains
before 3 months or after 7 months increases
incidences of development of CD1
Introduction of gluten while breast-feeding offers
protection or delays onset of celiac disease in at-risk
infants2
Recommendations:


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Introduce gluten grains in small amounts between 4 and 6
months while infant is breastfed
Continue breast-feeding for a further 2-3 months
Similar results for wheat allergy3
_______________
1Norris et al 2005
______________
2Guandalini 2007
____________
3Poole et al 2006
33
Introduction of Peanuts

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Directives from pediatric societies (1998 - 2007)
recommended avoidance of peanuts by mothers
during pregnancy and lactation, and delaying
introduction of peanuts until after 2 or even 3 years of
age
Research indicates that incidence of peanut allergy in
children rose dramatically in the years following
release of these directives
Recent research suggests:


Avoidance of peanuts reduced development of tolerance
Early exposure leads to reduced incidence of peanut allergy
_________________
Hourihane et al 2007
34
Introduction of Peanuts
Study (n=10,786) among primary school age Jewish
children in UK and Israel
 Prevalence of peanut allergy (PA):
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1.85%
0.17%
Median monthly consumption of peanut in infants
aged 8 – 14 months:
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In UK:
In Israel:
In UK:
In Israel:
0
7.1 g
Difference not due to atopy, genetic background,
social class, or peanut allergenicity
Israeli infants consume peanuts in high quantities
during the first year of life
______________
Du Toit et al 2008
35
Introduction of Fish

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Historically, fish consumption during infancy was
considered to be a risk factor for allergy
Recent research indicates otherwise:

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Regular fish consumption during the first year of life
associated with a reduced risk for allergic disease by age 4
years (n=4089)1
Babies of mothers who frequently consumed fish (2-3
times per week or more) during pregnancy had one third
less food sensitivities than those whose mothers did not
consume fish during pregnancy2
_____________
1Kull et al 2006
_______________
2Calvani et al 2006
36
Introduction of Fish
Study (n= 5,000); 20.9% developed eczema by 1 year:
 Babies who were fed fish before nine months of age
were 24% less likely to develop eczema by age 1 year
 Omega-3 content of fish did not seem to influence the
outcome
 The age at which egg and milk were introduced did
not affect development of eczema
 Breast-feeding did not have any significant impact on
development of eczema
____________
Alm et al 2009
____________________________
Hibbeln et al 2007 ALSPAC study
37
The Natural History of Food Allergy

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Food allergy most often begins in the first 1 to
2 years of life
Child is sensitized to the food protein by the
immune system developing allergen-specific
IgE to that protein
Sensitization does not necessarily mean that
the child will develop symptoms when that
food is eaten
Over time most food allergy is lost
_________
Wood 2003
38
Prognosis

Most children outgrow early food allergy

John’s Hopkins Children’s Center USA
 Milk allergy outgrown:

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Egg allergy outgrown:
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20% by 4 years
42% by 8 years
79% by 16 years
4% by 4 years
37% by 10 years
68% by 16 years
Allergy to some foods more often than others persists into
adulthood:
 Peanut
 Tree nuts
 Seeds
 Shellfish
 Fish
______________
Skripak et al 2007
39
Induction of Oral Tolerance

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Tolerance to a specific food can be induced by
oral administration of the offending food by
process of “low dose continuous exposure”
Designated (SOTI: specific oral tolerance
induction)
Starting with very low dosages
Gradually increasing daily dosage up to the
equivalent of the usual daily intake
Followed by daily maintenance dose
__________________
Niggemann et al 2006
_____________
Calvani et al 2010
40
Desensitization to
Cow’s Milk

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18 children with confirmed CMA >4 years of age
underwent SOTI
Starting dose 0.05 ml cow’s milk
Increased to 1 ml on first day
Increasing dosage weekly up to a daily dose of 200250 ml
Results: 16/18 tolerated 200-250 ml milk
Length of process median 14 weeks (range 11-17
weeks)
Tolerance has been maintained for >1 year
_______________
Zapatero et al 2008
41
Oral Tolerance Induction to
Milk, Egg, and Peanut


36% of children with IgE-mediated allergy to cow’s
milk and hen’s egg developed permanent tolerance of
the foods after a median 21 months specific oral
tolerance induction (SOTI)1
4 peanut-allergic children underwent SOTI:



Daily doses of peanut flour starting at 5 mg peanut protein
2-weekly dosage increase up to 800 mg protein
All subjects tolerated at least 10 whole peanuts (2.38 g
protein) on post-intervention challenge2
______________
1Staden et al 2007
______________
2Clark et al 2009
42
Progression of Peanut Allergy




Peanut allergy, like many early food allergies, can be
outgrown
In 2001 pediatric allergists in the U.S. reported that
about 21.5 per cent of children will eventually
outgrow their peanut allergy1
Those with a mild peanut allergy, as determined by
the level of peanut-specific IgE in their blood, have a
50% chance of outgrowing the allergy2
Only about 9% of patients are reported to outgrow
their allergy to tree nuts3
__________________
1Skolnick et al 2001
2Fleischer et al 2003
3Fleischer et al 2005
43
Maintaining Tolerance of Peanut
When there is no longer any evidence of
symptoms developing after a child has
consumed peanuts, it is preferable for that
child to eat peanuts regularly, rather than avoid
them, in order to maintain tolerance to the
peanut
 Children who outgrow peanut allergy are at
risk for recurrence, but the risk has been
shown to be significantly higher for those who
continue to avoid peanuts after resolution of
their symptoms
_________________

Fleischer et al 2004
44
Probiotics and Allergy Prevention


Probiotics and prebiotics may change the colonic
microflora of the neonate
Theory:
Change from Th2 to Th1 response in the neonatal period is
required to reduce potential for allergy
 This change is mediated by contact with micro-organisms
 Non-allergic children have a predominance of lactobacilli
and bifidobacteria
 Atopic children tend to have more clostridia and lower
levels of bifidobacteria
 Probiotics could be used to change the “atopic” to a more
“non-atopic flora”
____________

Ozdemir 2010
45
Studies on Probiotics in Allergy Prevention

Some studies indicate a positive outcome in
reducing the incidence of allergy:


Lactobacillus F19 in cereals fed to infants from 4
to 13 months of age reduced the incidence of
eczema1
Other studies showed no effect:

Bifidobacterium + Lactobacillus rhamnosus daily
for the first 6 months in at risk infants had no
effect compared to placebo2
____________________
___________________
1
2
West et al 2009
Soh et al 2009
46
Current Status of Probiotics in
Allergy Prevention

Beneficial effects of probiotic therapy depends on:






Type of bacteria selected
Dosage of the bacteria delivered to the digestive tract
Method of delivery of the bacteria to the GI tract (in
formulae; in cereals)
Age of the individual
Length of duration of delivery
Conclusion at the current state of research:
Probiotics cannot be recommended generally for primary
prevention of atopic disease
_____________

Ozdemir 2010a
47
Take Home Message




Allergy prevention emphasizes inducing
tolerance rather than avoiding sensitization
Beginning of tolerance to foods may occur in
utero or during breast-feeding
Restriction of maternal diet to avoid highly
allergenic foods during pregnancy or lactation
is contraindicated
Unless either mother or baby is allergic to
them
48
Take Home Message

Management of established food allergy
includes:
Accurate identification of the allergenic
food(s)
 Careful avoidance of the food allergens –
especially if there is any risk of anaphylaxis
 Avoidance of unnecessary food restrictions

49
Take Home Message
 Provision
of complete balanced
nutrition by substituting foods of equal
nutritional value
 Monitoring the child’s response at
intervals to determine when the food
allergy has been outgrown
 Maintenance of tolerance by feeding
tolerated foods regularly
50
Invitation to Further Information
www.allergynutrition.com
Joneja, J.M.Vickerstaff Dealing with Food Allergies in Babies
and Children Bull Publishing Company, Boulder, Colorado.
October 2007
51