GLORIA Module 6: Food Allergy

1. GLORIA Module 6:Food Allergy Updated: June 2011

2. Sponsored by an unrestricted educational grant from

3. Global Resources in Allergy (GLORIA™) Global Resources In Allergy (GLORIA™) is the flagship program of the World Allergy Organization (WAO). Its curriculum educates medical professionals worldwide through regional and national presentations. GLORIA modules are created from established guidelines and recommendations to address different aspects of allergy-related patient care.

4. World Allergy Organization (WAO) The World Allergy Organization is an international coalition of 89 regional and national allergy and clinical immunology societies.

5. WAO’s Mission WAO’s mission is to be a global resource and advocate in the field of allergy, advancing excellence in clinical care, education, research and training through a world-wide alliance of allergy and clinical immunology societies

6. Food AllergyA GLORIATM Module Authors Prof. Cassim Motala University of Cape Town and Red Cross Children's Hospital Cape Town, South Africa Dr. M. Dolores Ibáñez Hospital Nino Jesus Madrid, Spain Reviewer Prof. Alessandro Fiocchi Melloni University Hospital Milan, Italy Prof. Joaquín Sastre Fundación Jimenez Diaz, Department of MedicineUniversidad Autonoma de Madrid Madrid, Spain

7. Learning objectives At the end of this presentation you will be able to: • Recognise the main pathogenic food allergens in adults and children • Differentiate between IgE-mediated, cell-mediated and mixed IgE- and cell-mediated food-related diseases in different organ systems • Discuss the diagnosis of food allergy and the limitations of diagnostic techniques • Review the treatment of food allergy

8. Adverse reactions to food: definition Any abnormal clinical response attributed to ingestion, contact or inhalation of any food, a food derivative or a food additive • Toxic • Non toxic or hypersensitivity

9. Adverse reactions to food TOXIC Nontoxic Non-immune mediated Immune-mediated Intolerance Allergy Enzymatic Pharmacologic Undefined Non-IgE-mediated IgE-mediated Adverse Reactions to Food: Position Paper. Allergy 1995; 50:623-635

10. Prevalence of food allergy Precise prevalence is unknown, but estimates are: • Adults: 1.4% - 2.4% • Children < 3 years: ~ 6% • Atopic dermatitis (mild/severe): ~35% • Asthmatic children: 6 - 8% • Prevalence depends on: Genetic factors, age, dietary habits, geography and diagnostic procedures Adapted from Sampson HA. Adverse Reactions to Foods. Allergy Principles and Practice. 2003

11. Food allergy in children: international SINGAPORE Birds Nest Seafood Egg Milk USA & UK Milk Egg Peanut Tree Nuts Seafood ITALY Milk Egg Seafood AUSTRALIA Milk Egg Peanuts Sesame ISRAEL Milk Egg Sesame FRANCE Egg Peanuts Milk Mustard

12. “Second tier” foods • 10% reactions to foods • 160 foods • Fruits • Vegetables • Seeds (sesame, sunflower, poppy) • Spices

13. Pathophysiology: allergens • Proteins (not fat/carbohydrate)- 10-70 kD glycoproteins- Heat resistant, acid stable • Major allergenic foods (>85% of allergy)- Children: milk, egg, soy, wheat, other depending on geographical area - Adult: peanut, nuts, shellfish, fish • Single food (or related) > many food allergies • Characterization of epitopes underway - Linear vs conformational epitopes- B-cell vs T-cell epitopes

14. Pathogenesis of food hypersensitivity: gut barrier • The immune system associated with this barrier is capable of discriminating among harmless foreign proteins or commensal organisms and dangerous pathogens • Food allergy is an abnormal response of the mucosal immune system to antigens delivered through the oral route • The immature state of the mucosal barrier and immune system might play a role in the increased prevalence of gastrointestinal infections and food allergy in the first few years of life Adapted from J Allergy Clin Immunol 2004;113:808-809

15. Pathogenesis of food hypersensitivity: gut barrier • About 2 % of ingested food antigens are absorbed and transported throughout the body in an immunologically intact form, even through the immature gut • The underlying immunologic mechanisms involved in oral tolerance induction have not been fully elucidated Adapted from J Allergy Clin Immunol 2004;113:808-809

16. Pathophysiology: immune mechanisms • Protein digestion • Antigen processing • Some Ag enters blood IgE-Mediated IgE-receptor APC Mast cell Non-IgE- Mediated Histamine T cell B cell • TNF- • IL-5

17. Food allergy: clinical manifestations IgE IgE/Non-IgE Non-IgE Protein-inducedproctocolitis/enterocolitis Celiac disease Contact dermatitis Herpetiform dermatitis Heiner´s syndrome Urticaria/angioedema Rhinitis /Asthma Anaphylaxis Oral allergic syndrome Gastrointestinal symptoms (GIT) Atopic dermatitis Eosinophilic gastro-intestinal disorders Adapted from J Allergy Clin Immunol. 1999;103:717-728

18. Cutaneous food hypersensitivities:atopic eczema • Generally begins in early infancy • Characterized by typical distribution, extreme pruritus, and chronically relapsing course • Allergen-specific IgE antibodies bound to Langerhans cells play a unique role as “non-traditional” receptors • Double blind, placebo-controlled food challenges generally provoke a markedly pruritic, erythematous, morbilliform rash • Food allergy plays a pathogenic role in about 35 % of moderate-to-severe atopic dermatitis in children

19. Cutaneous food hypersensitivities Acute Urticaria and Angioedema: • The most common symptoms of food allergic reactions • The exact prevalence of these reactions is unknown • Acute urticaria due to contact with food is also common Chronic Urticaria: • Food allergy is an infrequent cause of chronic urticaria and angioedema

20. IgE mediated: respiratory manifestations Asthma • An uncommon manifestation of food allergy • Usually seen with other food-induced symptoms • Vapors or steam emitted from cooking food may induced asthmatic reactions • Food-induced asthmatic symptoms should be suspected in patients with refractory asthma and history of atopic dermatitis, gastroesophageal reflux, food allergy or feeding problems as an infant, or history of positive skin tests or reactions to food Rhinoconjunctivitis • Usually seen during positive controlled challenge tests, but occasionally reported by patients

21. IgE Mediated: systemic reactionanaphylaxis/anaphylaxis syndrome • Food-induced anaphylaxis- Rapid-onset- Multi-organ system involvement- Potentially fatal- Any food, highest risk: peanut, nut, seafood, milk, egg • Food-dependent - exercise-induced- Associated with a particular food- Associated with eating any food

22. Fatal food anaphylaxis • Frequency: ~ 100 deaths/yr • Risk:- Underlying asthma - Delayed epinephrine- Symptom denial - Previous severe reaction • History: known allergic food • Biphasic reaction • Lack of cutaneous symptoms

23. Food-dependent, exercise-induced anaphylaxis Exercise Wheat Temperature Gastrin Mediator release - Histamine - Others (LTD4,PAF, etc) ANAPHYLAXIS Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and Clinical Immunology

24. IgE-mediated: GIT manifestationoral allergy syndrome (OAS) • Elicited by a variety of plant proteins that cross-react with airborne allergens • Pollen allergic patients may develop symptoms following the ingestion of vegetable foods: - Ragweed allergic patients: Fresh melons and bananas - Birch pollen allergic patients: Raw potatoes, carrots,celery, apples, pears, hazelnuts and kiwi • Immunotherapy for treating the pollen-induced rhinitis may reduce/eliminate oral allergy symptoms Adapted from J Allergy Clin Immunol. 2004; 113:808-809

25. Food allergy prevalence in specific disorders

26. Mixed IgE/Non-IgE mediated: GITallergic eosinophilic disorders • Characterized by infiltration of the esophagus, stomach and/or intestinal walls with eosinophils, basal zone hyperplasia, papillary elongation, absence of vasculitis and peripheral eosinophilia in about 50 % of patients • AEE can occur in children and adults. Increasing yearly incidence (23/100.000 population in Switzerland) • In children symptoms similar to gastroesophageal reflux and in adults dysphagia and impaction is common • Almost 50% of patients have other atopic diseases • Diagnosis is based on endoscopic findings and biopsy (>15-20 eosinophils per High Power Field) Adapted from J Allergy Clin Immunol. 2006; 118:1054-9

27. Mixed IgE/non-IgE mediated: GIT allergic eosinophilic esophagitis (AEE) • Dysphagia • Abdominal pain • Poor response to anti - reflux drugs • Biopsy:Eosinophils ++++>20 eosinophils / HPF • Eotaxin – 3 tissue expression correlates with eosinophilia – crucial in pathogenesis of this disorder Bullock et J Pediatr Gastroenterol Nutr. 2007

28. Allergic eosinophilic esophagitis endoscopic findings White plaques (eosinophils) Rings

29. Mixed IgE/non-IgE mediated: GIT allergic eosinophilic gastroenteritis (AEG) • Weight loss, FTT+/_oedema • Vomiting, diarrhoea (post-prandial) • Blood loss • Iron deficiency • Protein/iron- losing enteropathy • ↑ TH2 in blood and mucosa • ↑ Mast cells, Eosinophils in mucosa • Eotaxin - 3 • Persistent food hypersensitivity at 5yr FU. Chehade M et al JPGN 2006;42;516-521

30. AEE and AEG • Food antigens have been implicated as one of the main etiologies • Skin prick test and atopy patch tests can be useful for food allergy diagnosis • Elimination diets or even amino-acid formula can be instituted on the basis of allergy testing, clinical history, biopsy and treatment response • Pharmacologic treatment: oral steroids and/or swallowed aerosolized fluticasone • ? Anti-IL-5 therapy Adapted from J Allergy Clin Immunol. 2006; 118:1054-9

31. Non-IgE mediated: GIT food protein induced syndromes (typically milk and soy induced) Enterocolitis # Enteropathy Proctocolitis Age Onset: Infant Infant/Toddler Newborn Duration: 12-24 mo ? 12-24 mo < 12mo Characteristics: Failure to thrive Malabsorption Bloody stools Shock Villous atrophy No systemic sx Lethargy Diarrhea Eosinophil Diarrhea # Solid foods implicated: fish, corn, chicken, turkey, vegetables Nowak-Wegrzyn et al Pediatrics 2003Zapatero Remon L et al. Allergol Immunopathol 2005

32. Non IgE mediated: GIT food protein-induced enterocolitis syndrome • Occurs in infants prior to 8-12 months of age, but may be delayed in breast-fed babies (milk or soy protein-based formulas are implicated) • Symptoms may include irritability, protracted vomiting 1- 3 hours after feeding, bloody diarrhoea (leading to dehydration), anaemia, abdominal distension, failure to thrive • In adults and older children, fish, shellfish and cereals hypersensitivity may provoke a similar syndrome with delayed onset of severe nausea, abdominal cramps and protracted vomiting • Resolved: 50% at 18 months, 90% at 36 months Adapted from J Allergy Clin Immunol. 2004; 113:808-809

33. Non-IgE Mediated: GIT food protein-induced enteropathy (excluding celiac disease) • Occurs from 0 - 24 months • Diarrhea (mild to moderate steatorrhea in about 80% of cases) • Food implicated: milk, cereals, egg, fish • Poor weight gain • Diagnosis: -Biopsy shows patchy villous atrophy with prominent mononuclear round cell infiltrate, few eosinophils, -Response to exclusion diet, -Challenge test • Resolved at 2 - 3 years old Adapted from J Allergy Clin Immunol. 2004; 113:808-809

34. Non-IgE Mediated: GIT food protein-induced protocolitis • Usually presents in the first few months of life and is thought to be due to food proteins passed to the infant in maternal breast milk, or to milk or soy-based formulas • Rectal bleeding is common • Diagnosis: endoscopy and colonic biopsy (eosinophils in epithelium and lamina propia) • Good response to extensively hydrolized formulas. Diet without dairy product in mother if lactating • Good prognosis with resolution at 12 months of life Adapted from J Allergy Clin Immunol. 2004; 113:808-809

35. Non-Ige Mediated: GIT celiac disease • Extensive enteropathy leading to malabsorption • Associated with an immune reaction to gliadin peptides (wheat, rye and barley) • Highly associated with HLA-DQ2 1 *0501. 1 *0201) • Serology: anti-transglutaminase IgA, Anti-gliadin IgA (asymptomatic and +ve serology is common) • Treatment: Elimination of gluten-containing foods Adapted from J Allergy Clin Immunol. 2004; 113:808-809

36. Non-IgE-mediated syndromes affecting the skin and lung • Dermatitis Herpetiformis- Vesicular, pruritic eruption- Gluten-sensitive- Associated with Celiac Disease • Heiner’s Syndrome- Infantile pulmonary hemosideroisis- Anemia, failure to thrive- Cow’s milk-associated- Precipitating antibodies to cow’s milk

37. Gastrointestinal food hypersensitivity?Infantile colic • Syndrome of paroxysmal fussiness characterized by inconsolable, agonized crying • Generally develops in the first 2 to 4 weeks of life and persists through the third to fourth months • Diagnosis can be established by the implementation of several brief trials of hypoallergenic formula Adapted from J Allergy Clin Immunol. 2004; 113:808-809

38. Disorders not proven to be related to food allergy • Migraines • Behavioral/Developmental disorders • Arthritis • Seizures • Inflammatory bowel disease

39. Diagnosis: history / examination • History: symptoms, timing, reproducibility Acute reactions vs chronic disease • Diet details / symptom diary Specific causal food/s “Hidden” ingredient/s • Physical examination: Evaluate disease severity • Identify general approach Allergy vs intolerance IgE-mediated vs non-IgE mediated

40. Diagnosing food hypersensitivity disorders: IgE-mediated • Identification and relationship with the food: Medical history • To identify specific IgE: Skin tests/serum specific IgE • To demonstrate that IgE sensitization is responsible for the clinical reaction: Controlled challenge tests • Diagnosis is based on the medical history, supported by identification of specific IgE antibodies to the incriminated food allergen and confirmed by challenge Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and Clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

41. Diagnosing IgE-mediated food hypersensitivity disorders Medical history: Symptoms • Symptoms described by patient • Length of time between ingestion and development of symptoms • Severity of symptoms • Frequency of symptoms • Time from last episode Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

42. Diagnosing IgE-mediated food hypersensitivity disorders Medical history: Timing of reaction An immediate reaction (1- 2 hours) is suggestive of an IgE mediated reaction to foods • It may be preceded by previous tolerance of minimal symptoms • It may occur apparently after the first contact Adapted from Adverse Reactions to Foods Committee, Spanish Society of Allergy and Clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

43. Diagnosing IgE-mediated food hypersensitivity disorders Medical history: food • Identification of food • How food was prepared • Quantity ingested • Previous tolerance • Cross-reactions with other food • Hidden foods, additives, contaminants Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

44. Diagnosing IgE-mediated food hypersensitivity disorders Medical history: Patient • Age at onset of symptoms • Other factors (eg, brought on by exercise) • Personal and family history of atopic diseases • Risk factors • Physical examination: Atopic dermatitis, dermographism, nutritional status Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

45. Diagnosing IgE-mediated food hypersensitivity disorders • The diagnosis of food allergy cannot be performed on the basis of a non-compatible medical history • No diagnostic analysis (skin tests, specific IgE in serum, etc) is of value if it is interpreted without reference to medical history Adapted from Adverse Reactions to Foods Committee. Spanish Society of Allergy and Clinical Immunology Alergol Inmunol Clin 1999; 14: 50-62.

46. Diagnosing IgE-mediated food hypersensitivity disorders Skin tests • Prick: Reproducible, sensitive, not irritant • Prick-prick: Use raw or cooked food. Highly recommended for fruits and vegetables (commercially prepared extracts are generally inadequate because of the lability of the allergens, so the fresh food must be used for skin testing)

47. Diagnosing IgE-mediated food hypersensitivity disorders • Skin Prick Tests are used to screen patients for sensitivity to specific foods • Allergens eliciting a wheal of at least 3 mm greater than the negative control are considered positive • Overall positive predictive accuracy is < 50 % • Negative predictive accuracy > 95 % (negative skin test results essentially confirm the absence of IgE-mediated reactions) + Diameter  3 mm

48. Diagnosing IgE-mediated food hypersensitivity disorders Skin tests • Intradermal: Not indicated • Atopy Patch test (APT): Atopic dermatitis, delayed reactions Fresh food or dry food recommended Non-standardized Difficult to interpret

49. Specific IgE to food (CAP / Radioallergosorbent tests) • Sensitivity similar to skin prick tests • Good correlation with other procedures • Efficiency: Depends on the allergen • Indicated if SPT are contraindicated (eg, skin disease, medications) • Useful if discrepancy exists between history and SPT • The use of quantitative measurements has shown to be predictive, for some allergens, of symptomatic IgE-mediated food allergy • Possibility to perform component-resolved diagnosis very useful in cross-reactivity reactions: profilins (Bet v2, Phl p12), polcalcins (Bet v4, Phl p7), LPT (Pru p3, Cor a8), Gly m4, Cross-reactive Carbohydrate Determinants or CCDs

50. Diagnostic food-specific IgE values (CAP-system fluorescent enzyme immunoassay) of greater than 95% positive predictive value Food Serum IgE Value (kU/L) Egg ≥7.0 ≤ 2 yr old ≥2.0* Milk ≥15.0 ≤ 2 yrs old ≥5.0** Peanut ≥14.0 Fish ≥20.0 Tree nuts ≥15.0 From Sampson HA: JACI 107:891-896,2001. * Boyano-Martinez T, Garcia-Ara C, Diaz-Pena JM, et al: Clin Exp Allergy 31:1464-1469,2001. ** Garcia-Ara C, Boyano-Martinez T, Diaz-Pena JM, et al: JACI 107:185-190,2001.