1. Food Allergy Highlights of the past 3 years Adam Fox Paediatric Study Day Cheltenham June 2004 Dr Adam Fox

2. Food Allergy Research ‘Food Allergy’ Pub Med articles

3. Highlights of the past 3 years Prevalence of food allergy Comorbidities Natural History Emerging Treatments

4. Highlights of the past 3 years Prevalence of food allergy Comorbidities Natural History Emerging Treatments

5. Anaphylaxis epidemic? National database 1997-2005 112 deaths (0.64/million) 350% increase in food induced anaphylaxis admissions over 11 yrs Liew WK et al. Anaphylaxis fatalities and admissions in Australia. JACI Feb 2009;123:434-42.

6. But no such increase in deaths ?better management

7. Main increase is in 0-5 yr olds and due to peanut allergic reactions

8. Is peanut allergy getting out of control? Rates of Peanut Allergic in UK Paediatric Cohorts

9. Peanut Allergy in US Sicherer et al JACI 2010 1997 20022008

10. Venter C et al. Time Trends in the prevalence of peanut allergy: 3 cohorts of children from the same geographical location in the UK. Allergy 2010;65:103-8. n=2181n=1273n=891 Pre-COT Post-COT

11. ..and it isn’t just here Ben-Shoshan M et al, JACI Apr 2009

12. Highlights of the past 3 years Prevalence of food allergy Comorbidities Natural History Emerging Treatments

13. Food Allergy & Eczema – beyond reasonable doubt What we knew: Link between AE & likelihood of FA Link between increasing severity of AE & likelihood of FA Hill DJ et al. PAI 2004;15:421-7. Hill DJ et al. J Pediatr 2000;137:475-9. Hill DJ et al. J Pediatr 2007;151:359-63.

14. Food Allergy increases with AD severity Hill D, Hosking C. Food Allergy and Atopic Dermatitis in infancy. Paed Allergy Immunol 2004;15:421-7.

15. Food Allergy & Eczema – beyond reasonable doubt What we knew: Link between AE & likelihood of FA Link between increasing severity of AE & likelihood of FA What we needed to know: Is this reproducible in a large cohort, international study Are there other important factors to predict likelihood of FA Hill DJ et al. PAI 2004;15:421-7. Hill DJ et al. J Pediatr 2000;137:475-9. Hill DJ et al. J Pediatr 2007;151:359-63.

16. Hill DJ et al. Confirmation of the Association between high levels of IgE food sensitisation & eczema in infancy: an international study. Clin Exp Allergy;38:161-8. 2222 children from 94 centres in 12 countries (mean 17months) with AE and allergic FHx SCORAD for eczema severity SpIgE to egg, milk and peanut Used previously validated ‘decision points’ based on 90% PPV to define HR-IgE-FS

17. Relationship between eczema & HR-IgE-FS

18. Limitations No DBPCFC but.... Used validated cut offs High specificity of cut offs means many true food allergics would have been missed Probably underestimating food allergy as only 3 allergens tested.

19. Summary In infants with AE, the earlier the age of onset and the more severe the eczema, the more likely there is to be food allergy Clinical Implication: Food allergies should be routinely assessed for in infants with moderate or severe eczema

20. Highlights of the past 3 years Prevalence of food allergy Comorbidities Natural History Emerging Treatments

21. Outgrowing Food Allergy What we knew: Upto 75% of IgE mediated milk allergy is outgrown by 3 years Danneus A et al 1981, Host A et al Allergy 1990, Bishop J et al J Paediatr 1990 Tolerance is unlikely if not obtained by school age –Hill DJ et al CEA 1993, Saarinen KM et al JACI 2005 SPT/SpIgE wheal size relates to likelihood of clinical allergy What we needed to know: Is this reproducible in a larger, more recent studies What predicts tolerance?

22. Skripak JM et al. The Natural History of IgE mediated Cow’s Milk Allergy. JACI;120:1172-77. Retrospective review of over 1000 IgE mediated milk allergic patients seen by author over 15 years Clinical history, test results and outcome collected on 807 patients Patients considered tolerant after they passed a challenge or experienced no reactions in the past 12 months and had a cow’s milk IgE <3 kU/L.

23. Natural History of IgE mediated milk allergy Skripak JM et al. The Natural History of IgE mediated Cow’s Milk Allergy. JACI Nov 2007.

24. Limitations Skewed tertiary care population Possible underestimation of tolerance – Lost to follow up probably more likely to be tolerant – Some not challenged due to high SPT/SpIgE may have outgrown

25. Patients with persistent CMPA had higher IgE levels in first 2 years of life The higher the peak IgE level, the lower the chance of tolerance Similar for egg Savage J et al. The Natural History of egg Allergy. JACI 2007 Benhamou et al. PAI 2008. Can Allergy Tests Predict Outgrowing?

27. Clinical Implication: Tolerance may be taking longer than expected but may still develop in adolescence – don’t stop following them up Initial allergy test results should be considered when counselling parents regarding prognosis Is milk allergy becoming a more persistent disease?

28. Highlights of the past 3 years Prevalence of food allergy Comorbidities Natural History Emerging Treatments

29. Managing Food Allergy - Milk What we knew: Allergen avoidance is the optimal management strategy Children who outgrew milk allergy had milk-specific IgE antibodies primarily directed against conformational epitopes. Children with persistent milk allergy also had IgE antibodies directed against specific sequential epitopes. Chatchatee P et al. CEA 2001;31:1256-62. Chatchatee P et al. JACI 2001;107:379-83. Jarvinen KM et al. JACI 2002;110:293-7. Vila L et al. CEA 2001;31:1599-606.

30. Jarvinen K-M et al. Allergy 2007 Linear/sequentialConformational

31. Managing Food Allergy - Milk What we knew: Allergen avoidance is the optimal management strategy Children who outgrew milk allergy had milk-specific IgE antibodies primarily directed against conformational epitopes. Children with persistent milk allergy also had IgE antibodies directed against specific sequential epitopes. What we needed to know: Can those with IgE to conformational epitopes tolerate cooked milk? – do they represent a milder phenotype & if so, how can we identify them? Will regular allergen exposure impact on tolerance? In other words..... Chatchatee P et al. CEA 2001;31:1256-62. Chatchatee P et al. JACI 2001;107:379-83. Jarvinen KM et al. JACI 2002;110:293-7. Vila L et al. CEA 2001;31:1599-606.

32. All mild Are we being too strict? After 3 months of HM – no effect on growth or intestinal permeability HM tolerant had smaller SPT & lower  LG/Casein SpIgE None with SPT<5 reacted to HM. 5kU was 90% cut off for reacting Nowak-Wegrzyn A et al. JACI, August 2008 100 Milk allergic children (2-17 yrs) with +ve allergy tests

33. Summary: 2 different phenotypes in IgE mediated milk allergy Mild – tolerate baked milk, milder reactions, smaller test and outgrow earlier Severe – don’t tolerate baked milk, severe reactions, larger test and outgrow later Clinical Implications: When do I start challenging....?

34. Impact on tolerance development? Kim et al JACI 2011 3 groups – Heated milk tolerant (mild phenotype) – Heated milk reactive (severe phenotype) – Comparison Group (retrospective age/sex/IgE matched controls who had ‘standard care’)

35. HM tolerant vs HM reactive 80% vs 24% tolerant of unheated milk over 5 years

36. HM tolerant vs comparison group 80% vs 33% tolerant of unheated milk over 5 years

37. Conclusions Baked milk, if tolerated, is safe convenient and well accepted Appears to enhance development of tolerance but prospective controlled study still to be done

39. Oral tolerance induction to peanut 4 confirmed peanut allergics Gradually increased doses of oral peanut 2 weekly supervised increments to 800mg All tolerated at least 10 peanuts at challenge 18 more patients successfully treated RCTs to follow.... ? Long term effect and ?safety Clarke A et al. Allergy 2009.

40. Desensitisation vs Tolerance Desensitisation – a change is threshold of allergen required to cause allergic symptoms Tolerance – induction of long term immunologic changes associated with the ability to ingest allergen without symptoms or ongoing therapy

41. Blumchen et al. Oral peanut Immunotherapy in children with peanut anaphylaxis, JACI 2010 23 kids aged 3-14 Unstable asthma excluded

42. Results Only 5/23 achieved 500mg dose on rush protocol. 1 too anxious to complete. 5 who achieved 500mg with rush had significantly lower peanut SpIgE than others Long term build up more successful – 14 reached 500mg dose Mean 4 fold increase in dose tolerated at final OFC, compared to initial OFC 3 patients tolerated less than their maintenance at final OFC whilst 3 tolerated 4g top dose

43. Results 4 patients withdrawn due to SE All worsening of pre-existing asthma No adrenaline used (but trained to use salbutamol first for moderate respiratory symptoms 0.9% of doses required salbutamol Peanut specific downregulation of IL2, IL4 & IL5 (but no increase in IL10) and increased IgG4

44. Implications Rush protocol does not seem suitable (except possibly for those with low SpIgE) Long term build up seems to be safe and effective at reaching clinically relevant thresholds Possible early evidence of long term tolerance induction