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Weaning: The Allergist’s Point of view
Dal mito alla realtà
Alessandro Fiocchi
Melloni Pediatria, Milano
Worldwide Temporal Trends in the Prevalence of
Eczema at 6-7 years
ISAAC Phase Three Study Group. Worldwide time trends in the
prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and
eczema in childhood: ISAAC Phases One and Three repeat multicountry
cross-sectional surveys. Lancet. 2006;368:733-43
Prevention of childhood allergy by dietary manipulation
“Weaning is potentially dangerous for the high-risk
baby, therefore special care should be addressed
when new foods are introduced into the infant diet,
and offending foods such as eggs, fish, and
peanuts should be further postponed.”
Businco L. Clin Exp Allergy, 1990;20:S3, 9-14
Timing of introduction of solid foods
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Kajosaari M. Atopy prophylaxis in high-risk infants: prospective 5-year follow-up
study of children with six months exclusive breastfeeding and solid food
elimination. Adv Exp Med Biol. 1991;310:453–458
Fergusson DM. Asthma and infant diet. Arch Dis Child. 1983;58:48–51
Fergusson DM. Early solid feeding and recurrent childhood eczema: a 10-year
longitudinal study. Pediatrics. 1990;86:541–546
Morgan J. Eczema and early solid feeding in preterm infants. Arch Dis Child.
2004;89:309–314
Zutavern A. The introduction of solids in relation to asthma and eczema. Arch
Dis Child. 2004; 89:303–308
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and
atopic sensitization: results from a prospective birth cohort study. Pediatrics.
2006;117:401–11
Poole JA. Timing of initial exposure to cereal grains and the risk of wheat allergy.
Pediatrics. 2006; 117:2175–2182
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on
Allergy and Immunology. Effects of early nutritional interventions on the development
of atopic disease in infants and children: the role of maternal dietary restriction,
breastfeeding, timing of introduction of complementary foods, and hydrolyzed
formulas. Pediatrics. 2008;121:183-91
AAP review of the literature
Endpoint
Finding
Solids 3 vs. 6 months
AD  FA  at 1 year
AD = FA = at 5 years
Fergusson DM 1983
Solids < 4 vs.
solids > 4 months
AD  Asthma = at 4
years
Fergusson DM 1990
“”
AD  Asthma = at 10
years
Kajosaari M. 1991
Morgan J. 2004
< 4 vs. > 4
solids at 4 months
AD  at 1 years
Zutavern A. 2004
Birth cohort
No effect
Zutavern A. 2006
Birth cohort
No effect
Poole JA. 2006
Early cereals (< 6 months)  Cereal-specific IgE
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on
Allergy and Immunology. Effects of early nutritional interventions on the development
of atopic disease in infants and children: the role of maternal dietary restriction,
breastfeeding, timing of introduction of complementary foods, and hydrolyzed
formulas. Pediatrics. 2008;121:183-91
Timing of introduction of solid foods
… there is no current convincing evidence that delaying their
introduction beyond 4 to 6 months has a significant protective
effect on the development of atopic disease regardless of
whether infants are fed cow milk protein formula or human milk.
This includes delaying the introduction of foods that are considered
to be highly allergic, such as fish, eggs, and foods containing
peanut protein.
Greer FR, Sicherer SH, Burks AW; AAP Committee on Nutrition – AAP section on
Allergy and Immunology. Effects of early nutritional interventions on the development
of atopic disease in infants and children: the role of maternal dietary restriction,
breastfeeding, timing of introduction of complementary foods, and hydrolyzed
formulas. Pediatrics. 2008;121:183-91
Weaning timing in Australia
Foods should be introduced individually
Initially, new foods should be offered no more often
than each five to 10 days
Avoid confusion
Rule out the (remote) possibility of food allergy or
sensitivity
Dietary guidelines for children and adolescents in Australia. Australian National
Health and Medical Research Council, endorsed 10 April 2003
GINI (German Infant Nutritional
Intervention Study Group)
2252 newborns
RCTenrolled (1995-98)
945 formula-fed vs. 865 breastfed
Randomised to four formulae:
Level Ib
CMF:
eHF – W:
pHF – W:
eHF – C:
16% incidence of atopic manifestations
14% incidence of atopic manifestations
11% incidence of atopic manifestations
9% incidence of atopic manifestations
OR = 1
OR = 0.86
OR = 0.65
OR = 0.51
Von Berg A, J Allergy Clin Immunol 2003; 111:533-40
Levels of evidence
Level I a
meta-analysis of randomised controlled trials (RCT)
Level I b
at least one RCT
Level II a
at least one well-designed controlled study without
randomisation or systematic review of RCT or cohort
studies with high probability of causal relationship
Level II b
well-designed case-control or cohort study with
confounding bias and/or moderate probability of causal
relationship
Level III
non-experimental descriptive studies (case reports, case
series)
Level IV
expert committee reports
or opinions
or clinical experience of respected authorities
Shekelle PG. Clinical guidelines: Developing guidelines.
BMJ, 1999; 318: 593 -6
Can the early introduction of solid foods
precipitate the development of food allergy?
Cohort study with high
• 1265 New Zealand
neonates
probability
of causal
• Prospectively followed-up
relationship
- solid foods introduced to 4 months   eczema
by 2 years
Level II a
- solid foods introduced to 4 months   recurrent chronic eczema by 10 years
Fergusson DM. Early solid food feeding and recurrent childhood eczema:
a 10-year longitudinal study. Paediatrics 1990; 86:541-6
Can an early introduction of solid foods
anticipate the development of food allergy?
A case-control retrospective epidemiological study
Case-control study
• early introduction of cereals  asthma from grass
allergy (OR = 5,95; CI = 3,89-9,10)
Level II b
• “early exposure to such foods may not be a direct
risk factor for asthma, but rather a marker of
increased risk for developing respiratory pathway
sensitization to other Poaceaes”
Armentia A. Early introduction of cereals into children’s diets as a risk factor for
grass pollen asthma. Clin Exp Allergy 2001;31:1250-5
Can an early introduction of solid foods
anticipate the development of food allergy?
Cohort study with high
Solid food at anprobability
early age (<of8 causal
weeks or 8-12 weeks)
relationship
  respiratory illness at 14-26 weeks of age
II aand 27-39 weeks of age
  persistent coughLevel
at 14-26
  eczema
Forsyth JS. Relation between early introduction of solid food to infants
and their weight and illnesses during the first two years of life.
BMJ. 1993;306:1572-6.
Eczema and early solid feeding
257 preterm infants
Follow-up one year
Number and type of solid foods and risk of eczema
Morgan J. Eczema and early solid feeding in preterm infants.
Arch Dis Child. 2004;89:309-14
Variables not statistically significant
for the development of eczema by 12 months post-term
Maternal age
Single infant vs. twin/triplet
Number of children in the family
Maternal/paternal smoking
Pets in home
Gestational age - birth weight
Duration of breastfeeding
Whether or not ever breast fed
Use of infant cows’ milk formula before solid food introduction
Use of hypoallergenic formula before solid food introduction
Week at which were introduced: CM, cheese, eggs, fish, fruit, meat,
vegetables, rice.
Morgan J. Eczema and early solid feeding in preterm infants.
Arch Dis Child. 2004;89:309-14
Variables statistically significant
for the development of eczema by 12 months post-term
Cohort study with high
probability of causalOR
Groups
relationship
4+ foods by 17 weeks
post-term
3.49
1.51 8.05
Solids < 10 weeks or atopic parents
1.57 5.52
2.94
limits
Level II a
Morgan J. Eczema and early solid feeding in preterm infants.
Arch Dis Child. 2004;89:309-14
Food allergy is a matter of geography after all
 prevalence of IgE-mediated food allergy in 9070
infants
and young
(0-2 years)
Cohort
studychildren
with high
probability of causal
 1.2% (104/9070)
patients with IgE-mediated food
relationship
allergy
Levelwith
II aIgE-mediated allergy to
 0.8% (79/9070) patients
sesame.
 Sesame seed the single major offender
Dalal I. Food allergy is a matter of geography after all: sesame as a major cause of
severe IgE-mediated food allergic reactions among infants and young children in
Israel. Allergy. 2002; 57:362-5
Eczema and early solid feeding
642 term infants
Follow-up 5½ years
Outcome measures:
1. eczema
2. skin prick test inhalants
3. preschool wheezing - transient wheezing, at age
5 years
4. Introduction of solids assessed retrospectively at
age 1 year.
Zutavern A. The introduction of solids in relation to asthma and eczema.
Arch Dis Child 2004: 89:303-8
Eczema and early solid feeding
Food
< 3 months
> 3 months
P<
Solid foods
34.4
35.0
0.88
Fish
35.2
35.7
0.90
Milk
32.3
41.2
0.032
Egg
30.5
39.3
0.025
Zutavern A. The introduction of solids in relation to asthma and eczema.
Arch Dis Child 2004: 89:303-8
Eczema and early solid feeding
Cohort study with
confounding bias
Level II b
“…results do not support the guidelines for the prevention
of asthma and allergy in general populations stating
that the introduction of solids should be delayed for at
least 4–6 months. “
Zutavern A. The introduction of solids in relation to asthma and eczema.
Arch Dis Child 2004: 89:303-8
Reverse causality: a Chinese shadow question?
Reverse causality: a Chinese shadow question?
Reverse causality: a Chinese shadow question?
AD, sensitization and early solid feeding
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LISA
3097 healthy fullterm infants
4 German cities (Munich, Leipzig, Wesel, Bad Honnef)
Self-completion questionnaires (0, 6, 12, 18, 24 months)
Clinical evaluation at 2 years:
a. CAP with CM, wheat, peanut, soybean, codfish, HDM,
cockroach, cat, grass, birch, molds
b. questionnaires: doctors’ diagnosis of AD, age of introduction
of solid foods, [vegetables, cereal, fruit, meat, dairy products,
egg, fish, others (soybean, nuts, cacao, chocolate)]
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and
atopic sensitization: results from a prospective birth cohort study.
Pediatrics 2006: 117: 401-11
OR for AD by introduction of foods < 6 months in 2612
children
All
No early AD
Early AD
Any solids
1.07 (0.83–1.39)
0.67 (0.44–1.02)
1.08 (0.73–1.59)
> 5 foods
0.80 (0.57–1.12)
1.06 (0.61–1.83)
0.61 (0.37–0.99)
Vegetables
1.02 (0.78–1.34)
0.66 (0.43–1.01)
1.03 (0.69–1.54)
Fruits
1.02 (0.78–1.35)
0.65 (0.42–0.99)
0.98 (0.65–1.50)
Cereals
0.94 (0.68–1.29)
0.44 (0.27–0.72)
1.16 (0.71–1.90)
Meat
1.08 (0.72–1.62)
0.83 (0.44–1.59)
1.17 (0.64–2.13)
Dairy products
1.39 (0.78–2.50)
0.54 (0.25–1.14)
1.39 (0.78–2.50)
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and atopic
sensitization: results from a prospective birth cohort study. Pediatrics 2006: 117: 401-11
OR for AD by introduction of foods < 6 months in 2612
children
Cohort study with
confounding bias
 no evidence for a protective effect of a delayed introduction
of solids on AD and sensitization at 2 years of age
Level II b
 no evidence for a protective effect of a delayed introduction
of solids on AD and sensitization in children of atopic parents
 strata of children without early skin or allergic symptoms
were interpreted as undistorted from reverse causality
Zutavern A. Timing of solid food introduction in relation to atopic dermatitis and atopic
sensitization: results from a prospective birth cohort study. Pediatrics 2006: 117: 401-11
Fish consumption during the first year of life and
development of allergic diseases during childhood.
• A birth cohort ofCohort
4089 new-born
studyinfants
with high
• Parental questionnaires at 2 months, 1, 2 and 4 years
probability of causal
• Parental allergic disease associated with delayed introduction of fish
relationship
in the child’s diet  exclusion
of such children
• Onset of eczema or wheeze during the first year of life associated
with delayed introduction of fish in the child’s diet  exclusion of
such children
Level II a
• Fish during the first year of life  reduced risk for allergic disease
 reduced risk of sensitization
• IgE-sensitization to fish in 18 of the 2614 children
Kull I. Fish consumption during the first year of life and development of allergic diseases
during childhood. Allergy 2006: 61: 1009-15
Introduction of solids and atopic conditions at
6 years of age (multivariate)
Ealrly vs late introduction of solids: 4-6 months
aOR
95%CI
Doctor diagnosis of eczema
0.71
0.39-1.33
Symptoms of eczema
0.60
0.24-1.51
Doctor diagnosis of asthma
1.10
0.36-3.32
Asthma symptoms
0.76
0.46-1.27
Diagnosis of allergic rhinitis
1.12
0.42-2.99
Allergic rhinitis symptoms
1.01
0.63-1.60
Food sensitisation
3.13
1.45-6.74
Inhalant sensitisation
0.92
0.57-1.49
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Introduction of solids and atopic conditions at
6 years of age (multivariate)
Ealrly vs late introduction of solids: >6 months
aOR
95%CI
Doctor diagnosis of eczema
0.44
0.18-1.08
Symptoms of eczema
0.51
0.15-1.70
Doctor diagnosis of asthma
1.20
0.31-4.70
Asthma symptoms
0.77
0.40-1.46
Diagnosis of allergic rhinitis
1.45
0.45-4.63
Allergic rhinitis symptoms
0.63
0.33-1.21
Food sensitisation
3.01
1.19-7.61
Inhalant sensitisation
1.01
0.54-1.87
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
One-year prevalences of doctor diagnoses of
eczema, asthma, and allergic rhinitis (n =2073)
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Eczema vs. age of first introduction of solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Asthma vs. age of first introduction of solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Allergic rhinitis vs. age of first introduction of
solids
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
Conclusions
• Delayed introduction of solids not associated with
decreased asthma, allergic rhinitis, or sensitization
against food or inhalant allergens at 6 years of age
• Food sensitization more frequent in late introduction
• Relationship between the timing of solid introduction
and eczema not clear.
• Eczema more frequent in children who received a
more diverse diet within the first 4 months.
Zutavern A, LISA Study Group. Timing of solid food introduction in relation to eczema,
asthma, allergic rhinitis, and food and inhalant sensitization at the age of 6 years:
results from the prospective birth cohort study LISA. Pediatrics. 2008;121:e44-52
To eat
or not to eat…
Can avoidance of solid foods prevent the
development of food allergy?
•
135 children with allergic parents – breastfed until 6 months
•
RCT
Group A (70) - 6 months: cooked vegetables, apple, pear, cereals
8 months: beef, fish
10 months: egg
Level Ib
•
Group B (65) - 3 months: potato, carrot, cereals, beef
4 months: egg, fish
5 months: fruits, commercial foods
6 months: free diet
 eczema a < b
 food allergy a < b
Saarinen UM, Kajosaari M Prophylaxis of atopic disease: role of infant feeding.
Lancet i: 166-167, 1980
Kajosaari M, Saarinen UM Prophylaxis of atopic disease by six months' total solid foods
elimination. Acta Paed Scand 72:411, 1983
GINI (German Infant Nutritional
Intervention Study Group)
2252 newborns enrolled (1995-98)
RCT vs. 865 breastfed
945 formula-fed
Randomised to four formulae:
Level Ib
CMF:
eHF – W:
pHF – W:
eHF – C:
16% incidence of atopic manifestations
14% incidence of atopic manifestations
11% incidence of atopic manifestations
9% incidence of atopic manifestations
OR = 1
OR = 0.86
OR = 0.65
OR = 0.51
Von Berg A, J Allergy Clin Immunol 2003; 111:533-40
LEAP Study – Immune Tolerance Network
Randomisation/
Stratification
Recruitment
4-8 month old
children
eczema and/or
egg allergy
Age
Intervention group – Peanut consumed 3 times per week(n≈240)
Control Group (n≈240) peanut avoidance
4-8 months
1 yr*
2.5 yr*
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
5 yr*♦
LEAP Study (Learning Early About Peanut Allergy):
Induction of oral tolerance to peanut
• Patients:
• Age:
• Criteria:
480
Primary endpoint: peanut
4-11 months
allergy at 5 years of age by
DBPCFC
Severe
eczema
Egg allergy
SCORAD>40
• Exclusion:
Peanut allergy
• Assessment:
1, 2.5 and 5 years
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
WAO Meeting Bangkok 2007 - Courtesy of Stephen Durham,
Final recommendations
1. Breastfeeding is indicated during the first 6 months
2. Complementary feeding from the sixth month of life
3. Delay exposure to solid foods for prevention of food
allergies
4. Introduce foods individually and gradually
5. Mixed foods containing various food allergens
should not be given as starting foods
6. Cooked, homogenised foods preferred to their fresh
counterparts when processing reduces allergenicity
ACAAI ARFC. Weaning and food allergy. Ann Allergy Asthma Immunol 2006; 97:10-21