Allergy Diagnostic Testing

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment of those items or services that are considered to be medically reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.

Title XVIII of the Social Security Act, §1862(a)(1)(D) excludes investigational or experimental from Medicare coverage.

Title XVIII of the Social Security Act, §1862(a)(7) excludes routine physical examinations.

42 U.S. Code §263a. Certification of laboratories

42 CFR §410.20 Physicians’ Services

42 CFR §410.32(a) tests not ordered by the physician or other qualified non-physician provider who is treating the patient are not reasonable and necessary. (See 42 CFR 411.15(k)(1)).

42 CFR §410.32(b) diagnostic tests must be furnished under the appropriate level of supervision by a physician. Services furnished without the required level of supervision are not reasonable and necessary.

42 CFR §493.3 Applicability

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80.1 Clinical Laboratory Services and §80.6 Requirements for Ordering and Following Orders for Diagnostic Tests

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 2, §110.9 Antigens Prepared for Sublingual Administration, §110.11 Food Allergy Testing and Treatment, §110.12 Challenge Ingestion Food Testing and §110.13 Cytotoxic Food Tests

CMS Internet-Only Manual, Pub. 100-08, Medicare Program Integrity Manual, Chapter 3, §3.6.2.2 Reasonable and Necessary Criteria

Overview

Allergy is a hyper-immunologic response to environmental substances, known as allergens, that commonly affect organs such as the skin, eyes, ears, nose, throat, and respiratory and gastrointestinal (GI) tracts.^1-4 An allergen is an antigenic substance that triggers this immune response.⁵

A Type I Hypersensitivity reaction is the primary mechanism driven by immunoglobulin E (IgE) antibodies. These antibodies activate mast cells and basophils which release histamine and other pro-inflammatory mediators upon encountering the allergen.^1,3,4,6,7 Symptoms can include itchy, watery eyes, sneezing, coughing, skin redness, local or wide-spread hives (urticaria), asthma, angioedema, vomiting, diarrhea, and in severe cases, anaphylaxis.^1,8,9

In some cases, allergens can also cause a Type IV Hypersensitivity reaction, which is delayed and mediated by chemical messengers (cytokines) released by sensitized helper T cells.^4,10,11

Allergic reactions vary from person to person, and not everyone reacts to allergens in the same way. Therefore, when symptoms are significant, diagnostic testing may be necessary to identify the specific allergen(s) and guide treatment.

This policy addresses both immediate IgE-mediated hypersensitivity reactions and delayed cell-mediated hypersensitivity. It includes guidelines for in vivo testing (such as skin tests), organ challenge tests, serum specific IgE in vitro testing, and details on limitations and provider qualifications. other diagnostic immunology testing for the evaluation of immune system function is outside the scope of this policy.

Coverage Indications

Indications for Allergy Testing

Allergic diagnostic testing is generally divided into 2 main types: in vivo and in vitro testing.

Allergy testing is covered when it has proven efficacy as demonstrated through scientifically valid peer reviewed published medical studies.

A comprehensive medical and immunologic history and physical examination with testing based on reasonable exposure to the suspected allergen(s) should be demonstrated in the documentation to support reasonable and necessary coverage requirements.

Due to the possibility of unforeseen severe allergic reactions, medical supervision and resuscitative equipment must be available during in vivo testing.

In Vivo Testing

In vivo testing includes various skin tests and other organ specific testing to diagnose allergic reactions. Findings must be correlated with clinical symptoms. The use of positive and negative controls is required.

1. Percutaneous Testing - commonly used for suspected IgE-mediated allergic reactions to inhalants, foods, and certain drugs and occupational exposures.
2. Intracutaneous/Intradermal Testing (IDT) - used when percutaneous tests are negative, yet suspicion remains high. Not recommended for food or latex allergy due to risk of systemic reactions.
3. Skin Endpoint Titration (SET) Testing (also known as Intradermal Dilutional Testing) - used to determine immunotherapy starting doses for primarily Hymenoptera venom or aeroallergen sensitivities.
4. Skin Patch Testing - used for diagnosis of allergic contact dermatitis (ACD) caused by various substances (e.g., detergents, oils, metals, drugs, chemicals, food products). Custom patch testing may be needed based on clinical history.
5. Photo Patch Testing - used if exposure to allergens is suspected to be worsened with ultraviolet (UV) light.
6. Photo Testing - involves skin irradiation with UV light to evaluate photosensitivity.
7. Delayed Hypersensitivity Skin Testing- commonly used for testing contact allergens (see skin patch testing) and infections with intracellular pathogens (such as tuberculin), or anergy tests.
8. Organ Challenge Testing/Allergen Provocation Testing - In vivo testing via organ challenge is reserved for cases where clinical history suggests allergy, but initial skin or serum specific IgE testing is inconclusive and/or when objective confirmation of a clinically relevant allergic response is required. Testing should be performed in a clinical setting in which immediate emergent response by the physician and/or clinical staff is readily available. Testing may be performed in an open, single-blinded or double-blinded fashion.
1. Nasal Mucous Membrane Challenge Test - Confirms the cause of allergic rhinitis.
2. Ophthalmic Mucous Membrane (Conjunctival) Challenge Test-Assesses localized eye symptoms in the diagnosis of allergic conjunctivitis and may assist in the diagnosis of allergic rhinitis.

3. Inhalation/Bronchial Challenge Test - Measures airway hyperresponsiveness, often used in asthma cases and in identifying hypersensitivity reactions to environmental or occupational exposures.

1. Must be measured objectively, compared with a placebo control, usually involving some form of pulmonary function testing (e.g., measurement of FEV₁ before and after introduction of suspected allergen or other direct/indirect stimuli).

1. 4. Oral Challenge Test - Administers food or drug allergens in increasing doses to monitor reactions. The service is allowed once per patient encounter, regardless of the number of items tested, and includes evaluation of the patient’s response to the test items.
2.  
   1. 1. Food Challenge Test: Considered reasonable and necessary for the following indications: suspected IgE- mediated food allergy, anaphylactic shock due to an adverse food reaction, and suspected food-related dermatitis.
         • The need for oral food challenge (OFC) would stem from non-confirmatory results after having performed more commonly utilized first line in vivo testing such as skin prick testing (SPT) or patch testing, or in vitro testing such as serum specific IgE testing; unless testing for suspected allergen is not readily available or unless there is further need to confirm the clinical relevance of the allergen hypersensitivity identified on skin and/or serum testing in order to avoid unnecessary food restriction.
         • OFC testing is discontinued if objective reactions are identified, or the last dose of food tested does not elicit any reactive systems.
         • Testing performed by the patient in the home, and not in the office setting under medical supervision, will not be covered.
         • Challenge ingestion food testing is not payable when used to diagnose rheumatoid arthritis, depression, or respiratory disorder. Please refer to CMS Pub. 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 2, Section 110.12 for additional coverage details.
         • Sublingual, intracutaneous and subcutaneous provocative and neutralization testing and neutralization therapy for food allergies are excluded from Medicare coverage. Please refer to CMS Pub. 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 2, Section 110.11 for additional details.
      2. Drug Challenge Testing: Gradual administration of suspected drug allergens under close medical supervision. Used in the diagnosis of suspected IgE-mediated drug allergy, especially drugs such as nonsteroid anti-inflammatory drugs (NSAIDs), local anesthetics, non-beta lactam antibiotics, and other medications.

• • • • The need for oral drug challenge would stem from non-confirmatory results after having performed more commonly utilized first line in vivo testing such as SPT or patch testing, or in vitro testing such as serum specific IgE testing; unless testing for suspected allergen is not readily available or unless there is further need to confirm the clinical relevance of the allergen hypersensitivity identified on skin and/or serum testing in order to avoid unnecessary drug restriction.
      • Oral drug challenge may be appropriate for the evaluation of previously avoided drugs when there is a remote and/or questionable history of suspected drug allergy to determine whether the allergy labeling is accurate or whether there is need to resolve a drug allergy label (de-label), especially of essential medications (e.g. antibiotics, chemotherapeutics). In these instances, documentation to support medical necessity is warranted.

In Vitro Testing

Immunoassays measuring serum IgE levels are an alternative diagnostic approach.

1. Total Serum IgE*: Covered for indications including:

• Follow up of Allergic bronchopulmonary aspergillosis (ABPA)
• Select immunodeficiency such as Hyper-IgE syndromes*
• Eczematous dermatitis
• Recurrent Pyogenic infections*
• Evaluation for omalizumab therapy

*Note: The indications for Total Serum IgE testing are not confined to traditional allergy testing (i.e. IgE-mediated and delayed hypersensitivities to external allergens upon exposure), where its use is limited. It is also recognized that Total Serum IgE may have additional roles in the diagnostic evaluation of other immunologic disorders, malignancies, and parasitic infections. These uses fall outside the defined scope of this LCD and are therefore not all specifically addressed. Any omission in this case should not be interpreted as a non‑coverage determination.

2. Allergen Specific Serum IgE: Covered for indications including:

• Contraindications to skin testing secondary to widespread skin disease (e.g., dermatographism, ichthyosis, extensive dermatitis, generalized eczema)
• Medication use impacting skin testing results that cannot be safely discontinued (e.g., long-acting antihistamines, tricyclic antidepressants)
• Uncooperative patients secondary to age and/or mental and/or physical impairment
• Patients for whom the potential benefits of skin testing do not outweigh the associated anaphylactic risk
• Uncontrolled asthma
• Inconclusive skin testing results to rule out cross-reactivity and/or in setting of persistent clinical suspicion for allergy

Limitations

1. Inhalant allergy evaluation may require up to 70 percutaneous tests and up to 40 intracutaneous tests if percutaneous tests are negative; therefore, greater than 70 percutaneous and 40 intracutaneous tests would not be reasonable and necessary.
2. Patch tests may require up to 80-90 tests; therefore, greater than 90 tests would not be reasonable and necessary.
3. Routine repeat testing is not considered reasonable and necessary unless documentation supports the need (e.g., changes in environmental exposure, new clinical signs/symptoms, lack of efficacy of current immunotherapy).
4. The total number of tests performed (e.g. skin prick, intracutaneous, patch testing, or serum testing) should not exceed generally accepted standards of testing set forth by professional associations.
5. Routine in addition to skin testing for the same antigen is not reasonable and necessary, except in the case of suspected latex sensitivity, or nut/peanut sensitivity where both the skin test and the in vitro test may be performed when indicated.
6. IgE-mediated allergy testing for substances such as newsprint, sugar, cornstarch, orris root, tobacco smoke, cotton, formaldehyde, and smog is not supported by evidence and hence is not reasonable and necessary.
7. Allergen‑specific IgE:
   1. Qualitative multiallergen screening tests (single result reported as positive or negative without identification or quantification of individual allergens) are not considered reasonable and necessary as the information they provide does not offer clinical utility in diagnosing allergen‑specific hypersensitivities.
   2. Multiplex microarray test utilizing a single platform or chip to simultaneously assess multiple categories of allergens (e.g. aeroallergens, food allergens, venoms, latex) is considered screening and is therefore not reasonable and necessary when not clearly supported by the patient’s documented clinical history, presenting signs and symptoms, relevant exposures and/or differential diagnosis.
   3. Singleplex testing directed at suspected allergen(s) is considered reasonable and necessary when ordered based on the patient’s documented clinical history, presenting signs and symptoms, relevant exposures and/or differential diagnosis.
8. Coverage for all serum lab testing requires performance in CLIA (Clinical Laboratory Improvement Amendments of 1988) certified laboratories. (42 CFR §493.3)

Background

In Vivo Testing 

Skin testing is the first line diagnostic method for assessing type I IgE mediated hypersensitivity related to allergic conjunctivitis, rhinitis, asthma, dermatitis, food, drug, venom, and some occupational related allergies.^1,2,4,12-15 Skin testing can be performed using various methods, including percutaneous testing, intracutaneous or intradermal testing, intradermal dilutional or SET testing, and/or patch testing. Type IV Cell Mediated (delayed) Hypersensitivity reactions may also be evaluated using certain types of skin testing. The diagnosis of IgE or cell mediated (delayed) hypersensitivity conditions does not rely on diagnostic testing alone. Results must be correlated with the patient’s clinical history and physical examination.^2,99

Percutaneous Testing (by scratch, puncture, or prick): SPT describes the most common, and preferred method, for diagnosing immediate hypersensitivity to allergens.^1,2,13,14 A small amount of allergen is introduced to the skin through a small prick or puncture, causing an allergic reaction that results in raised, red, and itchy areas (wheal and flare) which indicates sensitivity.^4,7,13 This method is quick, safe, and cost-effective. But, medical supervision is required due to the risk of anaphylaxis.^{1,,12-14,16,100} It is most sensitive for aeroallergens but may be less reliable for venoms, foods, and drugs. Intradermal testing is often performed when percutaneous results are negative, particularly for venom allergies.^13,14,17,18

Intracutaneous/Intradermal Testing (IDT): IDT is used to detect both immediate IgE-mediated and delayed hypersensitivity responses.¹² It is usually performed when increased sensitivity detection is the main objective, such as when percutaneous tests are negative, but there is a strong suspicion of allergy. ^{2,7,12,13,15-17,19} IDT is more sensitive but less specific than percutaneous testing and carries a higher risk of false positives and anaphylaxis.^{4,12,13,15,101} A diluted allergen extract (between 100 and 1000-fold more dilute) is injected intradermally into the skin, and the reaction is observed.^{2,4,7,12-17,19,21} IDT is usually not required to diagnose a respiratory allergy, but may be indicated when initial percutaneous testing is negative, or with venom and drug allergy testing.^{1,2,4,7,12-14,19,22} IDT is not used in the diagnosis of food or latex allergy in the United States (U.S.) due to an unacceptably high rate of systemic reactions.^{1,13,19,22,101}

Skin Endpoint Titration (SET): SET is a modified form of intradermal testing in which a series of increasing concentrations of a single suspected allergen are tested until an allergic response in the form of a wheal is noted in comparison to a negative control.^12,23,102 An orderly progression of antigen concentrations is prepared by making sequential dilutions with a ratio such as 1:3, 1:5, or 1:10. Both 1:5 and 1:10 dilution techniques are in use today. The choice appears to be based on where the physician trained and on personal preference. It appears that both methods have demonstrated safety and efficacy. After 15–20 minutes, the injection site is measured in terms of the size of the wheal and flare reaction. The end point response in SET is the lowest concentration of allergen that produces a wheal that is the first wheal 2 mm larger than the negative control wheal and is followed by a second wheal that is at least 2 mm larger than the preceding one. The weakest dilution that elicits an allergic response is often used to guide starting doses of allergen immunotherapy.^12,21 SET is mainly used for drug and venom allergy testing.^12,22

Patch Testing: Patch testing is used to evaluate and identify the etiology of a nonspecific dermatitis, ACD, and pruritic conditions.^{10,11,13,24,25} It is considered the gold standard for diagnosing ACD.^7,13,25-28 Small allergen patches are applied to the skin (usually upper back), and reactions are monitored over 48-72 hours but can be extended up to 4-7 days, if necessary.^{4,7,13,16,24,25,28} This test detects type IV cell-mediated (delayed) hypersensitivity to various allergens, including chemicals, drugs, and food.^{13,16,26,27,29} The number of allergens tested, and the effectiveness of patch testing rely heavily on the patient’s clinical history.^25,28 Fewer than 40 allergens produce most cases of ACD.¹³ The most common patch testing techniques include the T.R.U.E. test, an FDA approved test device, and use of the individual Finn Chamber.^{4,13,16,25,28,103} Custom patch testing may be required if clinical history supports ACD from an unknown allergen and standardized screening tests are unavailable or results unequivocal.^{13,24,25,30,104} Additional variants of patch testing include atopy patch testing (APT) and repeated use testing (RUT). APT may be used as a supporting diagnostic method for evaluation of inhalant and food allergen sensitivity in patients with atopic dermatitis and eosinophilic esophagitis, as well as in the diagnosis of drug hypersensitivity. RUT may be utilized to test suspected allergens thought to be weak sensitizers requiring repeated exposure in order to determine clinical hypersensitivity or those allergens that may have poor skin absorption/penetration. Notably, use of APT is less frequently performed in the U.S. due to lack of standardization of allergen extracts and testing protocol, lack of reproducibility of results as well as lack of consensus as to their clinical relevance. ^1,13,26

1. Photo Patch Testing: Photo patch testing uses application of duplicate patches that are then occluded (covered), with 1 of them being irradiated with UV light halfway through the occlusive period. At 24-48 hours, post irradiation, the patches are removed and evaluated for reaction.^13,25,28 Indicated to evaluate unique allergies resulting from light exposure.^25,28
2. Photo Testing: Photo testing is skin irradiation with a specific range of ultraviolet (UV) light. Photo tests are performed for the evaluation of photosensitivity disorders (photodermatoses). Photosensitivity disorders are most characterized by a pattern of skin findings involving primarily sun exposed areas such as the upper neck/chest, face, ears, and dorsum of the forearms. A thorough clinical history, including environmental, topical, medication and other exposures, family history, as well as physical examination are required as part of the initial workup. The most encountered photosensitivity disorders are subdivided into phototoxic, photoallergic, and immune-mediated conditions. Photo testing may be performed in coordination with photo patch testing as photoallergic conditions similarly induce a delayed cell-mediated response as ACD, with the distinguishing factor being activation by UV radiation. In the condition known as solar urticaria, urticarial skin lesions appear within minutes of sun exposure which resolves within 24 hours of sun avoidance. Although the exact mechanism is unknown, it is hypothesized that the development of urticarial wheals is a result of exposure to a specific wavelength of light that activates a type I IgE-mediated hypersensitivity response to an antigen that becomes allergenic upon exposure to UV radiation. The antigen(s), however, is unknown.^87-94

Delayed Hypersensitivity: Delayed hypersensitivity skin testing is most commonly used to test for sensitivity to contact allergens (see patch testing), testing for infection with intracellular pathogens, and anergy testing.^10,13 Type IV delayed hypersensitivity reaction is mediated by T cells inducing an inflammatory response when encountering allergen.^10,11 The number of skin tests for delayed, cell-mediated hypersensitivity is fairly limited, most commonly used in tuberculin testing and anergy testing with Candida, Trichophyton, and Tetanus toxoid antigens.¹³ The tuberculin skin test is elicited by the intracutaneous injection of 0.1 mL of standardized purified protein derivative (PPD) starting with the intermediate strength of 5 tuberculin units. The size of the delayed skin test response is measured 48 hours after allergen challenge.^10,13

Organ Challenge Testing/Allergen Provocation Testing: Direct exposure to suspected allergens is used to assess allergic reactions in organs such as the eyes, nose, lungs, or GI tract.^12,14,22,31 This may be appropriate when initial skin or serum specific IgE (sIgE) testing is inconclusive, yet suspicion for allergy is high.^12,13,15 It requires a controlled clinical environment with emergency support due to the potential risk of severe reactions like anaphylaxis.²⁰ Provocation may be performed in a single-blinded fashion, but ideally is performed as a double-blinded challenge.

1. Nasal Mucous Membrane Challenge: Nasal provocation confirms the cause of allergic rhinitis and is considered the gold standard for diagnosis.^1,7,13,19,32 Testing must be compared with placebo control.^13,32 Increasing quantities of allergen extract are introduced in the anterior part of the inferior nasal turbinate.^1,7,13,19,32
2. Ophthalmic Mucous Membrane Challenge: Conjunctival provocation assesses localized eye symptoms (e.g., conjunctival edema, erythema, itching) and may assist in the diagnosis of allergic rhinitis.^7,13,32 Testing involves the instillation of defined concentrations of allergen diluted in a solution in which a small amount is placed usually in the external quadrant of the ocular conjunctiva and results must be compared with a placebo control (often opposite eye).^7,13,22,32
3. Inhalation/Bronchial Challenge: Bronchial provocation involves the inhalation of suspected allergen and subsequent measure of airway hyperresponsiveness, as seen in asthma.^{1,7,13,15,19,32} The agents include but are not limited to environmental allergens, drugs that cause airway constriction, and chemical sensitizers usually related to occupational breathing problems.⁷ Demonstration of airway hyperreactivity must be measured objectively, compared with a placebo control, all of which most often involves some form of pulmonary function testing^{7,13,19,32,105} (e.g., measurement of FEV1 before and after introduction of suspected allergen).
4. Ingestion/Oral Challenge: Oral provocation involves the administration of food or drug allergens orally in increasing doses to monitor reactions.

Drug and Food Challenge Testing

1. Oral Food Challenge (OFC): OFC is conducted in a medical setting to confirm or exclude food allergies, especially when previous tests are non-confirmatory.^{7,16, ,32, ,75,106} Double-blind, placebo-controlled food challenges are considered the gold standard for diagnosing IgE-mediated food allergies.^{7,13,16,26,32,33} OFC testing should not occur if clinical history does NOT suggest an IgE-mediated reaction.^1,2,26,106 Adverse reaction to a certain food may be mediated by other factors, consequently false positive test results may occur.²
2. Drug Challenge: Oral drug provocation consists of the gradual administration of suspected drug allergens under close medical supervision.^{1,7,12,13,15,19,32,34,35,109} A limited number of adverse reactions to medications are IgE-mediated.¹² In addition, other factors limit effective testing for IgE-mediated drug reaction, such as with drugs that require protein binding to become a recognized allergen or allergic reactions occurring only with a drug’s metabolites.^7,12,107 Furthermore, only a few IgE specific serum tests, are commercially available for diagnosis of specific drug allergies.^12,13,34,108 Despite these limitations, before an oral drug challenge is initiated, skin testing and/or sIgE testing should be the initial diagnostic testing performed, unless not feasible or contraindicated.^7,12,32,35 Oral drug provocation can be used to identify allergies to drugs like NSAIDs, local anesthetics, non-beta lactam antibiotics, and other medications; and only performed when no alternative diagnostic method is available and/or there is no equally effective drug substitution.^7,32

In Vitro Testing

Serological Testing for IgE

Measures the immune system's type I hypersensitivity response and is an alternative to skin testing in allergy diagnosis.^{1,2,3,12,13,36,37}

Total Serum IgE

Elevated total serum IgE levels are common in individuals with allergic conditions (atopy), but they are not a reliable indicator of allergy, as high levels can also occur in non-allergic conditions like parasitic infections, immune disorders, malignancies, and smoking.^{1,2,12,13,110}

Total serum IgE is age-dependent, and low levels do not exclude the presence of an allergy.^12,36,111

Total serum IgE may be useful in specific cases, such as diagnosing ABPA and determining eligibility for anti-IgE therapy (e.g., omalizumab) in patients with moderate to severe asthma.^12,13,36,110

Aside from these exceptions, total serum IgE measurement is generally not indicated for routine allergy diagnosis.^12,13,111

Allergen-Specific IgE

Testing for allergen-specific IgE antibodies helps identify immediate hypersensitivity reactions to specific allergens.^{1,2,3,13,36,37} It is often used when patients cannot tolerate skin tests (e.g., young children, pregnancy, skin conditions) or when skin test results are inconclusive.^{2,5,12,13,36,37,112}

Immunoassay Testing

An immunoassay is a laboratory test that uses specific antibodies to antigens or other substances to identify the presence or concentration of a target substance. In this setting these tests detect allergen-specific IgE antibodies using antigen antibody reactions. Types of immunoassay techniques include:^3,12,37,39

Radioallergosorbent Test (RAST)

RAST is an older technique using radioactivity to measure antigen-antibody complexes.^13,36,37,38

It was one of the earliest methods for detecting allergen-specific antibodies. It employs radioactively labeled allergens to detect the binding of IgE antibodies in the patient's serum. While less commonly used today due to safety concerns associated with radioactive materials, it remains a historical milestone in allergen immunoassay development.

Enzyme-Linked Immunosorbent Assay (ELISA)

ELISA is a modern method using enzyme labeling for detection.³ It is widely used and currently the most common immunoassay technique in allergen testing. It involves the use of an enzyme-labeled antibody that binds to the allergen-specific antibodies in the patient's serum. The reaction produces a measurable color change, indicating the presence and quantity of allergen-specific antibodies.

Fluorescent Allergosorbent Test (FAST)

FAST is an in vitro assay using a fluorogenic detection system that looks for allergen-specific IgE antibodies in serum, indicating an allergy to the substance.^41,42,43 It has a similar mechanism of action as RAST, but instead of radiolabeling, uses fluorescence labeling and detects antigen-antibody activity using a spectrofluorometer.^40,45,46,47

Multiple Radioallergosorbent Test (MAST)

MAST is an in vitro assay using an enzymatic detection system that looks for allergen-specific IgE antibodies in serum, indicating an allergy to the substance. It is similar to RAST in that the specific allergen of interest is coupled to a solid phase (typically nitrocellulose instead of paper), antibodies from the added serum complex bind to the antigen if allergy exists, and a tagged anti-IgE is added to visualize the binding.^41,42 MAST is not a registered brand name, but rather a category of immunoassays. Some MASTs use chemiluminescence visualization, others use colored products resulting from the oxidation of various organic substrates.^40,44,45

Fluorescent Enzyme Immunoassays (FEIA)

Fluorescence enzyme-labeled assays are variations using fluorescence for detection. In FEIA, a fluorescent antibody binds to the patient's sIgE, and the amount of IgE present is calculated from the amount of fluorescence.^3,12

Chemiluminescent Immunoassays (CLIA)

These are assays in which the radioactive isotopes are replaced by chemiluminescent substances and electrochemiluminescent techniques.^3,12,48

ImmunoCAP

ImmunoCAP Specific IgE is an in vitro quantitative assay for the measurement of allergen-specific IgE in human serum or plasma (EDTA or Na-Heparin). ImmunoCAP Total IgE is an in vitro test system for the quantitative measurement of circulating total IgE in human serum or plasma.^5,49 They are intended for in vitro diagnostic use as an aid in the clinical diagnosis of IgE-mediated allergic disorders in conjunction with other clinical findings and is to be used in clinical laboratories.⁴⁹

Serum IgE tests may be qualitative (positive/negative results) or quantitative, measuring the amount of IgE to assess the likelihood of allergy.^3,12,13,31

Qualitative vs. Quantitative Testing

• Qualitative Testing: Provides simple positive or negative results but does not indicate the severity of an allergy or clinical relevance.^{2,12,31,37,39} With the advent of quantitative testing, this form of testing does not demonstrate clinical utility.
• Semi-Quantitative/Quantitative Testing: Measures the concentration of allergen bound IgE antibodies in the serum, giving more detailed information.³¹ It uses standardized references like the International Reference Preparation for Human IgE from the World Health Organization.³¹ Semi-quantitative assays provide a range of levels or increasing classes to indicate the amount of response.^{3,5,12,13,31,37,39}

Quantitative testing provides more clinical insight, especially when correlated with the patient’s history and physical examination.^12,31,37 However, results can vary between different immunoassay products due to differences such as in allergen extracts and testing methods, as well as autoanalyzer calibration and measurement algorithms.^{2,5,31,36,37,50} Thus, results of one type of test may not be equally compared to a different product, as the objective units of measurement may not directly correlate between assays.^{2,5,36,37,113} Consequently, switching between in vitro assays is not considered appropriate because results are not equally comparable or interchangeable, unless there is documented reasoning for change in specific assay.⁵ Of the different immunoassay products on the market, not every product is accompanied by robust laboratory testing to support its reproducibility and accuracy of results.⁵ Therefore, the expectation lies with the ordering provider when selecting which assay (manufacturer) to utilize to understand the technical characteristics of the available tests/assays, the differences between them, as well as which tests have evidence to support the clinical validity of its results and its clinical use in the diagnosis of the specific allergic condition.^{5,12,31,39,51} The serum IgE test of choice, should be validated according to the Clinical Laboratory Standards Institute (formerly called the National Committee for Clinical Laboratory Standards [NCCLS]) whenever possible.¹¹⁴ In addition, the Centers for Medicare and Medicaid Services (CMS) requires that all laboratory testing be performed in CLIA certified (Clinical Laboratory Improvement Amendments of 1988) laboratories or must be recognized by CMS as CLIA-exempt.^36,52

Singleplex vs. Multiplex Testing ^3,5,12,36,51

• Singleplex Testing: Targets individual allergens or specific allergen components.
• Multiplex Testing: Tests multiple allergens simultaneously using microarray chip technology, in which a panel of multiple allergens (allergoabsorbants) are embedded on a small chip undergoing similar IgE antibody detection all while using a small volume of a patient’s serum. This allows for comprehensive screening with small serum samples. Multiplex testing is efficient but may have variability due to differences between batches or manufacturers.^{3,12,13,36,37,51}

Allergens

Allergens used in in vitro testing platforms may be raw (whole) allergen extracts that are a mixture of allergenic and non-allergenic proteins or may consist of single molecules that make up a specific individual allergen component.^3,12,31

Currently, use of whole allergen extracts, or selected components of naturally sourced raw allergen extracts are utilized in the first/initial level diagnostic testing for allergy whether in singleplex or a multiplex testing platform.^{12,31,36,37,51}

• Recombinant Allergens

         Purified, genetically engineered allergenic components are increasingly used to standardize the makeup of the allergen being tested.^{3,12,36,37,39,51,53} However, some patients may not respond to such pure isolated allergenic molecules, as they may react to the native heterogeneous allergen itself.^12,36 Recombinant allergen               extracts developed in order to standardize extracts have been utilized in Europe but only cover a limited number of allergens, as well as limited to mostly research applications in the U.S..^12,14,115

• Molecular Allergology/Component Resolved Diagnostics (CRD)

As technology in diagnostic testing has improved over time, so has allergy testing. More recently, the field of molecular allergy based or Component Resolved Diagnostics (CRD) has become available.^37,50,51,53 This form of in vitro diagnostic testing involves the measurement of the serum concentration of IgE for a specific allergen component (molecule) of a suspected allergen source.^3,50 Most often the component (molecule) is a single protein.^3,50 The singular molecule/component may be extracted from a native (or natural) allergen or can be a recombinant molecule produced through genetic engineering.^3,50,51 Molecular allergology allows for the diagnosis of a specific allergen down to the molecular component level.⁴ Thus, theoretically ruling out any potential cross reactive components for which a patient may not be truly sensitized.^3,50 The move towards allergic diagnostic testing at the molecular level is also embedded in the principles of what is known as precision medicine or personalized medicine.^3,50,51

The serum testing for molecular allergenic components has already been integrated into certain multiplex immunoassay diagnostic testing platforms, such as the ISAC and ALEX tests, as well as singleplex studies.^3,50,51 Although one would theoretically benefit from identifying the culprit allergen(s) down to the molecular level, with the still potential variability amongst the different testing platforms, it is not currently efficient to include the sheer number of potential allergenic molecules that one would require testing for into 1 microarray panel. Especially considering identification and isolation of specific known allergenic molecules is still an area of research.^12,37 In addition, some allergenic molecules when separated from the entirety of its native allergen do not necessarily undergo the biochemical transformations that would induce an immune response, therefore potentially resulting in falsely negative results. Creation of a recombinant molecular allergen would be ideal to allow production of unlimited amounts of allergen for testing, however, recombinant components may not be recognized by the immune system to be allergenic due to lack of identifiable targeted epitopes, the specific region(s) on an antigen molecule that triggers the initial immune response.

Furthermore, of the current handful of multiplex diagnostic testing platforms available, the current technology is such that the simultaneous testing of the set specific allergens and/or allergenic molecular components is fixed and various allergenic reagents on one chip/panel cannot be interchangeable. Otherwise, reproducibility and accuracy of results would be negatively affected.^{3,5,12,37,50,51}

As the number of identified and isolated allergenic molecules available for diagnostic testing continues to expand, a substantial proportion of clinically relevant components remain unidentified or insufficiently validated for use in diagnosing IgE‑mediated allergy.^51,132 However, there is already increasing use of component‑resolved diagnostics (CRD) in select clinical circumstances. Examples include the evaluation of suspected IgE‑mediated food allergy—such as peanut, hazelnut, or cashew allergy—where components such as Ara h 2, Cor a 14, and Ana o 3 may enhance diagnostic specificity as well as the assessment of galactose‑α‑1,3‑galactose (alpha‑gal) sensitization.^{74,131,132,142} CRD may also be utilized in the diagnostic workup of Hymenoptera venom allergy, in which cross‑sensitization is common and accurate identification of the culprit venom is essential for appropriate allergen immunotherapy planning.^12,132 Despite these targeted applications, molecular allergy diagnostics in general are not typically considered first line testing in standard clinical practice and are generally guided by the individual clinical context. Their role is evolving, and it is anticipated that the use of allergen component testing will continue to expand over time.^64,74,132

In Vivo Testing

Skin testing is the first line diagnostic method for assessing type I IgE-mediated hypersensitivity related to allergic conjunctivitis, rhinitis, asthma, dermatitis, food, drug, venom, and some occupational related allergies. Skin testing can be in the form of percutaneous testing, intracutaneous or intradermal testing, intradermal dilutional or SET, and/or patch testing. The diagnosis of an IgE-mediated allergic condition does not rely on diagnostic testing alone. In addition, skin testing in the form of intradermal testing and/or patch testing may be utilized in detecting type IV delayed cell-mediated hypersensitivity.

Evidence-based practice guidelines and appropriate requirements are available for in vivo allergy testing. Percutaneous testing, including prick/puncture tests, is commonly used to assess sensitivity to various allergens. Prick/puncture or intracutaneous/intradermal skin tests are important for diagnosis of inhalant allergy. Food prick and puncture skin tests are excellent diagnostic modalities for the diagnosis of IgE-mediated clinical entities, which include anaphylaxis, food-dependent exercise-induced anaphylaxis, acute urticaria, atopic dermatitis, and oral allergy syndrome. The evidence-based guidelines recommend SPT and sIgE as first-line methods for evaluation of IgE sensitization to food allergens. While serious systemic reactions from prick/puncture tests are rare, prescreening can help prevent severe responses to intracutaneous tests. Intradermal testing offers high sensitivity in detecting skin sensitivity, often used when skin prick or puncture tests yield negative results despite a strong history of exposure. They are the tests of choice for evaluation of anaphylaxis, particularly drug (i.e., penicillin), and Hymenoptera venom anaphylaxis. Some clinicians may initially test with prick/puncture followed by intradermal tests if the results of the former are negative, while others exclusively use intradermal tests. SET, or intradermal dilutional testing (IDT), acts as a guide in determining a safe starting dose for immunotherapy. The guidelines state that when compared with specific nasal challenge, SET is equivalent to prick/puncture skin tests. Though not a substitute for skin testing, SET can serve as an alternative when determining a safe starting dose or when there is risk of severe systemic reaction or anaphylaxis, such as Hymenoptera venom.

The epicutaneous patch test is the primary method for diagnosing ACD, particularly important in chronic eczematous dermatitis in occupational setting. It is the gold standard for identification of a suspected contact allergen. There are variants like the APT and RUT. The guidelines recommend patch testing when exposure to a contactant is suspected. Patch tests are most effective when the patients are selected on the basis of a clear-cut clinical suspicion of contact allergy, and they are tested with the chemicals relevant to the problem; these conditions satisfy the prerequisites of high pretest probability. Up to 80-90 patch tests may be required for diagnosis.

Regarding photo patch testing, the guidelines point out that certain contactants (e.g., antibiotics, PABA) may induce photocontact ACD or phototoxic CD. When these are suspected, photo patch tests, primarily in the UV-A range of 320 to 400 nm, are recommended.

Phototesting, which involves MED testing, provocation phototesting and photopatch testing, can be used if it is suspected that photodermatoses or other skin conditions are caused or aggravated by UV exposure.

Evidence-based guidelines emphasize the role of dIDT for diagnosing suspected cell-mediated immunoallergic responses and state that positive dIDT within 48 hours in conjunction with patch testing can be useful in investigating delayed-hypersensitivity reactions to antibiotics. Other guidelines recommend the consideration of patch testing/dIDT when a patient has had a delayed adverse drug reaction that is suspected to be T-cell mediated. Other guidelines make this recommendation with conditional strength of evidence and very low certainty of evidence, citing that most evidence originated from poor quality case series study designs.

Some guidelines provide the insight that nasal challenges may serve as a confirmational test if clinical history, skin tests, and/or sIgE tests are discordant, and an identified allergen is suspected as the causal agent. Due to insufficient evidence, some of the evidence-based guidelines do not make a recommendation in favor nor against the usage of nasal allergen challenge and emphasize NAPT as an essential component to confirming diagnoses of both LAR and occupational rhinitis.

The guidelines agree that CAPT has a role in diagnosing allergic rhinoconjunctivitis or occasionally in nasal allergy, particularly in instances when clinical history, prior skin tests, and sIgE testing are inconclusive or discordant. One of the guidelines recommends CAPT as being indicated for seasonal allergic conjunctivitis (Grade B), perennial allergic conjunctivitis (Grade B), vermal keratoconjunctivitis (Grade C), and select cases of atopic keratoconjunctivitis (Grade C).

Some guidelines provide a weak endorsement of inhalation challenge testing, whereas the others offered more robust conclusion in favor of bronchial provocation testing. One of the guidelines states that specific bronchial provocation testing is the gold standard test for diagnosing OA with grade A evidence; but they state that the technicality of the test, high cost, and limited availability of capable facilities resulted in the panel decreasing the strength of evidence.

Skin prick testing and serum specific IgE assess sensitization rather than clinical reactivity and must be interpreted in the context of a compatible clinical history. OFCs can give definitive clinical answers that help differentiate true allergy versus sensitization noted on skin prick testing (SPT) or serum specific IgE (sIgE). As oral food challenges are the diagnostic standard for food allergy but carry inherent risk, they should be used judiciously, guided by stepwise adjunctive testing, when available, risk versus benefit considerations, and performed only by experienced clinicians in appropriately equipped settings.

Societal guidelines consistently identify drug provocation testing as the diagnostic gold standard for suspected drug allergy, particularly where skin and/or serum testing has limited value. Oral drug challenges are recommended selectively, based on clinical context and risk, including for de-labeling remote, non-severe antibiotic allergies, while generally avoided in cases of prior anaphylaxis unless safer alternative approaches are feasible. Overall, guidance supports a risk stratified, indication specific use of oral provocation when diagnosis cannot be reliably established by history alone.

The appropriate choice and specifics of allergy testing depend on multiple factors that need to be considered. Evidence-based guidelines state that although prick/puncture tests are generally age, sex, and race independent, certain age (children younger than 2 years and adults older than 65 years) and racial (African American children) factors may affect their interpretation. Compared with clinical history alone, the diagnostic accuracy of prick/puncture tests alone showed more limited capacity to predict clinical sensitivity for both inhalant and food allergens.

For some of the tests, availability of allergens is an issue. For instance, dIDT is not possible for many tests because the suspected allergen must be available in a parenteral formulation in order to be tested via dIDT.

Frequency also needs proper consideration. Guidelines suggest the number of skin prick/puncture tests to be 70. Guidelines on allergy diagnostic testing recommend 40 intradermal tests for inhalant allergens, and it is justified as an initial diagnostic evaluation. However, routine annual tests without a definite clinical indication are clearly not indicated. Guidelines suggest that because ACD is frequently caused by unsuspected substances, up to 80-90 patch tests may be required for diagnosis. Supplementary patch tests may be required as suggested by the patient’s exposure history.

For an individual patient, the choice of allergens for testing should be guided primarily by the patient’s history and physical examination and will reflect the physician’s knowledge, training, and experience. To accommodate the risk of serious adverse events, some guidelines make specific recommendations to only perform tests like OFC in the presence of medical personnel, who can monitor symptoms and intervene if necessary.

There are limitations and contraindications to certain testing. Some guidelines identified absolute contraindications to NAPT, which includes prior anaphylaxis to the suspected allergen, acute sinus inflammation, severe comorbidity, severe systemic disease, immunotherapy, and pregnancy. Notable contraindications for CAPT include, ensuring CAPT is performed outside of pollen season, concomitant ocular disorders, pregnant or lactating women, and non-IgE-mediated ocular surface diseases. In the event of a positive CAPT result, the authors suggest that patients should stay onsite for at least 2 hours for monitoring to ensure safety. Some tests like traditional patch testing for the diagnosis of ACD lack a proper gold standard to assess it for diagnostic accuracy and likelihood ratios.

Serum Specific IgE Testing

Clinical presentations of allergies often overlap with respiratory infections and autoimmune conditions, complicating diagnosis which highlights the need for allergy testing to clarify triggers and guide treatment.

While skin testing is generally preferred for diagnosing allergic diseases, sIgE in vitro testing is a valuable tool for assessing IgE-mediated sensitization, particularly when skin testing is contraindicated due to conditions such as generalized eczema, dermatographism, or unstable medical conditions. It has distinct advantages, such as eliminating the risk of adverse reactions, remaining unaffected by medications like antihistamines, and requiring only a blood draw. However, the results must always be interpreted in the context of the patient’s clinical history, as allergen-specific IgE presence indicates sensitization but does not confirm reactivity without a supervised challenge.

Various immunoassays are utilized in in vitro allergy testing with some like RAST being more antiquated. Modern third-generation assays with better accuracy and analytical sensitivity are available but their value remains debatable. Sensitivity levels for in vitro tests range between 50–90%, averaging 70–75%, but these values vary depending on factors such as allergen type, assay methodology, and total serum IgE levels, which can influence diagnostic reliability.

For inhalant allergies, although both skin prick and IgE-specific antibody testing can be used to test for inhalant allergies, skin testing is preferable. For food allergies, initial management involves eliminating the suspected allergenic food from the diet. If ineffective, IgE-specific antibody or skin testing can be helpful to confirm or exclude allergens but an OFC is recommended to confirm the diagnosis. Specific IgE testing has strong negative predictive value for ruling out allergies but limited positive predictive value for food and drug allergies. OFCs are thus crucial for definitive diagnosis. It is recommended against performing food IgE testing without a history consistent with potential IgE-mediated food allergy. For insect allergies skin prick, intradermal, or IgE-specific antibody testing can be utilized for patients with anaphylaxis and those with systemic diffuse cutaneous reactions involving multiple organs. Additionally, in vitro testing has been recognized as complementary in scenarios such as diagnosing Hymenoptera venom sensitivity when intradermal skin tests yield negative results despite a convincing clinical history. Reliable detection or exclusion of drug hypersensitivity based on in vitro diagnosis alone is not possible. Validated tests for the detection of sIgE antibodies in serum are only available for a few drugs, otherwise no standardized and evaluated in vitro methods exist. Nonetheless, the predictive value of sIgE results is limited when used independently, as detection of sensitization does not equate to a clinical diagnosis of allergy.

Total IgE serves as a marker for atopic conditions. It can be used in conjunction with serum specific IgE (sIgE) to help inform select clinical decisions. For example, while sIgE tests identify triggers for allergic reactions, total IgE quantifies how much allergic activity is present in the body. Clinicians use total IgE to help diagnose complex atopic conditions like Allergic Bronchopulmonary Aspergillosis (ABPA) and monitor patients for relapses. Total IgE is also clinically required for patients who are beginning anti-IgE medications like Omalizumab because the level of total IgE present determines the dose of medication required to neutralize allergic reactions. Total IgE can be used to help make sense of multiple sensitizations in severe cases of atopic dermatitis and may play a role in determining the likelihood of false positives on sIgE testing in extremely atopic individuals. Extremely high levels may indicate rare conditions such as Hyper-IgE Syndrome or a parasitic infection.

Ultimately, clinicians are advised to interpret in vitro test results within the context of patient history and clinical manifestations, incorporating in vivo testing when needed for optimal diagnostic accuracy. And so, while in vitro allergy tests provide critical insights into allergen-specific IgE levels, their limitations necessitate a judicious, integrative approach to ensure accuracy and clinical relevance.

Experimental/Investigational

Although this Local Coverage Determination (LCD) focuses on IgE-mediated or delayed type hypersensitivity reactions, any other forms of allergy diagnostic testing not otherwise included in this LCD will be subject to Medicare rules and regulations, including reasonable and necessary requirements as per Social Security Act (SSA) §1862(a)(1)(A) and Publication 100-08 of the Internet-Only Manual (IOM) Medicare Program Integrity Manual, chapter 3, section 3.6.2.2. Should the need arise to consider coverage for other allergy diagnostic tests other than what is included in this LCD, additional evidentiary analysis of peer reviewed literature may be conducted for future LCD development.

Provider Qualifications

It is expected that diagnostic services related to IgE‑mediated allergy and delayed type hypersensitivity be furnished by providers who possess the knowledge, training, clinical competency, and clinical judgment necessary to appropriately select, perform, and interpret allergy testing, including skin testing (i.e. skin prick, intracutaneous, and/or patch), serum specific IgE testing, and/or organ‑specific challenge testing when clinically indicated.

The selection of the diagnostic modality must be consistent with accepted standards of medical practice, the provider’s training and experience, and the resources available within the clinical setting. Because in vivo allergy testing may result in local or systemic allergic reactions, including anaphylaxis, such testing should be conducted in an appropriate clinical setting under the direct supervision of a physician trained in the recognition and management of allergic reactions and capable of initiating appropriate emergency intervention when necessary.

Conclusion

According to the Centers for Disease Control National Center for Health Statistics, as of 2021, roughly 1 in 3 adults (32%) in the U.S. are reported to have seasonal allergy, eczema, or food allergy. Nearly 25 million adults and children report to have asthma. As allergic conditions are treatable, it is important to address the approach to allergy diagnostic testing in the Medicare beneficiary.

As with all services covered by Medicare, the item/service provided must meet Medicare’s Reasonable and Necessary requirements as stated in the SSA §1862(a)(1)(A) and Publication 100-08 of the IOM Medicare Program Integrity Manual, chapter 3, section 3.6.2.2. Routine or preventative screening without specific clinical signs and symptoms is not covered (42 CFR §411.15).⁸¹ Allergy testing should be individualized and follow a structured diagnostic approach, beginning with a detailed clinical history and physical examination. The expectation lies with the ordering provider when selecting which route of testing to initiate the diagnostic workup. It is also imperative that the provider understands the technical characteristics of the available tests/assays, the differences between them, and whether evidence is available to support the clinical validity and utility of its results.

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