the growing problem of pediatric allergy: prevalence & prevention william j. cochran, md, faap...

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


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


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



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

(%)


* 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




0

20

40

60

80

Von Berg2003

Oldaeus 1997 Zeiger 1995 Mallet 1992 Chandra1989

Cum

ulat

ive

Inci

denc

e of

AD

(%)


0

20

40

60

80

Von Berg2003

Oldaeus 1997 Zeiger 1995 Mallet 1992 Chandra1989

Cum

ulat

ive

Inci

denc

e of

AD

(%)


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


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

(%)


* 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





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

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e of

AD

(%)


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

(%)


* 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


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





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


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


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



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


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







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

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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

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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.


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.


‡ 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.



0 0.5 1 1.5 2

Mallet 1992Mallet 1992


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





0 0.5 1 1.5 2


Exl 2000Exl 2000


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







0 0.5 1 1.5 2


Exl 2000Exl 2000


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

the growing problem of pediatric allergy: prevalence & prevention william j. cochran, md, faap...

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