Aetna considers specific allergy testing and allergy immunotherapy medically necessary for members with clinically significant allergic symptoms. Based on a review of the medical literature and the position statements of scientific organizations in the field of allergy and immunology, Aetna considers the specific allergy testing and treatment described below medically necessary in accordance with the selection criteria noted.

1. ALLERGY TESTING

   1. Aetna considers the following allergy tests medically necessary:

      Epicutaneous (scratch, prick or puncture) when IgE-mediated reactions occur to any of the following:

      1. Inhalants; or
      2. Foods; or
      3. Hymenoptera (stinging insects); or

      4. Specific drugs (penicillins and macromolecular agents).

      Intradermal (Intracutaneous) when IgE-mediated reactions occur to any of the following:

      1. Inhalants; or
      2. Foods; or
      3. Hymenoptera venom allergy (stinging insects); or

      4. Specific drugs (penicillins and macromolecular agents).

      Number of epicutaneous (percutaneous) and intracutaneous (intradermal) skin tests:

      The evaluation of inhalant allergy may require up to 70 percutaneous tests, followed by up to 40 intracutaneous tests (which are usually performed when percutaneous tests are negative). However, in most cases, fewer tests are required.

      Skin Endpoint Titration (SET) (also known as intradermal dilutional testing (IDT)) for determining the starting dose for immunotherapy for members highly allergic to:

      1. Inhalant allergy; or

      2. Hymenoptera venom allergy (stinging insects).

      Number of SET tests:

      It is inappropriate to use SET in place of skin testing; however, when used to determine the starting dose for immunotherapy in highly allergic members, up to 14 titration tests may be necessary. An additional 40 antigens or 80 IDT injections may be medically necessary if any of the initial test results is positive.

      Skin Patch Testing for diagnosing contact allergic dermatitis.

      Photo Patch Testing for diagnosing photoallergy (e.g., photo-allergic contact dermatitis.

      Photo Tests for evaluating photosensitivity disorders.

      Bronchial Challenge Test for testing with methacholine, histamine or antigens in defining asthma or airway hyperactivity when either of the following conditions is met:

      1. Skin testing is unreliable; or

      2. Bronchial challenge test is being used to identify new allergens for which skin or blood testing has not been validated.

      Exercise Challenge Testing for exercise-induced bronchospasm

      Ingestion (Oral) Challenge Test for any of the following:

      1. Food or other substances (i.e., metabisulfite); or

      2. Drugs when all of the following are met:

         1. History of allergy to a particular drug; and
         2. Treatment with that drug class is essential; and

         3. There is no effective alternative drug.

      RAST, MAST, PRIST, RIST, FAST, modified RAST (MRT), VAST, ELISA, ImmunoCAP when percutaneous testing of IgE-mediated allergies can not be done for:

      1. Inhalant allergy; or

      2. Food allergy;

      due to any of the following reasons:

      1. Member has severe dermatographism, ichthyosis, or generalized eczema; or
      2. Member is unable to discontinue antihistamines but is in need of allergy testing; or
      3. Difficulty in testing uncooperative members (e.g., small children or individuals with mental or physical impairments); or
      4. When clinical history suggests an unusually greater risk of anaphylaxis from skin testing than usual; or

      5. Direct skin testing is inconclusive.

      Also considered medically necessary as an alternative to percutaneous testing for:

      1. The evaluation of cross-reactivity between insect venoms; or
      2. As adjunctive laboratory tests for disease activity of allergic bronchopulmonary aspergillosis (ABPA) and certain parasitic diseases; or
      3. Direct skin testing for drugs is inconclusive.

      Intradermal skin tests, rather than in vitro tests, should generally be used for the definitive diagnosis of anaphylactic sensitivities to stinging insects and drugs.

      Number of Tests:

      In vitro tests may be medically necessary for the initial allergy screen in lieu of skin testing. An initial allergy screen is 12 tests. Additional tests may be medically necessary if any of the initial test results is positive. If all test results are negative, additional testing beyond the initial allergy screen of 12 tests/allergens is not considered medically necessary.

      Total Serum IgE for diagnostic evaluation in members with known or suspected ABPA and or hyper IgE syndrome.

      Lymphocyte transformation tests (lymphocyte mitogen response test, PHE stimulation test, lymphocyte antigen response assay) are considered medically necessary for evaluating persons with sensitivity to beryllium. Lymphocyte transformation tests are considered experimental and investigational for evaluation of persons with allergies or other hypersensitiviities. Note: Lymphocyte transformation tests are also considered medically necessary for evaluation of persons suspected of having congenital or acquired immunodeficiency diseases affecting cell-mediated immunity, such a severe combined immunodeficiency, common variable immunodeficiency, X-linked immunodeficiency with hyper IgM, Nijmegen breakage syndrome, reticular dysgensis, DiGeorge syndrome, Nezelof syndrome, Wiscott-Aldrich syndrome, ataxia telangiectasia, and chronic mucocutaneous candidiasis. Lymphocyte transformation tests are also medically necessary for evaluation of persons with thymoma and to predict allograft compatibility in the transplant setting. For lymphocyte transformation testing for infertility, see CPB - Infertility

      Allergy Re-testing: Routine allergy re-testing is not considered medically necessary.

   2. Aetna considers the following tests for routine allergy testing experimental and investigational as they have not been proven to be effective:

      1. ALCAT test
      2. Candidiasis test
      3. Chlorinated pesticides (serum)
      4. Complement (total or components); (may be appropriate in autoimmune disorders, complement component deficiencies, hereditary angioedema, vasculitis)
      5. C-reactive protein (may be appropriate in inflammatory diseases)
      6. Cytotoxic food testing (Bryans Test, ACT)
      7. Electrodermal acupuncture
      8. ELISA/ACT
      9. Food immune complex assays (FICA)
      10. IgG RAST/ELISA testing
      11. Immune complex assay (may be appropriate in autoimmune disorders, systemic lupus erythematosus, vasculitis)
      12. Leukocyte histamine release test
      13. Lymphocytes (B or T subsets); (may be appropriate for collagen vascular disease, immune deficiency syndromes, leukemia, lymphomas)
      14. Mediator release test (MRT)
      15. Testing for multiple chemical sensitivity syndrome (a.k.a., idiopathic environmental intolerance (IEI), clinical ecological illness, clinical ecology, environmental illness, chemical AIDS, environmental/chemical hypersensitivity disease, total allergy syndrome, cerebral allergy, 20th century disease)
      16. Muscle strength testing or measurement (kinesiology) after allergen ingestion
      17. Ophthalmic mucous membrane tests/conjunctival challenge tests
      18. Prausnitz-Kustner or P-K testing - passive cutaneous transfer test
      19. Provocative nasal test (also known as nasal provocation testing)
      20. Provocation-neutralization testing (Rinkel Test) either subcutaneously or sublingually
      21. Pulse test (pulse response test, reaginic pulse test)
      22. Rebuck skin window test
      23. Sublingual provocative neutralization testing and treatment with hormones
      24. Venom blocking antibodies
      25. Volatile chemical panels (blood testing for chemicals).

      26. Tests listed in section I.A., when performed for indications not listed as medically necessary.

2. ALLERGY IMMUNOTHERAPY

   1. Aetna considers allergy immunotherapy medically necessary for the treatment of the following IgE-mediated allergies:

      1. Allergic (extrinsic) asthma
      2. Hymenoptera (bees, hornets, wasps, fire ants) sensitive individuals
      3. Mold-induced allergic rhinitis
      4. Perennial rhinitis
      5. Seasonal allergic rhinitis or conjunctivitis

      6. Dust mite atopic dermatitis;

      when all of the following conditions are met:

      1. Member has symptoms of allergic rhinitis and/or asthma after natural exposure to the allergen, or
      2. Member has a life-threatening allergy to insect stings (bees, hornets, wasps, and fire ants), and
      3. Member has skin test and/or serologic evidence of IgE-mediated antibody to a potent extract of the allergen, and

      4. Avoidance or pharmacologic therapy can not control allergic symptoms or member has unacceptable side effects with pharmacologic therapy.

      Note: Also see CPB 670 - Xolair (Omalizumab).

   2. Aetna considers allergy immunotherapy experimental and investigational for all other indications, including the following:

      1. Food allergy
      2. Migraine headaches
      3. Non-allergic vasomotor rhinitis
      4. Intrinsic (non-allergic) asthma
      5. Chronic urticaria
      6. Atopic dermatitis (cover for dust mite atopic dermatitis)

      7. Angioedema.

3. OTHER TREATMENTS

   1. Aetna considers the following treatments medically necessary:
      
      Rapid desensitization (a.k.a., rush, cluster or acute desensitization) for members with any of the following conditions:

      1. Insect sting (e.g., wasps, hornets, bees, fire ants) hypersensitivity (hymenoptera); or
      2. IgE antibodies to a particular drug that can not be treated effectively with alternative medications; or

      3. Members with moderate to severe allergic rhinitis who need treatment during or immediately before the season of the affecting allergy.

      Rapid desensitization is considered experimental and investigational for other indications.

      Note: If a woman is contemplating pregnancy and requires initiation of allergy immunotherapy and/or it is anticipated that she will require allergy medications that may increase risk to her or the fetus, rapid desensitization is an acceptable approach.

      Epinephrine kits (e.g., Ana-Kit, Epi-Pen auto-injectors) to prevent anaphylactic shock for individuals who have had life-threatening reactions to insect stings, foods, drugs or other allergens or have severe asthma or if needed during immunotherapy. Epinepherine kits are considered experimental and investigational for other indications.

   2. Aetna considers the following allergy treatments experimental and investigational as they have not been proven to be effective:

      1. Acupuncture for allergies
      2. Autogenous urine immunization (autogenous urine therapy)
      3. Allergoids (modification of allergens to reduce allergenicity)
      4. Bacterial immunotherapy
      5. Detoxification for allergies
      6. Ecology units/environmental control units/environmental chemical avoidance for multiple chemical sensitivity syndrome
      7. Enzyme potentiated desensitization (EPD)
      8. Homeopathy for allergies
      9. Neutralization therapy (desensitization neutralization therapy)
      10. Photo-inactivated extracts
      11. Polymerized extracts
      12. Poison ivy/poison oak extracts for immunotherapy in the prevention of toxicodendron (Rhus) dermatitis
      13. Repository emulsion therapy
      14. Rhinophototherapy
      15. Sublingual drops.

Allergy is a hypersensitive reaction that is usually manifested in the clinical form of allergic asthma, hay fever or eczema developing within minutes to a few hours after exposure to an antigen. The most common types of allergies are rhinitis, asthma, food allergy, insect sting allergy, drug allergy and contact dermatitis. Allergy testing is focused on determining what allergens cause a particular reaction and the degree of the reaction and provides justification for recommendations of specific avoidance measures in the home or work environment or the institution of particular medicines or immunotherapy. There are virtually no age limitations for performance of skin tests. However, skin test reactivity may be diminished in infants and the elderly. Types of allergy testing include in vivo, in vitro, provocation testing, and controversial allergy tests.

1. Allergy Testing

   1. In-Vivo Diagnostic tests of IgE dependent reactions

      Epicutaneous (Scratch, Prick or Puncture) and Intracutaneous In-Vivo Diagnostic Skin Tests

      Skin tests for IgE-mediated disease with allergenic extracts have been shown to be effective aids in the assessment of allergic patients. These tests involve the introduction of small quantities of test allergens below the epidermis. Within 15 to 20 minutes, a characteristic wheal and flare reaction occurs in patients sensitive to one or more of the test allergens. The majority of allergists use prick or puncture and/or intracutaneous skin tests, since the amount of allergen delivered by these methods is better controlled than by scratch tests. Although skin testing is considered to be a safe procedure, adverse events, such as large local reactions and systemic symptoms may occur in extremely sensitive individuals. Deaths from anaphylaxis after skin testing have been reported. These extremely rare systemic symptoms are less likely to occur with prick or puncture than with intracutaneous tests. Prick or puncture tests are generally considered to be the most convenient, least expensive and most specific screening method for detecting the presence of IgE antibodies in patients with appropriate exposure histories. Prick or puncture tests are generally less sensitive than intracutaneous tests. For inhalant allergens, prick or puncture tests are generally felt to correlate better with the presence of clinical allergy. However, intracutaneous (within the skin) testing may detect relevant sensitivity and should be considered when the prick or puncture test is negative or equivocal to allergens strongly suggested by the patient's history or exposure, or when skin sensitivity may be decreased such as in infants or older patients. Intracutaneous tests permit identification of a larger number of clinically reactive patients, especially those with lower skin test sensitivity.

      Skin testing to drugs is generally unreliable, except for the penicillins and macromolecular agents, such as foreign antisera, hormone (e.g., insulin), enzymes (e.g., L-asparaginase, streptokinase, chymopapain), and egg-containing vaccines.

      In January 2003, the Board of Directors of the AAOA endorsed strategies for testing for inhalant allergy (Krouse and Mabry, 2003), stating that “[m]embers should practice in ethical and fiscally responsible ways.” The AAOA provided the following guidelines on the necessary number of tests for inhalant allergy (e.g., prick testing, intradermal testing, intradermal dilutional testing (IDT), and in vitro testing):

      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.

      Skin Endpoint Titration (SET)

      Skin endpoint titration (SET) (also known as intradermal dilutional testing (IDT))  is intradermal testing of sequential and incremental dilutions of a single antigen. SET involves serial testing with several dilutions of a single treatment allergen or mixture of allergens to identify the lowest dilution that produces a positive skin reaction. In performing the test, wheals of identical size are made in the most superficial layers of the skin and measured for uniformity. The first wheal is made with approximately 0.1 ml of a dilution estimated to be too weak to produce symptoms. Successive wheals are made with serial dilutions, each generally five times stronger than the previous one, until negative responses are replaced by positive responses of increasing size. The "endpoint" is the weakest dilution that produces a positive skin reaction and initiates progressive increase in the diameter of wheals with each stronger dilution. Proponents of SET emphasize that it quantifies skin testing and replaces a single equivocal reaction with a progressive pattern easily identified. When immunotherapy is initiated, starting with too strong an extract may precipitate dangerous allergic reactions, while starting with one too weak may delay treatment results. Skin endpoint titration allows the initiation of immunotherapy with a safe but relatively potent dose, and allows the beginning dosage for each positive responding allergen to be varied depending on its specific “endpoint.” Although traditional allergists often rely on single dilution “classical” testing, they have accepted SET over the last decade as effective for quantifying patient sensitivity and for providing a guide for a safe starting dose for immunotherapy noting that studies have not shown it to be an effective guide to a final therapeutic dose. The American Academy of Allergy also has advised that costly, repetitive endpoint titrations are usually unnecessary because, regardless of what the titration indicates, the dose will be advanced either until the patient can tolerate no more or until a dose is reached that produces satisfactory results. Skin endpoint titration is considered the gold standard of skin testing by the American Academy of Otolaryngic Allergy (AAOA); the American Medical Association’s Council of Scientific Affairs also is on record that SET is helpful for the delineation of patient-specific sensitivity to various antigens as well as to evaluate a patient’s response to various forms of immunotherapy. They note that controlled studies have shown that the intradermal method of SET is effective for quantifying sensitivity to ragweed pollen extract and for identifying patients highly sensitive to ragweed.

      While allowing that SET is a valid method for obtaining semi-quantitative information about a person's sensitivity and for determining a safe beginning dose for immunotherapy, the American College of Physicians (ACP) advises that the primary use of SET is to identify hymenoptera venom (yellow jacket, honey bee, hornet, wasp, fire ant) sensitivity and to determine the safe starting dose for venom immunotherapy.

      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 SET (Krouse & Mabry, 2003). The literature on screening supports, and the AAOA recommends, usually screening and billing for no more than 14 antigens (plus the appropriate controls) for an initial allergy evaluation. In most geographic regions, a range of up to 14 allergens is sufficient to check the most prevalent molds, dust components, grasses, trees, animals, and weeds. If screening is positive and immunotherapy is contemplated, the AAOA recommends no more than 40 antigen be tested unless indicated by unusual clinical circumstances. For SET, the AAOS says that up to 80 injections are usually necessary to identify the offending antigen and find a safe starting point for immunotherapy.

      Provocation (Challenge) Testing

      In provocation or challenge testing, a suspected allergen in a clinically relevant exposure is administered in an attempt to reproduce symptoms. Challenge tests have been broadly applied under research conditions for many years, but there also may be clinical situations in which they can be useful for confirmation of clinical disease. Considerable experience with these methods is required for proper interpretation and analysis.

      Patch Testing

      Patch testing is an accepted method of differentiating allergic contact dermatitis and irritant contact dermatitis. Twenty to thirty antigens are used in the usual routine screening panel of patch tests. The patches are removed after 48 hours and an initial reading is taken 1 hour later. The final reading is taken a further 48 hours later.

      Photo Patch Testing

      Some chemicals or medications (e.g., lomefloxacin, ofloxacin, ciproflaxacin and norfloxacin) produce an allergic reaction only when exposed to light (usually ultraviolet type A, UVA). Patients who are over-sensitive to light and those with a rash that appears on parts of the body normally exposed to light but that does not appear in areas shielded from the light should have a photo-patch test. With photo patch testing, two identical sets of allergens are placed onto the patient's back on day-1. One of the sets is exposed to UVA light, and the sites are then examined as described above for patch testing. A positive photo patch test is recorded when an allergic reaction appears only on the light-exposed site.

      Photo Tests

      Photo testing is skin irradiation with a specific range of ultraviolet light. Photo tests are performed for the evaluation of photosensitivity disorders.

      Bronchial Challenge Testing

      Bronchial challenge testing with methacholine, histamine, or allergens is an accepted method of defining asthma or airway hyperactivity when skin testing results are not consistent with the patient's medical history. Results of these tests are ordinarily evaluated by objective measures of pulmonary function and occasionally by characterization of bronchoalveolar lavage samples. Recommended dosage is an incremental increase of pharmacologic dose until a response is produced.

      Exercise Challenge Testing

      Exercise challenge testing is an accepted method of diagnosing exercise induced bronchospasm in asthmatic and non-asthmatic patients.

      Ingestion (Oral) Challenge Testing

      Ingestion (oral) challenge testing is an accepted method of diagnosing allergies to food, drug or other substances (i.e., metabisulfite). Drug challenge testing should not be confused with cutaneous or sublingual provocation and neutralization therapy, which is a non-covered modality.

      Nasal or Conjunctival Provocative or Challenge Tests

      Nasal or conjunctival provocative or challenge tests employed for the diagnosis of either food or inhalant allergies, involve the direct administration of the allergen to the mucosa. The patient is then observed for signs and symptoms and the presence of symptoms is interpreted as a positive indication of allergies. These tests are time consuming, only one antigen may be administered per session, a non-standardized quantity of allergen is administered and they have the potential of inducing severe symptoms. There is currently no standard of techniques for nasal or conjunctival challenge tests that can be applied to clinical practice.

      Prausnitz-Kustner or P-K Testing

      Prausnitz-Kustner testing has been used in patients with dermatographia or generalized skin eruptions. A control site on the forearm of a non-allergic recipient is selected. This site is injected intradermally with allergy serum from a patient on whom direct skin tests cannot be done. Allergenic extract is later injected intradermally into the initial injection site of the recipient and observed for the development of a wheal and flare. Because of the risk of transmitting hepatitis or AIDS, this test is contraindicated.

      Provocation-Neutralization (Rinkel Test)

      Provocation-neutralization is a method of testing for the presence of food, inhalant or environmental chemical allergies by exposing the individual to test doses of these substances intradermally, subcutaneously, or sublingually with the purpose of either producing or preventing subjective symptoms. Provocation-neutralization evolved from the serial end-point titration skin testing procedure (a covered modality), and is based on the concept that extremely small quantities of allergens can cause immediate disappearance (“neutralization”) of ongoing symptoms. Once a test is considered positive (results are interpreted either by subjective symptom provocation or objective skin whealing), a progressive series of lower concentrations are administered under the tongue or skin until a dose is reached at which the patient reports no sensations. This amount of the test substance is considered the “neutralizing dose”, which is then used for future treatment. Sublingual testing has been used mainly in diagnosing food allergy, although extracts of chemicals, inhalant allergens, drugs, and hormones have been administered by the sublingual route. Published literature frequently combines the discussion of testing and treatment as a single entity. Provocation-neutralization is used by those physicians who subscribe to the concept of multiple food and chemical sensitivities (a.k.a., idiopathic environmental intolerance's (IEI), clinical ecological illness, clinical ecology, environmental illness, chemical AIDS, environmental/chemical hypersensitivity disease, total allergy syndrome, cerebral allergy, 20th century disease) and “delayed food allergy”. When used for the latter, provocative testing may be identified as the intracutaneous progressive dilution food test (IPDFT). Since provocation-neutralization requires the provoking and neutralizing of symptoms to a single item at a time, the patient could be required to undergo hundreds of individual tests requiring weeks or months of full-day testing.

      Traditional allergists believe that food hypersensitivities are primarily IgE-mediated and treat with avoidance diet and/or drug therapy. Diagnosis is by history, elimination diets, skin tests, or food challenge. Non IgE-mediated food intolerance is classified as non-immune adverse reactions to food of a pharmacologic (caffeine, histamine, tyramine, serotonin, dopamine, etc.); metabolic (lactose intolerance); or idiosyncratic nature, e.g., food dyes, preservatives (sulfites), flavor enhancers (MSG). The AAOA indicates that provocation-neutralization techniques were developed primarily for these delayed, less obvious, non-IgE-mediated food hypersensitivities and not for confirmation of immediate food allergy obvious by history. Test substances have also included chemicals such as formaldehyde and alcohol, histamine, tobacco, newsprint and inhalant allergens.

      Sublingual provocative neutralization with hormones utilizes the same principles as noted above and involves preliminary extensive blood testing for allergies to hormones and the subsequent administration of small doses of hormones suspected of causing the allergic symptoms. There have been no well controlled studies that have shown this procedure to be effective in the diagnosis and treatment of symptoms thought to be caused by allergy to hormones.

      Both the ACP and the American Academy of Allergy and Immunology (AAAI) consider provocation-neutralization therapy an unproven modality. In a Training Program Directors' Committee Report on Controversial Practices published by the AAAI, provocation-neutralization testing and neutralization therapy are listed as unproven. The AMA's Council on Scientific Affairs, based on the reports in the peer-reviewed scientific literature, stated that there are no well-controlled studies establishing a clear mechanism or cause for multiple chemical sensitivity syndrome. More importantly, there are no well-controlled studies that have demonstrated either diagnostic or therapeutic value for provocation-neutralization therapy.

      Provocation-neutralization must not be confused with the recognized forms of target-organ challenge testing (bronchial, ingestion, patch testing), which are covered modalities.

   2. In-Vitro Testing

      RAST/MAST/PRIST/RIST/FAST/MRT/VAST/ELISA/ImmunoCAP

      For most allergens, in-vitro allergen - specific immunoassays detect IgE antibody in the serum of most but not all patients who respond clinically to those allergens. The precise sensitivity of these immunoassays compared with skin tests has been reported to range from < 50% to > 90% with the average being about 70 to 75%. In a joint statement, the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of allergy, Asthma and Immunology (the Joint Council) concluded that allergen skin testing is the most sensitive method for detecting specific IgE antibody. Therefore, skin tests are presently the preferred tests for the diagnosis of IgE-mediated sensitivity. Because of the inherent pitfalls in the sensitivity and reliability of IgE specific immunoassays, clinical applications are not completely defined and are still evolving.

      According to the Joint Council, although skin tests are presently the preferred method of testing in making the diagnosis of allergy, in vitro tests may also be useful in specific clinical situations. Specific IgE immunoassays may be preferable to skin testing under special clinical circumstances: 1) testing of patients with severe dermatographism, ichthyosis, or generalized eczema; 2) testing in patients who have been receiving long-acting antihistamines, tricyclic antidepressants, or medications that interfere with skin testing and may put the patient at undo risk if they are discontinued; 3) testing of uncooperative patients with mental or physical impairments; 4) the evaluation of cross-reactivity between insect venoms; 5) postmortem examination for IgE antibodies to identify allergens responsible for lethal anaphylaxis; 6) as adjunctive laboratory tests for disease activity of allergic bronchopulmonary aspergillosis and certain parasitic diseases; 7) when clinical history suggests an unusually greater risk of anaphylaxis from skin testing than usual; and 8) direct skin testing is inconclusive.

      According to the National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma, advantages of RAST and other in vitro tests over skin tests include the fact that they do not require knowledge of skin testing technique, they do not require availability of allergen extracts, they can be performed on patients who are taking medications that suppress the immediate skin test (e.g., antihistamines, antidepressants), they carry no risk of systemic reactions, and they can be done on patients with extensive eczema. Despite the advantages, there are two major concerns limiting the use of in-vitro tests for allergen-specific IgE in the United States. The first limitation is the rather consistent finding that in-vitro tests are not as sensitive as skin tests for detecting allergen-specific IgE. The second limitation is that on a per test basis skin tests have lower time and reagent costs. Other advantages of skin tests are that they are faster (results are available within an hour), and the results are visible to the patient (this may enhance patient compliance).

      A variety of modifications have been made to tests related to RAST (such as MAST, PRIST, RIST, FAST, MRT, VAST, ELISA, and ImmunoCAP).

      ImmunoCAP (Pharmacia Diagnostics, Clayton, N.C.) is an in vitro-specific immunoglobulin E test that uses a three-dimensional cellulose solid allergen phase; by contrast, the older modified Phadezym-Rast (Pharmacia Diagnostics) uses a two-dimensional solid phase. The ImmunoCAP provides more rapid results (available in 6 hours) compared to traditional RAST tests (Phadezym-RAST results take 3 days to obtain). With the ImmunoCAP, solid-phase bound allergens are allowed to react with IgE antibodies in the sample; the IgE antibodies are detected by labeled anti-IgE. To minimize handling and increase safety, the system includes instrumentation and computer software that handles the technical manipulations, the measurements and the data management. The assay is calibrated against the WHO standard for IgE and includes two sets of calibrators, one for specific IgE Ab and low range total IgE, and the other for wide range total IgE. Results from published studies report the overall sensitivity and specificity of different allergens compared to expert clinical diagnosis range from 78-94% and 77-94% respectively.

      Intradermal skin tests, rather than in-vitro tests, should be used for the definitive diagnosis of anaphylactic sensitivities to stinging insects and drugs.

      Total Serum IgE

      An elevated serum IgE level is one of the diagnostic criteria of allergic bronchopulmonary aspergillosis (ABPA). IgE levels can be used to follow the course of the disease. Serum IgE levels will fall when the disease is successfully treated with corticosteroids; rising IgE levels indicate disease exacerbations.

      Total serum level of IgE is correlated with allergic disease in only a general way. Elevated levels are associated with the presence of allergy, while normal levels are not. However there are many individuals with clinical symptoms and allergen-specific IgE who have serum IgE levels within the normal range. Because of this, routine measurement of serum IgE is not a useful screening test for allergy.

      IgG RAST/ELISA Testing

      There is no evidence that IgG antibodies are responsible for delayed allergic symptoms or intolerance to foods.

      ALCAT

      ALCAT food allergy testing utilizes an indirect method of measuring mediator releases and the effects of other pathogenic mechanisms of allergy and delayed hypersensitivity. It employs semi-automated Coulter Electronics and fully automated computer analysis. This automated testing has not been validated and has not been established as a useful allergy test in clinical practice.

      Cytotoxic Testing (Bryans Test)

      Cytotoxic testing is based on the theory that the addition of a specific allergen to either whole blood or a serum leukocyte suspension from a suspected allergic patient will result in reduction of the white blood cell count or death of the leukocytes, thereby indicating the presence of an immune response. Controlled studies have failed to substantiate the value of cytotoxic testing for the diagnosis of allergies, whether they are airborne, foods, or chemicals.

      ELISA/ACT

      ELISA/ACT tests lymphocytes in a laboratory culture for their reaction to up to 300 purified foods, preservatives, chemicals and minerals. This test is not FDA approved and is not established as a useful test in clinical practice.

      Food Immune Complex Assays (FICA)

      FICA are based on the standard solid phase radioimmunoassay methodology. These assays have not yet been subjected to rigorous study of potential false-negative and false-positive results. Clinical studies to date indicate that circulating immune complexes can be found in a normal population of people having no food allergy. The value of the measurement of FICA toward the diagnosis of food allergy remains unproven and does not have a place in current clinical practice.

      Rebuck Skin Window Test

      Rebuck skin window test is an immunologic test in which the skin is abraded with a scalpel. Laboratory cover slips are placed over the abraded areas for 24 hours. The coverslips are then stained and analyzed. An immune deficiency may be present if there is an abnormality of monocytes displayed either by their absence or their inability to migrate to intracellular sites of antigen within 12 hours. This test is not useful in documenting allergies since other immunodeficiencies can be found in patients with allergic conditions.

      Leukocyte Histamine Release Test

      The leukocyte histamine release test is a measurement of the amount of histamine released in-vitro. Varying concentrations of an allergen extract are added to the patient's peripheral blood leukocytes. Histamine is normally released as a consequence of the interaction of allergen with cell-bound IgE antibodies. If an individual is atopic to a specific antigen, the leukocytes will not release the histamine in-vitro. Only a limited number of allergens can be tested from a single aliquot of blood and quality control studies have shown considerable variability in the measurement of histamine results.

      Mediator Release Test

      The mediator release test (MRT) (Signet Diagnostic Corporation) has primarily been used to detect intolerance to foods and additives in patients with irritable bowel syndrome. The MRT measures the aggregate release of inflammatory mediators from the patient's immunocytes in vitro after exposure to specific foods and food additives. The results of the mediator release test have been used to design a patient-specific diet to treat IBS by avoiding foods and additives that trigger significant inflammatory mediator release. For the mediator release test, the patient's blood sample is incubated with various extracts of foods and food additives and then analyzed for the presence and aggregate amount of release of inflammatory mediators from the patient's leukocytes. Results are compared to control samples of the patient's blood that have not been exposed to food extracts or additives The MRT-directed patient-specific diet is one component of the Lifestyle Eating and Performance (LEAP) Disease Management Program (Don Self & Associates, Inc., Whitehouse, TX). The LEAP program is based on the theory that symptoms irritable bowel syndrome and other certain conditions are caused by the physiological effects of non-IgE mediated immune reactions in response to sensitivities to specific foods and food additives. The LEAP program also includes patient selection tools, a self-directed stress reduction program, and outcomes assessment tools. According to the manufacturer, the LEAP program has been successful in reducing or eliminating symptoms in 84 percent of patients with irritable bowel syndrome, functional diarrhea, and related conditions. However, there is no evidence in the peer-reviewed published medical literature to substantiate these claims.

      The mediator release test has also been promoted for use in patients with chronic fatigue syndrome, metabolic conditions (e.g., diabetes, obesity), gastrointestinal disorders (e.g., gastroesophageal reflux disease, chronic ulcerative colitis, and Crohn's disease), neurologic disorders (e.g., migraine headaches, cluster headaches), rheumatologic disorders (inflammatory arthritis, arthralgias, fibromyalgia), otolaryngologic disorders (e.g., perennial rhinitis, chronic sinusitis, chronic otitis media with effusion), dermatologic conditions (e.g., eczema, urticaria, dermatitis), and in patients with behavioral conditions (e.g., attention deficit disorder, hyperactivity, frequent mood swings, inability to concentrate). There are, however, no studies of the mediator release test reported in the peer-reviewed published medical literature that demonstrate improvements in clinical outcomes by incorporating the mediator release test and associated dietary modifications into the clinical management of patients with these conditions. Thus, the mediator release test is considered experimental and investigational.

2. Allergy Immunotherapy

   The treatment of allergy is approached three ways: avoidance therapy, pharmacologic therapy, and immunotherapy. Complete avoidance of the known allergen responsible for inducing the signs and symptoms of the allergy is the most effective treatment for any allergic condition and results in a cure. When avoidance of a specific allergen such as house dust, molds or pollens is impossible, pharmacologic therapy is used (e.g., antihistamines, adrenergic agonists, anticholinergics, beta-adrenergic agonists, corticosteroids, cromolyn sodium and methylxanthines). It has been advocated that the utilization of air cleaners, humidifiers, or dehumidifiers is helpful in reducing allergic irritant substances in the environment; however, research indicates that the use of these mechanical devices was ineffective in reducing clinical symptoms.

   Allergy immunotherapy (a.k.a., desensitization, hyposensitization, allergy injection therapy, or "allergy shots"), is indicated in patients whose triggering allergens are not readily avoidable, the allergy is IgE-mediated as documented by skin testing or RAST, the symptoms are not easily controlled with medication, the symptoms encompass more than one season and the patients are likely to cooperate in the program. The severity, duration and frequency of episodes should be explored. Patients with life-threatening allergy (severe anaphylactic reaction) to hymenoptera (venom from bees, hornets, wasps or fire ants) have been shown to respond well to allergy immunotherapy, as well as patients with severe seasonal allergic rhinitis or conjunctivitis, perennial allergic rhinitis, allergic (extrinsic) asthma and mold induced allergic rhinitis. Allergy immunotherapy will help desensitize the patient to the effects of the allergen. The documented allergy should correspond to the allergen planned for immunotherapy. A trial of systemic medications or avoidance of the allergens should be attempted. Two or more medications (antihistamines, steroids, bronchodilators, intranasal cromolyn) if not contraindicated should have been prescribed during the past year or the patient should be currently receiving immunotherapy.

   Allergy immunotherapy is defined as the repeated administration of specific allergens to patients with IgE-mediated conditions, for the purpose of providing protection against the allergic symptoms and inflammatory reactions associated with natural exposure to these allergens. The exact mechanism of action is not known but may involve an increase in allergen-specific IgG antibodies, a decrease in IgE synthesis, and alteration in T-lymphocyte activity. The principal and most effective route of allergen application is by subcutaneous injection. Oral/sublingual application of allergen extracts is discussed controversially in the literature (see provocation-neutralization therapy). There is a great assortment of different allergen extracts available, but only standardized extracts should be used. In the United States, the Food and Drug Administration (FDA) determined that the intracutaneous technique should be used for assigning standardized unitage (i.e., bioequivalency allergy units [BAU]). Patients with allergic rhinitis and/or asthma from tree and grass pollens in the spring, ragweed pollen in the fall and year-round dust-mite sensitivity who have had inadequate response to acceptable symptomatic medication and allergen avoidance are excellent candidates for immunotherapy. Immunotherapy is recommended for patients with allergic asthma unresponsive to allergen avoidance, even when symptomatic relief can be achieved with drug therapy. Treatment plans vary, but generally follow an initial dosing of short intervals (2-7 days) and should be increased one and one-half to two times with each injection if no reaction occurs. This dosing is followed by a maintenance dosage regimen at three- or four-week intervals and is determined by patient tolerance and relief of symptoms. Length of therapy varies from 3 to 5 years. The progress of the patient should be reviewed at regular intervals by the physician. Progressive improvement may be observed over the first 2 to 3 years of treatment. Discontinuation of therapy may be considered any time after a 2 to 3 year trial. The risk of relapse must be weighed against patient preference for continuation of therapy. Examples of potential allergens for which immunotherapy is effective include: animal dander, animal feathers, animal fur, dust, grasses, insects, mites, molds, mushrooms, orris root, plants, pyrethrum, seeds, trees, vegetable gums, weeds, hymenoptera or stinging insects (bees, hornets, wasps, fire ants).

   There is no evidence that immunotherapy is beneficial for food allergy, migraine headaches, vasomotor rhinitis, intrinsic (non-allergic) asthma, or chronic urticaria. In addition, there is little evidence that immunotherapy benefits atopic dermatitis and angioedema. The major risk factor of allergy immunotherapy is anaphylaxis. Immunotherapy should be administered under the supervision of an appropriately trained physician who can recognize early signs and symptoms of anaphylaxis and administer emergency medications if needed.

   A structured evidence-based assessment of sublingual immunotherapy for adults conducted by the BlueCross BlueShield Association Technology Evaluation Center concluded that “[w]hether [sublingual immuotherapy] improves health outcomes when compared with injection [allergen-specific immunotherapy] has not yet been demonstrated in the investigational setting. It is uncertain whether FDA-licensed allergen preparations manufactured for allergy testing and injection [allergen-specific immunotherapy] are suitable for sublingual administration. Based on the above, use of sublingual immunotherapy for patients with allergies does not meet the TEC criteria.” 

   Cox and colleagues (2006) stated that sublingual immunotherapy (SLIT) has been utilized with increasing frequency in Europe and is viewed with increasing interest by allergists in the United States.  To address this interest, a Joint Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology's Immunotherapy and Allergy Diagnostic Committees evaluated the evidence on the effectiveness of SLIT.  The task force concluded that despite clear evidence that SLIT is an effective treatment, there are still many unanswered questions, including effective dosage, treatment schedules, and overall duration of treatment.  Until these questions have been answered, an assessment of the cost/benefit ratio of the treatment cannot be made.  Sublingual immunotherapy does seem to be associated with few severe side effects, but it has not been used in high-risk asthmatic patients, nor in the studies reviewed has it been used as a mixture of non-cross-reacting allergens.  Furthermore, there is currently no allergy extract approved for this use in the United States, nor is there a Current Procedural Terminology code for billing purposes.  All of these factors should be considered before contemplating initiation of SLIT treatment for allergic patients.

   Allergoids

   Allergoids are formalin treated allergens which have been shown to be as effective as conventional aqueous extracts and superior to placebo in terms of reduction of symptom medication scores, production of an increase in ragweed IgG levels, and a decrease in seasonal rise in ragweed IgE levels. Allergoids are licensed and manufactured for general distribution in Europe, but not yet in the United States.

   Enzyme Potentiated Desensitization (EPD)

   EPD is patented in Europe under the brand name of Epidyme. This immunotherapy consists of a mixture of allergens to molds, grass, weeds, trees, dust mites, dog and cat dander, and house dust. These allergens are administered in the doctor's office. While this is common practice in Europe, it is not on the United States market or regulated/approved by the FDA. There is a lack of clinical trials supporting the efficacy of this product.

   Photo-inactivation

   Photo-inactivation of an antigen with ultraviolet may allow larger doses of antigen to be administered with fewer adverse effects. Currently, these preparations are used for research purposes only and not in clinical practice.

   Polymerized Ragweed Extract

   Polymerized ragweed extract has been employed for treatment of ragweed hay fever in placebo-controlled trials and has been shown to produce a significant decrease in symptoms and medication scores. However polymerized ragweed extracts have not yet been licensed or manufactured for general distribution in the United States.

   Rhinophototherapy

   Phototherapy has a profound immunosuppressive effect and is able to inhibit hypersensitive reactions in the skin. Leimgruber (2006) stated that phototherapy applied inside the nose (rhinophototherapy) is among new therapeutic options being developed for allergic rhinitis to counteract its impact on quality of life and health costs. The author noted that the immunosuppressive effect of phototherapy has been tested in nasal mucosa. This application has shown anti-inflammatory results in nasal cleaning fluid and, consequently, may reduce allergic rhinitis. The author noted that long-term studies involving large cohorts of patients are needed if rhinophototherapy is going to be prescribed without restrictions.

   In a randomized, double-blind study (n = 49), Koreck, et al. (2005) examined if phototherapy using a combination of UVB (5 %), UVA (25 %), and visible light (70 %), referred to as mUV/VIS (rhinophototherapy), is effective in treating allergic rhinitis. The study was carried out during the ragweed season. Each intra-nasal cavity was illuminated 3 times a week for 3 weeks with mUV/VIS or with low-intensity visible light (control group). Symptom scores, inflammatory cells, and their mediators were assessed in nasal lavages. In vitro effects of mUV/VIS irradiation on T-cell and eosinophil apoptosis, and its inhibitory effect on mediator release from basophils were examined. Rhinophototherapy was well-tolerated, and resulted in a significant improvement of clinical symptoms for sneezing (p < 0.016), rhinorrhea (p < 0.007), nasal itching (p < 0.014), and total nasal score (p < 0.004). None of the scores improved significantly in the control group. The investigators reported that scores for nasal obstruction slightly improved after rhinophototherapy and significantly increased in the control group (p < 0.017). In the nasal lavage, rhinophototherapy significantly reduced the number of eosinophils and the level of eosinophil cationic protein and IL-5. In vitro irradiation of T-cells and eosinophils with rhinophototherapy dose-dependently induced apoptosis. In addition, rhinophototherapy inhibited the mediator release from RBL-2H3 basophils. These promising results would need to be replicated in a larger clinical trial with longer-term followup.

3. Urine Auto-injection

   The practice of injection of an extract of the patient's own urine for diagnosis and treatment of allergy is clearly unacceptable and must be discouraged. It is not based on rational theory, and there have been no scientific investigations of efficacy and safety. There is a potential danger for autoimmune nephritis with this procedure.

4. Multiple Chemical Sensitivity Syndrome

   Multiple chemical sensitivity (MCS) (a.k.a., idiopathic environmental intolerance (IEI), clinical ecological illness, clinical ecology, environmental illness, chemical AIDS, environmental/chemical hypersensitivity disease, total allergy syndrome, cerebral allergy, 20th century disease) has been used to describe a condition whereby an individual becomes chronically ill from exposure to chemicals in foods and the environment at doses far below the levels normally considered safe. Resulting “allergies” to these chemicals have been postulated to cause a number of troubling symptoms (e.g., fatigue, irritability, behavior problems, depression, confusion, and nervous tension in children) in the absence of objective physical findings. The existence of such a syndrome has been based on anecdotal reports and uncontrolled studies. Several well-designed investigations suggest that most people diagnosed with MCS have a medical or psychosomatic disorder that they cannot accept, preferring instead to interpret their symptoms as environmental sensitivities. If this is true, the diagnosis of MCS may delay proper medical and psychiatric care.

   The theories and practices involving environmental allergies of this type have been severely criticized by the American Medical Association, the American College of Physicians, the Canadian Psychiatric Association, the International Society of Regulatory Toxicology and Pharmacology, the American Academy of Allergy, Asthma and Immunology (AAAAI), and several scientific panels that have investigated them. Based on the reports in the peer-reviewed scientific literature, the American Medical Association's Council on Scientific Affairs stated that “there are no well controlled studies establishing a clear mechanism or cause for multiple chemical sensitivity syndrome.” Recently (January 1999), the AAAAI reviewed the evidence again and concluded, “Rigorously controlled studies to verify the patient's reported subjective sensitivity to specific environmental chemicals have yet to be done. Moreover, there is no evidence that these patients have any immunologic or neurologic abnormalities. In addition, no form of therapy has yet been shown to alter the patient's illness in a favorable way.”

   Confinement in an environmental control unit or facility (ecology unit), which has been used as a treatment for environmental illnesses and hypersensitivities, has not been established as an effective or appropriate treatment.