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The term food allergy is often applied to adverse reactions that are not immunologic responses to food. This practical guide describes true hypersensitivity reactions and how to diagnose them.
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The term food allergy is often applied to adverse reactions that are not immunologic responses to food. This practical guide describes true hypersensitivity reactions and how to diagnose them.
A basic understanding of the classification of adverse food reactions is critical to any discussion of food allergy.1 Adverse food reaction is a general term that can be applied to a clinically abnormal response to an ingested food or food additive. Adverse food reactions may be caused by food hypersensitivity (allergy) or food intolerance. Use of these terms has allowed better communication in the scientific literature regarding reactions to food components.
(Note: Tables 1 through 7, Adapted from Sampson HA, Anderson JA: Summary and recommendations: Classification of gastrointestinal manifestations due to immunologic reactions to food in infants and young children. J Pediatr Gastroenterol Nutr 200:30(suppl 1):S91, are available in the print edition.)
Food hypersensitivity (allergy) is an immunologic reaction resulting from the ingestion of a food or food additive. It occurs only in some patients, may occur after only a small amount of the substance is ingested, and is unrelated to any physiologic effect of the food or food additive. To most physicians, the term is synonymous with reactions that involve the immunoglobulin E (IgE) mechanism, of which anaphylaxis is the classic example.
Food intolerance is a general term describing an abnormal physiologic response to an ingested food or food additive. It has not been proved to be immunologic in nature and may be caused by many factors, including toxic contaminants (such as histamine in scombroid fish poisoning and toxins secreted by Salmonella, Shigella, and Campylobacter), pharmacologic properties of the food (caffeine in coffee, tyramine in aged cheese), characteristics of the host such as a metabolic disorder (lactase deficiency), and idiosyncratic responses. The term food intolerance has often been overused and, like food allergy, has been applied incorrectly to all adverse reactions to foods.
IgEmediated (Type I) hypersensitivity accounts for most well-characterized allergic food reactions, although nonIgE mediated (Type II) immune mechanisms are believed to be responsible for a variety of hypersensitivity disorders. In this discussion, I will examine allergic food reactions that are IgE mediated and nonIgE mediated as well as those that have characteristics of both types of hypersensitivity.
The signs and symptoms of food-induced IgEmediated gastrointestinal allergy may be evident in a variety of syndromes, including the oral allergy syndrome and immediate gastrointestinal hypersensitivity. A small subgroup of these syndromesallergic eosinophilic gastroenteritisis caused by mixed IgEmediated and non-IgEmediated hypersensitivity.
The oral allergy syndrome is considered a form of contact urticaria that is confined almost exclusively to the oropharynx. Symptoms include rapid onset of pruritus and angioedema of the lips, tongue, palate, and throat, and generally resolve rapidly. The syndrome is most commonly associated with ingestion of fresh fruits and vegetables.
Interestingly, patients with allergic rhinitis caused by certain airborne pollens (especially ragweed and birch pollens) are often afflicted with the oral allergy syndrome. Patients with ragweed allergy may experience symptoms of the syndrome after contact with certain melons (watermelons, cantaloupe, honeydew) and bananas. Patients with birch sensitivity often have symptoms after eating raw potatoes, carrots, celery, apples, and hazelnuts.
The diagnosis of oral allergy syndrome is made on the basis of a suggestive history and positive skin prick tests with the implicated fresh fruits or vegetables.2 Because commercially available allergen extracts for fresh fruits and vegetables often do not have the reliability of other food extracts, it may be necessary to use the "prick-by-prick" method, in which the device used to introduce the allergen into the skin is first "pricked" into the food.
Immediate gastrointestinal hypersensitivity is a form of IgEmediated gastrointestinal hypersensitivity that may accompany allergic manifestations in other organs.3 Symptoms vary but may include nausea, abdominal pain, abdominal cramping, vomiting, and diarrhea. In studies of children with atopic dermatitis and food allergy, frequent ingestion of a food allergen appears to induce partial desensitization of gastrointestinal mast cells, resulting in less pronounced symptoms (as suggested in the rodent model).
The diagnosis of immediate gastrointestinal hypersensitivity is based on a suggestive clinical history, positive skin prick tests, resolution of symptoms after complete elimination of the suspected food allergen from the diet for as long as two weeks, and oral food challenge. After avoiding a particular food for 10 to 14 days, it is not unusual for a patient to vomit during a challenge even though he or she previously ate the food without vomiting.
Allergic eosinophilic gastroenteritis (gastritis and gastroenterocolitis, Tables 3 and 4, available in the print issue, adapted from Sampson HA, Anderson JA: Summary and recommendations: Classification of gastrointestinal manifestations due to immunologic reactions to food in infants and young children. J Pediatr Gastroenterol Nutr 200:30(suppl 1):S90) is characterized by infiltration of the gastric and intestinal walls with eosinophils and the absence of vasculitis and, in many cases, the presence of peripheral eosinophils.4 Patients with this syndrome often have postprandial nausea and vomiting, abdominal pain, and diarrhea, and may occasionally have steatorrhea. Failure to thrive in young infants and weight loss in children, adolescents, and adults are common in this condition.
A subset of patients with allergic eosinophilic gastroenteritis have symptoms caused by food (what causes symptoms in other patients is unknown). They generally have the mucosal form of the disease, with IgEstaining cells in jejunal tissue, an elevated IgE level in duodenal fluids, atopic disease, an elevated serum IgE concentration, positive skin prick tests in response to a variety of foods and inhalants, peripheral blood eosinophils, iron deficiency anemia, and hypoalbuminemia.
The diagnosis of allergic eosinophilic gastroenteritis is based on an appropriate history and a gastrointestinal biopsy that demonstrates characteristic eosinophilic infiltration. It may be necessary to obtain biopsy specimens from multiple sites (as many as eight) to confidently exclude eosinophilic gastroenteritis because the distribution of eosinophilic infiltrates may be quite patchy.5 Patients with the mucosal form of the disease may have atopic symptoms, including an elevated serum IgE concentration, positive skin tests or radioallergosorbent tests (RAST) and peripheral eosinophillia. Other laboratory findings consistent with this disease include Charcot-Leyden crystals in stool, anemia, hypoalbuminemia, and abnormal D-xylose tests. An elimination diet for as long as 12 weeks may be necessary before symptoms resolve completely and intestinal histology returns to normal.
Conditions caused by non-IgEmediated food allergy include dietary protein enterocolitis, dietary protein proctitis, and celiac disease.
Dietary protein enterocolitis, also known as protein intolerance, is a disorder that appears most often in infants between 1 week and 3 months of age. Typically, symptoms are confined to the gastrointestinal tract and consist of recurrent vomiting and diarrhea.6 They can be severe enough to cause dehydration. Cow's milk and soy protein (particularly in infant formulas) are most often responsible for the syndrome, although egg sensitivity has been reported in older patients. The disorder tends to disappear by 18 to 24 months of age.
Children with dietary protein enterocolitis often produce stool that contains occult blood, polymorphonuclear neutrophils (PMNs), eosinophils, and reducing substances (indicating malabsorbed sugars). Skin prick tests for the suspected food protein are characteristically negative. Jejunal biopsy classically reveals flattened villi, edema, and increased numbers of lymphocytes, eosinophils, and mast cells. A food challenge with the responsible protein generally results in vomiting and diarrhea within minutes to several hours, occasionally leading to shock. A number of children with this condition are sensitive to both cow's milk and soy protein.
Elimination of the offending allergen generally leads to improvement or resolution of symptoms within 72 hours, although secondary disacchoridase deficiency may persist longer.6 Oral food challengewhich should be done in a medical setting because it can induce severe vomiting, diarrhea, dehydration, or hypotensionconsists of administering 0.6 g/kg of body weight of the suspected food allergen.6
Dietary protein proctitis generally appears in the first few months of life and is often caused by cow's milk or soy protein hypersensitivity.7 Infants with this disorder often do not appear ill and have normally formed stools; the allergy is discovered because of blood (gross or occult) in their stools. Gastrointestinal lesions are confined to the small bowel and consist of mucosal edema with eosinophils in the epithelium and lumina propria. If lesions are severe with crypt destruction, PMNs are also prominent.8
Hematochezia resolves within 72 hours of eliminating the offending food allergen, but the mucosal lesionswhich range from patchy injection to severe friability with small aphthoid ulcerations and bleedingmay take as long as one month to disappear. Colitis induced by cow's milk and soy protein is believed to resolve after six months to two years of allergen avoidance, although few well-controlled studies exist to confirm or refute this.8,9
Celiac disease is an extensive enteropathy leading to malabsorption. Total villous atrophy and widespread cellular infiltrate are associated with sensitivity to gliadin, the alcohol-soluble portion of gluten found in wheat, oats, rye, and barley. The general incidence is thought to be 1:4,000 but has been reported to be as high as 1:500 in Ireland.10 There is apparently a genetic predisposition to this disease: Approximately 90% of patients are HLA-B8-positive and nearly 80% have the HLA-DW3 antigen.
Presenting symptoms include diarrhea or frank steatorrhea, abdominal distention and flatulence, weight loss, and, occasionally, nausea and vomiting. Other extraintestinal symptoms and oral ulcers resulting from malabsorption are rare.11
As with all medical conditions, the diagnostic approach to a patient with a suspected adverse food reaction begins with the medical history and physical examination. Based on information obtained from these initial steps, various laboratory studies may be helpful (see "A practical approach to diagnosing food allergy").
History and physical The true value of the medical history depends largely on the patient's recollection of symptoms and the examiner's ability to differentiate disorders provoked by food hypersensitivity and other causes. The history may be directly useful in diagnosing food allergy in acute events, such as systemic anaphylaxis after eating fish. In many studies, however, fewer than 50% of reported allergic reactions to food could be substantiated by double-blind, placebo-controlled food challenge (DBPCFC).12,13
Several pieces of information are important to establish that an allergic reaction to food has occurred:
Any food may cause an allergic reaction, although only a few foods account for 90% of reactions. In children, these foods are egg, milk, peanuts, soy, and wheat (and fish in Scandinavian countries). In the case of a chronic disorder such as atopic dermatitis, the history is often an unreliable indicator of the offending allergen.
A diet diary is often used as an adjunct to the medical history. Patients are asked to keep a chronologic record of all foods eaten over a specified period of time and to record any symptoms they experience during this time. You can review the diary during the patient's visit to determine whether any relationship exists between the foods ingested and the symptoms experienced. Although this method rarely detects an unrecognized association between a food and a patient's symptoms, it enables you to collect information on a prospective basisinformation that is not as dependent on the patient's or parent's memory as the medical history is.
An elimination diet is often used to both diagnose and manage an adverse food reaction. A certain food, or foods, suspected of provoking the reaction are completely eliminated from the diet.
The success of an elimination diet depends on several factors, including correct identification of the allergen(s) involved, the ability of the patient to maintain a diet completely free of all forms of the possible offending allergen, and the assumption that other variables will not provoke similar symptoms during the study period. The likelihood that all these conditions will be met is often slim. In a young infant who reacts to cow's milk formula, for example, resolution of symptoms once a soy formula or casein hydrolysate (Alimentum, Nutramigen) is substituted for cow's milk formula strongly suggests an allergy to cow's milk but does notrule out the possibility that the symptoms are the result of lactose intolerance.
Avoiding suspected food allergens before blinded challenge is recommended to heighten the reaction. An elimination diet is rarely diagnostic of food allergy, howeverparticularly in children with a chronic disorder such as atopic dermatitis or asthma.
Allergy skin prick tests are highly reproducible14 and often used to screen patients in whom IgEmediated food allergy is suspected. The glycerinated food extracts (1:10 or 1:20)12 and appropriate positive (histamine) and negative (saline) controls are applied by either the prick or puncture technique. A food allergen that elicits a wheal at least 3 mm greater in diameter than the negative control (not including erythema) is considered positive; anything else is considered negative.
The allergy skin prick test yields two important pieces of information: First, a positive test indicates that the patient may have symptomatic reactivity to that food (overall positive predictive accuracy is less than 50%). Second, a negative test confirms the absence of an IgEmediated reaction (overall negative predictive accuracy is greater than 95%). Both statements are justified if appropriate, good quality food extracts have been used.15
The skin prick test is, therefore, an excellent means of excluding IgEmediated food allergy but only suggestive of the presence of clinical food allergy. There are some minor exceptions to the general statement, however:
An intradermal skin test is a more sensitive tool than the skin prick test but is much less specific when compared to a DBPCFC.16 A patient who has a negative skin prick test but a positive intradermal skin test to a specific food does not have a positive challenge to that food. In addition, intradermal skin testing carries a greater risk of inducing a systemic reaction than skin prick testing.
Radioallergosorbent tests and similar in vitro assays (including enzyme-linked immunosorbent assays) are used to identify food-specific IgE antibodies. These tests are often used to screen for IgE mediated food allergy. Although generally considered slightly less sensitive than skin tests, one study that compared Phadebos RAST with DBPCFCs found skin prick tests and RASTs to have similar sensitivity and specificity when a Phadebos score of three or greater was considered positive.17 In this study, if a two was considered positive there was a slight improvement in sensitivity while the specificity decreased significantly.
In general, in vitro measurement of serum food-specific IgE performed in high quality laboratories provides information similar to skin prick tests. The newest generation of in vitro studies for specific IgE include the CAP-RAST (RAST-FEIA). There is now an accepted level of specific IgE that is greater than 95% predictive that a patient is allergic to a particular food.18,19 The CAP-RAST is best used for patients with a possible allergic reaction to milk, eggs, or peanuts.
The double-blind, placebo-controlled food challenge has been called the gold standard for the diagnosis of food allergy.20 It has been used successfully in both children and adults for the last several years to examine a wide variety of food-related complaints. The foods tested in the oral challenge are chosen based on history and skin prick test (RAST) results.21
A DBPCFC is the best means of controlling for the variability of chronic disorders (such as chronic urticaria and atopic dermatitis), any potential temporal effects, and acute exacerbations caused by reducing or discontinuing medications.22 It eliminates psychogenic factors and observer bias. Rarely, false-negative challenges occur when a patient receives insufficient material during the challenge to provoke the reaction or when lyophilization of the food antigen alters the relevant allergenic epitopes (fish, for example). Overall, the DBPCFC has proved to be the most accurate means of diagnosing food allergy at the present time.
IgEmediated hypersensitivity reactions account for the majority of well-documented food allergy reactions, but non-IgEmediated immune mechanisms do cause some hypersensitivity disorders. A variety of gastrointestinal cutaneous, respiratory, and generalized symptoms and syndromes have been associated with IgEmediated food allergy.
The diagnostic approach to adverse food reactions begins with a careful medical history and physical examination followed by appropriate laboratory studies. Once the diagnosis of food allergy is established, the only proven therapy is strict elimination of the food from the patient's diet.
A significant number of families alter their eating habits based on a misunderstanding of the symptoms actually caused by foods and the ability of the available tests to provide an accurate diagnosis. Studies in both children and adults indicate that symptomatic reactivity to food allergens is often lost over time, with the possible exceptions of peanuts, tree nuts, and seafood.
1. Sampson H: Food allergies, in Sleisenger M, Fordtran J, Schar-schmidt B, et al (eds): Gastrointestinal Disease: Pathophysiology/Diagnosis/Management. Philadelphia, WB Saunders, 1993, pp 12331240
2. Ortaloni C, Ispano M, Pastorello EA, et al: Comparison of results of skin prick tests (with fresh foods and commercial food extracts) and RAST in 100 patients with oral allergy syndrome. J Allergy Clin Immunol 1989;83:683
3. Sampson HA: Food allergy. J Allergy Clin Immunol 1989;84:1062
4. Waldman T, Wochner R, Laster R, et al: Allergic gastroenteropathy. A cause of excessive gastrointestinal protein loss. N Engl J Med 1967;276:761
5. Perera DR, Weinstein WM, Rubin CE: Small intestinal biopsy. Hum Pathol 1975;6:157
6. Powell GK: Milk- and soy-induced enterocolitis of infancy: Clinical features and standardization of challenge. J Pediatr 1978;93:553
7. Gryboski JD: Gastrointestinal milk allergy in infants. Pediatrics 1967;40:354
8. Goldman H, Proujansky R: Allergic proctitis and gastroenteritis in children. Am J Surg Pathol 1986;10:75
9. Machida HM, Smith AGC, Gall DG, et al: Allergic colitis in infancy: Clinical and pathologic aspects. J Pediatr Gastroenterol Nutr 1994;19:22
10. Langman MJJ: Can epidemiology help us to prevent coeliac disease? Gastroenterology 1986;90:489
11. Grodzinsky E, Jansson G, Skogh T, et al: Anti-endomysium and anti-gliadin antibodies as serological markers for coeliac disease in childhood: A clinical study to develop a practical routine. Acta Paediatr 1995;84;294
12. Bock SA, Lee WY, Remigio LK, et al: Studies of hypersensitivity reactions to foods in infants and children. J Allergy Clin Immunol 1978;62:327
13. Sampson HA: Role of immediate food hypersensitivity in the pathogenesis of atopic dermatitis. J Allergy Clin Immunol 1983;71:473
14. Taudorf E, Malling HJ, Laursen LC, et al: Reproducibility of histamine skin prick test. Allergy 1985; 40:344
15. Sampson HA: Comparative study of commercial food antigen extracts for the diagnosis of food hypersensitivity. J Allergy Clin Immunol 1988;82:718
16. Bock SA, Buckley J, Houst A, et al: Proper use of skin tests with food extracts in diagnosis of food hypersensitivity. Clin Allergy 1978;8:559
17. Sampson HA, Albergo R: Comparison of results of skin tests, RAST, and double-blind placebo-controlled food challenges in children with atopic dermatitis. J Allergy Clin Immunol 1984;74:26
18. Sampson HA, Ho DG: Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100:444
19. Sampson HA: Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107(5):891
20. Sampson HA: Immunologically mediated food allergy: The importance of food challenge procedures. Ann Allergy 1988;60:262
21. Metcalfe DD, Sampson HA: Workshop on experimental methodology for clinical studies of adverse reactions to foods and food additives. J Allergy Clin Immunol 1990;86:421
22. Executive Committee of the Academy of Allergy and Immunology. Personnel and equipment to treat systemic reactions caused by immunotherapy with allergic extracts (position statement). J Allergy Clin Immunol 1986;77:271
The diagnosis of food allergy rests on a careful history, selective skin prick tests or RAST results (if an IgEmediated disorderis suspected), appropriate exclusion diet, and blinded provocation. Diagnostic tests that do not appear to be of significant value include food-specific IgG or IgG4 antibody levels, food-antigen-antibody complexes, evidence of lymphocyte activation (tritium [3H] uptake, interleukin [IL]-2 production, leukocyte inhibitory factor), and sublingual or intracutaneous provocation. Blinded challenges may not be necessary to diagnose all suspected gastrointestinal disorders. Prechallenge and postchallenge laboratory values and biopsies are often used in an open challenge to document the clinical sensitivity.
An exclusion diet that eliminates all foods suspected by history, skin prick testing, or RAST should be conducted for at least oneor two weeks. For some gastrointestinal disorders, the exclusion diet may have to be extended for as long as 12 weeks after appropriate biopsies have been done. If no improvement is noted after the diet, it is unlikely that food allergy is involved. In the case of some chronic diseases, such as atopic dermatitis and chronic asthma, additional precipitating factors may make it difficultto differentiate the effects of the food allergen from other provocative influences.
Single-blind challenges may help screen suspected food allergens in a clinic setting. A presumptive diagnosis of food allergy based on history and skin prick tests or RAST results is no longer acceptable, except in such circumstances as severe anaphylaxis after isolated ingestion of a specific food. It is important that the medical care provider make an unequivocal diagnosis of food allergy. If the present practice of presumptive diagnosis persists, more than one quarter of the population will continue to alter its eating habits based on misconceptions about food allergy.
Wesley Burks. It's an adverse food reaction--but is it allergy?. Contemporary Pediatrics 2002;5:71.