Food Allergy: Brief Review

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

Definition of food allergy

Ingestion of a small amount of food elicits an abnormal immunologically mediated clinical response.


Figure 1. Food Allergy (click to enlarge the figure).

Adverse food reactions are classified in 2 categories: immunologically-mediated reactions and food intolerance. The term "food allergy" refers to immunologically-mediated reactions to food.

Immunologically-mediated adverse reactions to foods are 2 groups:

- IgE-mediated reactions, e.g. to peanuts, within minutes

- non–IgE-mediated reactions, e.g. protein-induced enterocolitis syndrome, within hours

IgE-mediated reactions develop within 2 hours of food ingestion. If the symptoms develop beyond the 2-hour window, it is not food allergy.

Food intolerance is not immunologically mediated, e.g. lactose intolerance. Food intolerance can also be divided in 2 groups: toxic and non-toxic reactions:

- toxic reactions, e.g. bacterial food poisoning, scromboid fish poisoning
- non-toxic reactions, e.g. lactose intolerance

Oral Allergy Syndrome

Oral allergy syndrome is defined as pruritus and edema of the oral mucosa after the ingestion of a particular food. Symptoms rarely (9%) spread beyond the mouth. Oral allergy syndrome is observed in 25-75% of pollen allergic patients. It is also called pollen-food allergy syndrome.

Examples of oral allergy syndrome:

Patients allergic to grass may react to tomato, melon and watermelon.
Patients allergic to ragweed may react to banana, melon, cucumber, zucchini.

Food-dependent exercise-induced anaphylaxis (FDEIA) (click to read the full article)

In FDEIA, patients develop anaphylaxis after eating and exercising. They have no symptoms are rest.

Sequence of events: eating --> exercise --> anaphylaxis

Heiner Syndrome

Heiner syndrome is an uncommon non-IgE-mediated adverse pulmonary reaction to food. There is an immune reaction to cow's-milk proteins with IgG to cow milk protein resulting in pulmonary infiltrates, pulmonary hemosiderosis, anemia, recurrent pneumonia and failure to thrive.

Prevalence of food allergy

The lumen of the gastrointestinal tract is exposed daily to many dietary proteins. Six percent of children and 4% of adults in the US do not tolerate those proteins and develop food hypersensitivity.

Adults 2-4%
Children 5-7%

Food-induced anaphylaxis is the most common cause of anaphylaxis treated in ED. The prevalence of certain food allergies, such as peanut, is increasing.

Eight top allergens account for 90 percent of all food allergies. The 8 top allergens can be remembered by the mnemonic TEMPS WFS:

Tree nuts (almonds, cashews, walnuts)
Egg white (not egg yolk)
Milk
Peanuts
Shellfish (crab, lobster, shrimp)
Wheat
Fish (bass, cod, flounder)
Soy


Figure 2. Eight top allergens account for 90 percent of all food allergies (click to enlarge the figure).

What is the most common food allergy in children?
Cow's milk allergy is the most common childhood food allergy.

Mnemonic for the 3 ways of antigen sampling in the gut: DMD

Dendritic cells "capture" antigens from the lumen
M cells overlying Peyer’s patches take up antigens
Direct transport through epithelium by soluble antigens

Symptoms and signs

Usually within minutes

Swelling in the mouth and oropharynx
Two or more of organ systems (GI, skin, respiratory)
Anaphylaxis

Food-induced anaphylaxis is the most common cause (85%) of anaphylaxis treated in ED. The median age of presentation is 2.4 years. Peanut and cashew nut are the most common cause of anaphylaxis.

Diagnosis

Diagnostic algorithm for food allergy: SAD Child:

1. Symptoms: close relation between specific food intake and symptoms, often affect 2 or more organs
2. Allergy testing: skin prick testing or ImmunoCAP.
3. Diagnostic diet: restricted diet leads to symptoms disappearance or significant reduction.
4. Challenge - oral food challenge (read more in Food Challenges for Diagnosis of Food Allergy)

References: Clinical review: ABC of allergies, Food allergy. BMJ 1998;316:1299, figure.

Skin Prick Tests

Skin prick test (SPT) is the quickest and cheapest test for diagnosing food allergy. SPT can be performed with non-standardized allergens, for example, fresh apple. Some allergists reportedly use themselves as controls to rule out non-IgE mediated reactions.

Positive predictive accuracy of SPT is less than 50%. Negative predictive accuracy is higher than 95%. Negative skin test results essentially confirm the absence of IgE-mediated reactions.

Positive skin prick test or CAP indicates presence of IgE antibody NOT clinical reactivity (~50% false positive).

Negative skin prick test or CAP essentially excludes IgE antibody (higher than 95% accuracy).

ImmunoCAP Test

ImmunoCAP is a IgE fluoroenzyme immunosorbent assay. The levels vary from 0.1 to 100. The previous threshold was 0.35.

Food specific IgE cut off levels which predict 50% pass rate for challenge tests (Perry et al. JACI 2004):

Food IgE level (KUA/l)
Milk 2
Egg 2
Peanut 2
Wheat 2

CAP threshold levels (less than 0.1) are well-established for 4 foods: milk, egg, peanuts and wheat.

The new cut-off threshold is 0.1. Specific IgE level of less than 0.1 predicts a negative food challenge test in most patients.

Negative CAP and negative SPT give a 90% chance of a negative food challenge test. SPT provides a lower threshold than CAP.

Food Challenges for Diagnosis of Food Allergy (click on the title for full text)


Food challenges, mind map diagram (click to enlarge the figure).


8 top allergens account for 90 percent of food allergies. Specific IgE levels (sIgE) that predict the likelihood of passing an oral food challenge are shown in the figure. (click to enlarge the image).



Comparison of diagnostic methods for peanut, egg, and milk allergy - skin prick test (SPT) vs. specific IgE (sIgE) (click to see the spreadsheet). Sensitivity of blood allergy testing is 25-30% lower than that of skin testing, based on comparative studies (CCJM 2011).

Read more in Food Challenges for Diagnosis of Food Allergy.

3 Types of oral food challenges: DOS:

Double-blind placebo-controlled food challenge (DBPCFC)
Open food challenge (OFC)
Single-blind placebo-controlled food challenge (SBPCFC)

Treatment

The most common treatment is avoidance of the offending food (TEMPS WFS).

There is no current active treatment for food allergy in the U.S. Traditional injection immunotherapy (SCIT) has been proved unsafe, and therefore there is a need for other forms of immunotherapy. Studies of oral immunotherapy (OIT) are currently conducted.

EpiPen Jr. is life saving in cases of anaphylaxis.

Dietary prevention of allergic diseases

According to the current guidelines, breastfeeding is highly recommended for all infants irrespective of atopic heredity.

Recommendations for prevention of allergic diseases in high-risk infants:

1. The most effective dietary regimen is exclusively breastfeeding for at least 4–6 months.
2. In absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months.
3. Avoidance of solid food and cow's milk for the first 4 months.

What is the risk of cross-reactivity for different foods?

If allergic to one one type of shellfish, there is a 50% cross-reactivity.
Cow milk --> 92% --> goat milk
If allergic to one one type of tree nut, there is a 37% cross-reactivity.
Peanut --> 1% --> treenuts

What is the chance of "outgrowing" a food allergy?

20% for peanuts.

For milk allergy: 19% by 4 years, 42% by 8 years, 64% by 12 years, 79% by 16 years

For egg allergy: 4% by 4 years, 12% by 6 years, 37% by 10 years, 68% by 16 years

80% chance of outgrowing egg allergy by the time they reach college

90% of infants allergic to milk and 50 % those allergic to eggs outgrow their clinical reactivity by the age of 3 but most patients allergic to peanuts or cod do not. Therefore, diagnosis should therefore be re-evaluated yearly.

Remission of peanut allergy can be predicted by low levels of IgE to peanut in the first 2 years of life or decreasing levels of IgE sensitization by the age of 3 years.

There is a correlation between IgE titres and the severity of clinical reaction to egg after the diagnosis has been established. A cut-off level of 8.20 kU/l had a 90% probability of clinical reactivity. IgE titres may help determine which patients are at risk of a reaction to eggs.

In children, 85% of cow’s milk, egg, wheat, and soy allergy resolves by five years. In contrast, only 20% of children “outgrow” their peanut allergy, and only 9% of tree nut-allergic patients do so.

Who will "outgrow" food allergy? It depends on the epitope

Each food is composed of many proteins and these proteins have multiple areas, termed epitopes, to which the immune system can respond. Epitopes that are dependent upon the folding of the proteins are called conformational epitopes. Epitopes that are not dependent upon folding are called linear epitopes.

A linear epitope oftens means a more prolonged allergy which is “stable” and persistent. A conformational epitope (egg, milk) often means a mild, transient allergy.

Paradigm shift in treatment of food allergy?

Inducing tolerance has been used as a strategy for preventing allergic reactions for centuries. For example, certain populations of Native Americans ate poison ivy leaves to avoid contact hypersensitivity reaction to urushiol.

Low doses of antigen favor tolerance driven by suppression by regulatory cells; high doses favor
tolerance driven by anergy or clonal deletion. Defects in regulatory T-cell activity contribute to the development of food allergy. For example, CD4/CD25 regulatory T cells mediate suppression through cell surface–bound TGF-b.

Randomized controlled trials are underway to see if high doses of peanut protein in high-risk infants are more effective at preventing peanut allergy than avoidance therapy (98% of peanut oil does not contain protein and is not immunogenic). The LEAP study (Learning Early About Peanut Allergy) is enrolling children with eczema, allergic to egg (they have a 20% chance of developing peanut allergy). Each child will be randomly assigned to either avoid consumption of peanuts or to be fed an age-appropriate peanut snack, and the cohort will be followed until the age of 5.

Both sublingual immunotherapy (SLIT) and oral immunotherapy (OIT) have been tested to induce desensitization in patients with food hypersensitivities. Both methods involve administering small doses (micrograms, milligrams, grams) of antigen in a controlled setting followed by home dosing of a maximum tolerated amount of antigen. In a standardized OIT protocol for treatment of different food allergies, desensitization occurred in 77% of treatments. Such effect has not yet been reproduced by the clinical trials conducted in the U.S.

What is the most common food allergen in children?
(A) Gal d (egg)
(B) Tri a 19 (wheat)
(C) Mal d 1 (apple)
(D) Gly m (soy)
(E) Ara h (peanut)
(F) Bos d (milk)
(G) Api g 4 (celery)

Answer: F.

References


Food allergy - 2012 international consensus (ICON) statement in JACI.
Food Challenges for Diagnosis of Food Allergy
Food Allergies. eMedicine.
Risk of oral food challenges. JACI, Volume 114, Issue 5, Pages 1164-1168 (November 2004).
Safety of open food challenges in the office setting. Ann Allergy Asthma Immunol. 2008 May;100(5):469-74.
What is a food challenge? National Jewish Health.
Manifestations of Food Allergy: Evaluation and Management. AFP, 1999.
Food Allergy Clinical Resources. Health Sciences Library, The University of Alabama.
10-minute consultation: Food allergy. BMJ 2002;325:1337.
Clinical review: ABC of allergies, Food allergy. BMJ 1998;316:1299, figure.
New Guidelines Issued for Food Allergies. Medscape, 2006.
New Guidelines for Introducing Solid Foods to Avoid Development of Infant Allergies. Medscape, 2006.
Manifestations of Food Allergy: Evaluation and Management. AFP, 1999.
About Food Allergies. ACAAI, Patient information.
Food Allergies--Just the Facts. AFP, Patient information, 1999.
Egg Allergy: A Short Review. Allergy Notes, 01/2008.
Review Up-date: Dietary prevention of allergic diseases in infants and small children. EAACI. Pediatr Allergy Immunol 2008: 19: 1–4.
Correlation between specific immunoglobulin E levels and the severity of reactions in egg allergic patients. Avigael H. Benhamou, Samuel A. Zamora, Philippe A. Eigenmann. Pediatric Allergy and Immunology 19 (2), 173–179, 2008.
Early clinical predictors of remission of peanut allergy in children. JACI, 03/2008.
Treatment of Food Allergies Reviewed. Medscape, 06/2008.
Oral tolerance, food allergy, and immunotherapy: implications for future treatment. J Allergy Clin Immunol. 2008 Jun;121(6):1344-50.
Paediatric anaphylaxis: a 5 year retrospective review. de Silva IL, Mehr SS, Tey D, Tang ML. Allergy. 2008 Aug;63(8):1071-6.
Food allergy in childhood. Katrina J Allen, David J Hill and Ralf G Heine. MJA 2006; 185 (7): 394-400.
Food Allergen Avoidance

PowerPoint Presentations

Food Allergy. Global Resources in Allergy (GLORIA) Module 6.
Food Allergy. Againdra K. Bewtra, M.B.B.S., M.D.
Food Allergy Update. Suzanne S. Teuber, M.D.
Oral Challenge Studies: Purpose, Design and Evaluation. Stefano Luccioli, MD.
Food Allergies in 2006: From The Clinic to The Classroom. Jeffrey M. Factor, MD.
Food Allergy… the nuts and bolts. Tom Gerstner, MD, FRCPC.

Audio and Video

Food Allergy and Additives. Presented by Sami L. Bahna, MD, DrPH. ACAAI Vodcasts 2007 (video).
When And How Do You Perform Food Challenges? ABC.com.
Food Challenges For Children With Allergies. ABC.com.
General Questions About Food Allergies. ABC.com.
AAAAI: Gradual Exposure Reduces Kids' Peanut Allergy. MedPage Today, 03/2008 (video).
News Video: Living with Food Allergies. Allergy Notes.
Food Allergies and Intolerances. Check Up. BBC 4 (audio).
Food Allergies. ICYou, 04/2007.

Related Reading

Putting a face on food allergies - USA Today readers share their stories about dining out with food allergies, 2010.
Food Allergy: What You Need to Know. Medscape review, 2010. http://goo.gl/8lyRO
New Rules for Food Allergies - WSJ - Check the illustration showing what not to do vs. what to do: http://goo.gl/QNXZT

Published: 07/07/2007
Updated: 03/26/2012

2 comments:

AllergyExpert said...

This is a very nice summary on food allergies!!
One minor note: RAST (for foods) has been reported to have about 15% false positive rate - it is NOT 95% accurate if negative.

Wood et al. Accuracy of IgE antibody laboratory results Ann Allergy Asthma Immunol. 2007;99:34-41.

Anonymous said...

It is perhaps understated that the recent changes in feeding guidelines (January 2008) is a dramatic shift from prior recommendations (e.g. avoid certain foods until certain ages, etc.). Many generalists are yet unaware of these changes, and still recommend unproven avoidance techniques to their patients and breastfeeding mothers.

Grandmas around the world may have been right all along: just feed the baby.