FROM THE AMERICAN ACADEMY OF PEDIATRICS

Guidance for the Clinician in Rendering Pediatric Care

CLINICAL REPORT Testing in Childhood: Using -Specific IgE Tests

Scott H. Sicherer, MD, Robert A. Wood, MD, and the SECTION ON ALLERGY AND abstract KEY WORDS A variety of triggers can induce common pediatric allergic diseases allergy, allergy testing, immunoglobulin, IgE, immunotherapy, which include asthma, allergic , atopic , , pediatrics and anaphylaxis. Allergy testing serves to confirm an allergic trigger ABBREVIATIONS fi IgE— suspected on the basis of history. Tests for allergen-speci c immuno- sIgE—allergen-specific IgE globulin E (IgE) are performed by in vitro assays or skin tests. The tests SPT—skin prick test are excellent for identifying a sensitized state in which allergen-specific — IgG immunoglobulin G IgE is present, and may identify triggers to be eliminated and help This document is copyrighted and is property of the American guide immunotherapy treatment. However, a positive test result does Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American not always equate with clinical allergy. Newer enzymatic assays based Academy of Pediatrics. Any conflicts have been resolved through on anti-IgE have supplanted the radioallergosorbent test a process approved by the Board of Directors. The American (RAST). This clinical report focuses on allergen-specific IgE testing, em- Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of phasizing that the medical history and knowledge of disease character- this publication. istics are crucial for rational test selection and interpretation. Pediatrics The guidance in this report does not indicate an exclusive 2012;129:193–197 course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be INTRODUCTION appropriate. Allergic diseases ( [hay fever], asthma, atopic der- All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, matitis, and allergic or anaphylactic reactions to foods, drugs, insect revised, or retired at or before that time. venom, or other ) often warrant identification of specific allergic triggers for treatment. Most allergic responses are mediated by immunoglobulin E (IgE) antibodies specific for the trigger allergen, which can be detected with in vitro tests or skin testing. This clinical report focuses on using in vitro allergen-specific IgE (sIgE) testing, which is widely available to pediatricians. A full description of the use of tests for diagnosis and management of allergic disease is beyond the scope of this report, but is described in recent guidelines and practice parameters.1–9 www.pediatrics.org/cgi/doi/10.1542/peds.2011-2382 TESTS AVAILABLE FOR DETECTING sIgE doi:10.1542/peds.2011-2382 A number of enzymatic assays that are based on anti-IgE antibodies PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). have supplanted the radioallergosorbent test.10 Commercial labora- Copyright © 2012 by the American Academy of Pediatrics tories that are federally licensed under the Clinical Laboratory Im- provement Act of 1988 often use automated systems capable of detecting and quantifying sIgE. Laboratory reports may indicate a number of readouts (eg, classes, counts, or units), but quantifica- tion of results in units reflecting concentrations of sIgE is becoming

more common (eg, kUA/L). Although the 3 commercial detection sys- tems approved by the Food and Drug Administration have excellent

performance characteristics (analytical sensitivity, 0.1 kUA/L), the

PEDIATRICS Volume 129, Number 1, January 2012 193 Downloaded from www.aappublications.org/news by guest on September 26, 2021 individual systems appear to detect specific trigger when there is suspicion which increases diagnostic value by different populations of IgE of one, or in less common circum- applying previous probability.4 or do not measure IgE antibodies with stances, screening for atopy. A positive A physician interested in screening for comparable efficiencies. Thus, a result serum sIgE or skin test denotes a sen- atopy (eg, distinguishing recurrent viral foranallergenin1ofthe3testsystems sitized state. However, detection of sen- infections from allergic rhinitis) might may not be equivalent to the same al- sitization to an allergen is not equivalent select a small panel of common trig- lergen tested in a different system. to a clinical diagnosis. In fact, many gers. Another means to screen for at- The skin prick test (SPT), typically used children with positive tests have no opy is to use a multiallergen test that by allergy specialists, is another clinical illness when exposed to the contains several common allergens in means of detecting sIgE antibodies.11 A allergen.2,3,7,9,11,13 This limitation high- one test (eg, one test that includes number of devices are available for lights the need for the clinician to several perennial allergens, such as introducing allergen into the surface use a detailed medical history and dust mite, dog dander, and mold). of the skin with minimal discomfort; have knowledge of the features of the Availability and composition of these a resulting wheal-and-flare response specific illness when selecting and in- tests varies by manufacturer. A posi- canbemeasuredin10to20minutes. terpreting tests. For example, there is tive result will not identify IgE to a Saline and histamine controls are no need to test for an allergen that is specific antigen but can, at less cost placed for comparison. Intradermal clearly tolerated (eg, egg in a child than performing many individual tests, skin testing is performed in special who eats egg without symptoms) or identify a child whose symptoms may circumstances when increased sensi- when exposure is not relevant (eg, relate to exposure to a specific allergen tivity is required (eg, after negative testing a pollen to which the child is and warrant further specifictestingor SPT for vaccines, venom, penicillin, not geographically exposed). Knowl- referral. The multiallergen test had and some inhalant allergens, such as edge of local aerobiology is, therefore, excellent predictive value for identifying Alternaria organisms and perhaps essential. Testing large panels of aller- atopic children compared with SPTs 14,15 other outdoor molds). gens without consideration of the his- and an allergist’s diagnosis. Both serum sIgE tests and SPT are tory, geographic relevance, and disease sensitive and have similar diagnostic characteristics may result in many ISSUES SPECIFIC TO RESPIRATORY properties.11,12 Advantages of the SPT clinically irrelevant positive results, ALLERGY1,6,11 include immediate results visible to the which, if overinterpreted, may lead to The disorders that respiratory allergy patient/family and low cost compared costly and socially, emotionally, and/or comprises are allergic asthma and with serum sIgE tests. Disadvantages nutritionally detrimental actions of un- seasonal or perennial allergic rhinitis. include the need to withhold medi- necessary allergen avoidance. Similarly, National asthma guidelines1 suggest cations with antihistamine properties caution is advised when testing is neg- that patients with persistent asthma and having rash-free skin available for ative despite a convincing history. Test- be evaluated for the role of allergens testing. Advantages of the serologic ingforsIgEwouldalsogenerallynotbe as contributing factors, with an em- tests include availability and lack of useful when the disorder has no path- phasis on testing for perennial indoor interference from antihistamines or ophysiological basis for a relationship allergens (eg, dust mite, animal dan- extensive dermatitis. Disadvantages to sIgE (eg, behavioral disorders; aller- der, cockroach, mold) that might other- include the need to obtain blood sam- gic disorders not related to sIgE, such wise not be identified as contributing ples, delayed results, and cost. Some as allergic contact dermatitis). to disease and also suggest testing discrepancies exist, however; one test Few studies have correlated clinical seasonal or perennial allergens for or the other may be more sensitive to outcomes to test results.2,3,4,11 Studies selected patients with any level of detect specific allergens, probably be- have generally supported the notion asthma severity as a basis for edu- cause different proteins or IgE binding that increasingly strong tests correlate cation about the role of allergens for sites are represented.2,3,7,9,11,13 with increasing likelihood of clinical re- avoidance and for immunotherapy. activity.2,3,11 Patients should not be told The clinician may be interested in TEST SELECTION AND they are allergic based solely on either identifying specific indoor (eg, dust INTERPRETATION a skin test or the identification of sIgE. mite, animal dander, molds, mice, and Tests might be selected to identify The test characteristics underscore the cockroach) or outdoor (eg, pollens, triggers from a number of potential need to select and interpret tests with molds) triggers. Rational selection common allergens, for confirming a consideration of the medical history, and interpretation of specifictests

194 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 26, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS requires consideration of the envi-  Screening panels of food allergens  Testing for total IgE does not iden- ronmental exposures (housing, pets, without previous consideration of tify specific . Atopic individ- and geographic floristic patterns), the history is not recommended, be- uals often have elevated total IgE, medical history (nature of symptoms, cause sensitization without clinical but there is no current evidence timing in relation to exposures), and allergy is common. For example, ∼8% to support the interpretation of sIgE disease characteristics (eg, pollen al- have positive test results for peanut, in relation to total IgE. lergy is uncommon in infancy; patients but ∼1% are clinically allergic.16  Tests measuring immunoglobulin G are unlikely to have acute symptoms  A negative SPT or serum sIgE test (IgG) antibodies for diagnosis are from dust mite exposure; food aller- result does not entirely exclude a not recommended. gens do not typically cause chronic diagnosis of a food allergy. One test  Intradermal tests are not recom- respiratory disease). Provocation tests may be positive when the other mended, because they are too sen- can confirm environmental allergy but is negative. SPT using fresh food sitive and carry risk of a severe are not often undertaken for clinical extracts may increase sensitivity, es- allergic reaction. purposes. pecially for fruits. Caution is needed  Food protein-induced enterocolitis when tests are negative when a spe- and proctocolitis (eg, cell-mediated ISSUES SPECIFIC TO FOOD cific food allergy history is convinc- food allergic disorders) are not as- 2,3,4,11 ALLERGY ing; a medically supervised oral food sociated with positive IgE tests. Food allergy may be suspected when challenge may be needed. specificsymptoms(eg,urticaria,  Cross-reactivity among proteins angioedema, cough, wheeze, vomit, may result in a much higher degree ISSUES SPECIFIC TO OTHER and anaphylaxis) occur minutes to of positive sIgE test results among ALLERGIES (DRUG ALLERGY, hours after the ingestion of a food, and related foods than clinical reactions INSECT VENOM, VACCINES, in children diagnosed with certain (eg, >50% of patients with peanut LATEX)7-9 disorders, such as moderate to severe allergy test positive to other le- The general caveats regarding sensi- atopic dermatitis, eosinophilic esoph- gumes, but <5% have clinical symp- tization and clinical allergy described agitis, and other allergic gastrointes- toms of allergy from ingestion of previously also apply to allergy tests tinal tract disorders. Testing for sIgE legumes). Cross-reactivity among for substances that may cause acute to foods might be considered to id- homologous proteins of aeroaller- allergic reactions or anaphylaxis, such entify or confirm triggers, to assist in gens and food allergens may result as medications, insect venom, vac- diagnosis of chronic disorders, or to in positive tests to foods, often cines, and latex. The medical history is monitor for allergy resolution. How- without clinical allergy (eg, birch essential in decision making regarding ever, they are not considered diag- pollen with hazelnut, peanut, soy; testing and interpretation, including nostic in and of themselves. SPT and grass pollen with wheat, peanut; understanding whether the symptoms serum sIgE provide similar sensitivity dust mite with shrimp). are likely to be IgE mediated. and specificity.12 It is common to have  Strong positive test results cor- positive test results for tolerated Tests for drug allergy (eg, acute allergic relate with increasing probability foods; therefore, indiscriminate test- reactions) are generally not standard- of clinical allergy, and particularly ing (ie, panels that include foods that ized, and the sensitivity of serum tests high values may indicate a high 8 are already tolerated) is not advised. appears poor. IgE tests are not rele- degree (>95%) of likely allergy; Additional means to assist in diagnosis vantformanydrugreactions(mac- include the medical history and results however, there are few studies cor- ulopapular rashes, Stevens-Johnson of medically supervised oral food chal- relating outcomes to test results, syndrome). SPT and intradermal tests lenges. Elimination diets, if initiated, and results vary by age, disease, for penicillin allergy using recently should not be maintained in the ab- and other factors. available reagents have potential utility 8 sence of a convincing previous history  sIgE serum concentration or SPT for IgE-mediated allergies. of a reaction or a medically supervised wheal size do not accurately pre- Allergy testing for venom allergy should oral food challenge. A comprehensive dict the severity of allergic reac- be considered when symptoms of description of the diagnostic and man- tions, but do reflect the likelihood anaphylaxis occur after a sting. When agement process is reviewed in recent of an allergic reaction of variable anaphylactic allergy to venom is con- guidelines.2–4 Key observations include: intensity. firmed by skin testing, immunotherapy

PEDIATRICS Volume 129, Number 1, January 2012 195 Downloaded from www.aappublications.org/news by guest on September 26, 2021 is indicated and highly effective.7,9,11 A number of tests have no evidence to 7. Use of a multiallergen serum test Isolated, localized swelling at a sting support their use and are not recom- can be helpful for screening for site does not identify a risk of ana- mended, including: lymphocyte stimu- atopic disease if there is a clini- phylaxis, and testing is not warranted. lation, facial thermography, gastric cal suspicion. If positive, allergen- Generalized urticaria without other juice analysis, hair analysis, applied specific testing may be considered. symptoms of anaphylaxis in children 16 kinesiology, provocation-neutralization, 8. Tests for allergen-specific IgG anti- years and younger usually does not allergen-specific IgG/IgG4, cytotoxic as- bodies are not helpful for diagnos- warrant testing, because more severe say, electrodermal test (VEGA), and me- ing allergies. reactions appear to be unlikely; how- diator release assay.2,3,11 9. Because test limitations often war- ever, systemic anaphylaxis in any age rant additional evaluation to con- group and generalized urticaria in SUMMARY firmtheroleofspecific allergens, adolescents older than 16 years war- 1. Treatment decisions for infants and consultation with a board-certified rant testing. SPT and intradermal test- children with allergy should be allergist-immunologist should be ing are considered the standard means made on the basis of history and, considered. of diagnosis, although serum IgE tests when appropriate, identified through for venom or venom components may directed serum sIgE or SPT testing. be performed when skin tests are Newer in vitro sIgE tests have sup- negative and the history is suggestive. LEAD AUTHORS planted radioallergosorbent tests. Scott H. Sicherer, MD SPT and intradermal tests can be 2. Allergy tests for sIgE must be se- Robert A. Wood, MD performed for vaccines suspected lected and interpreted in the con- of triggering allergic reactions, al- SECTION ON ALLERGY AND text of a clinical presentation; test though care is needed to choose the IMMUNOLOGY EXECUTIVE relevance may vary according to COMMITTEE, 2009–2011 proper dilution to prevent irritant the patient’s age, allergen expo- Scott H. Sicherer, MD, Chairperson reactions.7,17,18 Skin tests are not sure, and performance character- Stuart Abramson, MD, PhD available for latex; serum tests are Bradley E. Chipps, MD istics of the test. available, but the diagnostic utility is Thomas Fleisher, MD not well characterized.7,11 3. Positive sIgE test results indicate Mitchell R. Lester, MD sensitization, but are not equiva- Todd A. Mahr, MD Elizabeth C. Matsui, MD TESTS UNDER DEVELOPMENT AND lent to clinical allergy. Large pan- Frank S. Virant, MD UNPROVEN TESTS els of indiscriminately performed Paul V. Williams, MD, Immediate Past Chair screening tests may, therefore, pro- Tests are under development that de- vide misleading information. STAFF tect IgE binding to specificproteinsin Debra L. Burrowes, MHA 4. Tests for sIgE may be influenced by foods (component-resolved diagnosis), cross-reactive proteins that may or with a potential to more accurately ACKNOWLEDGMENTS may not have clinical relevance to identify people likely to react or with Comments on this clinical report were disease. more severe allergies; however, further solicited from committees, sections, validation of these tests is needed.2,3,11 5. Increasingly higher levels of sIgE and councils of the AAP; 3 responded. Additional tests requiring more vali- (higher concentrations on serum The Specific IgE Task Force Commit- dation include basophil activation and tests or SPT wheal size) generally tee of the American Academy of Al- atopy patch tests with foods.2,3,11 These correlate with an increased risk of lergy, Asthma and Immunology and tests are currently primarily research clinical allergy. the American College of Asthma, Al- tools, although specific uses have been 6. sIgE test results typically do not lergy and Immunology also reviewed identified.8,11 reflect the severity of allergies. this clinical report.

REFERENCES

1. National Asthma Education and Prevention J Allergy Clin Immunol. 2007;120(5 suppl): diagnosis and management of food allergy Program. Expert Panel Report 3 (EPR-3): S94–S138 in the United States: report of the NIAID- Guidelines for the Diagnosis and Manage- 2. Boyce JA, Assa’ad A, Burks AW, et al; NIAID- sponsored expert panel. J Allergy Clin ment of Asthma-Summary Report 2007. Sponsored Expert Panel. Guidelines for the Immunol. 2010;126(6 suppl):S1–S58

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3. Burks AW, Jones SM, Boyce JA, et al. NIAID- allergy: an updated practice parameter. American College of Allergy, Asthma and sponsored 2010 guidelines for managing Ann Allergy Asthma Immunol. 2010;105(4): Immunology/American Academy of Allergy, food allergy: applications in the pediatric 259–273 Asthma and Immunology SpecificIgETest population. Pediatrics. 2011; Published online 9. Moffitt JE, Golden DB, Reisman RE, et al. Task Force. AnnAllergyAsthmaImmunol. October 10. doi:10.1542/peds.2011-0539 Stinging insect hypersensitivity: a practice 2008;101(6):580–592 4. American College of Allergy, Asthma, & parameter update. J Allergy Clin Immunol. 14. Ballardini N, Nilsson C, Nilsson M, Lilja G. Immunology. Food allergy: a practice pa- 2004;114(4):869–886 ImmunoCAP Phadiatop Infant—a new rameter. Ann Allergy Asthma Immunol. 10. Hamilton RG, Williams PB; Specific IgE blood test for detecting IgE sensitisation in 2006;96(3 suppl 2):S1–S68 Testing Task Force of the American Acad- children at 2 years of age. Allergy. 2006;61 5. Krakowski AC, Eichenfield LF, Dohil MA. emy of Allergy, Asthma & Immunology; (3):337–343 Management of atopic dermatitis in the American College of Allergy, Asthma and 15. Wood RA, Schuberth KC, Sampson HA. Value pediatric population. Pediatrics. 2008;122 Immunology. Human IgE antibody : of a multiantigen radioallergosorbent test (4):812–824 a primer for the practicing North American in diagnosing atopic disease in young 6. Wallace DV, Dykewicz MS, Bernstein DI, allergist/immunologist. J Allergy Clin children. J Pediatr. 1990;117(6):882–885 et al; Joint Task Force on Practice; American Immunol. 2010;126(1):33–38 16. Liu AH, Jaramillo R, Sicherer SH, et al. Na- Academy of Allergy; Asthma & Immunology; 11. Bernstein IL, Li JT, Bernstein DI, et al; tional prevalence and risk factors for food American College of Allergy; Asthma and American Academy of Allergy, Asthma and allergy and relationship to asthma: results Immunology; Joint Council of Allergy, Asthma Immunology; American College of Allergy, from the National Health and Nutrition Ex- and Immunology. The diagnosis and man- Asthma and Immunology. Allergy diagnostic amination Survey 2005-2006. J Allergy Clin agement of rhinitis: an updated practice testing: an updated practice parameter. Immunol. 2010;126(4):798–806, e13 parameter. J Allergy Clin Immunol. 2008;122 Ann Allergy Asthma Immunol. 2008;100(3 17. Wood RA, Setse R, Halsey N; Clinical Im- (2 suppl):S1–S84 suppl 3):S1–S148 munization Safety Assessment (CISA) 7. Lieberman P, Nicklas RA, Oppenheimer J, 12. Chafen JJ, Newberry SJ, Riedl MA, et al. Network Hypersensitivity Working Group. et al. The diagnosis and management of Diagnosing and managing common food Irritant skin test reactions to common anaphylaxis practice parameter: 2010 up- allergies: a systematic review. JAMA. 2010; vaccines. J Allergy Clin Immunol. 2007;120(2): date. J Allergy Clin Immunol. 2010;126(3): 303(18):1848–1856 478–481 477–480, e1–e42 13. Cox L, Williams B, Sicherer S, et al; American 18. Kelso JM, Li JT, Nicklas RA, et al; Joint Task 8. Joint Task Force on Practice Parameters College of Allergy, Asthma and Immunology Force on Practice Parameters; Joint Task American Academy of Allergy, Asthma and Test Task Force; American Academy of Forcce on Practice Parameters for Allergy ImmunologyAmerican College of Allergy, Allergy, Asthma and Immunology Specific & Immunology. Adverse reactions to vac- Asthma and ImmunologyJoint Council of IgE Test Task Force. Pearls and pitfalls of cines. Ann Allergy Asthma Immunol. 2009; Allergy, Asthma and Immunology. Drug allergy diagnostic testing: report from the 103(4 suppl 2):S1–S14

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