Allergy : An Overview Alyson W. Smith, M.D. Department of Allergy and Immunology

1. Allergy : An Overview Alyson W. Smith, M.D. Department of Allergy and Immunology St. Barnabas Hospital

2. Allergy Allergyrefers tocertain diseasesin which immune responses to environmental antigens cause tissue inflammation and organ dysfunction. Hypersensitivity and sensitivityare synonyms for allergy. Allergenis any antigen that causes allergy. The allergen is processed by the dendritic cell, an antigen-presenting cell. It can be complete protein antigens or low molecular weight proteins capable of eliciting an IgE response. Atopyis the inherited propensity to respond immunologically to such common naturally occurring allergens with continuous production of IgE antibodies. It affects a significant portion of the general population, estimated at 10%-30% in developed countries.

3. Allergic Reaction The body’s overreaction to a harmless substance(an allergen) The harmless substance may contacted through the skin, inhaled into the lungs, swallowed, or injected.

4. Types of Hypersensitivity Reactions • Hypersensitivity reactions require a pre-sensitized (immune) state of the host. • Hypersensitivity reactions can be divided into four types: type I, type II, type III and type IV, based on the mechanisms involved and time taken for the reaction. • Frequently, a particular clinical condition (disease) may involve more than one type of reaction.

5. Type I hypersensitivity Also known asimmediateoranaphylactichypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor to death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 - 12 hours). Immediate hypersensitivity is mediated byIgE. The primary cellular component in this hypersensitivity is themast cellorbasophil.

6. Type IV hypersensitivity Also known ascell mediatedordelayed type hypersensitivity. e.g.Tuberculinreaction which peaks 48 hours after the injection of antigen (PPD) The lesion is characterized byinduration anderythema. Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy , chemicals, heavy metals, etc.) in which the lesions are more papular.

7. Etiology of Atopy • Etiology is unknown but there is strong evidence for a complex of genes that can influence the propensity for atopy through the regulation of total IgE production and specific IgE antibodies to allergen. • Environmental factors play a role in etiology. The initial age of exposure to a particular food or pollen determine the intensity of the subsequent IgE antibody response. A coexisting viral respiratory infection during allergen exposure may have an adjuvant effect on both specific and total IgE production. Tobacco smoking have similar effect.

8. Immunopathogenesis

9. The major mediators Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vasopermeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: heparin seems to be important in storing the preformed proteases and may play a role in the production of alpha-tryptase. Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity of neutrophils, cause significant tissue damage in the later phases of allergic reactions.

10. Common Allergens

11. Mechanism • Repeated exposures to an allergen may lead to more serious reactions. Once a person is sensitized (has had a previous sensitivity reaction), even a very limited exposure to a very small amount of allergen can trigger a severe reaction. • Allergic reactions vary. They can be mild or serious. They can be confined to a small area of the body or may affect the entire body. • Most occur within seconds or minutes after exposure to the allergen, but some can occur after several hours, particularly if the allergen causes a reaction after it is partially digested. In very rare cases, reactions develop after 24 hours.

12. Allergy Testing for IgE mediated diseases • Skin testing: • Indicates presence of IgE antibody NOT clinical reactivity • ~90% sensitivity • ~50% specificity • ~50% false positives • Larger skin tests/higher IgE correlates with likelihood of reaction but not severity • Negative prick test or specific IgE • Essentially excludes IgE antibody (>95% specific) Immunocap (blood) testing: quantifies amount of IgE to specific allergens

13. Immunocap blood testing (previously known as RAST)

14. Allergy Testing for non IgE mediated diseases (type 4 hypersensitivity) Patch testing for foods or other allergens (nickel, cosmetics, shampoos)

15. Allergic Rhinitis/Conjunctivitis Most common clinical expression of atopic hypersensitivity. IgE mediated allergy localized in the nasal mucosa and conjunctiva. Pollens and fungal spores, dust and animal danders can all trigger this response.

16. Allergic Rhinitis Diagnosis

17. Allergic Rhinitis Treatment Medications: Intranasal steroids, oral antihistamines (diphenhydramine and hydroxyzine (short acting) and fexofenadine, cetirizine, loratadine (long acting)), intranasal and ocular antihistamine/mast cell stabilizers Environmental controls

18. Urticaria Diffuse hives or wheals occur and cause significant pruritus (itching) Individual wheals resolve after minutes to hours, but new wheals can continue to form. Acute Urticaria: (Lasting <6 wk) can be caused by infections, foods, drugs, or contact allergens. Usually treat symptomatically. Chronic Urticaria: (Lasting > 6 weeks) can be idiopathic, autoimmune, or a sign of an underlying illness. Very unlikely to be caused by allergies!

19. Chronic Urticaria • In approximately 80% of cases there is no cause found! • 25-45% autoimmune • An autoantibody to the IgE receptor has been recently discovered as a cause of chronic urticaria.

20. Angioedema Angioedema is localized tissue swelling that can occur in soft tissues throughout the body, which may account for a substantial volume of fluid loss from the intravascular compartment. Patients may report pain at the site of swelling instead of pruritus, which occurs with urticaria. Angioedema can occur with or without urticaria. Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or hoarseness may be present. It can be life threatening requiring rapid intubation or even cricothyroidotomy. Causes are similar to urticaria but there is a disease of hereditary angioedema (episodes of severe angioedema without urticaria)

21. Angioedema

22. Atopic Dermatitis (eczema) Atopic Dermatitis is a chronic, relapsing, itchy skin disease. Clinical features: Chronic relapsing disease Dry, itchy, flaky skin Oozing, weeping and fissuring Erythema Excoriation Edema Lichenification Moderate-severe AD ( up to 33%) have clinically significant food allergy

23. Atopic Dermatitis

24. Evaluation and Treatment Skin testing, Immunocap testing, Food avoidance for moderate-severe atopic dermatitis Moisturization (ointments>creams>lotions) Antihistamines Hypoallergenic soaps, detergents, etc Environmental, occupational, and temperature control Topical steroids Antibiotics for superinfection

25. Anaphylaxis Anaphylaxis is highly likely when any one of the following three criteria are fulfilled: • Acute onset of an illness (minutes to hours) with involvement of the skin and/or mucosal tissue and respiratory compromise and/or reduced blood pressure. • Symptoms involving two or more organ systems( skin /mucosal, respiratory, cardiovascular, GI) that occur rapidly after exposure to a likely allergen for that patient. • Reduced BP following exposure to a known allergen for that patient.

26. The causes of anaphylaxis are divided into two major groups: • IgE mediated:This form is the true anaphylaxis that requires an initial sensitizing exposure, the coating of mast cells and basophils by IgE, and the explosive release of chemical mediators upon re–exposure. Ex: foods, venom • Non–IgE mediated: These reactions, the so called "anaphylactoid" reactions, are similar to those of true anaphylaxis, but do not require an IgE immune reaction. They are usually caused by the direct stimulation of the mast cells and basophils. The same mediators as occur with true anaphylaxis are released and the same effects are produced. Ex: vancomycin (red man syndrome) • The most commonly identified triggers are: • Food • Insect bites • Medications

27. Symptoms • Patients may report dizziness, faintness, diaphoresis, and pruritus. Difficulty breathing can result from angioedema of the pharyngeal tissue and from bronchoconstriction. • Patients may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. • Patients may experience uterine cramping or urinary urgency. • Patients can have a sudden onset of respiratory and/or circulatory collapse and go into anaphylactic shock.

28. Anaphylaxis Treatment Epinephrine: drug of choice Self-administered epinephrine readily available at all times If administered, seek medical care IMMEDIATELY Train patients, parents, contacts: indications/technique Antihistamines: secondary therapy only: WILL NOT STOP ANAPHYLXAXIS Corticosteroids IV fluids

29. Food Allergy Food Allergy may be defined as a complex of clinical syndromes resulting from the sensitization of the patient to one or more foods, in which symptoms manifest locally in the GI tract. This can result in reactions from hives to anaphylaxis. Some reactions are classically allergic (immediate reactions alone), or may reflect non IgE-mediated mechanisms. Food allergy is different than food intolerance. Ex: Lack of digesting enzymes (lactose intolerance)

30. Food Allergy Proteins or glycoproteins (not fat or carbohydrate) Major allergenic foods (>85% of food allergy) Children: milk, egg, soy, wheat, peanut, tree nuts Adults: peanut, tree nuts, shellfish, fish, fruits and vegetables Allergies to peanuts, tree nuts, seafoods, and seeds typically persist ~20% of cases of peanut allergy resolve by age 5 years. Prognostic factors favoring loss of allergy include: PST <6mm ≥2 years avoidance History of mild reaction Few other atopic diseases Low levels of peanut-specific IgE

31. Pollen-Food Syndrome or Oral Allergy Syndrome Clinical features: rapid onset oral pruritus, rarely progressive Epidemiology: prior sensitization to pollens Key foods: raw fruits and vegetables Allergens: Profilins and pathogenesis–related proteins Heat labile (cooked food usually OK) Cause: cross reactive proteins pollen/food Some studies have shown that up to 9 percent of people with OAS may experience more severe symptoms of food allergy, and up to 2 percent may experience anaphylaxis. Birch Apple, carrot, celery, cherry, pear, hazelnut Ragweed Banana, cucumber, melons Grass Melon, tomato, orange Mugwort Melon, apple, peach, cherry

32. Latex-Fruit Syndrome • It is estimated that 50-70 % of latex-allergic people have IgE antibodies cross-reactive to the antigens coming from some vegetable foods • Avocado • Banana • Chestnut • Potato • Tomato • Kiwi • Pineapple • Papaya • Eggplant • Melon • Passion Fruit • Mango • Wheat • Cherimoya

33. Pediatric Gastrointestinal Syndromes Enterocolitis Enteropathy Proctitis Age Onset: Infant Infant/Toddler Newborn Duration: 12-24 mo ? 12-24 mo 9 mo-12 mo Characteristics: Failure to thrive Malabsorption Bloody stools Shock Villous atrophy No systemic sx Lethargy Diarrhea Eosinophilic Vomit Diarrhea • Non-IgE-mediated, typically milk and soy induced • Spectrum may include colic, constipation and occult GI blood loss \

34. Evaluation Prick skin testing and/or Immunocap blood testing Elimination diets (1 - 6 weeks) most useful for chronic disease (eg. AD, GI syndromes) Eliminate suspected food(s) or Prescribe limited “eat only” diet or Elemental diet Oral challenge testing (MD supervised, emergency meds available) Open Single-blind Double-blind, placebo-controlled (DBPCFC)

35. Food Allergy: Treatment • Complete avoidance of specific food trigger • Ensure nutritional needs are being met • Education • Anaphylaxis Emergency Action Plan if applicable • most accidental exposures occur away from home

36. Prevention • Avoid triggers such as foods and medications that have caused an allergic reaction, even a mild one. This includes detailed questioning about ingredients when eating away from home. Ingredient labels should also be carefully examined. • A medical ID tag should be worn by people who know that they have serious allergic reaction. • If any history of a serious allergic reactions, carry emergency medications (such as diphenihydramine and injectable epinephrine

37. 10 Countdown A 10 yo boy presents for evaluation of hives of 4 months duration. His parents are frustrated by the lack of change in their son’s symptoms despite changes in soaps, detergents, and fabric softener. They would like their son to be seen by a specialist for evaluation. They describe the hives as raised, erythematous, pruritic, 1-2 cm lesions that involve the trunk and extremities. The hives resolve spontaneously in a few hours and occur in the day and at night. The child is otherwise healthy and only taking an antihistamine for pruritus. Of the following, the most likely cause of the hives are: • Allergy to a food additive or preservative • Allergy to dust mites • Autoantibody to the IgE receptor • Autoimmune thyroid disease • Systemic mastocytosis

38. 10 Countdown In early May, a 12-year-old girl comes to your office with symptoms of rhinitis, congestion, and fatigue most mornings, but she says she is well by mid-day. The symptoms have been occurring for the past 3 weeks, which coincides with the start of tree pollen season. An oral antihistamine and intranasal steroid are being used appropriately and have provided incomplete benefit. She wants to do something now that can improve her symptoms for this season. Of the following, your BEST option is to: • Begin allergy immunotherapy (allergy shots) • Begin antileukotriene monotherapy • Change her intranasal steroid • Change her oral antihistamine • Recommend she close her bedroom windows.

39. 10 Countdown You are evaluating a 14 year old female for allergic rhinitis. Despite a regimen of multiple allergy medications, she continues to have sneezing, rhinorrhea, and nasal congestion. You decide to consult an allergist for further evaluation, specifically aeroallergen skin testing and evaluation for allergy shots. Of the following, the most likely medication to alter the results of skin testing is: • Corticosteroid nasal spray • Inhaled beta 2 agonist • Low dose inhaled corticosteroid • Oral antihistamine • Oral leukotriene antagonist

40. 10 Countdown You are evaluating a 3-year-old boy who is new to your practice. His mother states that he is allergic to the following foods: eggs, peanuts, fish sticks, pancakes, cake, Raisinettes, M&Ms, tuna fish salad, macaroni salad, and ice cream from an ice cream store. He can eat Spaghetti, macaroni and cheese, and chocolate ice cream from a carton. When he reacts, he immediately breaks out in hives, vomits, and sometimes wheezes. He has injectable epinephrine, but has not used it because his symptoms do not seem bad enough. The mother has brought him to you because she feels she needs more guidance with his food allergies. Of the following, your BEST advice is that: • Allergy shots should be started immediately for his food allergies • Daily oral antihistamine should be started to prevent anaphylaxis • He is not really allergic to macaroni salad because he can spaghetti • It is unlikely he is allergic to all these foods and further evaluation is needed • The treatment of choice for anaphylactic reactions is an oral antihistamine

41. 10 Countdown A 5-year-old girl presents with rhinitis, congestion, and sneezing of several months’ duration. Antihistamine therapy has been somewhat helpful, but the girl still has symptoms. You have recommended removing the stuffed animals from her bed and closing the bedroom windows. There are no animals in the home, but some relatives do have pets. Of the following, the BEST next step is to: • Add an intranasal steroid to her regimen • Begin antileukotriene therapy • Change the type of antihistamine • Not allow the child to visit her relatives • Order immediate-type skin testing

42. 10 Countdown A father brings in his 7-year-old daughter to be evaluated for a rash and swelling on her entire body. These symptoms have been present for about 2 weeks. After obtaining a careful history and performing a physical examination, you determine that the child has urticaria. Of the following, the MOST likely cause is • artificial food coloring • milk • new laundry detergent • shrimp • upper respiratory tract viral infection

43. 10 Countdown A 12-year-old boy presents with a 6-month history of a raised erythematous rash involving the trunk, arms, and legs that recurs daily. The rash is pruritic but resolves within 1 hour without bruising or discoloration. Despite trying various food elimination diets, his parents have seen no change in his symptoms. The rash resolves within 15 minutes after taking diphenhydramine, but he is so sedated from the medication that he misses school. He is otherwise healthy, but his parents are frustrated. Of the following, the MOST appropriate initial long-term treatment for this boy's rash is: • Fexofenadine • Hydroxyzine • Ranitidine • Prednisone • Montelukast

44. 10 Countdown 10 yo boy comes to clinic complaining of tongue and mouth itching a few minutes after eating fresh apples. The oral symptoms resolve in a few minutes. Other than allergic rhinitis in the Spring months, he is healthy. Of the following, you are MOST likely to recommend: • Allergy skin testing to fresh apples probably will have negative results • Cooking the apple will not alter its allergenicity • Her son should avoid eating all fruits • Her son should avoid milk products • Her son’s symptoms are related to his allergic rhinitis

45. 10 Countdown The mother of a 14 yo girl with asthma is concerned that her daughter’s recent exacerbation is due to mold exposure. Their home sustained flood damage earlier this year. The mother provides you with a list of diagnostic tests she found on the internet. Of the following, the MOST appropriate testing to evaluate the girl for possible mold allergy is: • Allergy skin testing • Applied kinesiology • Cytotoxic testing • Provocation-neutralization • Pulse test

46. 10 Countdown A patient with a latex allergy may react to what food? • Apple • Banana • Peach • Soy

47. 10 Countdown A 12 month old female presents with a 3 month history of a pruritic rash that involves her cheeks, neck, anterior trunk, and antecubital areas. The rash improves with OTC corticosteroid cream but returns upon stopping. On PE, you observe a raised erythematous rash that has areas of lichenification. Of the following, the MOST helpful intervention is: • Eliminate milk, soy, eggs, and wheat from diet • Perform food skin testing • Perform aeroallergen skin testing • Recommend a skin biopsy

48. 10 Countdown A mother brings in her 12 month old son who broke out in hives after eating breakfast. Immediately after eating eggs, he developed a diffuse, erythematous, pruritic rash. She is concerned about an egg allergy. Of the following, the BEST statement regarding IgE mediated egg allergy: • A. cooking the egg eliminates its allergic potential • B. egg is the most common food allergy in the 1st year of life • C. egg white is more allergenic than egg yolk • D. Most children do not outgrow their egg allergy • E. The MMR vaccine is contraindicated in patients with an egg allergy

49. References & Online Further Reading Atopic diseases: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), tenth edition. Anaphylaxis and Urticaria: in Medical Immunology .eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), tenth edition. Brostoff J and Challacombe, S. Food Allergy and Intolerance. Bailliere Tindall, London. 1987. pp 431-794Shapiro, RS, Isenberg, BC. Allergic Headache. Annals of Allergy. 23 (3): 1965Monroe J, Brostoff, J. Food Allergy and Migraine. Lancet. July 5, 1980Egger J, Will J, Carter CM. Is Migraine Food Allergy? A Double-Blind Control Trial of Oligoantigenic Diet Treatment. Lancet. 865, 1983Mansfield L, Vaughn R, et al. Food Allergy and Adult Migraine: Double-Blind Mediator Confirmation of an Allergic Etiology. Annals of Allergy. 55:126-129, . Nsouli TM, et al. Serous Otitis Media and Food Allergy. Annals of Allergy, 73:215-219Sandberg, DH. Gastrointestinal complaints related to diet. Intern Pediatrics, 5(1):23-29, 1990Hill, DJ. A low allergy diet is a significant intervention in infantile colic: results of a community based study. J of Allergy and Clinical Immunology, 1995 (Dec): 886-890Randolph TG. Allergy as a Causative Factor of Fatigue, Irritability, and Behavioral Problems of ChildrenJ Pediatrics. 31:560-572, 1947.Boris M and Mandel FS. Foods and additives are common causes of the attention deficit hyperactive disorder in children. Annals of Allergy. 72(5):462-468, 1994 Adkinson NF Jr. Middleton’s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa: Mosby; 2003. Rakel RE. Textbook of Family Medicine. 7th ed. Philadelphia, Pa: WB Saunders; 2007. American Gastroenterological Association medical position statement: guidelines for the evaluation of food allergies. Gastroenterology. 2001 Mar;120(4):1023-5. American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006 Mar;96(3 Suppl 2):S1-68. Adkinson NF Jr. Middleton’s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa: Mosby; 2003