Allergy Diagnostic Testing

Title XVIII of the Social Security Act, Section 1833 (e) prohibits Medicare payment for any claim which lacks the necessary information to process the claim.

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

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

42 U.S. Code § 263a

42 CFR, Section 410.20 – Physicians’ Services

42 CFR Section, 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, Section 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 Pub 100-02 Medicare Benefit Policy Manual, Chapter 15 – Covered Medical and Other Health Services, Sections
20.2 – Physician Expense for Allergy Treatment
80.1 – Clinical Laboratory Services
80.6 – Requirements for Ordering and Following Orders for Diagnostic Tests

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

CMS Pub 100-04 Medicare Claims Processing Manual, Chapter 12 – Physicians/Nonphysician Practitioners, Section
200 - Allergy Testing and Immunotherapy

Chapter 16 – Laboratory Services, Section 40.7 – Billing for Noncovered Clinical Laboratory Tests

CMS Pub. 100-08 Medicare Program Integrity Manual, Chapter 3, section 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 GI tract.^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.

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.

Unrelated multi-allergen panels are not considered reasonable and necessary.

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 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, Hymenoptera venoms (wasps, honeybees, yellow jackets, hornets, imported fire ants, and others), foods, and certain drugs and occupational
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: Further in vivo testing via organ challenge is reserved for cases where clinical history suggests allergy, but initial skin or serum IgE testing is inconclusive. Testing should be performed in a clinical setting in which immediate emergent response by the physician and/or clinical staff is readily available. Testing should be performed in a double-blinded, if not single-blinded fashion.
   1. Nasal Mucous Membrane Challenge Tests- Confirms the cause of allergic rhinitis
   2. Ophthalmic Mucous Membrane (Conjunctival) Challenge Tests- 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.
      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).
      2. Generally, 3 measures of each determination (e.g., spirometry, prolonged post exposure evaluation of bronchospasm) are performed. The best of the 3 is accepted and represents 1 unit of service. A unit is defined as each set of 3 measurements.
      3. Pulmonary function studies are not included in the bronchial challenge test.
   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. Oral challenge 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.
      1. Food Challenge Test: Considered reasonable and necessary for the following indications: food allergy, anaphylactic shock due to an adverse food reaction, and suspected food related dermatitis.
         • It is Noridian's expectation that 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 food specific IgE testing, unless testing for suspected allergen is not readily available.
         • 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.
      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. Testing should only be performed when no alternative diagnostic method is available and/or there is no equally effective drug substitution.
         1. It is Noridian's expectation that 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 IgE testing, unless testing for suspected allergen is not readily available.

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 in the treatment of moderate-to-severe allergic asthma

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 at significant risk of anaphylaxis
  • 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.
2. Patch tests may require up to 80 tests.
3. Routine repeat skin 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, i.e. prick or intracutaneous, should not exceed generally accepted standards of testing set forth by professional associations. Exceeding these parameters may be justified if preliminary testing failed and immunotherapy failed to control symptoms. In this case, documentation of medical necessity is warranted.
5. In-vitro testing performed in addition to skin testing for the same antigen is not usually necessary, except in the case of suspected latex sensitivity, Hymenoptera, or nut/peanut sensitivity where both the skin test and the in-vitro test may be performed.
6. 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 covered.
7. Payment 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 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 (WHO).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

         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 1 chip/panel cannot be interchangeable. Otherwise, reproducibility and accuracy of results would be negatively affected.^{3,5,12,37,50,51}

         Consequently, the testing of molecular allergens is not considered first line diagnostic testing. Rather, this method is more applicable to research than routine clinical use.^12,31,37,50

Evidentiary Analysis

Literature Review

Based on an a priori scoping review of the evidence base, it was determined that in vivo allergy testing modalities have been utilized routinely for a long duration of time. Because they are utilized as a standard of care, the academic community has long ceased conducting further research, resulting in a dearth of clinical literature.

In situations where this arises, the academic community suggests consideration of clinical context and investigation of subject matter expert consensus methodology in lieu of reliance on primary literature^54,55,56 When relying exclusively on professional society recommendations and evidence-based guidelines, it is essential to do so systematically, search for consensus between numerous societies on the same topics, and weigh evidence-based findings more heavily than consensus opinions. To ensure scientific rigor was upheld to a high standard for this evidentiary review, the analysis plan was designed a priori to adhere to the systematic review of clinical practice guidelines outlined by Johnston et al., 2019.⁵⁶

In Vivo Testing

In vivo allergy testing is an umbrella term that describes an array of tests that vary widely in rationale, technique, safety, efficacy, intended indication, and best practice. To structure this evidentiary review, 8 different categories of in vivo tests were designated a priori. These classifications include: (A.) Percutaneous testing; (B.) Intracutaneous/Intradermal testing; (C.) Skin endpoint titration (SET); (D.) Skin patch testing; (E.) Photo patch testing; (F.) Photo testing; (G.) Delayed hypersensitivity skin testing; and (H.) Organ challenge testing.

The systematic literature search and review that were employed for this evidentiary analysis were structured around investigating both of the following key questions for each of the 8 aforementioned categories of in vivo allergy tests:

1. Is there consensus among published professional society statements and clinical practice guidelines on the efficacy and safety of [designated category of in vivo allergy testing] for diagnosing and managing allergies?
2. Do any published professional society statements or clinical practice guidelines provide recommendations pertaining to the number of tests for [designated category of in vivo allergy testing] that are considered reasonable and necessary within a given timeframe?

Percutaneous Testing

Percutaneous testing, including prick/puncture tests are commonly used for confirming clinical sensitivity to a number of aeroallergens, foods, some drugs, and a few chemicals. The American Academy of Allergy, Asthma & Immunology (AAAAI) 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.¹³ Compared with clinical history alone, the diagnostic accuracy of prick/puncture tests showed more limited capacity to predict clinical sensitivity for both inhalant and food 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 European Academy of Allergy and Clinical Immunology’s (EAACI) states that in vivo SPT and sIgE for food allergens are the first-line tests to assess IgE sensitization.⁵⁸ Life-threatening generalized systemic reactions are rarely caused by prick/puncture tests. In a recent retrospective survey stated by the AAAAI, one death was reported in a patient who received 90 food prick/puncture tests at one time. Prescreening with prick/puncture tests is helpful in avoiding life-threatening reactions to intracutaneous/intradermal tests. Only prick/puncture tests should be performed to define food sensitivity. The Joint Task Force on Practice Parameters on Allergy Diagnostic Testing suggests the number of skin prick/puncture tests to be 70. Routine annual tests without a requirement or an indication are not suggested.

Intracutaneous/Intradermal Testing

Intradermal testing offers increased sensitivity and will identify a larger number of patients with skin sensitivity. It is generally done when percutaneous tests, skin prick or puncture, 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 prefer to initially screen with prick/puncture followed by intradermal tests if the results of the former are negative, while others exclusively use intradermal tests. The Joint Task Force for Practice Parameters 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.¹³

Skin Endpoint Titration (SET)

SET, or intradermal dilutional testing, is a modified quantitative testing method where a series of increasing dilutions of a single suspected allergen is tested, mainly to guide the safe starting dose for immunotherapy. The AAAAI states that when compared with specific nasal challenge, SET is equivalent to prick/puncture skin tests. The SET may not be a substitute for skin testing. But it can be an alternative when determining a safe starting dose or when there is possibility of severe systemic reaction or anaphylaxis, like in the case of Hymenoptera venom. Initial prick/puncture screening followed by end point intracutaneous serial titration is an accepted regimen for evaluation of Hymenoptera and several clinical drug sensitivities. When used to determine the starting dose for immunotherapy in highly allergic patients, up to 14 titration tests may be necessary. In most places, up to 14 allergens is sufficient to check the most prevalent molds, dust components, grasses, trees, animals, and weeds. Up to 40 antigens and 80 injections may be needed for immunotherapy.^12,13,63

Skin Patch Testing

The epicutaneous patch test has evolved as the definitive diagnostic technique for the diagnosis of ACD. Although patch tests are indicated in any patient with a chronic eczematous dermatitis if ACD is suspected, patch tests are especially important in identifying both irritant contact dermatitis (ICD) and ACD in the occupational setting. It is the gold standard for identification of a suspected contact allergen and is indicated in any patient with a chronic, pruritic, eczematous, or lichenified dermatitis if underlying or secondary ACD is suspected. Patch tests are especially important in identifying occupational dermatitis. Two major variants of traditional patch tests are available: the APT and RUT. The AAAAI states that when clinical evaluations suggest that exposure to a specific contactant has occurred either in an occupational or nonoccupational clinical setting, patch testing can be used to confirm the diagnosis. The most common patch test techniques are the individual Finn Chamber and the T.R.U.E. test, an FDA-approved screening method for screening contactant allergens.¹³

The AAAAI states that 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. Although the diagnostic accuracy of contactants cannot be compared with other in vivo or in vitro tests, diagnostic concordance between patch test sensitivity and the outcomes of repeated open provocation tests has been demonstrated for some contactants. Systemic ACD after patch testing is rare, as is reactivation of patch test reactions after oral ingestion of related allergens or even by inhalation of budesonide in patients with sensitization to topical corticosteroids. The appropriate number of APTs is indeterminate because they are not routinely performed. APTs are being evaluated as diagnostic adjuncts chiefly to evaluate the role of inhalant and food allergens in atopic dermatitis and less often for the diagnosis of drug hypersensitivity. Because ACD is frequently caused by unsuspected substances, up to 65 patch tests may be required for diagnosis. Supplementary patch tests are often required as suggested by the patient’s exposure history, and up to 65 contactant tests are recommended by the North American Contact Dermatitis Research Group.^12,58,68

Photo Patch Testing

If photocontact sensitivity is suspected, the appropriate allergens should be subjected to photo patch tests. Certain contactants (e.g., antibiotics, PABA) may induce photocontact ACD or phototoxic CD (e.g., carrot, celery, fennel, lemon-lime, grapefruit). When these are suspected, photo patch tests, primarily in the UV-A range of 320 to 400 nm, are recommended.^13,69

Phototesting

Phototesting is a diagnostic procedure used to evaluate suspected photodermatoses or other skin conditions caused or aggravated by UV exposure. It generally involves 3 main steps. First, minimal erythema dose (MED) testing identifies the lowest UV dose that causes skin redness by irradiating small skin areas with increasing doses using devices like a solar simulator, UVB lamps, or a monochromator, and grading the erythema response 22–26 hours later (with additional readings when using a monochromator). Abnormal responses may indicate conditions such as solar urticaria, chronic actinic dermatitis, or actinic prurigo, with solar urticaria having a distinct grading system. Second, provocation phototesting aims to reproduce photodermatosis symptoms by exposing the skin to repeated doses of polychromatic UVA or UVB, ideally over 4 consecutive days. Lastly, photo patch testing identifies photoallergic reactions, commonly to sunscreen agents, by applying allergens in duplicate for 24–48 hours; one site is then irradiated with broad-spectrum UVA while the other serves as a control. Reactions are scored using the International Contact Dermatitis Research Group (ICDRG) system at multiple time points, and their clinical relevance is assessed using the COADEX system.^87,95-98

Delayed Hypersensitivity Skin Testing

Three professional society positions identified by the literature search contained guidance for delayed intradermal testing (dIDT).^13,34,70 All 3 position statements emphasized the role of dIDT for diagnosing suspected cell-mediated immunoallergic responses. Two of the 3 position papers specifically addressed dIDT for diagnosing delayed, cell-mediated adverse drug reactions.^34,70 In the 2009 British Society for Allergy & Clinical Immunology (BSACI) guidance on the management of drug allergy, Mirakian et al., provide a GRADE B recommendation that patch tests and/or dIDT can provide evidence for a delayed or T-cell mediated drug allergy when interpreted in the appropriate clinical context. Later in the guidance, authors mention that positive dIDT within 48 hours in conjunction with patch testing can be useful in investigating delayed-hypersensitivity reactions to antibiotics. This document also contains an algorithmic decision-tree to recommend the appropriate allergy tests in varying scenarios. In this figure, BSACI recommends the consideration of patch testing/dIDT when a patient has had a delayed adverse drug reaction that is suspected to be T-cell mediated.⁷⁰ The Joint Task Force on Practice Parameters (JTFPP) has more recent guidance on allergy testing for drug allergy from 2022. In this 2022 position statement, Khan et al., recommend dIDT/patch tests as adjunctive diagnostic aids for identifying drug causality in instances where delayed cell-mediated hypersensitivity allergy is suspected, specifically mentioning severe cutaneous adverse reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS). However, the JTFPP issued 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. In the body paragraph justifying this recommendation, the authors expound upon how to choose between patch test and dIDT. Khan et al., mention that dIDT has a higher sensitivity for detecting many drug-induced SCARs, and has some clinical benefit to patients, since the reaction is quick (occurs within 24-48 hours). However, 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.³⁴

The 2008 AAAAI guidelines contain guidance for the use of dIDT for bacterial and fungal pathogen hypersensitivity. Bernstein et al. provided a Grade C recommendation in favor of the utilization of all 3 recall antigens that were available at the issuance of this guideline (Tetanus toxoid, Candida, and trichophyton). The authors also provided a grade D recommendation that adverse reactions and anaphylaxis have been reported after tuberculin tests.¹³

Organ Challenge Testing

Nasal Mucous Membrane Challenge Testing

Of the studies meeting the review’s inclusion criteria, 6 included recommendations on nasal allergen provocation testing (NAPT).^{12,13,17,64,71,72} Of these 6 societal positions, only the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) 2015 publication does not provide a favorable recommendation of NAPT.¹⁷ Due to insufficient evidence, the AAO-HNS stated that they could not make a recommendation in favor nor against the usage of nasal allergen challenge.¹⁷ Among the other 5 position statements, 3 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.^12,13,64 Furthermore, 3 of the societal guidelines also emphasize NAPT as an essential component to confirming diagnoses of both local allergic rhinitis (LAR) and occupational rhinitis.^64,71,72 Of particular note, the World Allergy Organization (WAO) 2020 guidance on IgE allergy diagnostics cross-references the 2018 EAACI position paper on NAPT as a standard for best practice.^12,71 In terms of technique, the EAACI recommends bilateral challenge and assess both nasal patency (Grade D) and a standardized patient-assessed visual analog scale (VAS) (Grade A). The EAACI guidance also identified absolute contraindications to NAPT, which includes prior anaphylaxis to the suspected allergen, acute sinus inflammation, severe comorbidity, severe systemic disease, immunotherapy, and pregnancy.⁷¹

Conjunctival/Ophthalmic Challenge Testing

Four of the guidance documents retrieved included societal statements on the utilization of conjunctival allergen provocation tests (CAPT).^12,13,64,73 All 4 societal statements 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. Of note, the 2020 WAO guidance on IgE allergy diagnostics cross-references the EAACI 2017 position paper on CAPT as a standard for CAPT guidance.^12,73 The EAACI paper 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). Additionally, Fauquert et al., also detail an exhaustive list of contraindications for CAPT. Notable contraindications 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.⁷³

Inhalation/Bronchial Challenge Testing

Three position statements meeting inclusion for this review pertained to the use of bronchial provocation testing.^12,13,67 Of the 3 publications, 1 provided a hesitant endorsement of inhalation challenge testing¹², whereas the other 2 offered more robust conclusion in favor of bronchial provocation testing.^13,57 The former was a 2020 WAO position paper conducted by Ansotegui et al. In this document, the WAO concludes that all organ challenge testing (i.e., conjunctival, bronchial, or nasal mucosal) can be utilized to evaluate IgE-mediated hypersensitivity if SPT or IgE in vitro testing is indeterminate. However, Ansotegui et al., go on to discuss the potential risks of systemic reactions with inhalation challenges, and the lack of standardization for conducting these provocation tests.¹²

Both latter guidelines contain recommendations in favor of specific bronchial challenge testing.^13,57 The 2008 AAAAI position paper provides a grade B recommendation in favor of inhalation provocation testing for measuring lower airway sensitivity in the event of diagnostic uncertainty or dispute from initial allergy testing.¹³ The 2015 American College of Occupational and Environmental Medicine (ACOEM) society paper is specific to work-related asthma. In this guidance, the ACOEM states that specific bronchial provocation testing is the gold standard test for diagnosing occupational asthma (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 ACOEM panel in decreasing the strength of evidence 2 levels to a grade C. However, Jolly et al., also strongly recommend in favor of nonspecific bronchial provocation testing for diagnosing general asthma (evidence level A) and moderately recommend in favor of nonspecific bronchial provocation testing for diagnosing work-related asthma (evidence level B). ⁵⁷

Ingestion/Oral Provocation Challenge Testing

Oral Food Challenge Testing

Of the publications meeting inclusion, 7 issued guidance on OFC for the diagnosis of suspected food allergy.^{13,62,67,7482,83} All 7 societal position papers offer recommendations in favor of OFC when there is a conflict between patient history and other preliminary in vivo skin test results. Although OFC is recognized as the most accurate method for detecting direct allergenic causation in food allergy, the associated risks with provocation universally relegate OFC to a secondary or tertiary confirmatory test. To accommodate the risk of serious adverse event, 2 of the guidelines make specific recommendations to only perform OFC in the presence of medical personnel who can monitor symptoms and intervene if necessary.^13,74 Common IgE-mediated food allergens used for OFC mentioned across the guidance documents include cow’s milk, peanut, tree nut, egg, and codfish.^{13,67 82,83} The 2007 EAACI/Ga2LEN differed from the others in that it focused on atopic eczematous reactions secondary to food allergy. In this guidance document, Werfel et al., recommend OFC only after discordant initial test results (e.g., clinical history, sIgE, SPT, and/or patch test), and an elimination diet occurring over a minimum of 4-6 weeks.⁶² The 2023 EAACI position paper on the diagnosis of IgE-mediated food allergy provides specific guidance on the type of OFC trial that should be conducted. Although the double-blind placebo-controlled food challenge (DBPCFC) is the highest standard of quality, the EAACI panel concluded that an open OFC is the recommended design for a routine OFC. They then recommend conducting a DBPCFC if an open OFC outcome is inconclusive.⁷⁴

Oral Drug Challenge Testing

Five societal statements were identified that provided recommendations pertaining to oral drug provocation in the case of suspected drug allergy.^{13,34,60,69,70} Among these, 2 practice parameters are specific to suspected allergy to anesthesia. Both position statements mention that skin testing offers little diagnostic value. Both then conclude that drug challenge is the gold standard for establishing a diagnosis of local anesthesia allergy, although the 2009 BSACI guidance still recommends only conducting drug provocation if skin tests are negative.^13,34 Both BSACI guidelines identified in this section advise that drug challenge is not typically advised if there was an anaphylactic reaction, but state that an oral preparation can be used as an antigenic challenge if prior reactions were via intravenous (IV) or intramuscular (IM) injection, with a closely related preparation if the suspected allergen is not readily available in oral form.^60,70 The 2023 German Society for Allergology and Clinical Immunology (DGAKI) guidance on drug hypersensitivity also reached a strong consensus that oral provocation can be performed if the drug was administered IM, IV, or rectally for the index reaction.⁶⁹ Two of the position statements identified recommend against the use of oral aspirin challenge to diagnose Aspirin-exacerbated respiratory disease (AERD) unless there is high diagnostic uncertainty, since AERD diagnoses can often be made with high accuracy by clinical history alone.^13,34 In addition, the same 2 guidelines both provided recommendations for using oral drug provocation to delabel adults who had a distant (≥5 years) history of reaction to sulfonamides and penicillin, given that the initial reaction was not severe.^13,34 The 2009 BSACI guidance on general anesthesia also provided recommendations in the form of an algorithmic decision tree. For opiates, NSAIDs, and paracetamol allergy testing, the decision tree comments that skin testing is rarely helpful and recommends proceeding with oral challenge. In the same figure, BSACI recommends oral drug challenge for antibiotics, local anesthetics, and chlorhexidine only if SPT and intradermal are negative, and drug allergy is still suspected.⁶⁰

Serum specific IgE In Vitro Testing

The systematic literature search and review that were employed for this evidentiary analysis were structured around investigating both of the following key questions for in vitro allergy tests:

1. Is there a consensus among professional societies and evidence-based guidelines regarding the efficacy and safety of in vitro allergy testing in diagnosing and managing allergic conditions?
2. What are the clinical guidelines/ literature for the use of in vitro allergy testing?

Specific IgE

Thirteen of the included publications provide guidance related to sIgE testing.^{12,13,17,58,63-65,67-69,74-76}

AAAAI allergy diagnostic testing updated practice parameter (2008) notes that sIgE immunoassays are calibrated using WHO reference standards, ensuring consistent reporting across laboratories. These tests generally achieve sensitivity levels ranging from less than 50% to over 90%, with an average of 70–75%, depending on allergen type, testing method, and clinical context. However, interpretation requires correlation with patient history, physical examination, and observed allergen exposure symptoms.¹³

Related to inhalant allergens, while sIgE assays with defined quantifiable threshold levels can predict positive respiratory responses after allergen exposure, skin testing is more sensitive for identifying sensitization to inhalant allergens and confirming clinical allergy. Immunoassays are sensitive for detecting allergens such as pollens, dust mites, fungi, and stable foods. Their positive predictive value is higher for these allergens compared to venoms, drugs, or chemicals.¹³

For food allergies, the AAAAI says that tests for food-specific IgE antibodies have high sensitivity (about 85%) but modest specificity (40–80%), making them useful when suspicion of a particular allergen is high. However, indiscriminate testing using panels without clinical context is discouraged.¹³

Regarding venom allergies, these assays have lower sensitivity compared to venom skin tests, but elevated sIgE levels can be used to confirm venom allergy. Both skin and serum IgE tests are recommended for patients with histories of venom-induced systemic reactions due to predictive inconsistencies.¹³

Regarding drug hypersensitivity, sIgE assays are beneficial for confirming the diagnosis and prediction of future IgE-mediated reactions, such as anaphylaxis and urticaria caused by certain drugs, but neither skin nor IgE assays are diagnostic of cytotoxic, immune complex, or cell-mediated drug-induced allergic reactions.¹³

For work-related allergies, sIgE testing may support diagnosis but cannot independently establish OA. Validation using standardized protocols is essential before these can be considered reliable for routine evaluation of suspected OA. In patients undergoing evaluation for suspected work-related natural rubber latex (NRL) allergy, a positive skin test result is preferred to demonstration of elevated sIgE with an FDA-cleared assay due to higher sensitivity of the former. Elevated in vitro sIgE levels can be used to confirm NRL allergy, but a negative result does not exclude NRL allergen sensitization.¹³

Specific IgE immunoassays are preferable to skin testing under certain conditions, such as widespread skin disease, when suppressive therapy affects skin testing, uncooperative patients, or when there is a higher risk of anaphylaxis from skin testing. The utility of sIgE testing varies based on allergen binding affinity, cross-reactivity, and total serum IgE levels. Specific IgE immunoassays are not recommended as a definitive confirmatory test for several specific clinical conditions. They do not have sufficient sensitivity to predict anaphylaxis from venoms or penicillin. Furthermore, its reliability is influenced by the variable allergenicity, potency, and stability of reagents used.¹³

The AAO-HNS clinical practice guidelines on allergic rhinitis (2015) note that for the diagnosis and management of AR, sIgE testing, whether via skin or serum assays, is a useful tool when empirical treatments fail or when allergen identification is necessary. According to the AAO-HNS guideline, using in vitro immunoassays for sIgE testing is advantageous because it eliminates the risk of adverse reactions (such as anaphylaxis) and does not require patients to withhold medications like antihistamines or β-blockers. This approach is especially valuable for patients with skin conditions, such as dermatographism or severe eczema, where skin testing may be difficult to interpret.¹⁷

Complementing this, the International Consensus Statement on Allergy and Rhinology (ICAR) (2023) consensus statement on AR reinforces that sIgE testing is a safe and effective alternative for patients who cannot undergo SPT, ensuring that their specific sensitivities are accurately identified.⁶⁴

The BSACI guidelines emphasize the role of sIgE assays in scenarios where skin testing may not be feasible, or the results remain inconclusive. For allergic and non-allergic rhinitis in their 2017 guideline, sIgE testing is recommended when patients cannot undergo skin tests or when SPT combined with clinical history does not yield a clear diagnosis. While both SPTs and sIgE demonstrate similar sensitivity for detecting house dust mite allergens, SPTs tend to be more sensitive for other inhalant allergens, including cat epithelium, mold, and grass pollen.⁶⁵

The (1996) American Academy of Otolaryngic Allergy (AAOA) guideline in line with other guidelines supports the use of either in vitro or skin testing in allergic rhinitis, noting that certain patients (for instance, those who are dermatographic or have mold sensitivity) may benefit more from one method over the other while cautioning against redundant dual testing.⁶³

In the context of cow’s milk allergy, the BSACI guideline for the diagnosis and management of cow’s milk allergy (2014), standardized in vitro assays offer a quantitative measure of cow’s milk-specific IgE, with a cut-off of 0.35 kU/L providing performance characteristics similar to a positive SPT (defined as a weal diameter of ≥3 mm) with a good sensitivity but poor specificity. However, the guidelines discourage measuring cow’s milk sIgE in the absence of a relevant ingestion history due to poor sensitivity and low negative predictive value, recommending an oral challenge when the sIgE level is positive but low.⁶⁷

Conversely, the EAACI 2023 guidelines on IgE-mediated food allergy recommend (high strength of recommendation) SPTs and/or sIgE measurements as first-line diagnostic tools for patients with suspected IgE-mediated food allergies. For patients with suspected allergies to peanuts, hazelnut, or cashew nut, the guidelines advise measuring sIgE to Ara h2, Cor a 14, and Anao 3, respectively to support the diagnosis.⁷⁴

The EAACI (2014) Food Allergy and Anaphylaxis Guidelines also indicate that either SPTs or sIgE assays can be used for detecting sensitization, with the choice often depending on local availability and contraindications to skin testing. In the presence of a suggestive history, a negative SPT or sIgE needs to be interpreted with caution particularly as these are expected in non-IgE-mediated food allergy and when clinical history combined with test results is not highly predictive, an OFC becomes necessary.⁵⁸

The WAO position paper on IgE diagnostics and other relevant tests in allergy (2020) highlights that these tests performed on either whole allergen extracts or molecular components offer significant added value in formulating precise diagnosis before starting allergen immunotherapy, particularly in food and Hymenoptera allergies, although they remain largely ineffective for most drug allergies. The sensitivity of specific serum IgE antibody measurements could be considered as comparable to that obtained with SPT for respiratory and food allergy, but only complementary to the intradermal skin test for drug and venom allergy diagnosis.¹²

The National Institute of Allergy and Infectious Diseases (NIAID) (2010) recommends the use of sIgE tests as an aid in identifying foods that might provoke IgE-mediated reactions, though these tests alone are not diagnostic of food allergy.⁷⁵ Similarly, the Japanese Guideline for Food Allergy (2020) points out that although the presence of sIgE antibodies confirms sensitization, their diagnostic value can vary based on the testing method and population, meaning that sensitization does not always equate to clinical food allergy.⁶⁸

The DGAKI 2023 guideline for drug hypersensitivity emphasizes that validated sIgE tests are available only for a few drugs, primarily beta-lactam antibiotics and strongly advises against using non‐validated IgE assays for drug allergies. It stresses that in vitro test results cannot reliably detect or exclude drug hypersensitivity on their own and must be interpreted in the context of the patient’s clinical history and, whenever possible, be supplemented with in vivo testing.⁶⁹

In the context of drug hypersensitivity, the Practical Guidance for the Evaluation and Management of Drug Hypersensitivity (2020) notes that while skin testing has a higher sensitivity (95%-99%) compared with IgE testing (35%-76%), in the absence of a skin test reagent to latex in the U.S., IgE-antibody testing may be performed at the time of the reaction or later. Other tests for the detection of sIgEs directed to certain neuromuscular blocking agents can also be utilized.⁷⁶ The recommendations emphasize that sIgE testing serves as a valuable diagnostic tool when used as part of a broader clinical evaluation.

Total Serum IgE

Seven societal statements were identified that provided guidance pertaining to total serum IgE testing.^{12,13,17,64,65,75,77} The AAAAI allergy diagnostic testing Practice Parameter (2008) states that total serum IgE levels have modest clinical applications, with notable exceptions such as ABPA, where it can guide therapeutic response, and its utility in omalizumab therapy where total IgE is essential in assessing eligibility and dosage for the therapy.¹³ Many leading organizations find its value for AR to be minimal, leading them to question the routine use in allergy diagnostics. The AAO-HNS clinical practice guideline for allergic rhinitis (2015) explicitly recommends against its use in allergic rhinitis, as it does not provide meaningful information for disease management.¹⁷ Similarly, the ICAR consensus statement on AR (2023) does not endorse total IgE for routine use.⁶⁴ The BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (2017) acknowledges that total IgE alone can be misleading but suggests it may aid in interpreting sIgE results.⁶⁵ The WAO IgE allergy diagnostics and other relevant tests in allergy position paper (2020) notes that while total IgE levels can be markedly elevated in non-allergic conditions, such as parasitic infestations, IgE myeloma, and primary immunodeficiencies like IPEX syndrome and Omenn syndrome, ABPA is the only clinical condition described to date where the presence of high levels of IgE is strictly related to disease severity.¹² Additionally, the guidelines for the diagnosis and management of food allergy in the U.S. report of the NIAID-Sponsored Expert Panel (2010) explicitly advises against using total serum IgE for food allergy diagnosis.⁷⁵ The WAO White Book on Allergy (2013) further highlights that nearly half of allergic patients have total IgE levels within the normal range, with significant overlap between allergic and non-allergic individuals, underscoring the value of pairing total IgE with further investigations for sIgE sensitivity.⁷⁷

Analysis of Evidence (Rationale for Determination)

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 screen 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.

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.

Evidence-based guidelines emphasize the role of dIDT for diagnosing suspected cell-mediated immunoallergic responses and state that 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 recommend 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.

All included guidelines offer recommendations in favor of OFC when there is a conflict between patient history and other preliminary in vivo skin test results. Although OFC is recognized as the most accurate method for detecting direct allergenic causation in food allergy, the associated risks with provocation universally relegate OFC to a secondary or tertiary confirmatory test. To mitigate the risk of serious adverse events, it is important to only perform OFC in the presence of medical personnel, who can monitor symptoms and intervene if necessary.

Some evidence-based guidelines conclude that drug challenge is the gold standard for establishing a diagnosis of local anesthesia allergy, although one other recommends only conducting drug provocation if skin tests are negative. Two of the position statements identified recommend against the use of oral aspirin challenge to diagnose AERD unless there is high diagnostic uncertainty, since AERD diagnoses can often be made with high accuracy by clinical history alone. Another guideline for opiates, NSAIDs, and paracetamol allergy testing, comments that skin testing is rarely helpful and recommends proceeding with oral challenge. They also recommend oral drug challenge for antibiotics, local anesthetics, and chlorhexidine only if SPT and intradermal are negative, and drug allergy is still suspected.

The appropriate choice and specifics of allergy testing depends 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.

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. 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.

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.

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. For highly allergic patients, up to 14 titration tests may be needed, while immunotherapy could require testing of up to 40 antigens and 80 injections targeting common allergens such as molds, dust components, grasses, trees, animals, and weeds. Guidelines suggest that because ACD is frequently caused by unsuspected substances, up to 65 patch tests may be required for diagnosis. Supplementary patch tests may be required as suggested by the patient’s exposure history, and up to 65 contactant tests are recommended.

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 now while others like ImmunoCAP may be preferable. Various 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 levels, while potentially indicative of atopic conditions, offer limited utility in identifying specific allergens and are instead used to assess the suitability of therapies like omalizumab for allergic asthma.

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, Noridian may conduct evidentiary review of peer reviewed literature in future LCD development.

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. Allergic rhinitis has resulted in an estimated 4.1 million physician office visits annually (2019), and as the sixth leading cause of chronic illness in the U.S., the annual cost of treating allergies is estimated to be $18 billion. 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. If symptoms suggest an allergic condition that cannot be managed with conservative treatments or avoidance, diagnostic testing—such as skin testing or serum IgE testing—may be warranted to identify allergens. Results from skin testing and/or serum IgE testing may be followed by organ challenge should the need for direct clinical correlation arise and if deemed safe to perform. 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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