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The Growing Problem of Pediatric Allergy:
Prevalence & Prevention
The Growing Problem of Pediatric Allergy:
Prevalence & Prevention
William J. Cochran, MD, FAAP
Department of Pediatric GI & Nutrition
Geisinger Clinic
William J. Cochran, MD, FAAP
Department of Pediatric GI & Nutrition
Geisinger Clinic
Allergy Prevalence 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
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- 2001American Academy of Allergy, Asthma and Immunology (AAAAI). The Allergy Report: Science Based Findings on the Diagnosis & Treatment of Allergic Disorders, 1996- 2001
Adverse Reactionsto Food
Adverse Reactionsto Food
Pharmacological(Toxic)
Pharmacological(Toxic)
• Bacterial food poisoning• Scromboid fish poisoning• Caffeine• Tyramine• Histamine
• Bacterial food poisoning• Scromboid fish poisoning• Caffeine• Tyramine• Histamine • Lactase deficiency
• Galactosemia• Pancreatic insufficiency
• Lactase deficiency• Galactosemia• Pancreatic insufficiency
Allergies:• Dermatologic• GI• Respiratory• Anaphylaxis
Allergies:• Dermatologic• GI• Respiratory• Anaphylaxis
Non ImmuneMediated
Non ImmuneMediated
Non Pharmacological
Non Pharmacological
ImmuneMediatedImmuneMediated
Food AllergiesFood 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
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.
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.
Most Common Food Allergy ManifestationsMost 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)
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)
Spectrum of Allergy ManifestationsSpectrum of Allergy Manifestations
Acute urticariaAngioedema
Acute urticariaAngioedema
Atopicdermatitis
Atopicdermatitis
Dermatitisherpetiformes
Dermatitisherpetiformes
Immediate GIhypersensitivity
Oral allergysyndrome
Immediate GIhypersensitivity
Oral allergysyndrome
Eosinophilicgastroentero-
colitis
Eosinophilicgastroentero-
colitis
Protein inducedenterocolitis
Protein inducedenterocolitis
Acute RAD
(High riskanaphylaxis)
Acute RAD
(High riskanaphylaxis)
Asthma
(Risk ofanaphylaxis)
Asthma
(Risk ofanaphylaxis)
Food inducedhemosiderosis
Heiner syndrome
Food inducedhemosiderosis
Heiner syndrome
IgE MediatedIgE MediatedMixed
MechanismMixed
MechanismNon-IgEMediatedNon-IgEMediated
SkinSkin
GIGI
RespiratoryRespiratory
CommonCommon UncommonUncommon
Adopted from HA Sampson, 2000Adopted from HA Sampson, 2000
Atopic DermatitisAtopic 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.
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 1992;26:485-8.Drake et al. J Am Acad Dermatol 1992;26:485-8.
Trends in Prevalence of Atopic DermatitisTrends in Prevalence of Atopic Dermatitis
0
5
10
15
20
25
1946 1958 1970 1996
% P
reva
lenc
e
0
5
10
15
20
25
1946 1958 1970 1996
% P
reva
lenc
e
*Secular trends in the UKEichenfield et al , 2003 Pediatrics 111: 608-16
*Secular trends in the UKEichenfield et al , 2003 Pediatrics 111: 608-16
Atopic Dermatitis: SignificanceAtopic 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**
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, 13:134
* Moore MM - Pediatrics - 01-MAR-2004; 113(3 Pt 1): 468-74
** Burkes et al. J Pediatr 1998, 132(1):132-610
† NIH- HHS Publication No. 03-4272, Rev April 2003
‡ CDC Nat Ctr for Health Statistics Vital and Health Statistics Series, 1996, 13:134
* Moore MM - Pediatrics - 01-MAR-2004; 113(3 Pt 1): 468-74
** Burkes et al. J Pediatr 1998, 132(1):132-610
Atopic Dermatitis and Quality of LifeAtopic 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
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 1999;140:381-4.
Reuveni et al. Arch Pediatr Adoles Med 1999;153:249-53
Chamlin et al. Pediatrics 2004; 114(3); 607-11
Howlett et al. Br J Dermatol 1999;140:381-4.
Reuveni et al. Arch Pediatr Adoles Med 1999;153:249-53
Chamlin et al. Pediatrics 2004; 114(3); 607-11
Atopic Dermatitis: Significance Atopic Dermatitis: Significance
Healthcare Costs in the U.S.• 1.6 billion (conservative) • 3.8 billion (all inclusive)
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: 361-70Ellis CN, Drake et al. J Am Acad Derm 2002, 46: 361-70
Atopic Dermatitis: SignificanceAtopic 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
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 118-27Leung DY - J Allergy Clin Immunol - 01-DEC-2003; 112(6 Suppl): S117Spergel J Allergy Clin Immunology 2003; 112 (6 Suppl): S 118-27
The Allergic MarchThe Allergic March
Cantani, 1999 Invest Allergol Clin Immunol 9(5)- 314-20Cantani, 1999 Invest Allergol Clin Immunol 9(5)- 314-20
Atopic GI and dermal allergyAtopic GI and dermal allergy
Allergic asthmaAllergic asthma
Lower respiratory tract (wheezing)
Lower respiratory tract (wheezing)
Upper respiratory tract (rhinitis, rhino-conjunctivitis, allergic otitis media)
Upper respiratory tract (rhinitis, rhino-conjunctivitis, allergic otitis media)
Increasing Prevalence of Asthma & Atopy
Increasing Prevalence of Asthma & Atopy
0
5
10
15
Eczema Hayfever Asthma
% P
reva
lenc
e (C
hild
ren
8-13
yrs
.)
1964 1989
0
5
10
15
Eczema Hayfever Asthma
% P
reva
lenc
e (C
hild
ren
8-13
yrs
.)
1964 1989
Ninan et al., 1992; BMJ 304: 873-75Ninan et al., 1992; BMJ 304: 873-75
Diagnosis Of Food AllergyDiagnosis 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 >95% PPV
• Egg 7kUa/L• Milk 15 kUa/L• Peanut 14 kUa/L• Fish 20kUa/L
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 >95% PPV
• Egg 7kUa/L• Milk 15 kUa/L• Peanut 14 kUa/L• Fish 20kUa/L
DIAGNOSIS OF FOOD ALLERGYDIAGNOSIS OF FOOD ALLERGY
Endoscopy and biopsy Double-blind placebo-controlled food challenges:
"gold standard"
Endoscopy and biopsy Double-blind placebo-controlled food challenges:
"gold standard"
Food Allergy — TreatmentFood Allergy — Treatment
Avoidance• Meticulous attention to labels• Education on sources of “hidden foods”
Extensive hydrolysate (hypoallergenic) formulas• 95% <1,500 Daltons
Amino acid formulas Partially hydrolyzed formulas are not hypoallergenic Those with severe allergy should have EpiPen
Avoidance• Meticulous attention to labels• Education on sources of “hidden foods”
Extensive hydrolysate (hypoallergenic) formulas• 95% <1,500 Daltons
Amino acid formulas Partially hydrolyzed formulas are not hypoallergenic Those with severe allergy should have EpiPen
Food Allergy — PreventionFood Allergy — Prevention
Tertiary prevention• Treatment to avoid recurrence of symptoms
Secondary prevention• Suppress disease expression after sensitization
Primary prevention• Prevention of sensitization
Tertiary prevention• Treatment to avoid recurrence of symptoms
Secondary prevention• Suppress disease expression after sensitization
Primary prevention• Prevention of sensitization
Zeiger, Pediatrics, 2003; 111:1662-1671Zeiger, Pediatrics, 2003; 111:1662-1671
Preventing Pediatric AllergyPreventing 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
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 PriorityPrimary Prevention is a Priority
Traditional Prevention Strategies Traditional Prevention Strategies
Nutritional strategies recommended for decreasing risk in the general pediatric population• Breast feeding• Delayed introduction of solid foods
Nutritional strategies recommended for decreasing risk in the general pediatric population• Breast feeding• Delayed introduction of solid foods
AAP, Pediatric Nutrition Handbook, 2003
Traditional Prevention StrategiesTraditional Prevention Strategies
Nutritional strategies recommended for decreasing risk in high risk infants • Maternal allergen avoidance during breast feeding
• Nuts, eggs, cow’s milk, fish
• Dietary avoidance / exclusion of allergens during and after weaning
• Cow’s milk >1 year of age• Egg >2 years of age• Nuts and fish >3 years of age
• Use of extensively hydrolyzed (hypoallergenic) formulas• Soy formula is of no benefit
Nutritional strategies recommended for decreasing risk in high risk infants • Maternal allergen avoidance during breast feeding
• Nuts, eggs, cow’s milk, fish
• Dietary avoidance / exclusion of allergens during and after weaning
• Cow’s milk >1 year of age• Egg >2 years of age• Nuts and fish >3 years of age
• Use of extensively hydrolyzed (hypoallergenic) formulas• Soy formula is of no benefit
AAP, Pediatric Nutrition Handbook, 2003
Identifying “At Risk” InfantsIdentifying “At Risk” Infants
*Approximate numbers in developed countries. Adapted from1. Bousquet J. et al. J Allergy Clin Immunol 1986;78: 1019-10222. Halken S et al. Allergy 2000;55: 793-8023. Kjellman N. et al. Acta Paediatr Scan 1977;66: 565-714. Exl BM, Nutr Res 2001;21: 355-79
One parent or sibling with history of AD, urticaria, allergic rhinitis(hay fever) or asthma = “At Risk” by Family HistoryOne parent or sibling with history of AD, urticaria, allergic rhinitis(hay fever) or asthma = “At Risk” by Family History
Risk by Parental Hx.*Risk by Parental Hx.* LowLow MediumMedium HighHigh
Percentage of newbornsPercentage of newborns
Likelihood of developing allergy SxLikelihood of developing allergy Sx
Predicting Pediatric Allergy Predicting Pediatric Allergy
Risk by Parental Hx.*Risk by Parental Hx.* LowLow MediumMedium HighHigh
Percentage of newbornsPercentage of newborns
Likelihood of developingallergy SxLikelihood of developingallergy Sx
Actual # of children/100 who will develop allergiesActual # of children/100 who will develop allergies
*Approximate numbers in developed countries
Predicting Pediatric AllergyPredicting Pediatric Allergy
Risk by Parental Hx.Risk by Parental Hx. LowLow MediumMedium HighHigh
Percentage of newbornsPercentage of newborns
Likelihood of developing allergy SxLikelihood of developing allergy Sx
Actual # of children/100 who will develop allergiesActual # 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
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
Food Allergies: 90% accounted for by 5 foods
Food Allergies: 90% accounted for by 5 foods
5 Most Common Allergens
5 Most Common Allergens
OtherOther
• Cow Milk• Soy• Wheat• Peanuts/Tree nuts• Egg
• Cow Milk• Soy• Wheat• Peanuts/Tree nuts• Egg
• Cow’s milk: the most common antigen infants are exposed to
• All routine infant formulas are made with cow’s milk protein
• Cow’s milk: the most common antigen infants are exposed to
• All routine infant formulas are made with cow’s milk protein
High Molecular WeightHigh Molecular Weight
Potential for Hypersensitivity (Allergic Reaction)Potential for Hypersensitivity (Allergic Reaction)
Low Molecular WeightLow Molecular Weight
Immune SystemImmune System
Protein size and AllergenicityProtein size and Allergenicity
Hydrolyzed ProteinHydrolyzed Protein
IntactProteinIntact
ProteinHydrolyzed
ProteinHydrolyzed
Protein
HydrolysisHydrolysis
Hydrolyzed proteins have a lower chance of inducing sensitization
Hydrolyzed proteins have a lower chance of inducing sensitization
Hydrolysis Can Reduce Allergenicity of Cow Milk Proteins
Hydrolysis Can Reduce Allergenicity of Cow Milk Proteins
4501,100
10,000
0
2,000
4,000
6,000
8,000
10,000
12,000
ExtensivelyHydrolyzed Casein
PartiallyHydrolyzed Whey
Whole ProteinCasein/Whey
Dal
tons
4501,100
10,000
0
2,000
4,000
6,000
8,000
10,000
12,000
ExtensivelyHydrolyzed Casein
PartiallyHydrolyzed Whey
Whole ProteinCasein/Whey
Dal
tons
Median Molecular Weight of Infant FormulasMedian Molecular Weight of Infant Formulas
Distribution of Peptide Molecular Weight (%)
Distribution of Peptide Molecular Weight (%)
0
20
40
60
80
100
<1,000 Da 1-10,000 Da >10,000 Da
Partial Whey HydrolysateIntact Whey Predominant FormulaIntact Casein Predominant Formula
0
20
40
60
80
100
<1,000 Da 1-10,000 Da >10,000 Da
Partial Whey HydrolysateIntact Whey Predominant FormulaIntact Casein Predominant Formula
Hydrolysate Formulas in Allergy Risk ReductionHydrolysate 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.
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.
Cumulative Incidence of Atopic Manifestations
Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies
Cumulative Incidence of Atopic Manifestations
Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies
0
20
40
60
80
Von Berg 2003 Oldaeus 1997 Ziger 1995 Mallet 1992
Cum
ulat
ive
Inci
denc
e of
AM
(%)
Extensively Hydrolyzed CaseinIntact Cow Milk
0
20
40
60
80
Von Berg 2003 Oldaeus 1997 Ziger 1995 Mallet 1992
Cum
ulat
ive
Inci
denc
e of
AM
(%)
Extensively Hydrolyzed CaseinIntact Cow Milk
* 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
p=0.025p=0.025
p<0.02p<0.02
p=0.032p=0.032p=NSp=NS
Cumulative Incidence of Atopic Dermatitis
Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies
Cumulative Incidence of Atopic Dermatitis
Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies
0
20
40
60
80
Von Berg2003
Oldaeus 1997 Zeiger 1995 Mallet 1992 Chandra1989
Cum
ulat
ive
Inci
denc
e of
AD
(%)
Extensively Hydrolyzed CaseinIntact Cow Milk
0
20
40
60
80
Von Berg2003
Oldaeus 1997 Zeiger 1995 Mallet 1992 Chandra1989
Cum
ulat
ive
Inci
denc
e of
AD
(%)
Extensively Hydrolyzed CaseinIntact Cow Milk
p=0.006p=0.006
p=0.007p=0.007p=NSp=NS
p=0.059p=0.059
p<0.005p<0.005
* 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 * 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
Cumulative Incidence of Atopic Manifestations
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies
Cumulative Incidence of Atopic Manifestations
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies
0
20
40
60
80
Becker 2004 Von Berg2003
Exl 2000 Chandra1997
Marini 1996 Vandenplas1995
de Seta 1994 Willems1993
Vandenplas1988
Cum
ulat
ive
Inci
denc
e of
AM
(%)
Partially Hydrolyzed WheyIntact Cow Milk
0
20
40
60
80
Becker 2004 Von Berg2003
Exl 2000 Chandra1997
Marini 1996 Vandenplas1995
de Seta 1994 Willems1993
Vandenplas1988
Cum
ulat
ive
Inci
denc
e of
AM
(%)
Partially Hydrolyzed WheyIntact Cow Milk
* 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
* 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
p=0.109p=0.109
p<0.05p<0.05
p<0.05p<0.05
p<0.05p<0.05
p=0.021p=0.021
p=NSp=NS p<0.001p<0.001
p=0.063p=0.063
p<0.05p<0.05
Cumulative Incidence of Atopic Dermatitis
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies
Cumulative Incidence of Atopic Dermatitis
Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies
0.0
20.0
40.0
60.0
Von Berg2003
Chan 2002 Exl 2000 Chandra 1997 Marini 1996 Vandenplas1995
Tsai 1991 Vandenplas1988
Cum
ulat
ive
Inci
denc
e of
AD
(%)
Partially Hydrolyzed WheyIntact Cow Milk
0.0
20.0
40.0
60.0
Von Berg2003
Chan 2002 Exl 2000 Chandra 1997 Marini 1996 Vandenplas1995
Tsai 1991 Vandenplas1988
Cum
ulat
ive
Inci
denc
e of
AD
(%)
Partially Hydrolyzed WheyIntact Cow Milk
* 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
* 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
p=0.048p=0.048
p=0.004p=0.004
p<0.05p<0.05
p<0.02p<0.02p=NSp=NS p<0.05p<0.05
p>0.05p>0.05
p>0.05p>0.05
Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of Life
The German Infant Nutritional Intervention (GINI) Study
Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of Life
The 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
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): 533-40Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40
Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of Life
The German Infant Nutritional Intervention (GINI) Study
Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of Life
The 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 (p=0.02)
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
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%• 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): 533-40Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40
Risk of AD at 12 months: Adjusted Odds RatioRisk of AD at 12 months: Adjusted Odds Ratio
0 0.2 0.4 0.6 0.8 1
Extensively HydrolyzedCasein
Partially Hydrolyzed Whey
Extensively HydrolyzedWhey
Intact Cow Milk
0 0.2 0.4 0.6 0.8 1
Extensively HydrolyzedCasein
Partially Hydrolyzed Whey
Extensively HydrolyzedWhey
Intact Cow Milk 1.0
0.56
0.42
44% risk reduction vs CMF44% risk reduction vs CMF
58% risk reduction vs CMF58% risk reduction vs CMF
Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40
0.81 P - NS vs CMF 19% risk reduction vs CMF19% risk reduction vs CMF
P< 0.048 vs CMF
P< 0.007 vs CMF
0
5
10
15
20
25
Birth 12mo 24mo 36mo
Intact Cow MilkPartially Hydrolyzed WheyExtensively Hydrolyzed WheyExtensively Hydrolyzed Casein
3 Yr. GINI study : Findings not published. Results presented at ESPACI Meeting, 2003
Cumulative Incidence of Atopic Dermatitis
Cumulative Incidence of Atopic Dermatitis
GINI Study ConsiderationsGINI 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
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): 533-40Von Berg et al., 2003 J Allergy Clin Immunol 111(3): 533-40
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, cow’s milk allergy incidence in infancy• Asthma, food allergy prevalence in childhood
• No significant difference between PHF and EHF
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, cow’s milk allergy incidence in infancy• Asthma, food allergy prevalence in childhood
• No significant difference between PHF and EHF
Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of Allergy
Osborn & Sinn, 2003 - The Cochrane Library
Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of Allergy
Osborn & Sinn, 2003 - The Cochrane Library
Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of Allergy
Osborn & Sinn, 2003 - The Cochrane Library
Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of Allergy
Osborn & Sinn, 2003 - The Cochrane Library
Reviewer’s conclusions: “When babies are not exclusively breastfed, using hydrolyzed
infant formulas instead of ordinary cow’s 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].”
Reviewer’s conclusions: “When babies are not exclusively breastfed, using hydrolyzed
infant formulas instead of ordinary cow’s 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].”
CONCLUSIONSCONCLUSIONS
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
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
CONCLUSIONSCONCLUSIONS
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
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
IT MAY BE POOP TO YOU BUT IT IS MY BREAD AND BUTTER!
IT MAY BE POOP TO YOU BUT IT IS MY BREAD AND BUTTER!
Thank you.Thank you.
Family History as Allergy PredictorFamily 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)
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 Bergmann et al., 1997 Clinical and Experimental allergy 27: 752-60
Adapted from Saarinen, 1995; Lancet. 346: 1065-69
0
10
20
30
40
1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years
Alle
rgy
Pre
vale
nce
%
0
10
20
30
40
1 2 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years
Alle
rgy
Pre
vale
nce
%
SkinSkin
RespiratoryRespiratory
GIGI
Prevalence of Allergic Manifestations by AgePrevalence of Allergic Manifestations by Age
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
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
Prevalence of Parental Atopic History: 64% 31% 5%Prevalence of Parental Atopic History: 64% 31% 5%
Prevalence of Atopic Disease in German Infants (total 17.6%): 9.6% 6.4% 1.6%Prevalence of Atopic Disease in German Infants (total 17.6%): 9.6% 6.4% 1.6%
Bergman, et al. Clinical and Experimental Allergy 1998; 28:905-907Bergman, et al. Clinical and Experimental Allergy 1998; 28:905-907
Odds Ratio — Allergic ManifestationsExtensively Hydrolyzed Casein vs. Intact Cow Milk
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
* 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
Mallet 1992Mallet 1992
Von Berg 2003Von Berg 2003
Zeiger 1995Zeiger 1995
Oldaeus 1997Oldaeus 1997
0 0.5 1 1.5 2
Odds Ratio — Atopic Dermatitis Extensively Hydrolyzed Casein vs. Intact Cow MilkOdds 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
* 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
0 0.5 1 1.5 2
Mallet 1992Mallet 1992
Von Berg 2003Von Berg 2003
Zeiger 1995Zeiger 1995
Oldaeus 1997Oldaeus 1997
Chandra 1989 ‡Chandra 1989 ‡
Osborn meta-analysis 2003
Osborn meta-analysis 2003
Odds Ratio — Allergic ManifestationsPartially Hydrolyzed Whey vs. Intact Cow Milk
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
* 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
0 0.5 1 1.5 2
Chandra 1997 ‡Chandra 1997 ‡
Exl 2000Exl 2000
Von Berg 2003Von Berg 2003
Willems 1993 ‡Willems 1993 ‡
Vandenplas 1988 Vandenplas 1988
Vandenplas 1995 ‡Vandenplas 1995 ‡
Osborn meta-analysis 2003Osborn meta-analysis 2003
Marini 1996 Marini 1996
De Seta 1994 ‡De Seta 1994 ‡
Odds Ratio — Atopic DermatitisPartially Hydrolyzed Whey vs. Intact Cow Milk
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
* 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
0 0.5 1 1.5 2
Chandra 1997 ‡Chandra 1997 ‡
Exl 2000Exl 2000
Von Berg 2003Von Berg 2003
Tsai 1991‡Tsai 1991‡
Vandenplas 1988 Vandenplas 1988
Vandenplas 1995Vandenplas 1995
Osborn meta-analysis 2003Osborn meta-analysis 2003
Marini 1996 Marini 1996
De Seta 1994 ‡De Seta 1994 ‡
Chan 2002Chan 2002
Immunologic SensitizationImmunologic Sensitization
Immunologic sensitization Immunologic sensitization
Re-exposure to sensitizing proteinRe-exposure to sensitizing protein
Manifestations of allergySigns and symptoms in target organs
Skin, GI, Lungs
Manifestations of allergySigns and symptoms in target organs
Skin, GI, Lungs