The Growing Problem of Pediatric Allergy: Prevalence & Prevention

1. The Growing Problem of Pediatric Allergy:Prevalence & Prevention William J. Cochran, MD, FAAP Department of Pediatric GI & Nutrition Geisinger Clinic

2. Allergy Prevalence • Affects as many as 50 million Americans • Up to 30% in some populations, particularly developed countries • In the U.S. allergies are a leading cause of chronic disease • Overall the incidence of allergies are on the rise • Food allergies are most common in infants and children American Academy of Allergy, Asthma and Immunology (AAAAI). The Allergy Report: Science Based Findings on the Diagnosis & Treatment of Allergic Disorders, 1996- 2001

3. Adverse Reactionsto Food Pharmacological (Toxic) Non Pharmacological • Bacterial food poisoning • Scromboid fish poisoning • Caffeine • Tyramine • Histamine Non Immune Mediated Immune Mediated • Lactase deficiency • Galactosemia • Pancreatic insufficiency • Allergies: • Dermatologic • GI • Respiratory • Anaphylaxis

4. Food Allergies • In the U.S., 7 million affected by food allergies • Infants and children particularly prone to allergy • Occur in 8 percent of children less than 6 years of age • Food allergies are the leading cause of anaphylactic reactions treated in the ER in US • Approximately 100 Americans, mostly children, die annually from food-induced anaphylaxis • Peanut allergy is the most common Allergy, Principles and Practice, 5th Ed., E. Middleton et al, ed. Mosby, St. Louis, 1998. AAAAI Board of Directors. Journal of Allergy and Clinical Immunology 102 (2):173-6. 1998.

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

6. Spectrum of Allergy Manifestations IgE Mediated MixedMechanism Non-IgEMediated Skin Acute urticariaAngioedema Atopicdermatitis Dermatitisherpetiformes GI Immediate GIhypersensitivity Oral allergysyndrome Eosinophilicgastroentero-colitis Protein inducedenterocolitis Respiratory Acute RAD (High riskanaphylaxis) Asthma (Risk ofanaphylaxis) Food inducedhemosiderosis Heiner syndrome Common Uncommon Adopted from HA Sampson, 2000

7. Atopic Dermatitis • The most common chronic skin disease in children. • In 80% to 90% of the cases, onset of the disease occurs before 5 to 7 years of age • Signs and symptoms • Rash: Erythematous patches with papules on the face, neck and extensor surfaces. Flexural lesions later. • Pruritis • Skin dryness, excoriations, erosions • Distress, irritability. Drake et al. J Am Acad Dermatol 1992;26:485-8.

10. Trends in Prevalence of Atopic Dermatitis *Secular trends in the UK Eichenfield et al , 2003 Pediatrics 111: 608-16

11. Atopic Dermatitis: Significance • Atopic dermatitis in the U.S. • Prevalence 10-20% overall† • Affects 15 million Americans‡ • 17% prevalence by 6 months of age* • 7 million visits per year ‡ • Up to 60% of children with severe atopic dermatitis have food hypersensitivity** † NIH- HHS Publication No. 03-4272, Rev April 2003 ‡ CDC Nat Ctr for Health Statistics Vital and Health Statistics Series, 1996, 13:134 * Moore MM - Pediatrics - 01-MAR-2004; 113(3 Pt 1): 468-74 ** Burkes et al. J Pediatr 1998, 132(1):132-610

12. Atopic Dermatitis and Quality of Life • In infants • Itchiness & Irritability & Altered Sleep • Pain / Colic when associated to GI allergy • Disruption of family- child interactions • In children • Disruption of daily routine • Sleep deprivation, nighttime scratching during all stages of sleep • Affects school, social interactions, personal relationships, and self-consciousness Howlett et al. Br J Dermatol 1999;140:381-4. Reuveni et al. Arch Pediatr Adoles Med 1999;153:249-53   Chamlin et al. Pediatrics 2004; 114(3); 607-11  

13. Atopic Dermatitis: Significance • Healthcare Costs in the U.S. • 1.6 billion (conservative) • 3.8 billion (all inclusive) Ellis CN, Drake et al. J Am Acad Derm 2002, 46: 361-70

14. Atopic Dermatitis: Significance • May be the first step in the Allergy March: the relationship between allergic manifestations throughout life • Approximately 75- 80% of atopic dermatitis patients develop allergic rhinitis • More than 50% of atopic dermatitis patients develop asthma Leung DY - J Allergy Clin Immunol - 01-DEC-2003; 112(6 Suppl): S117Spergel J Allergy Clin Immunology 2003; 112 (6 Suppl): S 118-27

15. The Allergic March Atopic GI and dermal allergy Upper respiratory tract (rhinitis, rhino-conjunctivitis, allergic otitis media) Lower respiratory tract (wheezing) Allergic asthma Cantani, 1999 Invest Allergol Clin Immunol 9(5)- 314-20

16. Increasing Prevalence of Asthma & Atopy Ninan et al., 1992; BMJ 304: 873-75

17. 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 • Egg 7kUa/L • Milk 15 kUa/L • Peanut 14 kUa/L • Fish 20kUa/L

18. DIAGNOSIS OF FOOD ALLERGY • Endoscopy and biopsy • Double-blind placebo-controlled food challenges: "gold standard"

21. 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

22. Food Allergy — Prevention • Tertiary prevention • Treatment to avoid recurrence of symptoms • Secondary prevention • Suppress disease expression after sensitization • Primary prevention • Prevention of sensitization Zeiger, Pediatrics, 2003; 111:1662-1671

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

24. Traditional Prevention Strategies • Nutritional strategies recommended for decreasing risk in the general pediatric population • Breast feeding • Delayed introduction of solid foods AAP, Pediatric Nutrition Handbook, 2003

25. Traditional Prevention Strategies • Nutritional strategies recommended for decreasing risk in high risk infants • Maternal allergen avoidance during breast feeding • Nuts, eggs, 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

26. Identifying “At Risk” Infants One parent or sibling with history of AD, urticaria, allergic rhinitis(hay fever) or asthma = “At Risk” by Family History Risk by Parental Hx.* Medium Low High Percentage of newborns Likelihood of developing allergy Sx *Approximate numbers in developed countries. Adapted from1. Bousquet J. et al. J Allergy Clin Immunol 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

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

28. Predicting Pediatric Allergy Medium Risk by Parental Hx. Low High Percentage of newborns Likelihood of developing allergy Sx Actual # of children/100 who will develop allergies There is no good public health mechanism to predict all children who will develop allergy. At least half of infants who go on to develop allergy could not have been predicted

29. Food Allergies: 90% accounted for by 5 foods 5 Most Common Allergens • Cow Milk • Soy • Wheat • Peanuts/Tree nuts • Egg Other • Cow’s milk: the most common antigen infants are exposed to • All routine infant formulas are made with cow’s milk protein

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

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

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

33. Distribution of Peptide Molecular Weight (%)

34. 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.

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

36. Cumulative Incidence of Atopic DermatitisExtensively Hydrolyzed Casein Formula vs Cow Milk Formula in Prevention Studies p<0.005 p=0.006 p=0.059 p=0.007 p=NS * 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

37. Cumulative Incidence of Atopic ManifestationsPartially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies p<0.05 p<0.05 p=0.021 p<0.05 p<0.001 p=NS p=0.063 p<0.05 p=0.109 * Graph depicts only published, peer-reviewed, prospective trials with data collection at time points ≤12 months. ** For all studies except Becker 2004, AM includes AD as one of the allergic outcomes assessed; for Becker 2004, AM refers to asthma alone. *** 4 months: Vandenplas 1988; 6 months: Exl 2000, De Seta 1994; 12 months: Becker 2004, Von Berg 2003, Chandra 1997, Marini 1996, Vandenplas 1995, Willems 1993 **** p-values in italics indicate that no p-value is reported in publication; p-value is based on calculated OR and CI

38. Cumulative Incidence of Atopic DermatitisPartially Hydrolyzed Whey Formula vs Cow Milk Formula in Prevention Studies p<0.05 p=NS p=0.004 p<0.02 p<0.05 p>0.05 p=0.048 p>0.05 * Graph depicts only published, peer-reviewed, prospective trials with data collection at timepoints ≤12 months. ** 4 months: Vandenplas 1988; 6 months: Exl 2000; 12 months: Von Berg 2003, Chandra 1997, Marini 1996, Vandenplas 1995, Tsai 1991 **** p-values in italics indicate that no p-value is reported in publication; p-value is based on calculated OR and CI

39. Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of LifeThe German Infant Nutritional Intervention (GINI) Study • Independent, government-sponsored study • Double blind randomized study • 2,252 high-risk infants randomized at birth to: • Intact cow milk formula • Partially hydrolyzed whey formula • Extensively hydrolyzed casein formula • Extensively hydrolyzed whey formula • As needed, randomized formula was given to 6 months of age (no other foods besides breast milk) • Allergic manifestations assessed at 1, 4, 8,12 mo • Atopic dermatitis • Allergic urticaria • Food allergy with manifestation in the GI tract Von Berg et al., 2003J Allergy Clin Immunol 111(3): 533-40

40. Effect of Hydrolyzed Cow Milk Formulafor Allergy Prevention the First Year of LifeThe German Infant Nutritional Intervention (GINI) Study • 2,252 infants enrolled in the study: • 889 exclusively breastfed to 4 mo • 945 infants included in per protocol • 418 infants either non-compliant or drop-outs • Extensively hydrolyzed casein had significantly higher number of non-compliant subjects than other formula groups (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., 2003J Allergy Clin Immunol 111(3): 533-40

41. Risk of AD at 12 months: Adjusted Odds Ratio 1.0 0.81 19% risk reduction vs CMF P - NS vs CMF 0.56 44% risk reduction vs CMF P< 0.048 vs CMF 0.42 58% risk reduction vs CMF P< 0.007 vs CMF Von Berg et al., 2003J Allergy Clin Immunol 111(3): 533-40

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

43. GINI Study Considerations • Lack of efficacy of extensively hydrolyzed whey formula • Method of hydrolysis is as important as degree of hydrolysis • Drop-out rate highest with extensively hydrolyzed casein • Blinding difficult with extensive hydrolysates • Statistical Analysis • Statistically significant for both extensively hydrolyzed casein formulaand partially hydrolyzed whey formula for atopic dermatitis • Statistically significant for extensively hydrolyzed casein formula but not partially hydrolyzed whey formula for all atopic manifestations Von Berg et al., 2003J Allergy Clin Immunol 111(3): 533-40

44. Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of AllergyOsborn & Sinn, 2003 - The Cochrane Library • Inclusion criteria • Randomized trials comparing use of hydrolyzed infant formula to human milk or intact cow milk formula •  80% follow-up of subjects • 18 / 72 studies were eligible for inclusion • Main results • Prolonged feeding of hydrolyzed formula (PHF and EHF combined) significantly reduced: • Allergy, eczema, cow’s milk allergy incidence in infancy • Asthma, food allergy prevalence in childhood • No significant difference between PHF and EHF

45. Meta-Analysis: Formulas containingHydrolysed Protein for Prevention of AllergyOsborn & 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].”

46. 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

47. 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

48. IT MAY BE POOP TO YOU BUT IT IS MY BREAD AND BUTTER!

49. Thank you.

50. Family History as Allergy Predictor • Specificity of 86-91% • Proportion of true negatives that are correctly identified (will not falsely predict a child at risk most of the time) • Sensitivity of 17-22% • Proportion of true positives that are correctly identified (will not correctly predict a child at risk most of the time) Bergmann et al., 1997 Clinical and Experimental allergy 27: 752-60