Allergy : An OverviewAlyson W. Smith, M.D.

Department of Allergy and ImmunologySt. Barnabas Hospital

Allergy

• Allergy refers to certain diseases in which immune responses to environmental antigens cause tissue inflammation and organ dysfunction. Hypersensitivity and sensitivity are synonyms for allergy.

• Allergen is 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.

• Atopy is 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.

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.

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.

Type I hypersensitivity

• Also known as immediate or anaphylactic hypersensitivity. 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 by IgE. • The primary cellular component in this

hypersensitivity is the mast cell or basophil.

Type IV hypersensitivity• Also known as cell mediated or

delayed type hypersensitivity. • e.g. Tuberculin reaction which peaks

48 hours after the injection of antigen (PPD)

• The lesion is characterized by induration and erythema.

• 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.

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.

Immunopathogenesis

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 anaphylaxiscauses eosinophil chemotaxis; an inflammatory factor of anaphylaxisresults in neutrophil chemotaxis. Eosinophils release major basicprotein and, together with the activity of neutrophils, cause significanttissue damage in the later phases of allergic reactions.

Common Allergens

• 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.

Mechanism

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

• Immunocap blood testing (previously known as RAST)

Allergy Testing for non IgE mediated diseases (type 4 hypersensitivity)

• Patch testing for foods or other allergens (nickel, cosmetics, shampoos)

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.

Allergic Rhinitis Diagnosis

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

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!

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.

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)

Angioedema

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

Atopic Dermatitis

Evaluation and TreatmentSkin 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

Anaphylaxis

Anaphylaxis is highly likely when any one of the following Anaphylaxis is highly likely when any one of the following

three criteria are fulfilled:three criteria are fulfilled:

1. 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.

2. Symptoms involving two or more organ systems( skin

/mucosal, respiratory, cardiovascular, GI) that occur rapidly

after exposure to a likely allergen for that patient.

3. Reduced BP following exposure to a known allergen for that

patient.

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

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.

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

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)

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

BirchBirch Apple, carrot, celery, cherry, pear, hazelnut Apple, carrot, celery, cherry, pear, hazelnut RagweedRagweed Banana, cucumber, melonsBanana, cucumber, melonsGrassGrass Melon, tomato, orangeMelon, tomato, orangeMugwortMugwort Melon, apple, peach, cherryMelon, apple, peach, cherry

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.

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

EnterocolitisEnterocolitis Enteropathy Enteropathy ProctitisProctitis

Age Onset:Age Onset: InfantInfant Infant/ToddlerInfant/Toddler NewbornNewborn

Duration:Duration: 12-24 mo12-24 mo ? 12-24 mo? 12-24 mo 9 mo-12 mo9 mo-12 mo

Characteristics:Characteristics: Failure to thriveFailure to thrive MalabsorptionMalabsorption Bloody Bloody stoolsstools ShockShock Villous atrophy No systemic sx Villous atrophy No systemic sx

LethargyLethargy DiarrheaDiarrhea EosinophilicEosinophilicVomitVomit

Diarrhea Diarrhea

Non-IgE-mediated, typically milk and soy inducedNon-IgE-mediated, typically milk and soy induced Spectrum may include colic, constipation and occult GI blood lossSpectrum may include colic, constipation and occult GI blood loss

\

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)

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

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

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:

CountdownCountdown

10

1 2 3 4 5

20% 20% 20%20%20%

1. Allergy to a food additive or preservative

2. Allergy to dust mites

3. Autoantibody to the IgE receptor

4. Autoimmune thyroid disease

5. Systemic mastocytosis

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:

1 2 3 4 5

20% 20% 20%20%20%1. Begin allergy immunotherapy

(allergy shots)

2. Begin antileukotriene monotherapy

3. Change her intranasal steroid

4. Change her oral antihistamine

5. Recommend she close her bedroom windows.

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%

1. Corticosteroid nasal spray

2. Inhaled beta 2 agonist

3. Low dose inhaled corticosteroid

4. Oral antihistamine5. Oral leukotriene

antagonist

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%1. Allergy shots should be started immediately for his food allergies

2. Daily oral antihistamine should be started to prevent anaphylaxis

3. He is not really allergic to macaroni salad because he can spaghetti

4. It is unlikely he is allergic to all these foods and further evaluation is needed

5. The treatment of choice for anaphylactic reactions is an oral antihistamine

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%1. Add an intranasal steroid to her regimen

2. Begin antileukotriene therapy

3. Change the type of antihistamine

4. Not allow the child to visit her relatives

5. Order immediate-type skin testing

CountdownCountdown

10

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

1 2 3 4 5

20% 20% 20%20%20%1. artificial food coloring

2. milk

3. new laundry detergent

4. shrimp

5. upper respiratory tract viral infection

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%1. Fexofenadine

2. Hydroxyzine

3. Ranitidine

4. Prednisone

5. Montelukast

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%1. Allergy skin testing to fresh apples probably will have negative results

2. Cooking the apple will not alter its allergenicity

3. Her son should avoid eating all fruits

4. Her son should avoid milk products

5. Her son’s symptoms are related to his allergic rhinitis

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%1. Allergy skin testing

2. Applied kinesiology

3. Cytotoxic testing

4. Provocation-neutralization

5. Pulse testCountdownCountdown

10

A patient with a latex allergy may react to what food?

1 2 3 4

25% 25%25%25%1. Apple

2. Banana

3. Peach

4. Soy

CountdownCountdown

10

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:

1 2 3 4

25% 25%25%25%

1. Eliminate milk, soy, eggs, and wheat from diet

2. Perform food skin testing

3. Perform aeroallergen skin testing

4. Recommend a skin biopsy

CountdownCountdown

10

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:

1 2 3 4 5

20% 20% 20%20%20%

• 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

CountdownCountdown

10

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 431-794 Shapiro, RS, Isenberg, BC. Allergic Headache. Annals of Allergy. 23 (3): 1965 Monroe J, Brostoff, J. Food Allergy and Migraine. Lancet. July 5, 1980 Egger J, Will J, Carter CM. Is Migraine Food Allergy? A Double-Blind Control Trial of Oligoantigenic Diet Treatment. Lancet. 865, 1983 Mansfield 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, 73:215-219 Sandberg, DH. Gastrointestinal complaints related to diet. Intern Pediatrics, 5(1):23-29, 1990 Hill, 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): 886-890 Randolph TG. Allergy as a Causative Factor of Fatigue, Irritability, and Behavioral Problems of Children J 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