How To Test For Food Allergy

Transcription

1 When Good Food Makes You Sick, Part 2: By Andre Valcour, PhD, DABCC Presented by qwertyui

2 When Good Food Makes You Sick, Part 2: Andre Valcour, PhD, DABCC, is employed by LabCorp as director of esoteric immunoassay at LabCorp s Center for Esoteric Testing, located in Burlington, NC. He reports no other relevant financial relationships. Introduction The clinical laboratory can play an important role in supporting the physician s ability to diagnose and treat immune-mediated adverse food reactions. In the first article of this series (published in the November issue of ADVANCE for Administrators of the Laboratory), we discussed celiac disease, a condition that occurs as a result of T-cell-mediated immune reaction that is triggered by a sensitivity to gliadin, a component of wheat. In this article, we focus on IgE-mediated hypersensitivity to food, i.e., food allergy. Clinical scientists have gained a tremendous understanding of food allergy in just the last few years. 1,2 They have discovered that IgEmediated food allergy is actually very common, especially in early childhood. 3-5 Between 6% and 8% of children less than three years of age have food allergy. The prevalence rate of food allergy is even higher (approximately one out of every three cases) in children with atopic dermatitis. The prevalence of food allergy drops with increasing age to the point where only about 2% of adults are affected by food allergy. 3,6 Atopy (or the tendency to develop allergy) seems to have a genetic component, as children of parents with allergies have a dramatically increased risk of developing allergies themselves. 7,8 Individuals with food allergy often present with nonspecific symptoms that can be similar to those seen in patients with food intolerance, celiac disease and numerous other conditions that do not involve food sensitivity. Moreover, many patients report symptoms that they believe to be associated with the ingestion of foods that are, in fact, not food allergy. 4,9 In fact, as many as 25% of adults suspect that they or their children may have food allergy. 9 This makes the diagnosis of food allergy particularly challenging. Recent reports have described the utility of laboratory testing for the assessment of food allergy, providing the practicing clinician with a powerful tool for the evidence-based diagnosis and management of individuals with this condition. 2,4 Allergy can be defined as the tendency of predisposed (or atopic) individuals to develop adverse symptoms as the result of an IgE-mediated response to normally innocuous substances. 7 Allergic reactions are mediated by allergen-specific IgE antibodies that are attached to the surfaces of mast cells. 10 Learning Objectives On successful completion of this module, the participant will be able to: 1. Discuss the epidemiology and prevalence of food allergy in various populations in the United States. 2. Identify the symptoms of food allergy, both gastrointestinal as well as those affecting other systems. 3. List the most common food allergens. 4. Discuss oral allergy syndrome and the allergens that cause this condition. 5. Relate the natural history of food allergy and the role of this condition to the Allergy March. 6. Review the principles employed by different assay methodologies for the assessment of food allergy. 1

3 When these cells encounter an allergen recognized by the IgE on their surface they release compounds that produce allergic symptoms. 10 Systemic food allergy symptoms often occur when food allergens penetrate the gastrointestinal barrier, initiating the classic immediate chain of hypersensitivity events. Some people with food allergy can have life-threatening anaphylactic reactions where their airways become restricted and their blood pressure drops dramatically. 10 Swelling of the tongue and throat during an anaphylactic reaction can result in suffocation. Approximately 150 people die every year from severe allergic reactions. 10 Food allergy is the most common cause of anaphylaxis in nonhospitalized individuals. 9 The more common symptoms of systemic allergy are listed in Table 1. Extremely low levels of the offending food can initiate a reaction in individuals with preëxisting, IgE-mediated food allergies. 6 Microgram quantities of peanut have been known to elicit an adverse reaction in food challenges in selected individuals. 6,11 The major food allergens that have been characterized are water-soluble glycoproteins with molecular weights ranging from 10 to 60 kd (M r ). These proteins tend to be resistant to food preparation and retain their allergenicity when incorporated in processed foods. 6 Treatment of these proteins with acid concentrations simulating stomach conditions typically has little effect on the specific IgE binding of the allergen. It should be noted that the major allergens in fresh fruits and some vegetables are labile and lose their allergenicity with processing. 6 Table 1 Symptoms Associated with Systemic Mouth/Throat Skin Airways Nose It is critically important that people with food allergies identify the foods that cause them to react so that they can avoid them. 10 The eight foods listed in Table 2 (next page) are responsible for 90% of food allergies. 3,5,7 While these food groups cause the great majority of food allergy, at least 160 different foods have been implicated in allergic reactions. 3 The incidence of various allergies can reflect the local diet in different parts of the world. 7 For example, celery allergy is quite common in Europe and buckwheat allergy is common in the Southeast Asia. Sesame seed allergy is prevalent in the Middle East, in large part due to the popularity of tahini, a paste made from sesame seeds. 7 The Oral Allergy Syndrome (OAS) Oral allergy syndrome, also referred to as the pollen-food Swelling of lips and/or tongue, itching of lips, palate, tongue or throat, hoarseness or sensation of tightness in the throat, dysphonia (difficulty in speaking) Urticaria, angioedema, atopic dermatitis, flushing, itching Chest tightness, wheezing, shortness of breath Nasal congestion, itching, rhinorrhea (runny nose), sneezing allergy syndrome, 9 is a unique form of food allergy characterized by a localized reaction of the mouth and throat that occurs when affected individuals eat certain fresh fruits and vegetables. 7 Individuals with oral allergy syndrome experience contact urticaria (itching and hives) that is confined almost exclusively to the mouth and throat upon ingestion of the triggering food. This condition only rarely affects other target organs. 7 Characteristic symptoms of oral allergy syndrome include itching of the lips, palate, tongue and throat. 7 Oral allergy syndrome is a self-limiting condition with symptoms that occur immediately on contact with foods and typically resolve rapidly. It is important to differentiate these symptoms from systemic and life-threatening allergic throat-constricting reactions that can occur during anaphylaxis. Individuals with oral allergy syndrome to certain food groups frequently suffer from allergy to related nonfood allergens; see Table 3 (next page). Allergy to certain nonfood allergens (such as pollens) appears to predispose individuals for the development of associated food allergy. 7 Eyes Anaphylaxis Itching, tearing, redness A potentially fatal reaction associated with a dramatic drop in blood pressure, which can lead to a loss of consciousness. Symptoms typically begin immediately after the food is ingested. An anaphylactic reaction can subside only to recur several hours later. Natural History of Many children outgrow allergies to eggs, milk, and soy, but most do not outgrow 2

4 Table 2 Most Common Food Allergens Milk Soy Eggs Peanuts Wheat * Tree Nuts Fish Shellfish Estimated worldwide prevalence of cow s milk allergy in infants and children is between 2.0% and 2.5%. 6 Children allergic to one type of milk often have symptoms when given milk from other species. 6 Generally occurs in response to dietary exposure to soy-based formulas. 6 Common in the US and Europe because eggs are a dietary staple both alone and in baked goods. 6 Allergic reactions to peanuts can be very acute and severe and are responsible for many of the cases of food-induced anaphylaxis. Wheat and other cereal grains are relatively common food allergens, especially in children. Tree nut allergy in adults is not generally associated with allergy to peanuts (a legume); however, children with peanut allergy have an increased tendency to develop tree nut allergy, relative to the general population. 6 Fish allergy is more common in countries where fish consumption is highest. For example, codfish allergy is extremely common in Scandinavian countries where cod is a staple. Shrimp is the most studied of this group. Crosssensitization can occur between crustaceans, cockroaches, and house/dust mites. 6 Foods responsible for 90% of food allergen reactions in children. Foods responsible for 90% of food allergen reactions in adults. *Gluten from wheat can cause celiac disease, a non-ige mediated immune condition. Table 3 Oral Allergy Syndrome Allergen Groups Allergen Ragweed pollen Birch pollen Mugwort pollen Latex Associated Foods melons (watermelon, cantaloupe, and honeydew), banana apple, carrot, hazelnut, raw potato, pear, plum, nectarine, cherry, apricot celery, apple, kiwi banana, kiwi, avocado, chestnut, allergies to peanuts, tree nuts, fish, and shellfish. A significant percentage of young children with food allergy go on to develop allergies to nonfood allergens as they grow into adulthood. Infants and young children will typically develop allergies to foods resulting in atopic dermatitis or some other allergic manifestation. 12,13 As they grow older, these children often develop sensitivity to inhalant allergens (such as pollens or dust mites), producing allergenic rhinitis and other respiratory symptoms Chronic inflammation associated with allergic reactions will then predispose the child for the development of asthma. Asthma is a chronic inflammatory disease that is characterized by airway obstruction and constriction of the bronchi of the lungs. 5,8,13 Asthma can be a debilitating condition and results in more pediatric hospital admissions than any other cause. 8 Food allergy has been shown to be an independent risk factor for the development of lifethreatening asthma. 15 Food allergy has been shown to be more common in asthmatic children than in healthy controls. 16 Asthmatic children with food allergy tend to have an increased number of hospitalizations and generally required more steroid interventions. 16 The progression of disease from early childhood food allergy to asthma has been referred to as the Allergy March. 5,13 Atopy is a strong identifiable predisposing factor for the development of asthma, 13 as more than threequarters of patients with asthma can be shown to have sensitivity to at least one common allergen. 8 The correct diagnosis of early childhood food allergy is critical for interrupting the Allergy March. A number of studies indicate that early treatment of allergy can change the course of disease progression. 13,15 Clinical intervention seems to be most effective if the treatments are initiated before the age of six, increasing the importance of early diagnostic testing. 17 Diagnosis of food allergy may also be critically important in patients who have already developed asthma. Recent studies have shown that poorly-controlled asthmatic patients with food allergy are at significantly increased risk of developing life-threatening asthma, relative to patients that are not allergic to foods. 18 Case-controlled studies in children and adults have shown that food allergy is a major risk factor for life-threatening asthma in asthmatic patients. 15 Diagnostic Testing for A thorough patient history and physical examination are the critical first steps in the 3

5 diagnosis of food allergy. 19 When allergy to a particular food is suspected, some clinicians employ elimination tests by identifying the foods most likely to be responsible for the patient s symptoms. Many clinicians in the United Quantitative Foodspecific IgE Testing In many cases, laboratory and UpJohn, Uppsala, Sweden) in the 1970s. 22,23 In these methods, the patient s serum is incubated with the diets to determine whether States use skin-prick testing measurement of circulating solid phase of activated cel- avoidance of the allergen(s) to screen for IgE-mediated levels of specific IgE in serum lulose to which a well-char- in question results in a loss of sensitivity to specific foods. 5,20 can serve as a practical alter- acterized allergen extract allergic symptoms. The effec- Skin testing for food sensi- native to skin testing for the has been chemically bound. tiveness of this approach is tivity has a high negative diagnosis of food allergy. 4,7,21 The activated cellulose solid limited by the clinician s abil- predictive accuracy; greater Use of these tests can allow phase can take the form of ity to identify the causative than 95% of individuals that primary care clinicians to a small sponge (or CAP) or a food as well as the patient s are negative will prove nega- screen for allergies. This test- paper disk. Exposing the solid ability to maintain a diet tive by confirmatory tests. 25 ing option also eliminates phase to the patient s serum completely free of all forms Unfortunately, the positive the expense of having to allows the food-specific IgE to of that food. Alternatively, the predictive value of skin test- purchase and store allergen bind to the allergen-coated potentially allergic patient ing for foods is relatively low extracts required for skin test- matrix. Unbound proteins can be challenged with the and approximately 50% of ing. Since specific IgE testing are washed off, leaving only food in question in order to positive screens do not con- can be performed on a single antigen-specific IgE bound determine whether eating firm. 5,25 Thus, a negative skin tube of serum, it is much to the solid matrix. Antibody that food produces an aller- test to a given food can effec- more convenient and com- to IgE (anti-ige) that has been gic reaction. The double-blind tively exclude IgE-mediated fortable for the patient than labeled with a radioisotope placebo-controlled food chal- allergy to a food, but positive skin testing. Recently, sev- or an enzyme is then added lenge (DBPCFC) is considered results are not diagnostic. eral groups have applied in to the solid matrix. After an the gold standard for the Skin testing is generally not vitro tests for the quantitative incubation period allowing diagnosis of food allergies. 4,5,7 applied in the primary care measurement of food-specif- the anti-ige to bind, excess Unfortunately, this procedure setting because it is highly ic IgE as a screening tool for labeled anti-ige is washed off. is time-consuming espe- technique-dependent and assessing risk of food aller- In the methods employing cially when multiple foods should only be performed by gy. 1,4,5,9,11,26-28 Because this lab- radiolabeled anti-ige, specifi- are suspected and can add specialists who are trained oratory-based approach does cally bound IgE is measured significantly to the cost of in proper procedures and not expose the patient to the using a gamma counter. In diagnosis. There is also some interpretation of results. 7,20 potential allergen, it elimi- these assays, the amount of risk associated with food chal- Because skin testing involves nates any risk of an adverse IgE bound to the antigen- lenge because of the poten- exposing the potentially reaction during the initial coated activated cellulose is tial for inducing a severe aller- allergic patient to the food in screen. Use of quantitative proportional to the amount of gic reaction. question, there is also some food-specific IgE testing can radioactivity measured in the Skin Testing Because of the limitations risk of inducing a dangerous allergic reaction. It is important that any office perform- allow for the identification of patients with food allergy that might not otherwise be tube at the end of the assay. In the methods employing an enzyme-labeled anti-ige, the of food elimination and chal- ing DPPCFC or skin testing referred to a specialist. amount of IgE bound to the lenge tests, some allergists have staff available who are The majority of in vitro allergen-coated cellulose is use other diagnostic tests to able to handle the potentially tests for allergen-specific IgE determined from the amount prescreen patients suspected life-threatening reactions that performed today continue to of enzyme activity in the tube of having IgE-mediated food can occur with the adminis- employ basic principles that at the end of the assay. allergy. 5 This approach allows tration of these tests. were introduced with the To improve the standard- for more efficient use of the first commercial assay, the ization of specific IgE meth- more costly confirmatory Phadebas RAST (Pharmacia ods between manufacturers, 4

6 the National Committee for stipulates requirements for ity to egg, milk, peanut, and tity of food-specific IgE and Clinical Laboratory Standards testing and supervisory per- fish. 18 Food-specific IgE levels the challenge threshold level. (NCCLS) has developed con- sonnel and the inclusion of were defined above which Vanto and coworkers were sensus document I/LA20-A. 24 quality control procedures for individuals in their studied able to predict the develop- This guideline defines crite- the assessment of daily assay population were greater than ment of tolerance to milk ria for assay design, perfor- performance. Many labora- 95% likely to experience an in children with cow s milk mance, standardization, and tories further verify quality allergic reaction upon inges- allergy using skin testing and quality assurance. Several of testing by participating in tion of the specific food. 18 quantitative food-specific manufacturers have used the interlaboratory proficiency In a subsequent study, the IgE. 27 Measurement of quanti- NCCLS guideline as a blue- programs from independent Sampson group went on to tative food-specific IgE could print for the development of providers such as the College verify the accuracy of their play a useful role in identify- new assays or the improve- of American Pathologists quantitative decision thresh- ing patients who should be ment of classic methods. This (CAP). olds in a group of children retested by food challenge to has resulted in the availability of a number of methods for the quantitative measurement of allergen-specific IgE. Clinical Application of in vitro Testing In a groundbreaking study, and adolescents suspected of having food allergy. 18 Several other groups have studied the utility of quan- determine whether they have developed tolerance. 4 It should be noted that thresholds documented in Recently, a number of Sampson and Ho measured titative specific IgE in the the literature for predict- assay manufacturers have the concentrations of food- assessment of food allergy. ing clinical allergy may not introduced quantitative test- specific IgE to six common Perry and coworkers deter- be readily transferable from ing for food-specific IgE that food allergens (egg, milk, mined the likelihood of pass- one population to another. 4,11 is calibrated to materials peanut, fish, soy, and wheat) ing a food challenge at lower Various investigators have that are traceable to World in previously diagnosed levels of food-specific IgE. 5 defined different specific IgE Health Organization (WHO) patients with food allergy. 25 They established diagnostic thresholds in different study International Reference Using a concentration of 0.35 thresholds where approxi- populations. 11 For example, Preparation (IRP) serum. 22,23 ku/l as a threshold for a posi- mately 50% of patients the 95% probability threshold With the introduction of this tive test, they showed that would likely pass a food chal- for predicting clinical reactiv- standardization, manufactur- they could predict food-spe- lenge. 5 In another study, it ity to egg developed using ers have been able to improve cific allergy with sensitivity was shown that food-specific the Pharmacia ImmunoCAP the comparability of their ranging from 94% and 100%. IgE levels could be used to system for the measurement results with those from other Unfortunately, the negative predict the probability that a of food-specific IgE has been manufacturers that use the predictive accuracy they real- given allergic patient will out- reported to range from 0.35 same reference preparation. ized with this low cut-off was grow their food allergy. 26 This ku/l to 17.5 ku/l in various Several commercial assays no better than that previously study s authors suggested studies. 11,25,28,29 Patient age employ multipoint calibration documented using skin-prick that food-specific IgE levels may be one critical determi- curves that allow results to testing. 18 Their data indicated might be useful for selecting nant of the appropriate clini- be reported in international that using 0.35 ku/l as a deci- patients for rechallenging cal thresholds. 4 Osterballe units (ku/l) traceable to the sion threshold would result in for food allergy. 26 Osterballe and Bindslev-Jensen sug- WHO IgE IRP 75/502. a specificity ranging from 25% and Bindslev-Jensen recently gested that discordant val- Laboratories performing to 65% and a large number showed that food-specific IgE ues for diagnostic thresholds the testing must do so in of false positives. This study concentration correlated to obtained in various studies accordance with the stan- went on to identify higher a positive outcome in food might represent differences dards for the level of complex levels of food-specific IgE that challenge in children with in study populations or in testing they are performing could be used as quantitative egg allergy 11 ; however, they lots of reagent used. 11 Foods established in the CLIA-88 decision thresholds for the found that there was no cor- are biological products com- guidelines. 22 This regulation prediction of clinical reactiv- relation between the quan- posed of complex mixtures 5

7 of proteins and other materials. 30 Any one of a number of proteins in food could elicit an allergic reaction in a particular individual. Each lot of food allergen used in assay production is subject to biological, geographic, and seasonal variations that can affect specific IgE binding. 30 Despite relatively standardized processes of allergen production, it is impossible to avoid some variation from lot to lot. 30 It is perhaps useful to realize when considering this inherent source of variation of in vitro IgE testing, that the materials used for food challenge or skin prick/puncture testing suffer from the same source of variability. The majority of studies involving the quantitative measurement of food-specific IgE performed, to date, have employed the Pharmacia ImmunoCAP FEIA (fluorescent enzyme immunoassay) system 6,18,25,26,28,29 ; however, alternate methodologies have been successfully used to define diagnostic thresholds for food-specific IgE in certain populations. 29 Also, a recent study has shown that the Hycor Turbo-MP quantitative food-specific IgE tests generated results that are highly comparable with the ImmunoCAP method. 31 This is not unexpected as both methods are based on the same general principle and employ multipoint calibration systems based on the same WHO international IgE reference preparation 75/ Conclusion It has become increasingly clear that food allergy adversely affects the quality of life of many individuals. In some cases, food allergy can be life-threatening. The diagnosis of food-related illness can be a tremendous challenge for the practicing clinician. Through the use of quantitative in vitro diagnostic testing, the clinical laboratory can play an important role in supporting the evidence-based diagnosis of food allergy. References 1. Wood RA. The natural history of food allergy. Pediatrics Jun; 111(6 Pt 3): Sampson HA. Current reviews of allergy and clinical immunology: Update on food allergy. J Allergy Clin Immunol May; 113(5): Taylor SL, Hefle SL. Food allergies and other food sensitivities. A publication of the Institute of Food Technologists Expert Panel on Food Safety and Nutrition. Food Techol. 2001; 55(9): Beyer K, Teuber SS. Food allergy diagnostics: Scientific and unproven procedures. Curr Opin Allergy Clin Immunol Jun; 5(3): Perry TT, Matsui EC, Kay Conover-Walker MK, Wood RA. The relationship of allergen-specific IgE levels and oral food challenge outcome. J Allergy Clin Immunol. 2004; 114(1): Burks W, Helm R, Stanley S, Bannon GA. Food allergens. Curr Opin Allergy Clin Immunol. 2001; 1(3): American Academy of Allergy, Asthma and Immunology. The Allergy Report. Milwaukee, Wis: AAAAI; Nimmagadda SR, Evans R 3rd. Allergy: Etiology and epidemiology. Pediatr Rev. 1999; 20(4): ; quiz Sampson HA. Food allergy accurately identifying clinical reactivity. Allergy. 2005; 60(Suppl 79): Formanek R Jr. Food allergies: When food becomes the enemy Osterballe M, Bindslev-Jensen C. Threshold levels in food challenge and specific IgE in patients with egg allergy: is there a relationship? J Allergy Clin Immunol. 2003;112(1): Titus K. Lab-based allergy testing on the march. CAP Today. March Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child. Pediatr Allergy Immunol. 1998; 9(3): Guerra S, Sherrill DL, Martínez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002; 109(3): Roberts G, Patel N, Levi- Schaffer F, Habibi P, Lack G. Food allergy as a risk factor for lifethreatening asthma in childhood: a case-controlled study. J Allergy Clin Immunol. 2003; 112(1): Wang J, Visness CM, Sampson HA. Food allergen sensitization in inner-city children with asthma. J Allergy Clin Immunol. 2005; 115(5): Martínez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics Feb; 109(2 Suppl): Sampson HA. Improving invitro tests for the diagnosis of food hypersensitivity. Curr Opin Allergy Clin Immunol. 2002; 2(3): Sampson HA. Food allergy, part 2: Diagnosis and management. J Allergy Clin Immunol Jun; 103(6): Dolen WK. Skin testing and immunoassays for allergen-specific IgE. Clin Rev Allergy Immunol. 2001; 21(2-3): Dolen WK. The diagnostic allergy laboratory. In Rose NR, Hamilton RG, Detrick B, eds. Manual of Clinical Laboratory Immunology. 6th ed. Washington, DC: ASM Press; 2002: Weiss J. Reliable, quantitative specific IgE measurement. Advance Laboratory Admin Jun; Yunginger JW, Ahlstedt S, Eggleston PA, et al. Quantitative IgE antibody assays in allergic diseases. J Allergy Clin Immunol Jun; 105(6 Pt 1): National Committee for Clinical Laboratory Standards. Evaluation Methods and Analytical Performance Characteristics of Immunological Assays for Human Immunoglobulin E (IgE) Antibodies of Defined Allergen Specificities; Approved Guideline. Wayne, Pa: NCCLS; NCCLS document I/LA20-A (ISBN ). 25. 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(4): Shek LP, Soderstrom L, Ahlstedt S, Beyer K, Sampson HA. Determination of food specific IgE levels over time can predict the development of tolerance in cow s milk and hen s egg allergy. J Allergy Clin Immunol. 2004; 114(2): Vanto T, Helppila S, Juntunen- Backman K, et al. Prediction of the development of tolerance to milk in children with cow s milk hypersensitivity. J Pediatr Feb; 144(2): Boyano Martínez T, García-Ara C, Díaz-Peña JM, et al. Validity of specific IgE antibodies in children with egg allergy. Clin Exp Allergy. 2001; 31(9): Roehr CC, Reibel S, Ziegert M, et al. Atopy patch tests, together with determination of specific IgE levels, reduce the need for oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2001; 107(3): Dolen, WK. Allergen extract standardization: Reality, myth, or dream? Ann Allergy Asthma Immunol. 1995; 75(2): Kontis KJ, Valcour A, Patel A, et al. Correlation of the Turbo-MP RIA with ImmunoCAP FEIA for the determination of food allergen-specific immunoglobulin E. Ann Clin Lab Sci (in press). 6

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