Laboratory Section - Allergy Testing

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

The American Academy of Allergy, Asthma, and Immunology (AAAAI) developed the following definitions: (2)

• Allergy refers to an acquired potential for developing adverse reactions that are immunologically mediated (via IgE antibodies), and allergic disease represent the clinical manifestations of these adverse immune responses.
• Atopy refers to an individual being prone to develop allergies because of a genetic state of hyperresponsiveness to allergens associated with the diseases of atopic diathesis.
• Allergens are often common, usually harmless, substances such as pollens, mold spores, animal danders, dust, foods, insect venoms, cockroaches, latex, and drugs. Allergens can induce IgE antibody responses.

Allergic or hypersensitivity disorders may be manifested by generalized systemic reactions as well as by localized reactions in any organ system of the body. The reactions may be acute, subacute, or chronic, immediate or delayed, and may be caused by numerous offending agents.

The optimum management of the allergic patient should include a careful history and physical examination and may include confirming the cause of the allergic reaction by information from some of the testing methods outlined below. Allergy testing can be broadly subdivided into in vivo and in vitro methodologies. In vivo methodologies include skin allergy testing (i.e., skin prick testing, skin scratch testing, intradermal testing, skin patch testing, and intradermal dilutional testing (also known as skin endpoint titration), bronchial provocation tests, and food challenges. In vitro tests include various techniques to test the blood for the presence of specific IgE antibodies to a particular antigen (i.e., RAST and ELISA tests), and leukocyte histamine release test (LHRT). LHRT may also be referred to as basophil histamine release test.

Once the allergy-causing agent is identified, treatment is provided by avoidance, medication or immunotherapy. The AAAAI recommends IgE skin testing or specific IgE in vitro assays when a patient with persistent symptoms is exposed to an indoor allergen; disease impacts quality of life; and immunotherapy is being contemplated (for indoor or outdoor allergens). The AAAAI recommends skin testing over specific IgE in vitro assays because skin testing generates results that are immediately available, more sensitive, and less costly in most cases. In vitro assays can be done if skin testing is not possible or contraindicated.

Percutaneous and Intracutaneous (Intradermal) Testing

The number of tests required may vary widely from patient to patient depending on the patient's history.

Intradermal Dilutional Testing (IDT) (also known as Skin Endpoint Titration [SET])

Intradermal dilutional testing is intradermal testing of sequential and incremental dilutions of a single antigen. The endpoint is determined by intradermal testing with the use of approximately 0.1-ml of generally serial five-fold dilution extract. It is the weakest dilution that produces a positive skin reaction and initiates progressive increase in the diameter of the wheals with each stronger dilution. In a guideline, revised in 2003, the American Academy of Otolaryngic Allergy (AAOA) recommends screening prick tests with relevant antigens to determine which to use in subsequent intradermal dilutional testing. (3) If screening is positive and immunotherapy is contemplated, the AAOA recommends no more than 40 antigen be tested unless indicated by unusual clinical circumstances.

Leukocyte Histamine Release Test

LHRH is a technique to evaluate the in vitro release of histamine from leukocytes (i.e., basophils) in response to exposure to an allergen, and thus is designed to provide an in vitro correlate to an in vivo allergic response (i.e., skin prick testing). In contrast, the RAST test (radioallergosorbent test) attempts to correlate the presence of allergy to serum levels of antigen-specific IgE as an index of allergic reactivity. Initially, measurements of histamine release required isolation of leukocytes from whole blood followed by the isolation of the released histamine; the laboratory techniques were difficult and time consuming and thus LHRT was primarily used as a research tool only. Recently, a special type of glass fiber has been developed that binds histamine with high affinity and selectivity. These glass fibers can be used as a "solid phase" to absorb the histamine that is released directly into the blood. The recent commercial availability of simplified and automated methods of laboratory analysis (i.e., both ELISA and radioimmunoassays) have renewed interest in the clinical applications of LHRT in the evaluation of food, inhalant, and drug allergies.

Patch Test

This testing modality identifies allergens causing contact dermatitis. The suspected allergens are applied to the patient's back under dressings and allowed to remain in contact with the skin for 48 hours. The area is then examined for evidence of delayed hypersensitivity reactions.

Photo Patch Test

This test reflects contact photosensitization. The suspected sensitizer is applied to a patch of skin for 48 hours. If no reaction occurs, the area is exposed to a dose of ultraviolet light sufficient to produce inflammatory redness of the skin. If the test is positive, a more severe reaction develops at the patch site than on surrounding skin.

Specific IgE in Vitro Test (RAST, MAST, FAST, and ELISA)

These tests detect antigen-specific IgE antibodies in the patient's serum. They are useful when testing for inhalant allergens (pollens, molds, dust, mites, animal danders), foods, insect stings, and other allergens such as drugs, when direct skin testing is impossible due to extensive dermatitis, marked dermatographism, or in children younger than four years of age.

Total Serum IgE Concentration

This testing modality is not indicated in most allergic patients, but may be indicated for those patients suspected of having allergic bronchopulmonary aspergillosis, immune deficiency disease characterized by increased IgE levels (e.g., Wiskott-Aldrich syndrome, hyper-IgE staphylococcal abscess syndrome), IgE myeloma, or pemphigoid.  In addition, a total IgE level is indicated in the evaluation of asthmatic patients being considered for therapy with monoclonal antibody to IgE.

Bronchial Challenge Test

Histamine or methacholine is used to perform this test when it is necessary to determine if the patient has hyper-responsive airways. Volatile chemicals are used to perform this test when the allergy is encountered in an occupational setting. If dust, ragweed, or other common allergens are the suspected cause of the problem, this test is not medically necessary, since skin tests can be used in these situations.

Double-blind Food Challenge Test

With this test, the patient ingests the food to which sensitivity is suspected. Both the patient and the physician are "blinded." This is usually done at home, but in some instances of suspected extreme hypersensitivity, it may be performed in the office setting. In the latter case, this is considered to be part of the office visit and not a separate benefit.

IgG allergen levels

There are four subclasses of immunoglobulin G. Selective deficiencies in one or more of the four IgG subclasses are seen in some patients with repeated infections. Measurements of  IgG and specifically IgG4 antibodies have been used in research settings to determine response to allergy treatments.

Policy/Criteria

The following allergy tests may be considered medically necessary in the diagnosis of the allergic patient:

1. Direct skin test
   1. Percutaneous (scratch, prick, or puncture) - The number of tests required may vary widely from patient to patient, depending upon the patient's history. More than 65 prick/puncture tests are required only for extraordinary clinical circumstances.
   2. Intracutaneous (intradermal) - The number of tests required may vary widely from patient to patient, depending upon the patient's history. More than 40 intracutaneous tests are required only for extraordinary clinical circumstances.
   3. Intradermal dilutional testing - The number of tests required may vary from patient to patient depending upon the patient's history and screening prick test or in-vitro tests. More than 40 antigens or 80 IDT injections are required only in extraordinary clinical circumstances.
2. Patch test (Application test)
3. Photo patch test
4. Specific IgE in vitro tests, with one of the following tests, may be considered medically necessary when skin testing for allergens in symptomatic individuals is impossible or inappropriate due to extensive dermatitis, marked dermatographism, ichthyosis, generalized eczema, in patients on medications that render skin tests ineffective, or in children less than four years of age. In addition, when skin testing is equivocal or negative and it is important to have a confirmatory test, in-vitro testing may be considered medically necessary.
   1. Radioallergosorbent test (RAST)
   2. Multiple radioallergosorbent tests (MAST)
   3. Fluorescent allergosorbent test (FAST)
   4. Enzyme-linked immunosorbent assay (ELISA)
5. Total serum IgE concentration
6. Bronchial challenge test
7. Double-blind food challenge test

The following allergy tests are considered investigational:

1. Provocative tests for food or food additive allergies
2. Nasal challenge test
3. Conjunctival challenge test (ophthalmic mucous membrane test)
4. Cytotoxic food tests
5. Leukocyte histamine release test (LHRT)
6. Rebuck skin window test
7. Passive transfer or P-X (Prausnitz-Küstner) test (now considered obsolete and replaced by Radioallergosorbent tests)
8. IgG allergen specific antibody levels
9. Dermatome allergy testing (electro-acupuncture)
10. Hair analysis

Scientific Background

Intradermal Dilutional Testing (IDT)

The policy criteria for intradermal dilutional testing (IDT) (formerly known as skin endpoint titration) are updated in March 2003 taking into consideration guidelines from the American Academy of Otolaryngic Allergy (AAOA) published in 2003 (3). Prior policy criteria were based on a 2002 BlueCross and BlueShield Association Technology Assessment (BCBSA TEC) which noted that "…the available literature on SET has many limitations. Many of the studies are from the late 1970s and early 1980s, and are of poor methodologic quality when judged by current quality assessment techniques." (4)

American Academy of Otolaryngic Allergy Guidelines (AAOA)

The current policy for IDT represents the current standard of care in the otolaryngic allergy community. The AAOA offers the following recommendations:

1. "The goal [of allergy testing] is to identify antigens to which patients are symptomatically reactive and to quantify the sensitivity if immunotherapy is contemplated.
2. There are a variety of acceptable techniques. For inhalants, the following are acceptable techniques: prick testing, intradermal testing, IDT, in-vitro testing
3. Allergy care shall be directed by a trained and competent physician who regularly participates in the care.
4. Members shall practice in ethical and fiscally responsible ways.
   1. Screening: Screen with no more than 14 relevant antigens plus appropriate controls.
   2. Antigen survey: If screening is positive and immunotherapy is contemplated, use no more than 40 antigens. More extensive testing may be justified in special circumstances.
   3. Quantification for safe starting point: Use no more than 80 IDT tests routinely. More extensive testing may be justified in special circumstances."

In 1987, the American Medical Association's Council of Scientific Affairs Allergy Panel published a report on in vivo diagnostic testing and immunotherapy for allergy. (5) Skin endpoint titration was addressed in this report, and the following conclusion was offered:

"Skin endpoint titration provides a safe and effective measure of patient sensitivity. Controlled studies have shown that the intradermal method of skin end-point titration is effective in quantifying sensitivity to ragweed extract and for identifying patients highly susceptible to ragweed. The method provides reliability comparable to that of in vitro leukocyte histamine release and radioallergosorbent test. Controlled studies have shown that the prick test methods of skin endpoint titration can be used as a measure of response to immunotherapy of cat extract."

IgG4
There are conflicting and incomplete data concerning the effectiveness of specific and nonspecific IgG4 levels as diagnostic and prognostic tests for allergy. (6)

Leukocyte Histamine Release Test (LHRT)

The published literature regarding LHRT is reviewed using the quality indicators for studies of diagnostic test trials:

1. Prospective enrollment
2. Representative patient population enrolled
   • Appropriate spectrum of patients
   • Unbiased enrollment (no referral bias)
   • Few patients not enrolled that are eligible
   • Appropriate accounting for all eligible patients
3. All eligible patients receive both tests
4. LHRT interpreted independently of alternative test (i.e., skin prick, RAST, or bronchial provocation test)
5. Alternative tests interpreted independently of LHRT

In assessing the diagnostic accuracy, the comparative reproducibility, sensitivity, and specificity of LHRT are the primary outcomes to be considered. In the absence of an accepted gold standard for the diagnosis of allergy, it is difficult to ascertain the comparative performance characteristics of available diagnostic tests. For this reason, the concordance, or correlation of results from different tests is typically reported for LHRT. The published literature regarding the commercially available LHRTs suffers from the fact that alternative tests have not been performed in a blinded manner, or studies did not indicate whether or not there were blinded interpretations of the tests. (7, 8) Some studies included patients with known allergies, and thus these highly selective populations do not represent the same population with equivocal allergy histories that would undergo testing. (8-12) In some situations, results were compared with bronchial provocation testing, considered the gold standard for inhalant allergies. However, bronchial provocation may only be performed on a subset of patients with a limited number of allergens. For example, bronchial provocation may only be performed when there are discordant results between RAST and skin prick testing. (13) Thus overall, these studies are potentially prone to spectrum bias, referral bias, ascertainment bias, and are not sufficient to permit conclusions on the diagnostic accuracy of LHRT. It has been suggested that LHRT may be a valuable test in those patients with discordant results of skin prick testing and RAST testing, but studies focusing on this subgroup of patients were not identified in a literature search.

An updated search of the literature through October 2006 and again through October 2007 reveals no new published clinical trials testing outcomes of any of the allergy tests listed as investigational in this medical policy.  Specifically, there are not randomized, controlled clinical trials documenting outcomes and impact on treatment decisions for provocation food tests, nasal challenge tests, conjunctival challenge tests, cytotoxic food tests, LHRT, IgG4 and dermatome testing.  Therefore, the policy statement is unchanged.  Specifically, three new studies continue to find that the use of IgG allergen specific antibody testing for food allergies continues to reveal inconclusive results.  The exact immunologic role of IgG4 in food allergy remains controversial. (14-16)

In 2006 the American Academy of Allergy, Asthma and Immunology and the American College of Allergy jointly developed practice parameters for the diagnosis and treatment of food allergies and offered the following conclusions: (17)

“Some tests, including provocation neutralization, cytotoxic tests, IgG antibodies directed to foods, and hair analysis, are either disproved or unproven; therefore, they are not recommended for the diagnosis of food allergy.”

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy Nos. 2.04.42 and 2.01.23
2. The Allergy Report 2000. American Academy of Allergy Asthma & Immunology. Overview of Allergic Diseases: Diagnosis, Management, and Barriers to Care
3. Krouse JH, Mabry RL. Skin testing for inhalant allergy 2003: Current strategies. Otolaryngol Head Neck Surg 2003;129(4):S33-S49
4. 2002 TEC Assessment: Serial Endpoint Testing for the Diagnosis and Treatment of Allergic Reactions
5. American Medical Association. Council of Scientific Affairs. In vivo diagnostic testing and immunotherapy for allergy. Report I, Part I, of the allergy panel. JAMA 1987;258(10):1363-7
6. The American Academy of Allergy, Asthma, and Immunology Position Statement. Measurement of specific and nonspecific IgG4 levels as diagnostic and prognostic tests for clinical allergy. J Allergy Clin Immunol 1995;95:652-4
7. Griese M, Kusenbach G, Reinhardt D. Histamine release test in comparison to standard tests in diagnosis of childhood allergic asthma. Ann Allergy 1990;65(1):46-51
8. Skov PS, Mosbech M, Norn S et al. Sensitive glass microfibre-based histamine analysis for allergy testing in washed blood cells. Results compared with conventional leukocyte histamine release assay. Allergy 1985;40(3):213-8
9. Ostergaard PA, Ebbensen F, Nolte H et al. Basophil histamine release in the diagnosis of house dust mite and dander allergy of asthmatic children. Comparison between prick test, RAST, basophil histamine release and bronchial provocation. Allergy 1990;45(3):231-5
10. Kleine-Tebbe J, Werfel S, Roedsgaard D et al. Comparison of fiberglass-based histamine assay with a conventional automated fluorometric histamine assay, case history, skin prick test, and specific serum IgE in patients with milk and egg allergic reactions. Allergy 1993;48(1):49-53
11. Kleine-Tebbe J, Galleani M, Jeep S et al. Basophil histamine release in patients with birch pollen hypersensitivity with and without allergic symptoms to fruits. Allergy 1992;47(6):618-23
12. Paris-Kohler A, Demoly P, Persi L et al. In vitro diagnosis of cypress pollen allergy by using cytofluorometric analysis of basophils (Bastotest). J Allergy Clin Immunol 2000;105(2 pt 1):339-45
13. Nolte H, Storm K, Schiotz PO. Diagnostic value of a glass fibre-based histamine analysis for allergy testing in children. Allergy 1990;45(3):213-23
14. Noh G, Ahn H-S, Cho N-Y et al. The clinical significance of food specific IgE/IgG4 in food specific atopic dermatitis. Pediatr Allergy Immunol 2007;18:63-70
15. Aberer W, Hawranek T, Reider N et al. Immunoglobulin E and G antibody profiles to grass pollen allergens during a short course of sublingual immunotherapy. J Investig Allergol Clin Immunol 2007;17(3):131-6
16. Huang S-W. Follow-up of children with rhinitis and cough associated with milk allergy. Pediatr Allergy Immunol 2007;18:81-5
17. Chapman JA, Bernstein IL, Lee RE et al. Food allergy: a practice parameter. Annals of Allergy, Asthma, & Immunol 2006;96:S1-68

Cross References

Diagnosis and Management of Idiopathic Environmental Intolerance (i.e., Clinical Ecology), Regence Medical Policy Manual, Medicine, Policy No. 37

Xolair®, omalizumab, Regence Medical Policy Manual, Drugs, Policy No. 087

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