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Food Allergy

Timothy J. Sullivan, M.D.

Mechanisms of Food Allergy Clinical Manifestations Diagnosis

Clinical assessment
Diagnostic tests


May 16, 2013

Food Allergy Timothy J. Sullivan, M.D.


Novartis/Genentec - Xolair No other potential conflict of interest with any organization or company that is involved in food allergy diagnosis, treatment, or tolerance induction

An immunologically specific Reaction to an exogenous antigen That results in a pathologic effect

Immune Exclusion

Immune surveilance of GI contents has at least two purposes

Identify and respond to pathogens

Identify and respond to digestion resistant proteins that reach the intestinal wall in significant amounts
IgA and IgG responses are common

IgE antibody responses

Signal 1 Signal 2


B cell

germline transcription

T cells

IgE synthesis

Isotype switching and expression of mature transcripts

IgE-Dependent Release of Inflammatory Mediators

IgE FcRI FcRI binding site Mediators

Immediate Release
Granule contents: Histamine, TNF-, Proteases, Heparin

Minutes to Hours Within Minutes

Lipid mediators: Prostaglandins Leukotrienes

Cytokine production: Including IL-4, IL-5, TNF-, IL-13, Chemokines

Mast Cells, Eosinophils, Parasites, and Protective Immunity

Clinical Manifestations of Food Allergy

IgE antibody-mediated

Anaphylaxis Urticaria and angioedema Gastrointestinal symptoms Rhinoconjunctivitis and asthma

Mixed IgE and Cell-Mediated

Atopic dermatitis
Eosinophilic esophagitis and enteritis

Clinical Manifestations of Food Allergy


Contact dermatitis Dermatitis herpetiformis Food protein-induced enteropathy syndromes Celiac disease Food-induced pulmonary hemosiderosis (Heiners syndrome)

Prevalence of Food Allergy

Based on questionnaire studies, 20% to 25% of Americans think they have a food allergy
Based on studies of patients, ~6% of children and 2% to 4% of adults in the US have, or have had, food allergy Peanut allergy has increased in prevalence 2fold in the US and UK over the past decade

The Big 8


Tree nuts



Assessment of Acute Reactions to Foods

A 6 year old boy ate dinner at a Chinese restaurant. He ate egg drop soup and then a stir-fry containing shrimp, fish, tofu, and a peanut sauce. Within 25 minutes he developed generalized pruritus, urticaria, angioedema of his lips, tongue, and larynx, wheezing and shortness of breath, and lost consciousness.

Assessment of Acute Reactions to Foods

In the ER vital signs were BP 60/0, P 126, R 22

Responded to IM epinephrine, IV saline, 1 mg/kg diphenhydramine IV, 4 mg/kg cimetidine IV, and was given 125 mg methylprednisolone IV

Serum tryptase was 58 ng/mL, 2.3 ng/mL on follow-up 2 months later

Analysis of Cause

Epicutaneous skin tests

Positive with shrimp wheal 15 mm/flare 38 mm Negative with egg, wheat, peanut, soybean, several fish antigens

ImmunoCap Assays for Specific IgE

Positive with shrimp 25 kU/L Negative with egg, wheat, peanut, soybean, several fish antigens < 0.35 kU/L

Avoid shrimp, crab, lobster, crayfish

Exercise & Food Induced Anaphylaxis

Maulitz RM, Pratt DS, Schocket AL. Exerciseinduced anaphylaxic reaction to shellfish. J Allergy & Clinical Immunology. 63(6):433-4, 1979.
Within a short time dozens of case reports published Two variations recognized

Subclinical specific food allergy + Exercise Eating any meal within 2 hours + Exercise

In Vitro assays for specific IgE

Williams PB, Barnes JH, Szeinbach SL, Sullivan TJ. Analytical precision and accuracy of commercial immunoassays for specific IgE: Establishing a standard. J Allergy Clin Immunol 2000;105:1221-1230.

Szeinbach SL, Barnes JH, Sullivan TJ, Williams PB. Precision and accuracy of commercial laboratories ability to classify positive and/or negative allergen-specific IgE results. Ann Allergy Asthma Immunol 2001;86:373-381.

In Vitro assays for specific IgE

17 serum samples with varying levels of specific IgE to aeroallergens sent to 6 labs using 5 different assays 3 times, a month apart.
Some strongly positive samples were serially diluted with negative sera and sent to these labs to see if their assays were linear with antibody concentration.

In Vitro Assays for Specific IgE

Accessible to any physician

ImmunoCap assays preferred Sensitivity less than with skin tests Provide quantitative data that are useful in detecting remission of clinical food allergy

Skin Tests for Specific IgE

May detect IgE that does not lead to allergic reactions when food is ingested

Antigens for some foods may be degraded by the time tests are done
Can use fresh food, especially fruit, to detect IgE to labile antigens

Patient Education
Food Allergy Research & Education (FARE)
http://www.foodallergy.org/ Food Allergy Action Plan http://www.foodallergy.org/document.doc?id= 125

Food allergen free products


Indications for Epinephrine

Glossal angioedema threatening the airway

Laryngeal edema threatening the airway Acute SOB, chest tightness, wheezing Lethargy or any other suggestion of hypotension

Epinephrine Administration

Small Children: Place the child on the ground face up. Administer the medication to the upper outer thigh.
Older Children: Stand behind the child. Hold the child with one hand across the chest. Administer the medication to the upper outer thigh. Independent Patients

Anaphylaxis Action Plan

EpiPens 0.3 mg and 0.15 mg

(1 mg/kg up to 30 kg)
EpiPen (epinephrine) Auto-Injector First, remove the EpiPen Auto-Injector from the plastic carrying case Pull off the blue safety release cap Hold orange tip near outer thigh (always apply to thigh)

Swing and firmly push orange tip against outer thigh. Hold on thigh for approximately 10 seconds.
Remove Auto-Injector and massage the area for 10 more seconds.

Auvi-Q 0.3 mg and 0.15 mg

Auvi-Q TM (epinephrine injection, USP) Remove the outer case of Auvi-Q. This will automatically activate the voice instructions. Pull off RED safety guard. Place black end against outer thigh, then press firmly and hold for 5 seconds.

Food Allergy in Children

Cows milk allergy most common food allergy in young children

Chicken egg allergy most common food allergy in children Peanut allergy most common food allergy beyond age 4 years

How do you know food allergy has remitted?

Tests for specific IgE every 6 months

1+ or 2+ positive skin tests Low levels of serum specific IgE Oral challenges in the office Avoidance is difficult. If the allergy has resolved, quality of life is improved when verified

IgE-Dependent Release of Inflammatory Mediators

IgE FcRI FcRI binding site Mediators

Immediate Release
Granule contents: Histamine, TNF-, Proteases, Heparin

Minutes to Hours Over Minutes

Lipid mediators: Prostaglandins Leukotrienes

Cytokine production: Including IL-4, IL-5, IL-13

Eosinophil recruitment & activation

Eosinophilic Esophagitis (EoE)

Active in ~4/10,000 children

Active in up to 4.8% of adults Food allergy, allergic rhinitis, asthma, or eczema present in 42% to 93% of children and 28% to 86% of adults with EoE Blood eosinophils increased in 40% to 50% Serum IgE elevated in 50% to 60%

Eosinophilic Esophagitis
Endoscopy and multiple esophageal biopsies essential to diagnose EoE

More than 15 eosinophils/hpf

Full thickness of esophagus involved

Symptoms of EoE

Infants & toddlers: Feeding difficulties

School age: Vomiting and pain Adolescents: Dysphagia Adults:

Dysphagia, chest pain, food impaction, upper abdominal pain 33% to 54% develop food impaction

Eliminate Causes of EoE

Elemental diet:

Up to 97% have clinical and biopsy improvement. Up to 84% can then identify foods to avoid

Limited food exclusion:

Avoid milk, corn, peanut, wheat, beef, soy, and eggs

Specific food exclusion:

Avoid foods to which the patient expresses IgE Remission in up to 80% of EoE patients

Aeroallergen immunotherapy

Treatment of EoE

Fluticasone MDI 2 puffs into mouth and swallowed twice a day

Viscous suspension of budesonide can be swallowed once a day Acid suppression if GERD is present Esophageal dilation may be needed

Oral Allergy Syndrome

Buccal, palatal, pharyngeal, laryngeal pruritus Without systemic symptoms of allergy




Latex Allergy and Food Allergy

Defense proteins in many foods cross-react

Oral Allergy Syndrome

Allergy Trigger Cross Reactors
Banana Cantaloupe

Ragweed Pollen

Cucumber Zucchini Honeydew

Chamomile tea

Type I and Type II Food Antigens

Type I food antigens elicit immune responses via the gastrointestinal route

Heat stable, acid stable, resistant to digestive enzymes More common in children

Type II food antigens cross-react with antigens in aeroallergens that have provoked an immune response by inhalation

Heat labile, acid labile, susceptible to digestive enzymes

More common in adults

How can fruit and vegetable antigens cross-react with pollen antigens?

Pathogenesis related proteins (PRP)

Lipid transport proteins (LPT) Chitinases Seed storage proteins Levels vary according to conditions during growth, conservation, and processing

What May The Future Hold?

Desensitization and tolerance induction by oral administration of specific foods

Normalization of Vitamin D levels

Monoclonal antibody neutralization of IgE

Oral immunotherapy

Sublingual immunotherapy for peanut allergy: a randomized, doubleblind, placebo-controlled multicenter trial. DM Fleischer et al. JACI

No serious reactions. Most patients had a modest level of desensitization.

2013. 131:119-127.

Safety and predictors of adverse events during oral immunotherapy for milk allergy: severity of reaction at oral challenge, specific IgE and prick test. M Vasquez-Ortiz et al. Clin Exp Allergy 2012. 43:92102.

Tolerance of 200 mL of cows milk in 86% of 81 children. 25% had frequent, fairly severe, and unpredictable reactions during and after reaching maintenance doses. High serum specific IgE and strong positive skin tests predicted strong reactions


Neutralization of specific IgE an attractive idea

One published trial with anti-IgE indicated significant protection in peanut allergic subjects. No indication for this use and no clinical trials underway.

Vitamin D and Food Allergy

Season of birth, latitude of residence data

Vitamin D levels and food and environmental allergies in the United States: results from the NHANES 2005-2006 survey. S Sharief et al. JACI 2011. 127:1195-202.

Normal 25 OH Vitamin D levels 30-100 ng/mL

Children and adolescents studied Compared those >30 ng/mL to those less than 15 ng/mL.

Peanut allergy Odds Ratio 2.39; 95% CI 1.20-2.80

Oak allergy Odds Ratio 4.75; 95% CI 1.53-4.94

Food Allergy 2013

History consistent with food allergy

Tests for specific IgE can be very helpful Written action plans important Resources available to help educate patients and families about food allergy

Physicians much better able to recognize and manage food allergy