Conferencia dictada en el XVII Congreso Latinoamericano de Alergia, Asma e Inmunología, Cartagena, 2012

1. Can we prevent
allergies in children?
Michael S. Blaiss, MD
Clinical Professor of Pediatrics and Medicine
University of Tennessee Health Science Center
Memphis, Tennessee USA

2. Introduction
 Allergic disorders continue to escalate throughout the
world
• Asthma-8.2% of US population; 9.4% of children
• Up to 30% in some populations, particularly
developed countries
• Food allergies are becoming most common in infants
and children
 Most present management treats symptoms; none of
our treatments cure these conditions
 Are there things we can do to reduce the risk of
allergies developing in our “high risk” population?

3. Who do we target to reduce
the risk of the atopic march?

4. Is Parental Atopic History a
Reliable Predictor of Allergy?
Family history increases the risk of developing
allergy, HOWEVER…
• Most infants with allergy do not have a family
history of atopy.
• Most infants with a family history of atopy
don’t develop allergies.
Parental history is not a reliable predictor of allergy
Bousquet J. et al. J Allergy Clin Immunol 1986;78: 1019-1022. Halken S et al. Allergy 2000;55: 793-802
Bergmann RL, et al. Clin and Exp Allergy.1997;:27:752-760. Exl BM, Nutr Res 2001;21: 355-79

5. Family History
50% to 80% of children will have some form of
allergy if both parents have an atopic history…
Both Parents
(5%) Potential for
Childhood
Allergy
One Parent Correlates
Or Sibling To Parents’
(31%) History of
Allergy
Neither Parent
(64%)
Percentage of children that developed an
allergic manifestation
Approximate numbers in developed countries. Adapted from
Bousquet J. et al. J Allergy Clin Immunol 1986; Halken S et al. Allergy 2000
Kjellman N. et al. Acta Paediatr Scan 1977 4. Exl BM, Nutr Res 2001;21: 355-79

6. Risk of Allergy Increases with a
Positive Family History, But…
70% of children with allergy do not have parental history of allergy
Neither Parent (70%) One Parent (25%)
Parental Atopic
History in Infants
with Allergy
Both Parents
(5%)
*Approximate numbers in developed countries. Adapted from
Bousquet J. et al. J Allergy Clin Immunol 1986;78: 1019-1022;
Halken S et al. Allergy 2000;55: 793-802. Bergmann RL, et al. Clin
6
and Exp Allergy.1997;:27:752-760. Exl BM, Nutr Res 2001;21: 355-79

7. Risk Reduction
Studies-What’s the
Data?

8. Maternal Dietary Avoidance
Intervention

9. Maternal Dietary Avoidance
Intervention
 Faith-Magnusson, K. JACI 1992
 The 209 mothers to be, enrolled in a randomized,
prospective, allergy-prevention study from allergy-
prone families, totally abstained from cow's milk
and egg from gestational week 28 to delivery.
 Looked at the development of allergic disease at 5
years of age in their children, compared with the
development of allergic disease in the children of
the control mothers
 There was NO significant difference in eczema,
allergic rhinoconjunctivitis, and asthma

10. Journal Allergy Clinical Immunology 2012

11. Methods
 Estimated maternal peanut and tree nut intake (n = 61,908)
using a validated mid-pregnancy food frequency
questionnaire.
 At 18 months, parental report of childhood asthma
diagnosis, wheeze symptoms, and recurrent wheeze (>3
episodes) was collected.
 Current asthma at 7 years as doctor-diagnosed asthma
plus wheeze in the past 12 months and allergic rhinitis as a
self-reported doctor’s diagnosis.
 Odds ratios (ORs) comparing intake of 1 or more times per
week versus no intake.

16. Delayed introduction of
“allergenic” foods

18. Is the Low Prevalence of Peanut Allergy in
Israel Due to Hypoallergenic Peanut
Products?
S. J. Maleki, S. L. Hefle, et al. JACI 2005 San Antonio
.
 RATIONALE: In Israel the majority of
infants less than 12 months old regularly
consume peanut products in contrast to
the UK where infants avoid peanut
products
 Are the peanut protein allergens
different in Israel than UK and USA?

19. Peanut Allergy in Israel
 RESULTS: Peanut protein levels from Israeli and U.K.
products were found to be between 68-100%. The Ara h
1, Ara h 2 and Ara h 3 proteins in each peanut product
were intact and the levels were comparable as seen in US
and UK
 CONCLUSIONS: The contents of peanut protein,
individual major allergens and IgE binding capacity of the
popular snacks from Israel CANNOT explain the large
discrepancies in the prevalence of peanut allergy among
the two countries.
 IS PROTECTION DUE TO EARLY INTRODUCTION OF
PEANUT??

21. Egg Introduction and Egg Allergy
“HealthNuts” study, 2589 infants population-based, cross-sectional study
4-6 mo
7-9 mo
10-12 mo
>12 mo
0 0.1 0.5 1 2 5 10
RR (95% CI)
Effects seen in high-risk and low-risk infants with cooked egg
introduction
Adjusted for confounding factors
Confirmed egg allergy Koplin et al JACI 2010

22. Introduction of milk/milk products
and atopy outcomes
• KOALA Birth cohort (n=2558, Netherlands)
• Followed to age 2: Delayed milk/milk
products associated with eczema; delayed
“other foods” with atopy, prolonged BFing-
protective.
Adjusted
Odds Ratio
Eczema
Snijders et al
Pediatrics
2008;122:e115-22 Age at introduction of milk protein (mo)

23. What’s the Bottom-Line?
What does it all mean?

24. Should all children have all
foods continuously in the first
few months of life?
 No! No! No!
 A one-time ingestion of a small amount
of cow’s milk, egg, peanut, etc. MAY
lead to oral tolerance
 Studies are going on—We may see an
oral vaccine of these foods given once in
infancy in the physician’s office.

25. Breast Feeding

26. Friedman and Zeiger JACI 2005

27. J Allergy Clin Immunol 2010;125:1013-9

30. Soy and Hydrolysate Formulas

31. Relative Risk of Atopic Dermatitis
Meta Analysis- Infants with a Family History of Atopy
Does breast feeding reduce the risk allergy?
Formula Feeding, Risk = 1
1.00
0.58
31
Gdalevich M, et al. J Am Acad Derm. 2001;45:520-527.

32. Relative Risk of Atopic Dermatitis
Meta Analysis - Infants with a Family History of Atopy
Same data: But Converting Breast feeding risk to “1”
Breast feeding does not “decrease” risk. Formulas “increase” risk.
1.72
Breast Feeding is THE Standard
1.00
32
Adapted. OR with BF= .58 vs CMF Gdalevich M, et al. J Am Acad Derm. 2001;45:520-527.

33. Today’s “modern formula” for
Non-breastfed Infants
Intact (allergenic) cow milk
protein formula in a sterile form.
Any alternatives?

35. Protein size and Allergenicity
High Molecular Weight Low Molecular Weight
Immune System
Potential for Hypersensitivity (Allergic Reaction)

36. Hydrolysis Can Reduce Allergenicity
of Cow Milk Proteins*
14,000
~12,000
12,000
10,000
Daltons
8,000
6,000
4,000
2,000 ~ 450 ~1,220
0
Extensively Partially Whole Protein
Hydrolyzed Casein Hydrolyzed Whey Casein/Whey
Median Molecular Weight of Infant Formulas**
*It must be noted that, unlike extensively hydrolyzed casein formulas, partially hydrolyzed whey formulas are routine infant formulas and not 36
intended for therapeutic use in infants who have already presented with allergic disease.
**Approximate values as reported by major manufacturers.

37. Extensively hydrolyzed casein formula can
reduce the incidence of AD in infancy
Cumulative Incidence of Atopic Dermatitis ≤ 12 Months: Extensively
Hydrolyzed Casein Formula vs Cow Milk Formula in Risk Reduction Studies
80 Extensively Hydrolyzed Casein
Intact Cow Milk
Cumulative Incidence of AD (%)
p=0.006
60
40
p=0.059
p<0.05
20 p=NS
0
V Berg 2008
on Oldaeus 1997 Zeiger 1995 Mallet 1992
* Graph depicts only published, peer-reviewed, prospective trials.
** 9 months: Oldaeus 1997; 12 months: Von Berg 2008, Zeiger 1995, Mallet 1992;
**** p-values in italics indicate that no p-value is reported in publication; p-value is based on calculated OR and CI 37
*****Because questions and controversy have arisen regarding the clinical trials carried out by Dr. R Chandra (1989, 1991, 1997), the information is not
presented here.

38. Extensively hydrolyzed casein formula can
reduce the incidence of AD in infancy
Cumulative Incidence of Atopic Dermatitis > 12 Months: Extensively
Hydrolyzed Casein Formula vs Cow Milk Formula in Risk Reduction Studies
Extensively Hydrolyzed
Casein
Cumulative Incidence (%AD)
60
p=NS Intact Cow Milk
50
40 p<0.002
30 p=NS p<0.01
20
10
0
Von Berg 2008 Oldaeus 1997 Zeiger 1995 Mallet 1992
*Graph depicts only published, peer-reviewed, prospective trials with data collection at timepoints >12 months. 38
**18 months: Oldaeus 1997, Chandra 1989; 4 years: Mallet 1992; 7 years: Zeiger 1995; 6 years: Von Berg 2008.
***Because questions and controversy have arisen regarding the clinical trials carried out by Dr. R Chandra (1989, 1991, 1997), the information is not presented here.

39. Extensively Hydrolyzed Casein
Formulas and Allergy Risk Reduction
 Extensively hydrolyzed casein formulas are
effective in reducing the risk of atopic dermatitis.
 These formulas have increased osmolality,
usually less palatable.
 Approved by the FDA as exempt (therapeutic)
formulas.
 Designed to treat symptoms of cow’s milk allergy.

40. Partially hydrolyzed whey formula can
reduce the risk of AD in infancy
Cumulative Incidence of Atopic Dermatitis ≤ 12 Months
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Risk Reduction
Studies
60.0 Partially Hydrolyzed Whey
Intact Cow Milk
Cumulative Incidence of AD (%)
p<0.05
p=0.004 p=NS
40.0
p<0.05
p>0.05
p<0.05
20.0 p>0.05
0.0
Von Berg Chan 2002 Exl 2000 Marini 1996 Vandenplas Tsai 1991 Vandenplas
2008 1995 1988
*Graph depicts only published, peer-reviewed, prospective trials with data collection at time points ≤12 months.
**4 months: Vandenplas 1988; 6 months: Exl 2000; 12 months: Von Berg 2008, Marini 1996, Vandenplas 1995, Tsai 1991
***p-values in italics indicate that no p-value is reported in publication; p-value is based on calculated OR and CI 40
****Because questions and controversy have arisen regarding the clinical trials carried out by Dr. R Chandra (1989, 1991, 1997), the information is not presented here.

41. Partially hydrolyzed whey formula can
reduce the risk of AD in infancy
Cumulative Incidence of Atopic Dermatitis > 12 Months
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Risk Reduction
Studies
P=0.09
P<0.021
NS
NS NS
*Graph depicts only published, peer-reviewed, prospective trials with data collection at timepoints >12 months.
**30 months: Chan 2002; 3 years: Marini 1996; 4 years: D’Agata 1996; 5 years: Chandra 1997, Vandenplas 1995; 6 years: Von Berg 2008 41
***p-values in italics indicate that no p-value is reported in publication; p-value is based on calculated OR and CI
****Because questions and controversy have arisen regarding the clinical trials carried out by Dr. R Chandra (1989, 1991, 1997), the information is not presented here.

42. Partially Hydrolyzed Whey Formulas and
Allergy Risk Reduction
 Partially hydrolyzed whey formulas may be
effective in reducing the risk of atopic dermatitis.
 They are designed for routine use to reduce the
risk of cow’s milk allergy symptoms.
 Unlike extensively hydrolyzed casein formulas,
partially hydrolyzed whey formulas are routine
infant formulas and not intended for therapeutic
use in infants who have already presented with
allergic disease.

43. The German Infant Nutritional
Intervention (GINI) Study
Effect of Hydrolyzed Cow Milk Formula
for Allergy Prevention
 Largest, longest, independent study assessing the risk of AD with
hydrolyzed infant formula
 2,252 infants enrolled in the study:
 889 exclusively breastfed to 4 mo
 945 infants included in per protocol
 418 infants either non-compliant or drop-outs
 Extensively hydrolyzed casein had significantly higher
number of non-compliant subjects than other formula groups
(p=0.02)
 Incidence of allergic manifestation at 12 months was 13% and by 6
years it was 39%
43
Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40
Von Berg et al. 2008 J Allergy Clin Immunol 121(6): 1442-1447

44. GINI Study - Risk of AD at 12 months:
Adjusted Odds Ratio
Intact Cow Milk 1.0
Extensively Hydrolyzed
Whey 0.81 CI (0.48-1.4) 19% risk reduction vs. CMF
Partially Hydrolyzed Whey 0.56 CI (0.32-0.99)
* 44% risk reduction vs. CMF
* 58% risk reduction vs. CMF
Extensively Hydrolyzed
Casein
0.42 CI (0.22-0.79)
0 0.2 0.4 0.6 0.8 1
*p < 0.05 vs Intact Cow Milk
44
Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40

45. GINI Study - Risk of AD at 6 years:
Adjusted Odds Ratio
Intact Cow Milk 1.0
Extensively Hydrolyzed
0.74 CI (0.56-0.98)
Whey * 26% risk reduction vs CMF
Partially Hydrolyzed Whey 0.64 CI (0.48-0.86)
* 36% risk reduction vs CMF
Extensively Hydrolyzed
Casein
0.55 CI (0..39-0.76)
* 45% risk reduction vs CMF
0 0.2 0.4 0.6 0.8 1
*p < 0.05 vs Intact Cow Milk 45
Von Berg et al., 2008 J Allergy Clin Immunol 121(6): 1442-47

46. Guidelines for the Diagnosis and Management of Food
Allergy in the United States: Summary of the NIAID
Sponsored Expert Panel Report; JACI 2010
 Guideline 39: The EP suggests that the
use of hydrolyzed infant formulas, as
opposed to cow’s milk formula, may be
considered as a strategy for preventing
the development of FA in at-risk infants
who are not exclusively breast-fed (‘‘at
risk’’ is defined in Guideline 32)
 Cost and availability of extensively
hydrolyzed infant formulas may be
weighed as prohibitive factors

47. Recommendation
 Maternal dietary restrictions during pregnancy and
breastfeeding are not recommended.
 There is evidence that exclusive breastfeeding for
at least 4 months compared with feeding intact cow
milk protein formula decreases the cumulative
incidence of atopic dermatitis and cow milk allergy
in the first 2 years of life.

48. Recommendations (cont.)
 There is evidence that breastfeeding for at
least 4 months protects against wheezing in
early life and decreased risk of asthma
 Breastfeeding should be recommended
because of other beneficial effects, BUT if
breast feeding is not possible, an extensively
hydrolyzed casein or partially hydrolyzed
whey formula is recommended (rather than
conventional cow’s milk formulas)
 Soy formulas and other formulas (eg, goat’s
milk) are not recommended for reducing food
allergy risk

49. Recommendation (cont.)
 Solid foods should not be introduced before 4 to
6 months, though studies are needed for a one
time introduction of allergenic foods during this
time frame for oral tolerance
 Delaying the introduction of solids past 6 months
shows no evidence of a protective benefit—
regardless of type of formula used or
breastfeeding. This includes solids that are
thought to be highly allergenic

50. Thank you!!
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