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  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,

Adverse Reactions to 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 Immune Mediated Non Immune Mediated Non Pharmacological Non Pharmacological Immune Mediated Immune Mediated

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  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, AAAAI Board of Directors. Journal of Allergy and Clinical Immunology 102 (2): Allergy, Principles and Practice, 5th Ed., E. Middleton et al, ed. Mosby, St. Louis, AAAAI Board of Directors. Journal of Allergy and Clinical Immunology 102 (2):

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)  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 Manifestations Acute urticaria Angioedema Atopic dermatitis Dermatitis herpetiformes Immediate GI hypersensitivity Oral allergy syndrome Immediate GI hypersensitivity Oral allergy syndrome Eosinophilic gastroentero- colitis Protein induced enterocolitis Acute RAD (High risk anaphylaxis) Acute RAD (High risk anaphylaxis) Asthma (Risk of anaphylaxis) Asthma (Risk of anaphylaxis) Food induced hemosiderosis Heiner syndrome Food induced hemosiderosis Heiner syndrome IgE Mediated Mixed Mechanism Non-IgE Mediated Skin GI Respiratory Common Uncommon Adopted from HA Sampson, 2000

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.  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.

Trends in Prevalence of Atopic Dermatitis *Secular trends in the UK Eichenfield et al, 2003 Pediatrics 111: *Secular trends in the UK Eichenfield et al, 2003 Pediatrics 111:

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**  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 , 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): ** Burkes et al. J Pediatr 1998, 132(1): † NIH- HHS Publication No , 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): ** Burkes et al. J Pediatr 1998, 132(1):

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  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: Reuveni et al. Arch Pediatr Adoles Med 1999;153: Chamlin et al. Pediatrics 2004; 114(3); Howlett et al. Br J Dermatol 1999;140: Reuveni et al. Arch Pediatr Adoles Med 1999;153: Chamlin et al. Pediatrics 2004; 114(3);

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:

Atopic Dermatitis: Significance  May be the first step in the Allergy March: the relationship between allergic manifestations throughout life Approximately % 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 % 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): S117 Spergel J Allergy Clin Immunology 2003; 112 (6 Suppl): S

The Allergic March Cantani, 1999 Invest Allergol Clin Immunol 9(5) Atopic GI and dermal allergy Allergic asthma Lower respiratory tract (wheezing) Upper respiratory tract (rhinitis, rhino-conjunctivitis, allergic otitis media)

Increasing Prevalence of Asthma & Atopy Ninan et al., 1992; BMJ 304:

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>95% PPV Egg7kUa/L Milk15 kUa/L Peanut14 kUa/L Fish20kUa/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 Egg7kUa/L Milk15 kUa/L Peanut14 kUa/L Fish20kUa/L

DIAGNOSIS 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 — 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 — 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:

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  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

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 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” Infants *Approximate numbers in developed countries. Adapted from 1. Bousquet J. et al. J Allergy Clin Immunol 1986;78: Halken S et al. Allergy 2000;55: Kjellman N. et al. Acta Paediatr Scan 1977;66: Exl BM, Nutr Res 2001;21: One parent or sibling with history of AD, urticaria, allergic rhinitis (hay fever) or asthma = “At Risk” by Family History Risk by Parental Hx.* Low Medium High Percentage of newborns Likelihood of developing allergy Sx

Predicting Pediatric Allergy Risk by Parental Hx.* Low Medium High Percentage of newborns Likelihood of developing allergy Sx Actual # of children/100 who will develop allergies Actual # of children/100 who will develop allergies *Approximate numbers in developed countries

Predicting Pediatric Allergy Risk by Parental Hx. Low Medium High Percentage of newborns Likelihood of developing allergy Sx Actual # of children/100 who will develop allergies 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

Food Allergies: 90% accounted for by 5 foods 5 Most Common Allergens Other 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 Weight Potential for Hypersensitivity (Allergic Reaction) Low Molecular Weight Immune System Protein size and Allergenicity

Hydrolyzed Protein Intact Protein Intact Protein Hydrolyzed Protein Hydrolyzed Protein Hydrolysis Hydrolyzed proteins have a lower chance of inducing sensitization

Hydrolysis Can Reduce Allergenicity of Cow Milk Proteins Median Molecular Weight of Infant Formulas

Distribution of Peptide Molecular Weight (%)

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.

Cumulative Incidence of Atopic Manifestations Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies * 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=0.025 p<0.02 p=0.032 p=NS

Cumulative Incidence of Atopic Dermatitis Extensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies p=0.006 p=0.007 p=NS p=0.059 p<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 *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=0.109 p<0.05 p=0.021 p=NS p<0.001 p=0.063 p<0.05

Cumulative Incidence of Atopic Dermatitis Partially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies *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=0.048 p=0.004 p<0.05 p<0.02 p=NS p<0.05 p>0.05

Effect of Hydrolyzed Cow Milk Formula for 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):

Effect of Hydrolyzed Cow Milk Formula for 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):

Risk of AD at 12 months: Adjusted Odds Ratio % risk reduction vs CMF 58% risk reduction vs CMF Von Berg et al., 2003 J Allergy Clin Immunol 111(3): P - NS vs CMF 19% risk reduction vs CMF P< vs CMF P< vs CMF

3 Yr. GINI study : Findings not published. Results presented at ESPACI Meeting, 2003 Cumulative Incidence of Atopic Dermatitis

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 formula and 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 formula and 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):

 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 containing Hydrolysed Protein for Prevention of Allergy Osborn & Sinn, 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].”

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  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

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  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!

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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)  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:

Adapted from Saarinen, 1995; Lancet. 346: Skin Respiratory GI Prevalence of Allergic Manifestations by Age

Population based prevalence of atopic disease in German infants during 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 Atopic Disease in German Infants (total 17.6%): 9.6%6.4%1.6% Bergman, et al. Clinical and Experimental Allergy 1998; 28:

Odds Ratio — Allergic Manifestations Extensively 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 1992 Von Berg 2003 Zeiger 1995 Oldaeus 1997

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 *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 Mallet 1992 Von Berg 2003 Zeiger 1995 Oldaeus 1997 Chandra 1989 ‡ Osborn meta-analysis 2003

Odds Ratio — Allergic Manifestations Partially 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 Chandra 1997 ‡ Exl 2000 Von Berg 2003 Willems 1993 ‡ Vandenplas 1988 Vandenplas 1995 ‡ Osborn meta-analysis 2003 Marini 1996 De Seta 1994 ‡

Odds Ratio — Atopic Dermatitis Partially 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 Chandra 1997 ‡ Exl 2000 Von Berg 2003 Tsai 1991 ‡ Vandenplas 1988 Vandenplas 1995 Osborn meta-analysis 2003 Marini 1996 De Seta 1994 ‡ Chan 2002

Immunologic Sensitization Immunologic sensitization Re-exposure to sensitizing protein Manifestations of allergy Signs and symptoms in target organs Skin, GI, Lungs Manifestations of allergy Signs and symptoms in target organs Skin, GI, Lungs