The Growing Problem of Pediatric Allergy: Prevalence

1
The Growing Problem of Pediatric
AllergyPrevalence Prevention

• William J. Cochran, MD, FAAP
• Department of Pediatric GI Nutrition
• Geisinger Clinic

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Allergy Prevalence

• Affects as many as 50 million Americans
• Up to 30 in some populations, particularly
  developed countries
• In the U.S. allergies are a leading cause of
  chronic disease
• Overall the incidence of allergies are on the
  rise
• Food allergies are most common in infants and
  children

American Academy of Allergy, Asthma and
Immunology (AAAAI). The Allergy Report Science
Based Findings on the Diagnosis Treatment of
Allergic Disorders, 1996- 2001
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Adverse Reactionsto Food
Pharmacological (Toxic)
Non Pharmacological

• Bacterial food poisoning
• Scromboid fish poisoning
• Caffeine
• Tyramine
• Histamine

Non Immune Mediated
Immune Mediated

• Lactase deficiency
• Galactosemia
• Pancreatic insufficiency

• Allergies
• Dermatologic
• GI
• Respiratory
• Anaphylaxis

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Food Allergies

• In the U.S., 7 million affected by food allergies
• Infants and children particularly prone to
  allergy
• Occur in 8 percent of children less than 6 years
  of age
• Food allergies are the leading cause of
  anaphylactic reactions treated in the ER in US
• Approximately 100 Americans, mostly children, die
  annually from food-induced anaphylaxis
• Peanut allergy is the most common

Allergy, Principles and Practice, 5th Ed., E.
Middleton et al, ed. Mosby, St. Louis, 1998.
AAAAI Board of Directors. Journal of Allergy and
Clinical Immunology 102 (2)173-6. 1998.
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Most Common Food Allergy Manifestations

• Gastrointestinal
• Oral allergy syndrome
• Immediate GI hypersensitivity
• Food allergy induced enterocolitis / enteropathy
• Eosinophilic gastroenteritis
• Respiratory
• Allergic rhinitis
• Asthma
• Skin
• Atopic dermatitis or eczema
• Urticaria (hives)

6
Spectrum of Allergy Manifestations
Common
Uncommon
Adopted from HA Sampson, 2000
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Atopic Dermatitis

• The most common chronic skin disease in children.
• In 80 to 90 of the cases, onset of the disease
  occurs before 5 to 7 years of age
• Signs and symptoms
• Rash Erythematous patches with papules on the
  face, neck and extensor surfaces. Flexural
  lesions later.
• Pruritis
• Skin dryness, excoriations, erosions
• Distress, irritability.

Drake et al. J Am Acad Dermatol 199226485-8.
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Trends in Prevalence of Atopic Dermatitis
Secular trends in the UK Eichenfield et al ,
2003 Pediatrics 111 608-16
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Atopic Dermatitis Significance

• Atopic dermatitis in the U.S.
• Prevalence 10-20 overall
• Affects 15 million Americans
• 17 prevalence by 6 months of age
• 7 million visits per year
• Up to 60 of children with severe atopic
  dermatitis have food hypersensitivity

NIH- HHS Publication No. 03-4272, Rev April
2003 CDC Nat Ctr for Health Statistics Vital
and Health Statistics Series, 1996, 13134
Moore MM - Pediatrics - 01-MAR-2004 113(3 Pt 1)
468-74 Burkes et al. J Pediatr 1998,
132(1)132-610
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Atopic Dermatitis and Quality of Life

• In infants
• Itchiness Irritability Altered Sleep
• Pain / Colic when associated to GI allergy
• Disruption of family- child interactions
• In children
• Disruption of daily routine
• Sleep deprivation, nighttime scratching during
  all stages of sleep
• Affects school, social interactions, personal
  relationships, and self-consciousness

Howlett et al. Br J Dermatol 1999140381-4.
Reuveni et al. Arch Pediatr Adoles Med
1999153249-53   Chamlin et al. Pediatrics
2004 114(3) 607-11  
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Atopic Dermatitis Significance

• Healthcare Costs in the U.S.
• 1.6 billion (conservative)
• 3.8 billion (all inclusive)

Ellis CN, Drake et al. J Am Acad Derm 2002, 46
361-70
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Atopic Dermatitis Significance

• May be the first step in the Allergy March the
  relationship between allergic manifestations
  throughout life
• Approximately 75- 80 of atopic dermatitis
  patients develop allergic rhinitis
• More than 50 of atopic dermatitis patients
  develop asthma

Leung DY - J Allergy Clin Immunol - 01-DEC-2003
112(6 Suppl) S117Spergel J Allergy Clin
Immunology 2003 112 (6 Suppl) S 118-27
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The Allergic March
Atopic GI and dermal allergy
Upper respiratory tract (rhinitis,
rhino-conjunctivitis, allergic otitis media)
Lower respiratory tract (wheezing)
Allergic asthma
Cantani, 1999 Invest Allergol Clin Immunol 9(5)-
314-20
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Increasing Prevalence of Asthma Atopy
Ninan et al., 1992 BMJ 304 873-75
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Diagnosis Of Food Allergy

• History
• Food(s) / Quantity / Timing / Reproducibility
• Validated by challenge in 30-40 of cases
• Skin tests
• False positive results are common
• Best use is as a negative predictor
• RAST
• Consider for those with cutaneous involvement
• CAP-FEIA (Fluorescein Enzyme Immunoassay)
• Food gt95 PPV
• Egg 7kUa/L
• Milk 15 kUa/L
• Peanut 14 kUa/L
• Fish 20kUa/L

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DIAGNOSIS OF FOOD ALLERGY

• Endoscopy and biopsy
• Double-blind placebo-controlled food challenges
  "gold standard"

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Food Allergy Treatment

• Avoidance
• Meticulous attention to labels
• Education on sources of hidden foods
• Extensive hydrolysate (hypoallergenic) formulas
• 95 lt1,500 Daltons
• Amino acid formulas
• Partially hydrolyzed formulas are not
  hypoallergenic
• Those with severe allergy should have EpiPen

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Food Allergy Prevention

• Tertiary prevention
• Treatment to avoid recurrence of symptoms
• Secondary prevention
• Suppress disease expression after sensitization
• Primary prevention
• Prevention of sensitization

Zeiger, Pediatrics, 2003 1111662-1671
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Preventing Pediatric Allergy

• Allergy, particularly atopic dermatitis, is a
  significant health issue
• High incidence in developed countries
• Increasing incidence and prevalence
• High costs
• Impact on quality of life
• Allergy March may greatly magnify the problem

Primary Prevention is a Priority
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Traditional Prevention Strategies

• Nutritional strategies recommended for decreasing
  risk in the general pediatric population
• Breast feeding
• Delayed introduction of solid foods

AAP, Pediatric Nutrition Handbook, 2003
25
Traditional Prevention Strategies

• Nutritional strategies recommended for decreasing
  risk in high risk infants
• Maternal allergen avoidance during breast feeding
• Nuts, eggs, cows milk, fish
• Dietary avoidance / exclusion of allergens during
  and after weaning
• Cows milk gt1 year of age
• Egg gt2 years of age
• Nuts and fish gt3 years of age
• Use of extensively hydrolyzed (hypoallergenic)
  formulas
• Soy formula is of no benefit

AAP, Pediatric Nutrition Handbook, 2003
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Identifying At Risk Infants
One parent or sibling with history of AD,
urticaria, allergic rhinitis(hay fever) or
asthma At Risk by Family History
Risk by Parental Hx.
Medium
Low
High
Percentage of newborns
Likelihood of developing allergy Sx
Approximate numbers in developed countries.
Adapted from1. Bousquet J. et al. J Allergy Clin
Immunol 198678 1019-10222. Halken S et al.
Allergy 200055 793-8023. Kjellman N. et al.
Acta Paediatr Scan 197766 565-714. Exl BM,
Nutr Res 200121 355-79
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Predicting Pediatric Allergy
Medium
Risk by Parental Hx.
Low
High
Percentage of newborns
Likelihood of developingallergy Sx
Actual of children/100 who will develop
allergies
Approximate numbers in developed countries
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Predicting Pediatric Allergy
Risk by Parental Hx.
Medium
Low
High
Percentage of newborns
Likelihood of developing allergy Sx
Actual of children/100 who will develop
allergies
There is no good public health mechanism to
predict all children who will develop allergy.
At least half of infants who go on to develop
allergy could not have been predicted
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Food Allergies 90 accounted for by 5 foods
5 Most Common Allergens

• Cow Milk
• Soy
• Wheat
• Peanuts/Tree nuts
• Egg

Other

• Cows milk the most common antigen infants are
  exposed to
• All routine infant formulas are made with cows
  milk protein

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Protein size and Allergenicity
Low Molecular Weight
High Molecular Weight
Immune System
Potential for Hypersensitivity (Allergic Reaction)
31
Hydrolyzed Protein
Hydrolysis
Intact Protein
Hydrolyzed Protein
Hydrolyzed proteins have a lower chance of
inducing sensitization
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Hydrolysis Can Reduce Allergenicity of Cow Milk
Proteins
Median Molecular Weight of Infant Formulas
33
Distribution of Peptide Molecular Weight ()
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Hydrolysate Formulas in Allergy Risk Reduction

•  Over the last decade, a growing body of evidence
  suggests that exclusive feeding with an extensive
  or a partial hydrolysate may reduce the incidence
  of allergy compared to intact cows milk protein
  in non-breast fed infants.

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Cumulative Incidence of Atopic
ManifestationsExtensively Hydrolyzed Casein
Formula vs Cow Milk Formula in Prevention Studies
plt0.02
p0.032
p0.025
pNS
Graph depicts only published, peer-reviewed,
prospective trials. Studies up to 12 mo of Age
For all extensively hydrolyzed casein formula
studies, AM includes AD as one of the allergic
outcomes assessed. 9 months Oldaeus 1997 12
months Von Berg 2003, Zeiger 1995, Mallet 1992
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Cumulative Incidence of Atopic
DermatitisExtensively Hydrolyzed Casein Formula
vs Cow Milk Formula in Prevention Studies
plt0.005
p0.006
p0.059
p0.007
pNS
Graph depicts only published, peer-reviewed,
prospective trials. 9 months Oldaeus 1997
12 months Von Berg 2003, Zeiger 1995, Mallet
1992 18 months Chandra 1989
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Cumulative Incidence of Atopic
ManifestationsPartially Hydrolyzed Whey Formula
vs Cow Milk Formula in Prevention Studies
plt0.05
plt0.05
p0.021
plt0.05
plt0.001
pNS
p0.063
plt0.05
p0.109
Graph depicts only published,
peer-reviewed, prospective trials with data
collection at time points 12 months. For
all studies except Becker 2004, AM includes AD as
one of the allergic outcomes assessed for Becker
2004, AM refers to asthma alone. 4 months
Vandenplas 1988 6 months Exl 2000, De Seta
1994 12 months Becker 2004, Von Berg 2003,
Chandra 1997, Marini 1996, Vandenplas 1995,
Willems 1993 p-values in italics indicate
that no p-value is reported in publication
p-value is based on calculated OR and CI
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Cumulative Incidence of Atopic
DermatitisPartially Hydrolyzed Whey Formula vs
Cow Milk Formula in Prevention Studies
plt0.05
pNS
p0.004
plt0.02
plt0.05
pgt0.05
p0.048
pgt0.05
Graph depicts only published,
peer-reviewed, prospective trials with data
collection at timepoints 12 months. 4
months Vandenplas 1988 6 months Exl 2000 12
months Von Berg 2003, Chandra 1997, 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
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Effect of Hydrolyzed Cow Milk Formulafor Allergy
Prevention the First Year of LifeThe German
Infant Nutritional Intervention (GINI) Study

• Independent, government-sponsored study
• Double blind randomized study
• 2,252 high-risk infants randomized at birth to
• Intact cow milk formula
• Partially hydrolyzed whey formula
• Extensively hydrolyzed casein formula
• Extensively hydrolyzed whey formula
• As needed, randomized formula was given to 6
  months of age (no other foods besides breast
  milk)
• Allergic manifestations assessed at 1, 4, 8,12 mo
• Atopic dermatitis
• Allergic urticaria
• Food allergy with manifestation in the GI tract

Von Berg et al., 2003 J Allergy Clin Immunol
111(3) 533-40
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Effect of Hydrolyzed Cow Milk Formulafor Allergy
Prevention the First Year of LifeThe German
Infant Nutritional Intervention (GINI) Study

• 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 (p0.02)
• Incidence of allergic manifestation at 12 months
  was 13
• 89 of all allergic manifestation was atopic
  dermatitis
• 12 month results published, 3-year publication
  pending, 6-year follow-up planned

Von Berg et al., 2003 J Allergy Clin Immunol
111(3) 533-40
41
Risk of AD at 12 months Adjusted Odds Ratio
1.0
0.81
19 risk reduction vs CMF
P - NS vs CMF
0.56
44 risk reduction vs CMF
Plt 0.048 vs CMF
0.42
58 risk reduction vs CMF
Plt 0.007 vs CMF
Von Berg et al., 2003 J Allergy Clin Immunol
111(3) 533-40
42
Cumulative Incidence of Atopic Dermatitis
3 Yr. GINI study Findings not published.
Results presented at ESPACI Meeting, 2003
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GINI Study Considerations

• Lack of efficacy of extensively hydrolyzed whey
  formula
• Method of hydrolysis is as important as degree of
  hydrolysis
• Drop-out rate highest with extensively hydrolyzed
  casein
• Blinding difficult with extensive hydrolysates
• Statistical Analysis
• Statistically significant for both extensively
  hydrolyzed casein formulaand partially
  hydrolyzed whey formula for atopic dermatitis
• Statistically significant for extensively
  hydrolyzed casein formula but not partially
  hydrolyzed whey formula for all atopic
  manifestations

Von Berg et al., 2003 J Allergy Clin Immunol
111(3) 533-40
44
Meta-Analysis Formulas containingHydrolysed
Protein for Prevention of AllergyOsborn Sinn,
2003 - The Cochrane Library

• Inclusion criteria
• Randomized trials comparing use of hydrolyzed
  infant formula to human milk or intact cow milk
  formula
• ? 80 follow-up of subjects
• 18 / 72 studies were eligible for inclusion
• Main results
• Prolonged feeding of hydrolyzed formula (PHF and
  EHF combined) significantly reduced
• Allergy, eczema, cows milk allergy incidence in
  infancy
• Asthma, food allergy prevalence in childhood
• No significant difference between PHF and EHF

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Meta-Analysis Formulas containingHydrolysed
Protein for Prevention of AllergyOsborn Sinn,
2003 - The Cochrane Library

• Reviewers conclusions
• When babies are not exclusively breastfed, using
  hydrolyzed infant formulas instead of ordinary
  cows and soy milk formulas can reduce allergies
  in babies and children.
• There is insufficient evidence to determine
  whether feeding with an extensively hydrolyzed
  formula has any advantage over a partially
  hydrolyzed formula for primary allergy
  prevention.

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CONCLUSIONS

• The prevalence of allergy is on the rise
• Atopic dermatitis is a common manifestation of
  allergy in children
• Allergic disorders have significant impact on the
  patient and the family
• There is no good means of predicting those who
  will develop allergy
• Traditional preventive strategies are not
  practical for the general population

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CONCLUSIONS

• Acceptable cost effective strategies are needed
  for primary allergy prevention in the general
  population
• Breastfeeding should be promoted as the primary
  means of allergy prevention
• Current evidence supports the use of extensively
  hydrolyzed casein and partially hydrolyzed whey
  formula to reduce the incidence of allergic
  disease

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IT MAY BE POOP TO YOU BUT IT IS MY BREAD AND
BUTTER!
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Thank you.
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Family History as Allergy Predictor

• Specificity of 86-91
• Proportion of true negatives that are correctly
  identified (will not falsely predict a child at
  risk most of the time)
• Sensitivity of 17-22
• Proportion of true positives that are correctly
  identified (will not correctly predict a child at
  risk most of the time)

Bergmann et al., 1997 Clinical and Experimental
allergy 27 752-60
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Prevalence of Allergic Manifestations by Age
Respiratory
GI
Skin
Adapted from Saarinen, 1995 Lancet. 346 1065-69
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Population based prevalence of atopic disease in
German infantsduring their first 2 years of life
according to the history of atopic disease
(life-time prevalence) in their parents
Bergman, et al. Clinical and Experimental Allergy
1998 28905-907
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Odds Ratio Allergic ManifestationsExtensively
Hydrolyzed Casein vs. Intact Cow Milk
Published, peer-reviewed, prospective trials
with data collection at timepoints 12 months.
OR and CI shown in yellow are published values
OR in white and CI in dashed lines are calculated
values. 9 months Oldaeus 1997 12 months Von
Berg 2003, Zeiger 1995, Mallet 1992
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Odds Ratio Atopic Dermatitis Extensively
Hydrolyzed Casein vs. Intact Cow Milk
Published, peer-reviewed, prospective trials
with data collection at timepoints 12 months.
OR and CI shown in black are published values
OR in white and CI in dashed lines are calculated
values. 9 months Oldaeus 1997 12 months Von
Berg 2003, Zeiger 1995, Mallet 1992 Included
in Osborn 2003
55
Odds Ratio Allergic ManifestationsPartially
Hydrolyzed Whey vs. Intact Cow Milk
Graph depicts only published, peer-reviewed,
prospective trials with data collection at
timepoints 12 months. OR and CI shown in
yellow are published values OR in white and CI
in dashed lines are calculated values. 4
months Vandenplas 1988 6 months Exl 2000, De
Seta 1994 12 months Von Berg 2003, Chandra
1997, Marini 1996, Vandenplas 1995, Willems
1993 Included in Osborn 2003
56
Odds Ratio Atopic DermatitisPartially
Hydrolyzed Whey vs. Intact Cow Milk
Graph depicts only published, peer-reviewed,
prospective trials with data collection at
timepoints 12 months. OR and CI shown in
yellow are published values OR in white and CI
in dashed lines are calculated values. 4
months Vandenplas 1988 6 months Exl 2000, De
Seta 1994 12 months Von Berg 2003, Chandra
1997, Marini 1996, Vandenplas 1995, Willems
1993 Included in Osborn 2003
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Immunologic Sensitization
Immunologic sensitization
Re-exposure to sensitizing protein
Manifestations of allergy Signs and symptoms in
target organs Skin, GI, Lungs