In-Vitro Allergy Testing

Lab Management Guidelines V2.0.2021

In-vitro Allergy Testing

MOL.CS.317.X v2.0.2021 Introduction

In-vitro testing for allergy is addressed by this guideline.

Procedures Addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedure addressed by this guideline Procedure code Allergen specific IgG; quantitative or 86001 semiquantitative, each allergen Allergen specific IgE; quantitative or 86003 semiquantitative, each allergen Allergen specific IgE; qualitative, 86005 multiallergen screen (e.g. disk, sponge, card) Allergen specific IgE; quantitative or 86008 semiquantitative, recombinant or purified component each Immunoassay for analyte other than 83516 infectious agent antibody or infectious agent antigen; qualitative or semiquantitative, multiple step method Gammaglobulin (immunoglobulin); IgE 82785 Peanut allg spec asmt 64 epi 0165U Peanut allg asmt epi clin rx 0178U

What Is Allergy

Definition

Allergy is defined as an immunologically mediated, hypersensitive response to an agent in a sensitized person.1-7 Mechanistically, there are several different pathways of hypersensitivity. In vitro allergy testing is largely concerned with Type I immediate hypersensitivity reactions mediated

by IgE.8 These reactions usually involve a response to an allergen in a previously sensitized individual that can manifest anywhere from minutes to a few hours. Typical clinical signs and symptoms have been described as follows:8  “Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:” o “Cutaneous (eg, acute urticaria, angioedema)” o “Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)” o “Cardiovascular (eg, tachycardia, hypotension)” o “Gastrointestinal (eg, vomiting, diarrhea)” o “Generalized (eg, anaphylactic shock)...” Allergy and allergy testing, is commonly divided into 5 categories:1  Allergic contact dermatitis (ACD)6  Stinging insect allergy caused by venoms7  Food allergy5  Inhalant allergy (aeroallergy)2,4  Drug allergy3 There is overlap between the categories and, in general, a patient with one type of allergy is at increased risk of experiencing another. An example of the overlap between categories is latex allergy, where the presentation can be cutaneous (mild contact urticaria), respiratory (asthma, rhinoconjunctivitis) or generalized (anaphylactic shock).9 Cross reactivity between different classes of allergens can result in unique clinical syndromes such as the oral allergy syndrome (OAS), which involves cross-reaction between food allergens and aeroallergens.10  Cross reaction between food allergens and pollen aeroallergens is known as the pollen-food syndrome. It is “a localized IgE-mediated reaction… which causes tingling and itching of the mouth and pharynx. This is typically triggered after consumption of certain fresh fruits and vegetables in pollen-allergic individuals. It is caused by cross reactivity between IgE antibodies to certain pollens with proteins in some fresh fruits and vegetables...”10  Latex-fruit syndrome is another OAS caused by cross-reaction between inhaled latex antigens and some fresh fruits and vegetables.11 Practice parameters published jointly by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) describe the diagnosis and management of the 5 types of allergy.1-7 The common themes in these practice parameters are: Allergy Testing

Lab Management Guidelines V2.0.2021

 The history and physical are the foundation of diagnosing allergy. For uncomplicated cases, if the history and physical are convincing enough, it is within the standard of care for providers treat the allergy without additional testing.  The focus of the diagnostic workup is identifying the allergen responsible for the allergic reaction.  Diagnostic testing is an adjunct to the history and physical and diagnostic testing alone without clinical correlation is insufficient to make a diagnosis. This is because sensitization to an allergen, which can produce a positive test, is not the same as disease. In allergic disease, the patient is sensitized and experiences a hypersensitivity reaction after allergen exposure.  Challenge testing is the gold standard of diagnosis. Thus, oral food challenges are the gold standard of food allergy testing. Challenges are time consuming, with potential serious side effects including anaphylaxis. Therefore, they must take place in a medical setting with appropriate safeguards.  After identifying a causative allergen, the basis of treatment is avoidance of the allergen, immune desensitization, or both. There are two general classes of first-line, high-volume testing methods used in the diagnosis of immediate hypersensitivity allergic disease. These are skin testing and in vitro testing of blood.1,12  Skin tests are generally performed in the office. There are several types, each useful in specific settings. In percutaneous skin testing (or skin prick testing, SPT), a specific allergen is pricked onto the skin with a device, and in intradermal testing the allergen is injected under the skin with a needle. Percutaneous testing is the method of choice for food allergy.5,13,14 In a third type of skin testing, patch testing, contact allergens are incorporated into a gel attached to a fabric backing to form a patch that is applied to the skin. This method has been highly standardized and is the test of choice to confirm ACD.6  In vitro testing of blood is most commonly performed by a clinical laboratory. The two most common blood tests are allergen-specific serum IgE testing (sIgE) and total IgE testing.1,8  The AAAAI/ACAAI practice parameters indicate that skin testing is recommended, and in vitro testing is not for ACD and drug allergy testing.3,6 For stinging insect allergy, inhalant allergy, and food allergy, skin testing is preferred over in vitro testing of blood, but both can be useful.2,5,7 In general, when either skin testing or blood testing is useful, physicians tend to prefer skin testing.12 Blood testing tends to be preferred when there are factors preventing accurate testing of skin, for example as occurs in patients with widespread eczema. Allergy Testing

Lab Management Guidelines V2.0.2021

Test Information

Introduction

In vitro tests for allergy include immunoglobulin and non-immunoglobulin tests.

Total IgE

This test is performed by automated immunoassay by one of several FDA-approved methods. The test is an adjunct to allergen specific IgE in selected clinical settings such as in patients with severe eczema.14 There is controversy regarding the clinical utility of this test, which has led to admonitions against routine use.5

Allergen Specific IgE (sIgE)

A summary of the fundamentals of in vitro testing of blood for allergen specific IgE has been published by Siles and Hsieh.8 This test is most commonly performed by automated immunoassay, and measures patient serum IgE binding to an extract of a specific allergen (e.g. peanut, sesame seed, honeybee venom, birch pollen), usually by fluorescence-labeled assay. In vitro testing for allergen specific IgE is indicated to help confirm a diagnosis of food allergy, inhalational allergy, allergy from stinging insect venoms, or latex. Depending on the antigen being tested, in vitro testing of blood for allergen specific IgE varies in sensitivity from 60 – 95% and in specificity from 30%- 95%.1,8,15,16 Although allergen specific IgE is usually performed by automated immunoassay, it is less commonly performed by an older multi-allergen dipstick method suitable for doctor’s offices.17,18 The dipstick method tests for a preset panel of multiple allergens even if testing some of the allergens is not supported by the patient history and physical. Another version of allergen specific IgE testing is component testing, also referred to as component-resolved diagnostics (CRD).5,19,20 Kattan and Wang describe the method as follows:  “Instead of using crude allergen extracts consisting of a mixture of allergenic and non-allergenic components, CRD uses pure allergen proteins, produced by purification from natural allergen sources or recombinant expression of allergen- encoding complementary DNA.” 19 CRD is performed by automated methods based on either a fluorescence enzyme immunoassay or a microarray.

Food Allergen Epitope Analysis

A method that attempts to further refine allergen specific IgE testing using as antigens a panel of synthetic peptides, usually 15 to 20 amino acids in length, selected from a library of overlapping peptides that tile the entire sequence of the allergenic protein(s) of interest. IgE binding to each individual peptide is measured to create a “map” of Allergy Testing

Lab Management Guidelines V2.0.2021

epitopes.21,22 The test is usually performed using a microarray chip or bead-based multiplex assay. It is considered a promising area of investigation but is still investigational and not currently recommended for use in the diagnosis and management of allergy.13,14

Allergen Specific IgG

This test is performed by automated or manual immunoassay. It is often misused in the workup of food intolerance and occasionally used for allergies to stinging insect venoms.1,8 It is not recommended for routine use in the diagnosis and management of allergy or food intolerance.1,23,24

Antigen Leukocyte Antibody Test (ALCAT)

This is a proprietary, laboratory-developed test for food sensitivity performed by Cell Science Systems Incorporated.25 It is an assay for cytotoxicity performed by flow cytometric immunoassay. It is not recommended for use in the diagnosis and management of allergy.1,23,26

Guidelines and Evidence

Introduction

Guidelines concerning allergy testing are based on the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) practice parameters and on general literature review.27 They are grouped below according to test-based recommendations.

Total IgE, Gammaglobulin (immunoglobulin) Testing (CPT 82785)

Measuring total IgE levels is occasionally considered medically necessary to interpret the significance of specific IgE-related allergy diagnoses. There are a variety of modest uses. For example, the allergy testing practice parameter states:  “The clinical applications of total serum IgE are of modest value. High serum IgE concentrations occur in allergic bronchopulmonary Aspergillosis (ABPA), the therapeutic response of which is evaluated by serial IgE values.” 1 The utility of total IgE in food allergy is also modest and the test should not be done haphazardly. Thus, the AAAAI/ACAII guideline on food allergy states:  “Do not routinely obtain total serum IgE levels for the diagnosis of food allergy.” 5 One application in food allergy is that high total serum IgE levels in the context of food allergy diagnosis support asymptomatic sensitization, and indicate decreased likelihood that a positive allergen specific test is a true positive. Thus, the EEACI guideline for food allergy states: Allergy Testing

Lab Management Guidelines V2.0.2021

 “Determination of total IgE is particularly useful in patients with severe eczema; a very high total IgE level suggests that positive sIgE results should be interpreted with care as they may represent asymptomatic sensitization.” 14 Another use of Total IgE is assessing which patients with allergic asthma or chronic spontaneous urticaria would benefit from therapy with omalizumab. The allergy testing practice parameter states:  “Total serum IgE is required for assessing the suitability of a patient for omalizumab therapy and determining the initial dose.” 1

Allergen Specific IgE (sIgE) (CPT 86003)

The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI), have created joint practice parameters for all 5 categories of allergy.27 Recommendations for in vitro testing for allergen specific IgE (CPT 86003) for each of the five types of allergy are considered below.

Allergic contact dermatitis (ACD) Although over 3000 contact allergens have been identified, just 65 specific allergens account for >90% of ACD diagnoses in the United States.1 The AAAAI / ACAAI practice parameter for ACD states that patch testing is the gold standard. In vitro blood tests are not recommended, even for the few allergens related to ACD where they are available.6 The Joint AAAAI/ ACAAI practice parameter states:

o “In patients suspected of ACD, patch testing is the gold standard to confirm the diagnosis.” 6 The recommendation is similar in pediatrics:

o “Patch testing should be performed and remains the gold standard for the diagnosis of ACD in children.” 6 Regarding in vitro testing of blood in ACD:

o “Although in vitro tests for delayed hypersensitivity to contact allergens (i.e., metals and bone cement) are available, routine use of such assays is not currently recommended as their sensitivity and specificity for diagnosing ACD has not been determined and should be considered investigational.” 6

Latex IgE-mediated allergy Latex allergy has a broad spectrum of signs and symptoms, ranging from mild contact urticaria to asthma or anaphylactic shock. Diagnostic algorithms for latex allergy are similar to the other categories of allergies, where clinical and laboratory testing is indicated only in the setting of appropriate clinical history.28 Testing can be performed by either skin prick or specific serum IgE. Each of these is subject to difficulties due to the variation in antigenicity of natural rubber latex, Allergy Testing

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and sensitivity and specificity vary by the specific extract used. For example, “studies indicate that the antigenic specificities of proteins in the extracts of the finished products differ from those proteins extracted from the raw material.” 29 Further complicating the diagnosis of latex allergy, there are no FDA-approved latex skin test reagents.30 Existing commercially available latex extracts “show considerable heterogeneity in their protein and major allergen composition, and this may negatively affect the accuracy of SPT testing.”28 Despite the lack of an FDA-approved skin prick test latex allergen, skin prick test may be the preferred initial diagnostic test. The AAAAI/ACAAI practice parameter summarizes the recommended evaluation for suspected work-related natural rubber latex allergy:1

o “...a positive skin prick test result with a NRL [natural rubber latex] extract (if available) is preferred to demonstration of elevated specific IgE with an FDA- cleared assay due to higher sensitivity of the former. Current IgE-mediated allergy and asthma caused by NRL allergens is highly unlikely in the presence of a negative skin prick test result with a reliable crude NRL allergen extract. Elevated in vitro specific IgE levels can be used to confirm NRL allergy, but a negative result does not exclude NRL allergen sensitization.” Latex sIgE assays also vary in their performance. The commonly available ImmunoCAP and Immulite sIgE assays have a diagnostic sensitivity and sensitivity of 70% and >95%, respectively, compared to skin prick testing. Because of the relatively low sensitivity, “care should be exercised when interpreting negative IgE antibody results from the CAP and AlaSTAT assays, even at their manufacturers' recommended positive cutoffs, since these assays misclassify approximately 25% of subjects who are skin test positive as IgE antibody negative (false negative).”31

Stinging insect venoms For allergies to stinging insect venoms, the AAAA /ACAAI practice parameter summarizes the nature of the disease and recommendations regarding diagnosis and treatment.7 The foundation of diagnosis is the history and physical combined with information regarding the geographic distribution of the suspected insect as well as its biology and behavior. Therapy is focused on avoidance, access to emergency medication to treat anaphylaxis, and desensitization with venom immunotherapy (VIT). The practice parameter indicates that testing, either by skin prick testing, serum allergen specific IgE, or both, is useful only for patients who have had a systemic reaction to an insect sting, and who are candidates for VIT. Testing is not indicated for patients who have had a local reaction only.7 Thus, the practice parameter makes the following three statements:7

o “Recommend to patients who have a history of systemic reactions to insect stings… referral for evaluation by an allergist/immunologist, the utility of specific Allergy Testing

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IgE testing for stinging insect sensitivity, and the potential advantages of VIT (testing is not necessary for patients in whom VIT is not required).” o “Perform skin tests and/or serum tests for IgE to stinging insect venoms on patients who are candidates for VIT.” o “Recommend and initiate VIT in all patients who have experienced an anaphylactic reaction to an insect sting and who have specific IgE to venom allergens.”

The practice parameter warns against therapy based only on test results without an appropriate history of systemic disease: “Avoid VIT based solely on in vivo and in vitro testing for venom IgE, without a history of systemic reaction to a sting.” 7 If the insect is not known, then the panel that is recommended consists of 5 tests as follows with a preference for skin testing over in vitro testing of blood for allergen specific IgE:7

o “Use skin tests as the preferred test for initial demonstration of venom-specific IgE. In vitro measurement of serum IgE should be used as a complementary or alternative test. Test for all 5 venoms, with the possible exception of individual patients in whom a single culprit is definitively known.”

The five venoms are as follows: “Extracts of honeybee, yellow jacket, white-faced hornet, yellow hornet, and wasp venom are available for skin testing and VIT.” 7 In addition, in special circumstances suggested by the history and physical, a sixth test for fire ant venom is sometimes indicated: “However, fire ant venom is only included under special circumstances.” 7

Food allergy For food allergy, the AAAAI and ACAAI have developed a joint practice parameter.5 In addition, evidence-based analysis and guidelines have been published by the United States National Institute of Health and the European Academy of Allergy and Clinical Immunology (EAACI).10,14,15 Lastly, the joint AAAI/ACAAI practice parameter on allergy testing has a significant section dedicated to food allergy testing.1 The various guidelines and practice parameters are consistent regarding the need to be guided by the clinical history and physical, the distinction between allergic sensitization and allergic disease, the importance of limiting the testing based on patient-specific clinical information, and the limitations of testing regarding both false positives and false negative results. The NIH guideline clearly states that sensitization is not the same as disease, and therefore exposure-related signs and symptoms must be present to diagnose food allergy:13

o “Because individuals can develop allergic sensitization (as evidenced by the presence of allergen-specific IgE (sIgE)) to food allergens without having clinical symptoms on exposure to those foods, an sIgE-mediated [food allergy] requires Allergy Testing

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both the presence of sensitization and the development of specific signs and symptoms on exposure to that food.” The AAAAI/ACAAI practice parameter on testing summarizes the overall diagnostic approach to food allergy, then states the limitations of testing from the perspective of both sensitivity and specificity, and how these limitations lead to restrictions on the usefulness of panels if they are not supported by clinical information:1

o “The primary tools available to evaluate patients’ adverse reactions to foods include history (including diet records), physical examination, prick/puncture skin tests, serum tests for food specific IgE antibodies, trial elimination diets, and oral food challenges.” o “A detailed dietary history, at times augmented with written diet records, is necessary to determine the likelihood that food is causing the disorder, identify the specific food, and determine the potential immunopathophysiology.” o “With regard to evaluations for IgE antibody–associated food allergies, tests for food specific IgE antibody include percutaneous skin tests (prick/puncture tests) and serum assays. In general, these tests are highly sensitive (generally 85%) but only modestly specific (approximately 40% to 80%) and therefore are well suited for use when suspicion of a particular food or foods is high. They are not effective for indiscriminate screening (eg, using panels of tests without consideration of likely causes) and therefore generally should not be used for that purpose.” Similar conclusions are drawn by the AAAAI/ACAAI food allergy practice parameter and the EAACI food allergies guidelines:5,14

o “The clinician should obtain a detailed medical history and physical examination to aid in the diagnosis of food allergy.” 5 o “The clinician should use specific IgE tests (skin prick tests, serum tests, or both) to foods as diagnostic tools; however, testing should be focused on foods suspected of provoking the reaction, and test results alone should not be considered diagnostic of food allergy.” 5 o “Detailed clinical history is essential for the diagnosis of food allergy.” 14 o “Where available, standardized tests and procedures should be used ...specific allergy testing should be directed by case history.” 14 o “Either SPT or sIgE can be the test of choice for sensitization depending on local availability and absolute and relative contraindications to SPT.” 14 The recommended or maximum size of an initial food allergy workup is not stated numerically in any of the food allergy or general allergy testing guidelines mentioned above. The AAAAI/ACAAI practice parameter suggests limiting the workup to the small number of allergens that cause the majority of food allergy:5 Allergy Testing

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o “Although more than 170 foods have been identified as triggers of food allergy, those causing most of the significant allergic reactions include peanut, tree nuts, fish, shellfish, milk, egg, wheat, soy, and seeds.” o “Evaluate the patient for possible food allergy with the understanding that a relatively small number of allergens cause a high proportion of food allergy (eg, cow’s milk, hen’s egg, soy, wheat, peanut, tree nuts, fish, and shellfish).” Overall, food allergy prevalence is approximately 5-10% in the United States, with allergy more common in children than adults and 95% of food allergies caused by one or more of 9 common foods listed above.5,13,16,32 The short list of common food allergens has led the Canadian government to create a modified list of 11 “priority allergens” which have food labeling requirements.33 The 11 allergens consist of the nine allergens from the AAAAI/ACAAI practice parameter (peanut, tree nuts, fish, shellfish, milk, egg, wheat, soy, and seeds); sulfites; and seeds are divided into two types, sesame and mustard.5 The rationale for not extending beyond this list, except in special cases guided by the clinical history, is the high frequency of over-diagnosis of food allergy because of sensitization in the absence of clinical correlation.5,16 This leads to a high number of false positive results. The over-diagnosis problem is best understood by using a predictive value calculator which incorporates prior probability of disease and test sensitivity and specificity to calculate the likelihood of a test being a true positive.34 The prior probability, which is also known as pretest probability of disease, is based on patient specific information from the history and physical as well as epidemiologic information about the likelihood of disease. Thus, a patient with significant allergic signs and symptoms after exposure to a particular food would have a high pretest probability of allergy to that food, and a patient with no signs or symptoms of allergy after exposure would have a near-zero pretest probability. Positive predictive value (PPV) is the likelihood that a positive test is a true positive, thereby indicating the presence of disease. PPV is highly dependent on the pretest probability and the specificity of the test, and dependent to a much lesser extent on test sensitivity. The below shows examples of PPV for a positive allergen-specific IgE test, starting from a range of pretest probabilities, assuming an average specificity of 60% and sensitivity of 85%, figures in line with those for many sIgE assays.1,15,16

o Pretest probability 1% - PPV 2% o Pretest probability 2% - PPV 4% o Pretest probability 5% - PPV 10% o Pretest probability 10% - PPV 19%

Beyond the 11 most common food allergens, the pretest probability of a food allergy in the absence of a strong clinical history is miniscule; most allergens have a pretest Allergy Testing

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probability of disease of far less than 5%. Even for a relatively high pretest probability of 5%, the likelihood that a positive sIgE test indicates true allergy is only 10%, while the chance that it represents a false positive is 90%. This is why large panel testing, in the absence of suggestive clinical history, leads to overdiagnosis. A recent review of food allergy testing highlights the problem of high false positive rates caused by large allergen panels and failure to consider prior probability in interpreting test results:16 o “The greatest source of misdiagnosis in food allergy might well be the lack of appreciation that a positive test result (sensitization) does not equate with allergy and that indiscriminate ‘‘panel testing’’ can result in a disaster of misdiagnosis. In a national sampling of pediatricians and family practice physicians, fewer than 30% of the participants felt comfortable interpreting laboratory tests to diagnose food allergy.” The joint AAAAI/ACAAI practice parameter on allergy testing also advocates for considering prior probability before testing and in test interpretation :1

o “The rational selection, application, and interpretation of tests for food specific IgE antibodies require consideration of the epidemiology and underlying immunopathophysiology of the disorder under investigation, estimation of prior probability that a disorder or reaction is attributable to particular foods, and an understanding of the test utility and limitations.”

Inhalation allergy For inhalational allergy, the AAAI and ACAAI have developed joint practice parameters that cover allergic rhinitis, allergic rhinosinusitis, and inhalational allergy testing.1,2,4 The practice parameters point out the same general principles discussed for the other forms of allergy apply to inhalational allergy. The main principle is that allergic sensitization is not the same as allergic disease and leads to false positive results and over diagnosis in patients who are sensitized but who are not clinically hypersensitive when challenged with the allergen. Thus, testing needs to be guided and limited by the clinical history and physical, as well as the geographic, environmental and seasonal characteristics of the aeroallergen. Overly large panels in the setting of low pretest probability of disease lead to poor positive predictive values and false diagnosis. It is difficult to determine a specific upper limit on the number of inhalational allergens to test. The AAAAI/ACAAI practice parameter on testing summarizes the problem:1

o “If inhalation allergy is narrowly confined to a single season (eg, ragweed in North America or birch in European northern countries), a limited number of relevant skin tests would suffice for confirmation of the clinical diagnosis and testing to irrelevant inhalant and food allergens would be inappropriate. By contrast, perennial symptoms would require a more extended skin test panel of both indigenous outdoor and indoor inhalants but not foods unless a history of food allergy happened to be a concurrent problem of the patient. There is general agreement that significant indoor allergens such as house dust mite, Allergy Testing

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prevailing indoor fungal allergens (Penicillium species, Aspergillus species, Alternaria alternata), cockroach, and epidermals (cat, dog, feathers), should be tested in patients with perennial respiratory symptoms. Pollens may also be found indoors when windows are kept open. The geographic variability of airborne-pollinating plants throughout the floristic zones of the world, particularly in North America, raises a cogent concern about how to select the number of skin tests and treatment reagents for this class of allergens.” o While this statement refers to skin testing, it can be extrapolated to in vitro testing of allergen specific IgE. The American Academy of Otolaryngic Allergy gave a specific recommendation regarding the size of an inhalational screening panel and the size of the confirmatory panel if the screening panel is positive.35 The guideline states:

o “Screen with no more than 14 relevant antigens plus appropriate controls. If screening is positive and immunotherapy is contemplated, use no more than 40 antigens.” 35 Regarding the constituents of the panel, the guideline states:

o “The screening battery must represent relevant classes of antigens, both seasonal and perennial, to which patients are commonly exposed. Pollens from each of the three major seasonal allergens (ie, grasses, weeds, and trees) are used to represent seasonal antigens. Pollens included in the panel should be representative of common antigenic substances in the relevant geographic region. Perennial antigens include mold, dust mite, animal dander, and (in certain circumstances) cockroach.” 35

Drug allergy For drug allergy, the AAAAI/ ACAAI practice parameter includes an algorithm for diagnosis and management.3 The foundation of diagnosis in drug allergy is the history and physical looking for signs and symptoms of allergy that are in temporal relation to the administration of a drug. Laboratory testing is an adjunct to diagnosis and testing is often not available. The parameter states:

o “Diagnosis of many cases of drug allergy is presumptive because specific confirmatory tests are usually not available.” 3 IgE mediated drug allergy is caused by a large number of drugs, most commonly penicillin. For IgE-mediated drug allergy, skin testing – either skin prick or intradermal - is preferred to in vitro testing of blood. The parameter states:

o “The most useful test for detecting IgE-mediated drug reactions caused by penicillin and many large-molecular-weight biologicals is immediate hypersensitivity skin testing.” 3 In addition, the lack of usefulness of in-vitro testing for IgE-mediated drug allergy is noted: Allergy Testing

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o “In situations where skin test results cannot be interpreted properly (ie, generalized eczema, dermatographism, or lack of response to the positive histamine control) some in vitro assays for specific IgE are available. However, they are not as sensitive as skin tests and generally do not have optimal negative predictive value.” 3

This is emphasized specifically for penicillin allergy testing: o “The usefulness of in vitro tests for penicillin specific IgE is limited by their uncertain predictive value. They are not suitable substitutes for penicillin skin testing.” 3

Allergen Specific IgE, Qualitative, Multiallergen Screen (CPT 86005)

The AAAAI/ACAAI practice parameter on testing does not mention the dipstick based multi-allergen methods.1 The use of an unchangeable list of pre-selected allergens is contrary to the approach recommended by the AAAAI/ACAAI practice parameters which focus on using the history and physical to select specific tests.1-7 Furthermore, the multi-allergen methods are more expensive than automated methods coded with CPT 86003. The combination of these factors indicates that allergen-specific IgE using CPT 86005 can be considered obsolete.

Allergen Specific IgE, Recombinant or Purified Component (CPT 86008)

Allergen component diagnostics has been suggested as a method for improving allergen-specific IgE testing in food allergy; this topic has been reviewed by Kattan and Wang.19 The authors state:  “There is clearly room for improvement in testing to differentiate asymptomatic sensitization from true clinical allergy prior to OFC [oral food challenge]. Allergen component-resolved diagnostics (CRD) have garnered a lot of attention in recent years in the diagnosis of food allergy, offering the possibility of a more accurate assessment while requiring less patient serum.” 19 Current AAAAI/ACAAI food allergy practice parameters recommend component testing in two specific situations. For diagnosing red meat allergy, the parameters recommend testing against a specific single component, galactose-alpha-1,3-galactose:  “Test for IgE antibodies specific for the immunogenic oligosaccharide galactose- alpha-1, 3-galactose (alpha-gal) in patients who report a delayed systemic reaction to red meat or unexplained anaphylaxis, particularly if they have a history of previous tick bites.” 5 Practice parameters published in 2014 indicated 5 peanut components (Ara h 1, 2, 3, 8, and 9) that showed promise in offering greater precision in the diagnosis and management of peanut allergy.5 An update in late 2020 recommends testing a single component, Ara h 2:5,36  “If a single diagnostic test were to be used, testing for the Ara h 2 component would

provide the most diagnostic accuracy, as determined by the more optimal Allergy Testing

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positive/negative likelihood ratio among the presently available testing options. However, this is contingent on Ara h 2 component testing becoming more commonly available as a stand-alone test, as opposed to being primarily offered by laboratories as a panel with other peanut components.” 36  “However, while Ara h 2 has the greatest specificity, it has lower sensitivity than [skin prick test] and sIgE [against whole peanut extract], and in a patient with a high prior probability, the clinician may use Ara h 2, SPT, or sIgE to confirm the diagnosis of peanut allergy.”36  Of note, the practice parameters specifically suggest against routinely combining whole peanut and Ara h 2 component testing, or skin prick test and Ara h 2 component testing, arguing that diagnostic accuracy is not increased by performing multiple tests  Regarding other peanut components, the authors observe there is still a paucity of data about the clinical significance of sensitization to other components, particularly Ara h 8, which, in the absence of sensitization to other peanut components, is associated with decreased likelihood of true allergy. They state, “Further research is needed to clarify the value of tandem testing, particularly with regard to Ara h 2, Ara h 6, and Ara h 8.”36 A separate expert review of the literature concluded that there is insufficient evidence for component testing in other food allergies:19  “For the diagnosis of food allergy, CRD offers the potential to identify patients with clinical allergy as opposed to patients who are merely sensitized but tolerant. CRD has been extensively studied for use in the diagnosis of peanut allergy, and there are well-known associations between particular peanut allergen components, risk of clinical allergy, and the possibility of tolerance. For other food allergens, the clinical relevance is not well established…CRD is not yet ready to replace current diagnostic tests, and oral food challenge remains the gold standard in the diagnosis of food allergy.”

Food Allergen Epitope Analysis (0165U, 0178U)

Food allergen epitope analysis such as VeriMAP™ proposes to refine allergy testing further. Most background studies utilize a microarray chip rather than a bead-based assay. In a study of 24 peanut sensitized children, this method found that sera from sensitized children bound a greater diversity of epitopes than controls.21 A subsequent study of 62 patients confirmed this finding.37 A bead-based microarray study of 160 patients (73 with peanut allergy) showed differences in binding to a number of epitopes.22 In small studies, epitope repertoire and sIgE levels appear to change in response to oral immunotherapy, and differences in epitope repertoire may be useful in predicting sustained response to immunotherapy in patients with milk allergy.22,26,38 It is not yet clear whether food allergen epitope analysis is clinically valid, either for diagnosis of peanut allergy, prediction of response to therapy, or monitoring therapy. A few small clinical studies evaluate food allergen epitope analysis in the diagnosis of peanut allergy, one on the VeriMAP platform.21,22,37 No published studies assess the Allergy Testing

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value of food allergy epitope testing in predicting response to therapy in peanut allergy. Only one small clinical study or 22 patients, using microarray, reported changes in food allergen epitope repertoire following oral immunotherapy for peanut allergy.38 There is no data to support clinical utility for food allergen epitope analysis. No published studies compare it to established methods of food allergy testing.

Allergen Specific IgG (CPT 86001)

The allergen specific IgG test is available widely on the clinical market despite lacking the evidence base required to support clinical validity and utility. The current joint AAAAI / ACAAI practice parameters state that allergen-specific IgG testing is not useful in the diagnosis of food allergy. Summary statements regarding this testing:5  “Unproved tests, including allergen specific IgG measurement, cytotoxicity assays, applied kinesiology, provocation neutralization, and hair analysis, should not be used for the evaluation of food allergy.”  “Measurement of food-specific IgG and IgG4 antibodies in serum are not recommended for the diagnosis of non–IgE-mediated food-related allergic disorders.”  “IgG and IgG subclass antibody tests for food allergy do not have clinical relevance, are not validated, lack sufficient quality control, and should not be performed.” The NIH expert panel (EP) guidelines for food allergy (FA) make the same recommendation:13  "The EP recommends not using any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA: o Basophil histamine release/activation... o Allergen-specific IgG4 o Cytotoxicity assays" The Choosing Wisely Campaign and AAAAI state:  “Don't perform unproven diagnostic tests, such as immunoglobulin G (lgG) testing or an indiscriminate battery of immunoglobulin E (lgE) tests, in the evaluation of allergy.” 24 One proposed use of allergen specific IgG testing is in the monitoring of venom immunotherapy (VIT) in the context of stinging insect allergy. Once again, the joint practice parameter indicates this is an unproven use:  “Although a number of investigators have reported modest increases of IgG4 during venom immunotherapy, confirmation and validation of the predictive value of IgG4 for therapeutic efficacy of venom immunotherapy are not yet proven.” 1 Allergy Testing

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 “Measurements of venom-specific IgG antibodies have no predictive value when discontinuing VIT.” 7

Antigen Leukocyte Antibody Test (ALCAT®; CPT 83516)

The antigen leukocyte antibody test (ALCAT®), is a proprietary test from Cell Science Systems Inc that tests for food sensitivity but not food allergy according to the company. The test is based on cellular toxicity related to white blood cell activity. This is often known as a “cytotoxic test”. In describing the ALCAT, the company’s website states:  “The laboratory analysis includes the immune biological reactions of the white blood cells. The Alcat Test® does not measure food allergies (type 1/IgE). Since these reactions can be serious, you should seek the help of an allergy specialist if you suspect or have food allergies.” 25 The joint AAAAI/ACAAI practice parameter on allergy testing states that cytotoxic testing is not diagnostically valid:  “Procedures for which there is no evidence of diagnostic validity include cytotoxic tests, provocation-neutralization, electrodermal testing, applied kinesiology, iridology, hair analysis, or food specific IgG, IgG4, and IgG/IgG4 antibody tests.” 1 Similarly, the joint AAAAI/ACAAI food allergy practice parameter recommends against cytotoxicity assays:  “Unproved tests, including allergen specific IgG measurement, cytotoxicity assays, applied kinesiology, provocation neutralization, and hair analysis, should not be used for the evaluation of food allergy.” 5 The NIH expert panel (EP) guidelines for food allergy (FA) make the same recommendation:13  "The EP recommends not using any of the following nonstandardized tests for the routine evaluation of IgE-mediated FA: o Basophil histamine release/activation o Lymphocyte stimulation o Facial thermography o Gastric juice analysis o Endoscopic allergen provocation o Hair analysis o Applied kinesiology o Provocation neutralization Allergy Testing

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o Allergen-specific IgG4 o Cytotoxicity assays"

Similarly, the Australasian Society of Clinical Immunology and Allergy (ASCIA) lists the ALCAT as an unorthodox, inaccurate, unproven allergy test along with a similar cytotoxic test called “Bryan’s Test”.23 The ASCIA position statement says:  “Cytotoxic testing (“Bryan’s test”) and the Alcat test (Evidence Level II: inaccurate test). In cytotoxic food testing (“Bryan’s test”), the size and shape of white cells is assessed after incubation with food extracts on a microscope slide. These results have been shown to not be reproducible, give different results when duplicate samples are analysed blindly, don’t correlate with those from conventional testing, and “diagnose” food hypersensitivity in subjects with conditions where food allergy is not considered to play a pathogenic role. The Alcat test is a variant on a theme; the results are analysed on a Coulter counter instead of under the microscope.” 23

Criteria

Introduction

This guideline addresses in-vitro testing of blood for allergic disease. It does not address either skin testing or oral tolerance testing for allergic disease.

Total IgE, Gammaglobulin (immunoglobulin) Testing

Total IgE, Gammaglobulin (immunoglobulin) testing (CPT 82785)

Medical necessity requirements Total IgE is indicated in the following circumstances:

o History and/or physical exam suggestive of allergic disease including any of the following signs or symptoms : . Cutaneous findings such as angioedema or urticaria, or . Respiratory findings such as rhinitis, conjunctivitis, or bronchospasm, or . Cardiovascular findings such as tachycardia or hypotension , or . Gastrointestinal findings such as vomiting or diarrhea , or . Signs or symptoms of anaphylaxis

Billing and reimbursement When testing is medically necessary, the following limitations apply:

o No more than 1 unit of CPT 82785 may be billed for the same date of service. Allergy Testing

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Allergen Specific IgE, Quantitative or Semiquantitiative

Allergen specific IgE (CPT 86003)

Medical necessity requirements Allergen specific IgE is indicated in the following circumstances:

o History and/or physical exam suggestive of allergic disease including any of the following signs or symptoms: . Cutaneous findings such as angioedema or urticaria, or . Respiratory findings such as rhinitis, conjunctivitis, or bronchospasm, or . Cardiovascular findings such as tachycardia or hypotension, or . Gastrointestinal findings such as vomiting or diarrhea, or . Signs or symptoms of anaphylaxis

o Testing for allergic contact dermatitis or drug allergy is not indicated. o Population-based screening for allergic disease is not considered medically necessary.

Billing and reimbursement Because allergy testing is not indicated without signs or symptoms of allergic disease, claims should be submitted with an ICD code adequately describing coverable signs and symptoms to be paid. Claims for CPT 86003 will not be payable when billed without any coverable ICD code defined in this policy. Exceptions may be made for uncommon presentations on a case-by-case basis. When allergen specific IgE testing is medically necessary, the following limitations apply to the number of allowable billed units (allergens tested). In the uncommon event that additional units are necessary, exceptions will be considered on a case- by-case basis.

o When CPT 86003 is billed with an ICD code from table ICD Codes Indicating Stinging Insect Venom Allergy Testing, up to 6 units will be coverable for the same date of service. o When CPT 86003 is billed with an ICD code from table ICD Codes Indicating Food Allergy Testing, up to 11 units for the same date of service. o When CPT 86003 is billed with an ICD code from table ICD Codes Indicating Inhalational Allergy Testing or ICD Codes Indicating Latex Allergy Testing, up to 14 units are coverable for the same date of service. Exceptions may be considered in some situations when follow-up testing for a positive screening test that requires a larger panel of allergens is being performed. Allergy Testing

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Because allergen specific IgE testing is not indicated for allergic contact dermatitis or drug allergy, the following limitations apply:

o When CPT 86003 is billed with an ICD code from table ICD Codes Indicating Drug Allergy Testing, no units will be payable given this is not a coverable indication. Exceptions may be considered in the rare event that skin testing cannot be performed for drug allergy testing. o When CPT 86003 is billed with an ICD code from table ICD Codes Indicating Acute Contact Dermatitis Testing, no units will be payable given this is not a coverable indication. Exceptions may be considered in the rare event that skin testing cannot be performed for allergic contact dermatitis testing. Claims submitted without an ICD code indicating specific allergy symptoms as defined in the ICD Codes section of this policy will not be considered medically necessary and will not be eligible for reimbursement. Given that no common indications support coverage of more than 14 units of CPT 86003, exceptions for uncommon indications that require more than 14 units of allergen specific IgE testing will be considered on a case-by-case basis.

Allergen Specific IgE, Qualitative, Multiallergen Screen

Allergen specific IgE (CPT 86005)

Medical necessity requirements The multi-allergen dipstick and related testing coded with CPT 86005 is considered obsolete and is not eligible for reimbursement for any clinical indications.

Allergen Specific IgE , Quantitative or Semiquantitative, Recombinant or Purified Component

Allergen specific IgE, component testing (CPT 86008)

Medical necessity requirements Component testing is indicated in the diagnosis of patients suspected of having peanut allergy. Component testing is indicated in the diagnosis of patients suspected of having red meat allergy. Component testing is not indicated in the evaluation of any other allergens.

Billing and reimbursement When allergen specific IgE component testing is medically necessary, the following limitations apply: Allergy Testing

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o When CPT 86008 is billed with an ICD code from table ICD Codes Indicating Nut Allergy Testing, up to 5 units are coverable for the same date of service. o When CPT 86008 is billed with an ICD code from table ICD Codes Indicating Red Meat Allergy Testing, one unit is coverable for the same date of service. Claims for CPT 86008 billed without a coverable ICD code, in accordance with these guidelines, will not be reimbursable. Exceptions may be made for uncommon presentations on a case-by-case basis.

Food Allergen Epitope Analysis

Food allergen epitope analysis (0165U, 0178U)

Medical necessity requirements Food allergen epitope analysis is considered investigational and experimental and is not eligible for reimbursement for any clinical indications.

Allergen Specific IgG

Allergen specific IgG (CPT 86001)

Medical necessity requirement Medical necessity of allergen specific IgG has not been demonstrated, and is therefore determined to be investigational and experimental. This procedure code is not eligible for reimbursement for any clinical indications.

Immunoassays for Allergy Testing, Including Antigen Leukocyte Antibody Test

Immunoassays for allergy testing, including Antigen Leukocyte Antibody Test (ALCAT®; CPT 83516)

Medical necessity requirements Allergy testing is coded with specific CPT codes and therefore, nonspecific Immunoassay codes – which are used to describe a huge variety of tests across a broad range of medical settings – have no role in allergy testing. The medical necessity of ALCAT has not been demonstrated.

o Immunoassays used for in vitro allergy testing in general, and ALCAT specifically, are determined to be investigational and experimental. Such testing is not eligible for reimbursement for any clinical indications.

Billing and reimbursement Because immunoassays are billed with a procedure code that is not specific to allergy or ALCAT testing, the following claim information will be used to identify presumed allergy or ALCAT testing: Allergy Testing

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o Claims from providers known to perform immunoassays for allergy testing, which include, but are not limited to, Cell Sciences, Inc o Claims for CPT code 83516 will be subject to post-service review when billed with:

. any allergy-related ICD code from any table in the ICD10 Codes section of this policy, or . any allergy-related procedure code as defined in this policy, or . an unusually large number of units of CPT 83516

Diagnosis Codes

Diagnosis codes in this section may be used to support or refute medical necessity as described in the above guidelines.

Table: ICD Codes Indicating Stinging Insect Venom Allergy Testing

Codes and descriptions

Code or Range Description Z91.03X Insect allergy status

Table: ICD Codes Indicating Food Allergy Testing

Codes and descriptions

Code or Range Description J30.5 Allergic rhinitis due to food K52.2X Allergic and dietetic gastroenteritis and colitis K90.41 Non-celiac gluten sensitivity L23.6 Allergic contact dermatitis due to food in contact with skin L24.6 Irritant contact dermatitis due to food in contact with skin L25.4 Unspecified contact dermatitis due to food in contact with skin L27.2 Dermatitis due to ingested food T78.0X Anaphylactic reaction due to food T78.1X Other adverse food reactions, not elsewhere classified Allergy Testing

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Code or Range Description Z91.01X Food allergy status Z91.02 Food additives allergy status

Table: ICD Codes Indicating Inhalational Allergy Testing

Codes and descriptions

Code or Range Description J30.0 Vasomotor rhinitis J30.1 Allergic rhinitis due to pollen J30.2 Other seasonal allergic rhinitis J30.8X Other allergic rhinitis J30.9 Allergic rhinitis, unspecified J31.X Chronic rhinitis, nasopharyngitis and pharyngitis J32.X Chronic sinusitis J39.3 Upper respiratory tract hypersensitivity reaction, site unspecified J45.X Asthma J60-J70.X Lung diseases due to external agents J82 Pulmonary eosinophilia, not elsewhere classified

Table: ICD Codes Indicating Latex Allergy Testing

Codes and descriptions

Code or Range Description Z91.040 Latex allergy status

Table: ICD Codes Indicating Drug Allergy Testing

Codes and descriptions

Code or Range Description L23.3 Allergic contact dermatitis due to drugs in contact with skin Allergy Testing

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Code or Range Description L24.4 Irritant contact dermatitis due to drugs in contact with skin L25.1 Unspecified contact dermatitis due to drugs in contact with skin L27.0 Generalized skin eruption due to drugs and meds taken internally L27.1 Local skin eruption due to drugs and meds taken internally T88.6X Anaphylactic reaction due to adverse effect of correct drug or medicament properly administered T88.7X Unspecified adverse effect of drug or medicament Z88.X Allergy status to drugs, medicaments and biological substances

Table: ICD Codes Indicating Acute Contact Dermatitis Testing

Codes and descriptions

Code or Range Description H01.11X Allergic dermatitis of eyelid L20.X Atopic dermatitis L23.0 Allergic contact dermatitis due to metals L23.1 Allergic contact dermatitis due to adhesives L23.2 Allergic contact dermatitis due to cosmetics L23.4 Allergic contact dermatitis due to dyes L23.5 Allergic contact dermatitis due to other chemical products L23.7 Allergic contact dermatitis due to plants, except food L23.8X Allergic contact dermatitis due to other agents L23.9 Allergic contact dermatitis, unspecified cause Allergy Testing

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Code or Range Description L24.0 Irritant contact dermatitis due to detergents L24.1 Irritant contact dermatitis due to oils and greases L24.2 Irritant contact dermatitis due to solvents L24.3 Irritant contact dermatitis due to cosmetics L24.5 Irritant contact dermatitis due to other chemical products L24.7 Irritant contact dermatitis due to plants, except food L24.8X Irritant contact dermatitis due to other agents L24.9 Irritant contact dermatitis, unspecified cause L25.0 Unspecified contact dermatitis due to cosmetics L25.2 Unspecified contact dermatitis due to dyes L25.3 Unspecified contact dermatitis due to other chemical products L25.5 Unspecified contact dermatitis due to plants, except food L25.8 Unspecified contact dermatitis due to other agents L25.9 Unspecified contact dermatitis, unspecified cause L30.X Other and unspecified dermatitis

Table: ICD Codes Indicating Other Allergy Presentations

Codes and descriptions

Code or Range Description D69.0 Allergic purpura D72.1 Eosinophilia E73.9 Lactose intolerance, unspecified J01.X Acute sinusitis Allergy Testing

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Code or Range Description J21.9 Acute bronchiolitis, unspecified J34.3 Hypertrophy of nasal turbinates J34.89 Other specified disorders of nose and nasal sinuses J98.01 Acute bronchospasm K30 Functional dyspepsia K52.81 Eosinophilic gastritis or gastroenteritis K52.89 Other specified noninfective gastroenteritis and colitis K52.9 Noninfective gastroenteritis and colitis, unspecified K58.X Irritable bowel syndrome K59.X Other functional intestinal disorders K90.0 Celiac disease K90.49 Malabsorption due to intolerance, not elsewhere classified K90.89 Other intestinal malabsorption K90.9 Intestinal malabsorption, unspecified L27.8 Dermatitis due to other substances taken internally L27.9 Dermatitis due to unspecified substance taken internally L28.2 Other prurigo L29.8 Other pruritus L29.9 Pruritus, unspecified L50.X Urticaria R05 Cough R06.X Abnormalities of breathing R07.1 Chest pain on breathing R07.2 Precordial pain R07.8X Other chest pain R09.81 Nasal congestion R09.82 Postnasal drip Allergy Testing

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Code or Range Description R10.817 Generalized abdominal tenderness R10.819 Abdominal tenderness, unspecified site R10.83 Colic R10.84 Generalized abdominal pain R10.9 Unspecified abdominal pain R11.0 Nausea R11.10 Vomiting, unspecified R11.11 Vomiting without nausea R11.2 Nausea with vomiting, unspecified R14.X Flatulence and related conditions R19.4 Change in bowel habit R19.5 Other fecal abnormalities R19.7 Diarrhea, unspecified R19.8 Other specified symptoms and signs involving the digestive system and abdomen R21 Rash and other nonspecific skin eruption R23.2 Flushing R23.3 Spontaneous ecchymoses R23.4 Changes in skin texture R23.8 Other skin changes R23.9 Unspecified skin changes R51 Headache R62.50 Unspecified lack of expected normal physiological development in childhood R62.51 Failure to thrive (child) R63.4 Abnormal weight loss T78.2X Anaphylactic shock, unspecified T78.3X Angioneurotic edema T78.4X Other and unspecified allergy T78.8X Other adverse effects, not elsewhere classified Allergy Testing

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Code or Range Description Z13.21 Encounter for screening for nutritional disorder Z87.892 Personal history of anaphylaxis Z91.041 Radiographic dye allergy status Z91.048 Other nonmedicinal substance allergy status Z91.09 Other allergy status, other than to drugs and biological substances

Table: ICD Codes Indicating Nut Allergy Testing

Codes and descriptions

Code or Range Description T78.01X Anaphylactic reaction due to peanuts T78.05X Anaphylactic reaction due to tree nuts and seeds T78.2X Anaphylactic shock, unspecified Z91.010 Allergy to peanuts

Table: ICD Codes Indicating Red Meat Allergy Testing

Codes and descriptions

Code or Range Description J30.5 Allergic rhinitis due to food L27.2 Dermatitis due to ingested food T78.00X Anaphylactic reaction due to unspecified food T78.09X Anaphylactic reaction due to other food products T78.1X Other adverse food reactions, not elsewhere classified Z91.018 Allergy to other foods Allergy Testing

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References

Introduction

These references are cited in this guideline.

1. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100(3 Suppl 3):S1-148. 2. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008;122(2 Suppl):S1-S84. 3. Solensky R, Khan DA, Bernstein IL, et al. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273. 4. Anju T. Peters, MD; Sheldon Spector, MD; et al. Diagnosis and management of rhinosinusitis: a practice parameter update. Ann Allergy Asthma Immunol. 2014;113:347-385. 5. Sampson HA, Aceves S, Bock A, et al. Food allergy: a practice parameter update- 2014. J Allergy Clin Immunol. 2014:134:1016-25. 6. Fonacier L, Bernstein DI, Pacheco K, et al. Contact Dermatitis: A Practice Parameter Update 2015. J Allergy Clin Immunol Pract. 2015;3:S1-S39. 7. Golden D, Demain J, Freeman T, et al. Stinging insect hypersensitivity: a practice parameter update 2016. Ann Allergy Asthma Immunol. 2017;118(1):28-54. 8. Siles RI, Hsieh FH. Allergy blood testing: a practical guide for clinicians. Cleve Clin J Med. 2011;78:585-592. 9. Cabanes N, Igea JM, de la Hoz B, et al. Latex allergy: position paper. J Investig Allergol Clin Immunol. 2012;22(5):313-30. 10. Waserman S, Bégin P, Watson W. IgE-mediated food allergy. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):55. 11. Kondo Y, Urisu A. Oral allergy syndrome. Allergol Int. 2009;58(4):485-491. 12. Ryan MW, Marple BF, Leatherman B, et al. Current practice trends in allergy: results of a United States survey of otolaryngologists, allergist-immunologists, and primary care physicians. Int Forum Allergy Rhinol. 2014;4:789–795. 13. Boyce JA, Assa'ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-S58. 14. Muraro A, Werfel T, Hoffmann-Sommergruber K, et al. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014;69:1008-25. 15. Soares-Weiser K, Takwoingi Y, Panesar SS, et al. EAACI Food Allergy and Anaphylaxis Guidelines Group. The diagnosis of food allergy: a systematic review and meta-analysis. Allergy. 2014;69(1):76-86. Allergy Testing

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16. Sicherer SH, Sampson HA. Food allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention, and management. J Allergy Clin Immunol. 2018;141:41-58. 17. Imam AA, Novey HS, Orgel HA, et al. A simplified screening test for the diagnosis of allergy. West J Med. 1990;152:313-316. 18. Straumann F, Straumann F, Wüthrich B. Food allergies associated with birch pollen: comparison of Allergodip and Pharmacia CAP for detection of specific IgE antibodies to birch pollen related foods. J Investig Allergol Clin Immunol. 2000;10(3):135-41. 19. Kattan JD, Wang J. Allergen component testing for food allergy: ready for prime time? Curr Allergy Asthma Rep. 2013;13:58-63. 20. Aquino AC. Component IgE testing offers food for thought. CAP Today. 2018 (November). https://www.captodayonline.com/component-ige-testing-offers-food- for-thought/ 21. Flinterman AE, Knol EF, Lencer DA, et al. Peanut epitopes for IgE and IgG4 in peanut-sensitized children in relation to severity of peanut allergy. J Allergy Clin Immunol. 2008;121(3):737-743. doi: 10.1016/j.jaci.2007.11.039. 22. Suprun M, Getts R, Raghunathan R, et al. Novel bead-based epitope assay is a sensitive and reliable tool for profiling epitope-specific antibody repertoire in food allergy. Sci Rep. 2019;9(1):18425. doi: 10.1038/s41598-019-54868-7. 23. Australasian Society of Clinical Immunology and Allergy. ASCIA Position Statement: Unorthodox techniques for the diagnosis and treatment of allergy, asthma and immune disorders. Updated 2010. Available at: www.allergy.org.au/health-professionals/papers/unorthodox-techniques-for- diagnosis-and-treatment#s4 www.allergy.org.au/health-professionals/papers/unorthodox-techniques-for- diagnosis-and-treatment#s4 24. American Academy of Allergy, Asthma and Immunology. Ten Things Physicians and Patients Should Question. Choosing Wisely website. http://www.choosingwisely.org/societies/american-academy-of-allergy-asthma- immunology/ Released April 4, 2012 and March 3, 2014. Reviewed 2018. 25. Patients: ALCAT Test. Cell Science Systems website. https://cellsciencesystems.com/patients/alcat-test/. 26. Kelso JM. Unproven diagnostic tests for adverse reactions to foods. J Allergy Clin Immunol Pract 2018;6:362-5. 27. AAAAI/ACAAI Joint Task Force on Practice Parameters. Published practice parameters. https://www.allergyparameters.org/published-practice-parameters/alphabetical- listing/testing-download. 28. Gabriel MF, Tavares-Ratado P, Peixinho CM, et al. Evaluation and comparison of commercially available latex extracts for skin prick tests. J Investig Allergol

Immunol. 2013;23(7):478-486. Allergy Testing

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29. Tomazic VJ, Withrow TJ, Hamilton RG. Characterization of the allergen(s) in latex protein extracts. J Allergy Clin Immonol. 1995:96(5):635-642. 30. Kim KT, Safadi GS, Sheikh KM. Diagnostic evaluation of type I latex allergy. Ann Allergy Asthma Immunol. 1998:80(1):66-70. 31. Biaginia RE, Krieg EF, Pinkerton LE, Hamilton RG. Receiver operating characteristics analyses of Food and Drug Administration-Cleared serological assays for natural rubber latex-specific immunoglobulin E antibody. Clin Diagn Lab Immonol. 2001;8(6):1145-1149. 32. Gupta RS, Springston BA, Warrier MR et al. The prevalence, severity and distribution of childhood allergy in the United States. Pediatrics. 2011;128:e9-17. 33. Food Allergy Canada. Priority food allergens. Available at: https://foodallergycanada.ca/about-allergies/food-allergens/. 34. Lowery R. Clinical calculator 2: Predictive values and likelihood ratios. VassarStats: Website for Statistical Computation website. http://vassarstats.net/clin2.html. 35. Krouse JH, Mabry RL. Skin testing for inhalant allergy 2003: current strategies. Otolaryngol Head Neck Surg. 2003;129(4 Suppl):S33-49. 36. Greenhawt M, Shaker M, Wang J, et al. Peanut allergy diagnosis: a 2020 practice parameter update, systematic review, and GRADE analysis. J Allergy Clin Immunol 2020;146:1302-34. 37. Lin J, Bruni FM, Fu Z, et al. A bioinformatics approach to identify patients with symptomatic peanut allergy using peptide microarray immunoassay. J Allergy Clin Immunol. 2012;129(5):1321-1328. doi: 10.1016/j.jaci.2012.02.012. 38. Vickery BP, Lin J, Kulis M et al. Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens. J Allergy Clin Immunol. 2013;131:128-134 doi: 10.1016/j.jaci.2012.10.048. Allergy Testing