Case 1
A 9 month old infant with severe eczematous rash is seen by his pediatrician. His mother reports that he has had this rash since 6 months of life when bottle feeding started. The skin rash did not respond to 1% hydrocortisone treatment and it has worsened in the past few weeks. On exam, he is noted to have generalized dry skin with subacute eczematous lesions on both cheeks and the extensor surfaces of his extremities without other abnormal findings. A diagnosis of cow's milk allergy is suspected which is confirmed by a highly positive CAP-RAST test for milk specific IgE antibody. He is successfully treated with 1% hydrocortisone cream, daily cetirizine (antihistamine), avoidance of cow's milk and dairy products, and a trial of soy milk formula feeding. His skin rash is controlled well within 2 weeks and this totally disappears after 1 year of age. At 3 years of age, cow's milk is accidentally given to him, however, no skin rash or other reaction is noticed. A cow's milk challenge is given to him in the physician's office and no reaction is noted. His cow's milk allergy has spontaneously resolved and he has no further problems with milk or dairy products.
Case 2
A 3 year old girl is brought to a pediatrician's office immediately since she develops her second episode of hives on her face and torso with dry coughing after eating peanut butter. Exam findings reveal normal vital signs, generalized expiratory wheezing and generalized urticaria. The symptoms respond well to diphenhydramine, subcutaneous epinephrine and an albuterol nebulizer treatment. Subsequently, she is evaluated by an allergist for possible peanut allergy. Her skin test demonstrates a strongly positive skin test (2 cm) and a CAP-RAST test shows a high level of peanut-specific IgE. Peanut avoidance is recommended. Her parents are given instructions on antihistamine and EpiPen use. In pre-school, she develops difficulty breathing and urticaria after eating a cookie given to her by another child. An ambulance is called and she is treated in an emergency department. At age 10, while on a school field trip, she develops urticaria, wheezing and she passes out after eating chili for lunch. An ambulance is called and she is treated with IV epinephrine, diphenhydramine, cimetidine and methylprednisolone for anaphylactic shock.
Case 3
A 16 year old female with seasonal allergic rhinitis is referred to see an allergist for evaluation of recurrent itching and swelling of her lips and tongue after eating bananas. The symptoms develop immediately after eating bananas and spontaneously resolve in 45 minutes. There is no history of sore throat, breathing difficulty, wheezing, GI symptoms, or skin rash. Physical examination at the visit are essentially normal. A skin test with a commercial extract yields a negative result; however, a skin test with fresh banana gives a positive result which confirms a diagnosis of oral allergy syndrome.
Case 4
An 11 month old boy develops a rash around his mouth after eating eggs. He is treated with hydrocortisone cream. He is taken to his physician and his parents ask if he might be allergic to eggs. A RAST test for eggs is ordered and the result is 1+ (very low). His parents are informed that he is not allergic to eggs. His parents feed him some scrambled eggs two days later and he immediately develops hives and wheezing. He is treated with diphenhydramine, subcutaneous epinephrine and albuterol in an emergency department, where his parents are informed that he is probably allergic to eggs.
The four case scenarios illustrate common presentations, diagnostic work up approaches and management of food allergies. Food allergies are an increasing problem in westernized countries. Although an unpleasant reaction to food is often thought to be a food allergic reaction, only 8% of children under 3 years of age and roughly 2% of the adult population are affected by food allergies, which are mediated by an allergic/immune mechanism (e.g., IgE mediated). An adverse food reaction is a general term for a clinically abnormal response to an ingested food or food additive. Adverse food reactions may be caused by food hypersensitivity (allergy) or food intolerance. Food intolerance is a descriptive term of an abnormal physiologic response to an ingested food or food additive. The response is not immunologic in nature and it may be caused by many factors such as a toxic contaminant (such as histamine in scombroid fish poisoning or toxins secreted by Salmonella or Shigella), pharmacologic properties of the food (such as caffeine in coffee or tyramine in aged cheese) and idiosyncratic responses or host factors (such as lactase deficiency).
Food allergy, with acute onset of symptoms after ingestion, is IgE-dependent and potentially involves 4 major target organs: skin, GI, respiratory tract and cardiovascular systems. Acute urticaria and angioedema are the most common food allergic reactions, but the reaction may be a severe, life threatening event, such as anaphylactic shock. In fact, food allergies account for a large proportion of anaphylaxis cases in the United States. Other forms of acute presentations include: oral allergy syndrome, immediate gastrointestinal reaction (nausea, emesis, and diarrhea), anaphylaxis, rhinitis, asthma, and exercise-induced anaphylaxis. Delayed onset of food allergy symptoms includes atopic dermatitis, eosinophilic gastroenteropathies, dietary protein enterocolitis, dietary protein proctitis, dietary protein enteropathy, celiac disease and dermatitis herpetiformis. This chapter will focus on the IgE mediated food allergies.
Atopic dermatitis is a mixed IgE and cell mediated disease. There is substantial evidence indicating that food allergies cause many cases of atopic dermatitis in children, although food allergy is rarely a trigger of atopic dermatitis in adults. In a study, food allergies were found in 35% of children with moderate-severe atopic dermatitis (4). The skin lesions are generally provoked by an oral food challenge and are resolved by avoidance of the causal foods.
The pattern of food allergy in children is somewhat different from that in adults. The most common foods that cause problems in children are eggs, milk, peanut, soy, wheat, and fish. Most children will outgrow food allergy for eggs, milk or soy by age 4. In contrast, food allergies for shellfish (shrimp, crayfish, lobster, and crab), fish, peanuts and tree nuts are usually life-long.
An association of food allergy and latex allergy has been reported and confirmed. Approximately 30-50% of individuals who are allergic to natural rubber latex show an associated hypersensitivity to some fruits and vegetables (known as latex-fruit syndrome) such as avocados, bananas, chestnuts, kiwi, peaches, tomatoes, potatoes and bell peppers. Individuals who are allergic to pollens may produce specific IgE antibodies directed to homologous allergens of both pollens and fresh fruits/vegetables such as: 1) birch pollen with apples, peaches, pears, almonds, hazelnuts, potatoes and carrots. 2) ragweed pollen with melons and bananas. 3) mug wort pollen with celery and carrots. 4) grass pollen with tomatoes. This cross reactivity accounts for oral allergy syndrome in individuals with seasonal allergic rhinitis. The classic presentation of oral allergy syndrome is an acute episode of swelling, itching, tingling sensation, angioedema of lips or palate and erythematous mucosa localized only in the oral cavity after eating certain fresh fruits and/or vegetables (such as bananas, apples, peaches, carrots, melons, tomatoes) but not cooked fruits or vegetables since the allergens for oral allergy syndrome are heat labile.
In general, individuals do not develop clinical symptoms after being exposed to food allergens in the GI tract since the mucosal immune system and local GI factors (including intestinal epithelial cells, dendritic cells, T cells, mediators and gut flora) induce a state of unresponsiveness known as oral intolerance. Food allergy develops in genetically predisposed persons when oral intolerance fails to develop properly. In infants, the developmental immaturity of various components of the gut barrier and immune system increases the risk of developing food allergies during the first few years of life. The maturation of the gut with reduced systemic absorption and maturation of immune responses are thought to be the mechanism explaining why children outgrow food allergies or develop tolerance. Acute IgE-mediated reactions develop when food specific IgE antibodies residing on mast cells and basophils, bind circulating food allergens and activate the cells to release a number of potent mediators and cytokines. The pathogenesis of cell-mediated food allergy or delayed onset types remains unclear.
The diagnostic approach begins with the medical history and physical examination, followed by appropriate diagnostic tests. The goal is to determine whether the patient is likely to have experienced an adverse reaction to food involving an immunologic (allergic) mechanism. One should obtain information on: 1) the suspected food, 2) the quantity of the ingested food, 3) the time between ingestion and development of the symptoms, 4) description of the symptoms, 5) whether similar symptoms developed on other occasions when the food was eaten, 6) whether other factors (such as exercise) are necessary to provoke the reaction, and 7) the time since the last reaction. If an allergic reaction is suspected, it is essential to categorize reactions mechanistically (i.e., IgE mediated or non-IgE mediated) because subsequent diagnostic tests depend on the suspected mechanism. Most of the histories are useful and reliable only when the reactions are acute in onset such as with acute urticaria or anaphylaxis. In the case of delayed onset of symptoms such as atopic dermatitis, the history is often unreliable in implicating the offending allergens.
There are three methods to more definitely confirm or rule out IgE mediated food allergies: 1) Skin testing, 2) RAST, and 3) Oral challenge. Skin prick testing is done by pricking the skin with commercially available allergen extract solutions. Skin testing is generally done by allergists (i.e., not primary care physicians). A positive test identifies food specific IgE antibodies (suspected IgE mediated food allergy). A positive result yields a wheal (not erythema) of at least 3 mm in diameter larger than the negative control. A skin test that provokes a serious allergic reaction should also be considered to be diagnostic of a food allergy. There are some exceptions for interpretation of the results: 1) When testing a patient suspected of oral allergy syndrome, false negatives often occur if commercial food extracts are used for the skin test because these extracts are heat treated (rendering the allergen non-immunogenic, typical of oral allergy syndrome). However, by using a fresh fruit or vegetable for skin prick testing, a positive result may be confirmed as noted in the example described in case 3. 2) Children under one year of age may have IgE mediated food allergy without a positive skin test, and children under 2 years of age may have smaller wheals, possibly the result of a lack of skin reactivity. Negative skin prick test responses have excellent negative predictive values for excluding the presence of IgE mediated food allergy.
RAST (radioallergosorbent test) is an in vitro measurement of serum food specific IgE. The test is more available and practical for primary care physicians to evaluate food specific IgE antibodies. It should be noted that RAST tests are heterogenous yielding potentially unreliable results. CAP-RAST (the Pharmacia CAP system FEIA) is a newer generation of RAST which provides more reliable quantitative measurements of specific IgE levels. Table 1 is a recommended interpretation of food allergen-specific IgE levels (kUA/L) by CAP-RAST in the diagnosis of food allergies (5). For example, if a child's egg-specific IgE level is 7 or greater by CAP-RAST, there is a greater than 95% likelihood that the child is truly allergic to eggs. In contrast, if the egg-specific IgE is less than 0.35 and there is no compelling history of egg allergy, there is a 95% chance that the child is not allergic to eggs. However, there is a 5% chance (1 in 20), that the child's CAP-RAST is falsely negative and that the child is allergic to eggs (as in case 4). If there is a strongly suggestive history of a food allergy, it should be noted that a low CAP-RAST can be misleading.
Table 1: CAP-RAST results
If a CAP-RAST value falls somewhere between the 95% positive and negative predictive values (between the two values in the columns), it is uncertain whether a food allergy for that food exists. The patient will have to be referred to an allergist for skin testing, or an oral food challenge will have to be performed.
An oral food challenge is performed by feeding gradually increasing amounts of the suspected food under observation by a physician over hours or days. The double-blind, placebo controlled food challenge (DBPCFC), by giving increasing quantities of the suspected food allergen or placebo, either in opaque capsules or camouflaged in a liquid or semisolid vehicle, is considered the gold standard test of both IgE and non-IgE mediated food allergy. Elimination of the suspected food from the patient's diet for at least 7-14 days; withdrawal of potentially interfering medications (e.g., antihistamines); control of symptoms of chronic allergic disease (such as atopic dermatitis or asthma); administration of the challenge in a fasting state; use of fresh or dehydrated foods; and use of challenge vehicles that do not contain fat which can interfere with protein absorption, have been suggested to optimize the outcome. The absence of an allergic reaction after ingesting up to an equivalent of 10 grams of the dehydrated food essentially rules out a food allergy in that such a result has a high negative-predictive value. However, an average false-positive rate of 0.7% and false-negative rate of 3.2% for the DBPCFC were reported (7). Since the patient with IgE mediated food allergy may develop severe reactions to the challenge, the test should be performed by a well-trained physician in a facility capable of close monitoring, which is well equipped with drugs, supplies and equipment for resuscitation. The contraindication for such a test is recent anaphylaxis. An alternative to the DBPCFC,is a supervised open (unblinded) food challenge to confirm the safety of eating the particular food. This is recommended for a patient with a low likelihood of food allergy based on a low CAP-RAST result or an individual with a negative DBPCFC result.
A differential diagnosis of food allergies first aims to distinguish food allergies from food intolerance or other illnesses. Food poisoning is a possibility when food is contaminated by microorganisms and their products (such as toxins). Lactase deficiency, resulting in lactose intolerance, in children and adults, is a common food intolerance that is often confused with food allergy. There are also natural substances, such as histamine in cheese, wines and certain kinds of fish, that can occur in foods and stimulate a reaction similar to an allergic reaction. If someone eats one of these foods with a high level of histamine, that person may have a reaction similar to an allergic reaction to food. This reaction is called histamine toxicity, and it is often responsive to antihistamines. Reactions to MSG (monosodium glutamate) are not due to allergy mechanisms since MSG contains sodium and glutamate, both of which are normally present in the body. Excess amounts of consumed MSG are metabolized to neurotransmitters which may cause a reaction to MSG (Chinese restaurant syndrome) which is not allergic in nature.
The primary treatment for a child with a food allergy is to remove the offending antigen from the diet. In exclusively breast fed infants, a strict elimination of the causal protein from the diet of the lactating mother should be tried. Over time, many children who have food allergy (such as egg or milk) will develop tolerance to the food, making cautious, periodic attempts to introduce the offending food possible. An elimination diet can often be successful in children who have a single food allergy. However, dietary modification and nutritional counseling may be necessary for children who have multiple food allergies to identify hidden ingredients in processed foods and cross-reacting foods (e.g., peanuts, legumes). Aggressive restriction of allergenic foods may compromise the nutritional adequacy of the diet and interfere with the normal growth of the child. Patients and their families should be educated to avoid accidentally ingesting food allergens (e.g., by reading food labels), to recognize early symptoms of an allergic reaction, and to initiate early management of an anaphylactic reaction.
Many foods are ubiquitous in the environment and are often hidden in foods. Some helpful information can be obtained from www.foodallergy.org or www.anaphylaxis.org.uk. For example, a person eating peanuts may aerosolize sufficient quantities of peanuts to cause a nearby peanut allergic patient to react. Young children may share foods. Adults (other than parents) who serve food or supervise children (e.g., teachers, pre-school aids) are often not familiar with hidden foods in labels or they are not familiar with simple precautions. For example, peanuts are found in chili and scooping ice cream at a party may contain microcontamination with nuts if nuts are used in the ice cream of other children.
Just as an example, patients who are allergic to peanuts must learn to avoid peanut oil (Asian cooking), almond chunks (may actually be peanuts), baked goods, sauces (Chinese hot sauce, barbecue sauce, etc.), gravy, egg rolls (glue for edges), enchilada sauce, chili and other substances as well. Patients who are allergic to tree nuts (i.e., other nuts) must learn to avoid salad dressings, dessert toppings, sauces, exotic nut oils, pie crusts (almonds, macadamia nuts), ice cream toppings, cookies, almond extract, etc. Patients who are allergic to eggs must learn to avoid albumin, lysozyme, ovalbumin, egg substitutes (low cholesterol only), pastry, sauces, salad dressings, some shampoos, pet foods, influenza vaccine, cosmetics, fresh pasta, etc. Patients who are allergic to milk are usually allergic to the whey or casein protein in milk so they must learn to avoid whey, casein, ghee, nougat, rennet, caramel color, "natural flavors", canned tuna, hot dogs, imitation butter flavor, non-dairy whipped cream, non-dairy coffee whitener, imitation cheese, calcium caseinate, etc. Patients who are allergic to wheat must learn to avoid cracker meal, semolina, spelt, couscous, cornstarch, bulgar, farina (Cream of Wheat), etc. Patients who are allergic to fish must learn to avoid imitation crab, Worcestershire sauce (anchovy), Caesar salad (anchovy), many Asian foods (fish sauce), etc.
The above list is already difficult. Many pet foods contain nuts, which could be aerosolized when scooping this out for the pet dog. Facial scrubs may contain pulverized walnut shells. "Bean bag" furniture may contain walnut shells. Egg substitutes still contain eggs (with a reduced cholesterol formulation). "Non-dairy" products may still contain whey and casein.
Restaurants present a serious risk for patients with food allergies. When a cook is told to avoid a certain food, any pans, pots, woks, griddle surfaces or cooking utensils must not be exposed to any of these substances. For example, if a cook is attempting to avoid eggs, dairy products and peanuts, then the cooking surfaces and utensils must have no eggs, no butter and no peanut oil. If eggs were cooked on the griddle 30 minutes ago and the griddle was cleaned several times since, there may still be microscopic amounts of egg remaining. Similarly, cooking with butter or peanut oil is likely to leave microscopic residues on utensils or cooking surfaces, which may be sufficient to cause an allergic reaction.
An antihistamine is sometimes the only medication needed to reduce the itching and rash. In an acute event of anaphylaxis, immediate resuscitation is required. Epinephrine (0.01 ml/kg of the 1:1000 dilution given IM or subcutaneously) is often required for more severe allergic reactions. The term "anaphylaxis" is vague, but it implies a severe allergic reaction. Anaphylactic shock with associated vasodilation and hypotension, generally requires an IV epinephrine infusion with fluid replacement, in addition to preliminary IM or subcutaneous epinephrine. Having medical alert bracelets, carrying epinephrine for self injection and antihistamines available at home and school are strongly recommended for patients who have experienced a severe food allergy reaction. Some food allergies are more serious than others. On average, peanut allergies are the most serious, thus early epinephrine treatment should be considered even if a severe allergic reaction has not yet been encountered. Skin care with topical corticosteroid therapy and food avoidance is advised in food allergy induced atopic dermatitis. Immunotherapy by injection or sublingual administration of offending antigens has not proven to be effective in the management of patients who have food allergy. A new anti-IgE therapy (TNX-901, a humanized IgG1 monoclonal antibody against IgE) may alleviate some severe allergic reactions of peanut allergy (8).
There is some potential for prevention. Breastfeeding should be encouraged for all infants for the first 4-6 months of life. Breastfeeding mothers should avoid potentially allergic foods. Breastfeeding and the late introduction of solid foods (beyond the 5th month of life) is associated with a reduced risk of food allergy and other atopic diseases in early childhood. In formula fed infants with a documented hereditary atopy risk (affected parent or sibling), the exclusive feeding of a formula with a confirmed reduced allergenicity (protein hydrolysate formulas such as Nutramigen, Pregestimil and Alimentum) is recommended because it can reduce the incidence of adverse reactions to food, especially to cow's milk protein. There is no conclusive evidence to support the use of formulas with reduced allergenicity for preventive purposes in healthy infants without a family history of allergic disease. Preventive dietary restrictions after the age of 4-6 months are not scientifically documented (9).
Questions
1. Which one is likely to be a food allergic reaction in a teenager?
. . . . . a. Recurrent dizziness after eating Chinese foods.
. . . . . b. Recurrent tingling sensation in the mouth after eating a piece of apple.
. . . . . c. Recurrent palpitations after drinking a cup of coffee.
. . . . . d. Recurrent diarrhea after drinking a glass of milk.
. . . . . e. Recurrent facial redness (flushing) after drinking a glass of wine.
2. Which one of the following is an IgE mediated food allergy?
. . . . . a. Oral allergy syndrome
. . . . . b. Eosinophilic gastroenteropathies
. . . . . c. Dietary protein enterocolitis
. . . . . d. Celiac disease
. . . . . e. Dermatitis herpetiformis
3. Which one is the common natural course of cow's milk allergy in children?
. . . . . a. spontaneously resolves by age 4.
. . . . . b. spontaneously resolves by age 10.
. . . . . c. persists without changing severity.
. . . . . d. increases severity through their lives.
. . . . . e. is an unpredictable pattern.
4. Which one is the least common food allergy in children?
. . . . . a. Egg
. . . . . b. Peanut
. . . . . c. Soy
. . . . . d. Wheat
. . . . . e. Shrimp
5. Which food/fruit potentially causes an allergic reaction in a latex allergy individual?
. . . . . a. Banana
. . . . . b. Kiwi
. . . . . c. Tomato
. . . . . d. Potato
. . . . . e. All of the above
6. Which of the following are considered safe for patients with peanut allergy?
. . . . . a. Chinese and Southeast Asian foods
. . . . . b. Ice cream
. . . . . c. Dry pet food
. . . . . d. Chili
. . . . . e. Pastry
. . . . . f. None of the above
7. Which of the following are considered safe for patients with milk protein allergy?
. . . . . a. Lactose
. . . . . b. Non-dairy creamer
. . . . . c. Canned tuna
. . . . . d. Soy infant formula
. . . . . e. Hot dogs
. . . . . f. Casein
References
1. Sicherer SH. Food allergy. Lancet 2002;360: 701-710.
2. Sampson HA. Food allergy. J Allergy Clin Immunol 2003;111:S540-S547.
3. Burks W. It's an adverse food reaction-but is it allergy? Contemporary Pediatrics 2002;19:71-89.
4. Eigenmann PA, Sicherer SH, Borkowski TA, et al. Prevalence of IgE-Mediated Food Allergy Among Children With Atopic Dermatitis. Pediatrics 1998;101:e8.
5. Sampson HA. Utility of food specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-896.
6. Wagner S, Breiteneder H. The latex-fruit syndrome. Biochem Soc Trans 2001;30:935-940.
7. Sampson HA. Use of food-challenge tests in children. Lancet. 2001; 358:1832-3.
8. Leung DY, Sampson HA, Yunginger JW, et al. Effect of anti-IgE therapy in patients with peanut allergy. N Engl J Med 2003;348: 986-993.
9. Høst A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. Joint Statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child 1999;81:80-84.
Answers to questions
1.b. Tingling in the mouth after eating fruits suggests the possibility of an oral allergy syndrome. Dizziness after eating Chinese food is more likely due to an adverse non-allergic reaction to MSG. Facial redness after drinking a glass a wine may be due to tyramine.
2.a
3.a
4.e
5.e
6.f. Chinese and southeast Asian foods are frequently cooked with peanut oil. None of the above are safe. Ice cream is potentially contaminated by nuts since nuts are frequently served with ice cream or mixed with ice cream. Dry pet food and chili frequently contain peanuts. Pastry may contain peanuts even if they are called other types of nuts such as almonds.
7.a. Lactose is merely a disaccharide. Lactose by itself is not part of milk protein. However, if the source of lactose is a dairy product, then this dairy produce should be avoided. All of the other products including "non-dairy" creamers and canned tuna may contain milk or milk products.