Cigna Allergy Testing and Non-Pharmacologic Treatment - (0070) Form

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Each coverage request should be reviewed on its own merits. Medical directors are expected to exercise clinical judgment where appropriate and have discretion in making individual coverage determinations. Where coverage for care or services does not depend on specific circumstances, reimbursement will only be provided if a requested service(s) is submitted in accordance with the relevant criteria outlined in the applicable Coverage Policy, including covered diagnosis and/or procedure code(s). Reimbursement is not allowed for services when billed for conditions or diagnoses that are not covered under this Coverage Policy (see “Coding Information” below). When billing, providers must use the most appropriate codes as of the effective date of the submission. Claims submitted Medical Coverage Policy: 0070 for services that are not accompanied by covered code(s) under the applicable Coverage Policy will be denied as not covered. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. This Coverage Policy addresses testing and non-pharmacologic treatment f or allergy. Allergy testing may be in vivo (i.e., testing on or near the patient and monitoring the patient’s physiological response(s)) or in vitro procedures (i.e., analyzing the individual’s serum). Non- pharmacologic immunotherapy may be allergen immunotherapy by subcutaneous injection and sublingual antigen extract drop immunotherapy preparations. Coverage Policy Testing: Medically Necessary The following in vivo allergy tests are considered medically necessary: prick/puncture allergy testing to diagnose suspected immunoglobulin E (IgE)-mediated hypersensitivity to inhalants, f oods, hymenoptera (e.g., bee venom), drugs and/or chemicals intradermal allergy testing to diagnose suspected immunoglobulin E (IgE)-mediated hypersensitivity to inhalants, hymenoptera (e.g., bee venom), drugs and/or chemicals skin patch testing to diagnose suspected contact allergic dermatitis photo patch testing to diagnose suspected contact photosensitization (e.g., photoallergic contact dermatitis) skin patch testing perf ormed prior to joint replacement surgery f or EITHER of the f ollowing:  previous surgery involving an implant with complications suspected to be caused by metal allergy  history of severe localized (i.e., blistering, hives, and/or extensive rash) or systemic cutaneous reaction to metals skin patch testing perf ormed f ollowing joint replacement surgery when BOTH of the f ollowing criteria are met:  presence of symptoms attributable to metal allergy/hypersensitivity (e.g., pain, swelling, cutaneous rash, loss of f unction)  etiology other than metal allergy/hypersensitivity (e.g., inf ection, mechanical f ailure) have been ruled out f ood/food additive ingestion double-blind challenge/provocation to diagnose suspected IgE- mediated hypersensitivity if skin testing is negative or equivocal, despite a history and physical f indings suggestive of hypersensitivity drug provocation/bronchial challenge test to diagnose suspected IgE-mediated hypersensitivity when there is a conf irmed history of allergy to a drug, and the individual requires the particular drug f or treatment of a diagnosed condition, and there is no ef f ective alternative drug available Medical Coverage Policy: 0070 skin serial endpoint titration (SET) f or determination of a saf e starting dose f or testing or immunotherapy when there is potential f or the specif ic allergen in question to produce a severe systemic reaction or anaphylaxis (such as with bee venom) When in vivo allergy testing is considered medically necessary as noted in the criteria above, the f ollowing f requency limits apply (rolling 12 months): percutaneous (scratch, puncture, prick) testing (CPT code 95004): 80 units • intracutaneous (intradermal) testing (CPT code 95024): 40 units In vivo allergy testing that exceeds the following limits is not covered or reimbursable: percutaneous (scratch, puncture, prick) testing (CPT code 95004): 80 units • intracutaneous (intradermal) testing (CPT code 95024): 40 units In vitro allergy testing (blood serum analysis, e.g., ImmunoCAP®, radioallergosorbent test [RAST], multiple radioallergosorbent test [MAST], fluorescent allergosorbent test [FAST], paper radioimmunosorbent test [PRIST], radioimmunosorbent test [RIST], enzyme-linked immunosorbent assay [ELISA], MRT [modified RAST], and VAST) is considered medically necessary when ANY of the following criteria is met: f or the diagnosis of suspected IgE-mediated f ood or inhalant allergies f or one of the f ollowing indications:     individual with severe dermatographism, ichthyosis or generalized eczema individual who cannot be saf ely withdrawn f rom medications that interfere with skin testing (such as long-acting antihistamines, tricyclic antidepressants) individual who has a history of a previous systemic reaction to skin testing individual in whom skin testing was equivocal/inconclusive and in vitro testing is required as a conf irmatory test as an alternative to skin testing f or the evaluation of cross-reactivity between insect venoms when specif ic IgE immunoassays are used as adjunctive testing f or disease activity of allergic bronchopulmonary aspergillosis and certain parasitic diseases When in vitro allergy testing is considered medically necessary as noted in the criteria above, the f ollowing f requency limit applies (rolling 12 months): allergen specif ic IgE; quantitative or semiquantitative testing (CPT code 86003): 80 units Allergen specific IgE; quantitative or semiquantitative testing that exceeds 80 units is not covered or reimbursable. In vitro metal lymphocyte transformation testing (LTT) performed prior to joint replacement surgery is considered medically necessary when ALL of the following criteria are met: previous surgery involving an implant, with complications suspected to be caused by metal allergy history of severe localized (i.e., blistering, hives, and/or extensive rash) or systemic cutaneous reaction to metals skin patch testing is contraindicated or results are equivocal Medical Coverage Policy: 0070 In vitro metal lymphocyte transformation testing (LTT) performed following joint replacement surgery is considered medically necessary when ALL of the following criteria are met: presence of symptoms attributable to metal allergy/hypersensitivity (e.g., pain, swelling, cutaneous rash, loss of f unction) etiology other than metal allergy/hypersensitivity (e.g., inf ection, mechanical f ailure) have been ruled out skin patch testing (detailed above) is contraindicated or results are equivocal In vivo or in vitro allergy testing is not covered or reimbursable for any other indication. Leukocyte histamine release (LHR) in vitro allergy testing for the diagnosis or management of allergic disease is considered experimental/investigational or unproven. Bead-based epitope assay (e.g., VeriMAP™ Peanut Dx, VeriMAP™ Peanut Sensitivity) is not covered or reimbursable. Treatment: Medically Necessary Subcutaneous allergen immunotherapy is considered medically necessary for the treatment of allergic asthma and allergic rhinitis (with or without allergic conjunctivitis) when ALL of the following criteria are met: presence of specific immunoglobulin E (IgE) to the allergen in question demonstrated by skin testing or serum/in-vitro testing hypersensitivity cannot be managed by medications or allergen avoidance • prof essional services f or the supervision of preparation and provision of antigens f or allergen immunotherapy, single or multiple antigens (CPT® code 95165) up to a maximum of 150 doses per year (i.e., rolling 12 months). Professional services for the supervision of preparation and provision of antigens for allergen immunotherapy, single or multiple antigens (CPT® code 95165) that exceeds a maximum of 150 doses per year (i.e., rolling 12 months) are not covered or reimbursable. Subcutaneous allergen immunotherapy is considered medically necessary for the treatment of Hymenoptera (e.g., hornet, wasp, bee, fire ant) venom allergy when ALL of the following criteria are met: history of systemic reaction to a Hymenoptera sting • presence of Hymenoptera-specif ic IgE demonstrated by skin testing or serum/in-vitro testing prof essional services f or the supervision of preparation and provision of antigens f or allergen immunotherapy, single or multiple antigens (CPT codes 95145-95149, 95170) Sublingual antigen extract drop immunotherapy preparations are considered experimental, investigational or unproven. Medical Coverage Policy: 0070 Note: Please ref er to Drug and Biologic Coverage Policies IP0515: Grass Pollen Sublingual Products, IP0516: Odactra, IP0518: Ragwitek and 2004: Peanut (arachis hypogaea) allergen powder-dnfp f or inf ormation regarding FDA-approved non-subcutaneous allergen immunotherapy. General Background Allergies result f rom an overreaction of the immune system to f oreign substances (e.g., pollen, dust, mold, animal f ur or dander, stinging insect venom, food). An allergy develops when the body is exposed to a substance that prompts the initiation of an immune response. This response involves the production of antibodies, called immunoglobulins (Igs), which are directed against proteins of the f oreign substance, called allergens or antigens. While there are f ive classes of immunoglobulins, it is IgE that is typically involved in allergic reactions. When an allergy-prone individual is exposed to a specif ic antigen, B-cells produce an IgE that recognizes only that antigen. This antigen-specif ic IgE then binds to receptors on specif ic cells that reside in tissue (mast cells) or circulate in the blood (basophils). Upon re-exposure to the same antigen, the antigen-specific IgE binds to membrane receptors on tissue mast cells and blood basophils and then releases a series of chemicals (histamine, leukotrienes, cytokines and proteases) that regulate the allergic reaction. While the allergic reaction begins immediately, signs and symptoms of the reaction may occur within seconds or minutes (immediate hypersensitivity), may be delayed f or several hours (delayed hypersensitivity), or may involve both early-and late-phase reactions. The American Academy of Allergy, Asthma and Immunology (AAAAI) published a workgroup report on health disparities in allergic and immunologic conditions in racial and ethnic underserved populations. Allergic rhinitis (AR) is underdiagnosed and underappreciated in certain racial and ethnic populations. Black children without a personal or f amily history of atopy had a higher odds of sensitization to any allergen as well as discrete sensitization to mold, cockroach, grass, weed and tree pollen compared to white children. Latino populations are also signif icantly affected by AR and under diagnosed in Puerto Rican and urban populations. Clinical studies have demonstrated that low-income and minority groups are less likely to receive allergen immunotherapy (AIT) and Medicaid insurance is associated with more emergency room care f or acute nasal symptoms compared to private insurance. The studies highlight that additional burdens f aced by lower income f amilies can contribute to a lack of resources necessary to adhere to AIT rigorous schedules. Disparities in f ood allergies (FA) are predominately seen among minority and lower income populations in the United States, with higher rates of FA-related anaphylaxis and ED visits. Black children have higher odds of wheat, soy, corn, f ish, and shellf ish allergy, and Hispanic children have higher odds of corn, f ish, and shellf ish allergy. Minority children are less likely to have prescribed FA action plans, have a shorter duration of specialist f ollow-up, and have higher rates of FA related anaphylaxis and ED visits. Food insecurity is a risk f actor in milk and egg allergy and was associated with lower health literacy (Davis, et al., 2021). Testing Allergy tests are performed to verif y or exclude the presence of IgE-mediated hypersensitivity and to identif y the causative allergen(s). Testing may involve in vivo procedures, which determine the presence of specific IgE by administering an IgE-specific allergen into, on or near the patient and monitoring the patient’s physiological response(s). Allergy tests may also be in vitro procedures that determine the presence of specif ic IgE or elevated total IgE by analyzing patient serum. The allergy testing methods and recommendations detailed below are based primarily on practice parameters and recommendations f rom the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American Academy of Otolaryngic Allergy (AAOA). Medical Coverage Policy: 0070 In Vivo Allergy Testing The number/frequency of tests needed to diagnose an individual with allergies is varied. Up to 80 percutaneous skin tests may be necessary to diagnose f ood allergies (scratch, puncture, prick, CPT code 95004). Up to 40 intracutaneous (intradermal) tests with allergenic extracts (CPT code 95024) is considered appropriate. If allergy skin tests cannot be perf ormed due to a skin condition, etc., up to 40 allergen-specif ic IgE tests may be considered appropriate (CPT code 86003). Frequency is based on a rolling 12 months basis. In vivo allergy tests f all into two general categories: skin tests and organ challenge (or provocation) tests. Both are designed to conf irm hypersensitivity and identif y the antigen(s) responsible f or the allergic reaction. The most common in vivo allergy tests are outlined below. The ef f icacy of some in vivo allergy tests has not been f irmly established, due to the limited numbers of well-designed clinical trials. Few prospective studies are available, and evidence is primarily in the f orm of expert opinion. Skin testing can be utilized to detect immediate hypersensitivity (IgE-dependent reactions) and delayed hypersensitivity (cell-mediated immune reactions). The two major methods of skin testing f or IgE-mediated disease include the prick-puncture test and the intradermal test. A positive response to skin testing is typically indicated by the presence of a wheal and/or f lare at the test site. Scratch testing is no longer a recommended allergy testing procedure, due to reproducibility issues and the high incidence of f alse-positive reactions. Skin testing is contraindicated in patients with severe dermatographism (allergy in which a pale, raised wheal is produced when skin is scratched), ichthyosis (condition in which skin is dry and scaly, resembling f ish skin) or generalized eczema; in patients who cannot be withdrawn f rom medications that interf ere with skin testing (such as long-acting antihistamines and tricyclic antidepressants); and in patients who have a history of a previous systemic reaction to skin testing. Prick/puncture tests are used f or conf irmation of clinical immediate hypersensitivity induced by inhalant and f ood allergens. Skin prick/puncture tests are generally considered the most specif ic screening method f or detecting the presence of IgE antibodies in patients with appropriate exposure histories. These tests may also be used in the diagnosis of drug and chemical hypersensitivity reactions. Prick/puncture tests are generally less sensitive than intradermal testing. For inhalant allergies, prick/puncture tests have been shown to correlate better with the presence of clinical allergy. Skin testing is considered the gold standard f or the diagnosis of IgE- mediated allergic disease. The Joint Task Force of Allergy, Asthma, and Immunology recommends skin prick/puncture tests as the primary test f or the diagnosis of IgE-mediated allergic diseases. Intradermal or intracutaneous tests are generally used when increased sensitivity is the main goal of testing (i.e., when prick/puncture tests are negative despite a compatible history of exposure). Intradermal tests are more sensitive but less specif ic than prick/puncture tests for most allergens but are superior to other skin tests f or assessing hypersensitivity to hymenoptera (stinging insects) and penicillin or allergens of lower potency. Intradermal testing f or f ood allergies is not recommended because of the high rate of f alse positive test results and the potential f or anaphylaxis. Repeat skin testing with multiple antigens is not indicated on a regular basis (e.g., yearly). Indications f or repeat testing include changing symptoms, new exposures, or 3–5 years of venom immunotherapy. Patch testing is used to determine the presence or cause of delayed hypersensitivity reactions originating on the skin. It is primarily used to assess allergic contact dermatitis, an eczema-type, Medical Coverage Policy: 0070 immunologically-mediated skin reaction which is largely cell-mediated but may contain an IgE- mediated component. The clinical utility of patch testing to identif y allergic reactions other than those originating on the skin (such as inhalants or f ood allergens) has not been determined. It is estimated that 20–30 antigens used in the panel of patch tests will identif y between 50% and 70% of the clinically relevant causes of contact dermatitis. Certain substances may elicit an allergic reaction only when exposed to light. In photo patch testing, the suspected chemical or medication is applied in two separate areas. One of the areas is exposed to a range of ultraviolet type A light and then examined f or the presence of a reaction. Testing is considered positive if only the area that has been exposed to the ultraviolet light demonstrates an allergic reaction. Oral challenge may be used to conf irm or diagnose IgE-mediated hypersensitivity to specif ic f oods, f ood additives and preservatives, or drugs. Food challenge is time-consuming and associated with the potential f or anaphylaxis. Simpler measures, such as skin tests and elimination of suspected f oods f rom the diet, are typically tried f irst. If skin tests are negative or equivocal and inconsistent with a history suggestive of f ood allergy, and symptoms abate af ter elimination of suspected f oods, one f ood at a time is added back into the diet (open f ood challenge) until symptoms recur. Blinded, controlled f ood challenge (by ingestion) may be undertaken when skin tests are negative or inconsistent with a history that suggests f ood allergy. Sublingual f ood allergy testing, in which the f ood in question is placed under the tongue and not ingested, is an unproven testing method (see "provocation-neutralization," below). Double-blind f ood challenges are typically reserved f or a select subset of patients. Drug provocation/bronchial challenge testing is typically undertaken only if the need to conf irm or exclude hypersensitivity outweighs the risk of severe reaction. This may occur in patients who have a history of allergy to a particular drug f or which there is no ef f ective alternative but who need that drug f or treatment. Bronchial challenge testing is used in the diagnosis and management of asthma to quantif y allergic airway responsiveness to pharmacological agents, such as methacholine or histamine. Bronchial provocation/challenge testing with extracts of common aeroallergens such as dust or ragweed, however, has no established clinical value and of fers no additional clinical inf ormation beyond that obtained by a well-taken clinical history and a caref ully perf ormed skin test. Serial endpoint titration (SET) is a variation of intradermal skin testing in which increasing doses of antigen are used to determine the concentration at which the reaction changes from negative to positive (i.e., the endpoint). SET has been used as an alternative to skin prick testing or in vitro testing and has also been used to guide initiation of immunotherapy, with the endpoint dilution used as the starting dose. Although not considered a replacement f or skin testing, SET may be indicated f or determination of a saf e starting dose f or testing or immunotherapy when there is potential f or the specif ic allergen in question to produce a severe systemic reaction or anaphylaxis (such as with bee venom). In Vitro Allergy Testing The discovery of the role of IgE in clinical allergy testing resulted in the development of in vitro diagnostic assays to test f or allergen sensitivity. The f irst immunoassays were developed to quantif y the serum concentration of total IgE. In normal individuals, IgE is usually present at low levels; 130 ng/ml represents the upper limit of the normal range. However, a signif icant number of asymptomatic normal individuals, such as those with parasitic diseases or with depressed cell- mediated immunity, exceed this level. Also, some allergic patients may exhibit normal total IgE levels in the presence of elevated levels of specif ic IgE. Methods were theref ore developed to assay allergen-specific IgE. The radioallergosorbent test (RAST) system was developed f or in vitro measurement of specific IgE in a patient’s serum. Other in vitro tests f or specif ic IgE have been Medical Coverage Policy: 0070 developed and employ the same principles as the RAST but use an enzymatic (MAST) or f luorogenic (FAST) detection system in place of a radioactive label. In vitro tests that screen f or multiple allergens in a single assay (Phadiatop®, Pharmacia Diagnostics) or that can be used in an automated system (ImmunoCAP®, Pharmacia Diagnostics) have been developed. The ImmunoCAP is designed as a "sandwich" immunoassay. The sensitivity and specif icity of the ImmunoCAP compares f avorably with those of the modified PhadezymRAST® system. Results f rom studies have indicated that, when compared to skin prick testing as the gold standard, the ImmunoCAP system has been shown to have a greater sensitivity (80–95%) than RAST and to have similar specif icity (85%). Other modified versions of the RAST test include the PRIST, RIST, MRT (modif ied RAST) and ELISA IgE tests. The overall sensitivity of in vitro immunoassays compared with prick/puncture skin tests has been reported to range f rom 50–90%, with an average of about 70–75% f rom most studies. Skin testing, theref ore, continues to be the pref erred method f or the diagnosis of IgE-mediated sensitivity. According to practice parameters issuedby the AAAI, selective use of in vitro tests may be justif ied f or patients in whom skin testing is inappropriate. Situations in which specif ic IgE immunoassays may be appropriate include: • testing of patients with severe dermatographism, ichthyosis or generalized eczema testing in patients who cannot be withdrawn f rom medications that interf ere with skin testing (patients receiving long-acting antihistamines or tricyclic antidepressants) testing in patients who have a clinical history suggesting an unusually greater risk f or anaphylaxis or who have had a previous systemic reaction to skin testing testing of patients with mental or physical impairments When there is a clear history of sting anaphylaxis and skin test results are negative, then serum IgE antibodies should be measured, and if necessary, skin tests should be repeated af ter 3 to 6 months (Kowal and DuBuske, 2021; Golden, et al., 2017). It should be noted that specif ic IgE immunoassays do not have suf f icient sensitivity f or absolute positive prediction of anaphylactic sensitization to venoms, penicillin and other drugs. This method of testing should not be used to provide def initive diagnoses, due to the potential f or serious consequences resulting f rom a f alse-negative outcome. Allergen-specif ic IgE immunoassays provide neither diagnostic nor prognostic inf ormation when measured in the cord blood of newborn inf ants. Arthroplasty Implants: In Vitro Testing for Metal Allergy/Hypersensitivity Metal implants are widely used in orthopedic surgery f or joint arthroplasty and f racture f ixation. Metallic implants are f requently composed of stainless steel, Vitallium, titanium, Zirconium, and cobalt-chromium-molybdenum alloys. These alloys are typically composed of metals including aluminum, chromium, cobalt, nickel, molybdenum, vanadium, titanium and iron. Intolerance reactions to metal implants include dermatitis, impaired wound healing, ef f usion, pain, or loosening. It is important to distinguish between cutaneous contact sensitivity and sensitivity to implanted devices. Local reactions at the time of contact (e.g., rash, urticarial, swelling) are seen with hypersensitivity related to cutaneous contact with metallic objects such as jewelry Metal contact allergy/hypersensitivity is quite common, and there is insuf ficient evidence to demonstrate that this places patients at increased risk of developing complications following orthopedic implant procedures. Routine testing f or metal allergy prior to joint implantation theref ore has not been established. There may be a role such testing, however, in patients with a history of severe localized (e.g., hives, blistering, extensive rash) or systemic cutaneous reactions, or in those with a history of complications suspected to be caused by metal allergy with a prior implant. Medical Coverage Policy: 0070 Evidence evaluating the relationship between metal allergy/sensitivity and implant outcomes is limited. In reviewing the approach to the clinical work-up of patients with putative allergic disease to metallic orthopedic implants, Thyssen et al. (2011) stated that the overall risk of developing extracutaneous allergic reactions following total hip arthroplasty is comparable in metal patch test positive and negative subjects. It has been proposed that up to 5% of total joint arthroplasty f ailure within seven years of surgery may be caused by debris-induced immune reactivity, including delayed-type hypersensitivity reactions to metals. The authors recommend that clinicians should not perf orm routine patch testing prior to surgery unless the patient has already had implant surgery with complications suspected to be allergic, or has a history of clinical metal intolerance of sufficient magnitude to be of concern. In this case it would be advisable to avoid an implant containing metal(s) that the patient reacted to during allergy testing. The authors propose that the clinical work-up of a patient suspected of having an allergic reaction to a metal implant would include patch testing and possibly in vitro testing. The toxicity of some metals may hamper in vitro testing, and patch testing may allow screening f or more metals. In vitro testing may be usef ul, however, in doubtf ul cases and of f er quantitative estimates. Granchi et al. (2012) published results of a systematic review and meta-analysis of metal sensitivity testing in patients undergoing total joint arthroplasty, to assess the risk of developing metal hypersensitivity postoperatively and the impact on outcomes, and also to investigate the advantages of performing hypersensitivity testing. A total of 22 studies (3654 patients) met the inclusion criteria. Fourteen studies were eligible f or calculating the risk of metal allergy in patients undergoing joint replacement. The f requency of positive tests increased f ollowing joint replacement, particularly in patients with implant f ailure or a metal-on-metal coupling. The probability of developing a metal allergy was higher postoperatively (odds ratio [OR] 1.52 (95% conf idence interval [CI] 1.06-2.31, p=0.02). Ten studies were eligible to calculate the risk of metal allergy according to the status of the replacement. The probability of having a metal allergy was more than double in patients who had a f ailed replacement than in those with a stable replacement (OR 2.76 [95% CI 1.14-6.70, p=0.02) There was signif icant heterogeneity between studies, however, and no predictive value regarding the status of the replacement could be attributed to the testing results f or metal sensitization. The meta-analysis conf irmed that the probability of developing a metal allergy is higher post-operatively, and the risk is even greater when f ailed replacements are compared with stable replacements. In terms of defining the advantage of hypersensitivity testing, the f indings demonstrated that pre- or post-operative screening has no predictive value. The authors noted, however, that most papers concluded that hypersensitivity testing should be perf ormed preoperatively in patients with a history of metal allergy, and should be perf ormed in those with a f ailed replacement when hypersensitivity is suspected, af ter excluding inf ection and mechanical f ailure. The authors stated that the question of which test is best is debatable, since both in vitro and in vivo testing have advantages and disadvantages. Limitations of large-scale application of in vitro testing include the cost and need f or specialized laboratories. The patch test is considered the ref erence method f or diagnosing contact allergy, but the use of patch testing in detecting hypersensitivity to implant materials is controversial. The f requency of positive patch tests increases, however, when more haptens are tested. Metal alloys are also used in other procedures; including dental implants, cardiovascular stents, and gastrointestinal wire mesh stents. There is insuf f icient evidence evaluate the clinical utility of metal allergy testing f or these indications In vitro allergy testing is not indicated when there are no contraindications to skin testing or in patients who are successfully being treated f or allergies, have mild symptoms and a short allergy season. Leukocyte Histamine Release (LHR) Medical Coverage Policy: 0070 Leukocyte histamine release testing is an in vitro test that evaluates the presence of specif ic IgE antibodies. The test has been proposed f or the diagnosis of various allergic conditions, including atopic disorders and stinging insect allergies. Leukocyte histamine release testing detects the release of histamine f rom basophils in a sample of whole blood exposed to allergens in vitro. It is a cumbersome test typically conducted in research laboratories, and has not been studied f ully f or its predictive value in determining specif icity and sensitivity. Its role in the diagnosis and management of allergic disease outside of the investigative setting has not been established. Bead-Based Epitope Assay (BBEA): A bead-based epitope assay (BBEA) has been proposed to diagnose and monitor patients with f ood allergies. The test breaks down allergenic proteins into smaller components, called epitopes. It then measures the reactivity of a patient’s IgE/IgG4 levels to each epitope to generate a detailed reactivity profile that can be used by clinicians to manage the allergy. There are several IgE epitope mapping methods based on the binding of IgE molecules to peptides that are derived f rom the allergen, thereby allowing f or the identif ication of epitopes. The epitope mapping technology of such peptide arrays, by means of immobilized peptides on a surf ace, have been subjected to substantial development over the last decades. Typically, overlapping peptides of 10– 20 amino acid residues are synthetized in parallel, f or example, on a glass slide or a nitrocellulose membrane. A f ew years ago standard peptide synthesis could only synthetize a f ew hundred peptides, but with the recent technological advances, synthesis of up to 2,100,000 peptides is now a possibility. These advances in peptide arrays have recently allowed f or the identif ication of epitopes on the amino acid level this being able to identif y the amino acids within an epitope contributing to the binding to IgE of peanut allergic patients (Broekman, et al., 2015). AllerGenis™ has developed technology using data-driven machine learning and multiplex immunoassay technology that is proposed to more precisely diagnose and monitor patients with f ood allergies. According to the manuf acturer’s website, the diagnostic technology subdivides allergenic proteins into smaller peptides, called epitopes, and measures the reactivity of a patient’s IgE to these epitopes. The platf orm uses a high-throughput, Luminex bead-based epitope assay (BBEA) to analyze IgE reactivity to discrete food allergen epitopes (e.g., VeriMAP™ Peanut Dx, VeriMAP™ Peanut Sensitivity). The evidence in the published peer-reviewed medical literature evaluating the ef f ectiveness of BBEA primarily consists of cohort studies and comparative case control studies with prospective and retrospective designs with relatively small sample sizes (Suprun, et al., 2019; Suárez-Fariñas, et al., 2019; Flinterman, et al., 2008; Shreffler, et al., 2005; Beyer, et al., 2003). More rigorous studies are needed to establish that the bead-based epitope assay improves outcomes compared to alternative testing modalities. Treatment Evidence-based clinical practice guidelines support the use of subcutaneous allergen immunotherapy f or the management of allergic asthma, allergic rhinitis (with or without conjunctivitis), and stinging insect venom hypersensitivity. Clinical studies do not support the use of allergen immunotherapy for treatment of angioedema, atopic dermatitis, chronic urticaria, and f ood hypersensitivity. Numerous allergy treatment methods have been proposed as alternatives to subcutaneous allergen immunotherapy, as detailed above. There is insuf f icient evidence in the published medical literature to demonstrate the saf ely and ef f icacy of these alternative treatments. The allergy treatment recommendations in this Coverage Policy are based primarily on practice parameters developed by a joint task f orce representing the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) (Cox, et al., 2011). Medical Coverage Policy: 0070 Subcutaneous Allergen Immunotherapy Subcutaneous immunotherapy (SCIT) consists of gradual administration of increasing amounts of allergen to which the individual is sensitive, in order to temper the immune response and alleviate allergic symptoms. Subcutaneous injection immunotherapy is an established f orm of treatment and may be considered f or individuals with symptoms of allergic rhinitis, allergic conjunctivitis, or allergic asthma with natural exposure to allergens and who demonstrate specific IgE antibodies to the relevant allergen(s). SCIT is usually only recommended f or the treatment of allergic respiratory disease following a period of pharmacologic management and observation. Factors to be considered in determining treatment include the severity/duration of symptoms, patient pref erence/acceptability, adherence, medication requirements, response to avoidance measures, and the adverse ef f ects of medications. The expected response to immunotherapy is antigen specif ic and depends on the accurate identif ication and selection of component allergens based on the individual’s history, exposure and diagnostic test results (skin testing or serum/in-vitro testing). There is insuf f icient evidence to support the use of allergen immunotherapy f or atopic dermatitis, f ood hypersensitivity, chronic urticarial, or angioedema. The allergy immunotherapy recommendations in this Coverage Policy are based primarily on practice parameters developed by a joint task f orce representing the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) (Cox, et al., 2011) Injection Schedules: There are two phases of allergy immunotherapy administration; the initial build-up phase and the maintenance phase. In the build- up phase, the dose and concentration of allergen immunotherapy extract are increased, and in the maintenance phase, the patient receives an ef f ective therapeutic dose over a period of time. With the most common build-up phase schedule, injections are administered one to three times per week. With this schedule, patients usually reach a maintenance dose in three to six months, depending on the starting dilution and occurrence of reactions. If a systemic reaction occurs, immunotherapy may be discontinued, or if continued, the dose is reduced. Immunotherapy schedules may need to be adjusted f or a variety of reasons, including missed visits, high pollen or mold seasons, addition of a new allergen, or systemic reaction. Once a patient reaches the maintenance phase, the interval between injections can be progressively increased as tolerated, to an interval of up to f our weeks f or inhalant allergens and up to eight weeks f or venom. The effective therapeutic dose or maintenance dose is the dose that provides therapeutic efficacy without signif icant adverse local or systemic reactions. Three to f ive years of maintenance therapy is generally considered optimal f or maximum clinical benef it. Accelerated Immunotherapy Schedules Accelerated immunotherapy schedules include cluster immunotherapy and rush immunotherapy. Accelerated immunotherapy schedules may permit an individual to reach a maintenance dose sooner, but are associated with a higher risk of systemic reactions f or inhalant allergens, especially with high-risk patients (e.g., those with markedly positive prick/puncture or in vitro IgE test responses). Cluster immunotherapy: With cluster immunotherapy, several injections (usually two or three) are administered during each visit in order to achieve a maintenance dose more rapidly than conventional schedules. In cluster immunotherapy, several injections at increasing doses (generally 2–3 per visit) are administered sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is usually achieved more rapidly that with a conventional (single injection per session) schedule. Cluster schedules usually include f ewer total Medical Coverage Policy: 0070 injections than are used with conventional schedules, and permit a patient to reach a maintenance dose sooner, usually in one to f our weeks. Rush Immunotherapy: With rush immunotherapy, incremental doses of allergen are administered at varying intervals between 15 and 60 minutes over one to three days until the target therapeutic dose is achieved. Rush immunotherapy f or inhalant allergies may be associated with a signif icant risk of systemic reactions. Rush schedules f or stinging Hymenoptera venom immunotherapy are not associated with an increased incidence of systemic reactions, however. Sublingual Antigen Extract Drop Immunotherapy Preparations: Please ref er to Pharmacy Coverage Policy: Sublingual Allergen Immunotherapy f or inf ormation regarding FDA-approved sublingual allergen immunotherapy. Standardized antigen extract drop immunotherapy preparations administered under the tongue allows absorption through the sublingual mucosa. This therapy has been proposed f or the treatment of patients with asthma and/or allergic rhinitis. Questions remain about the optimal dosing, duration of treatment, and the use of multiple allergens. Because of mixed study results, the therapy is controversial. There is insuf f icient evidence in the published, peer-reviewed scientif ic literature regarding improved outcomes using this therapy. Clinical trial data comparing sublingual antigen extract drop immunotherapy with other immunotherapy treatments are also lacking. Further, prof essional society support in the f orm of published consensus guidelines is lacking. In a Practice Parameter Update (2017) regarding the use of liquid extract drops the American Academy of Allergy, Asthma, and Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) note that although alternative regimens and preparations f or liquid sublingual immunotherapy or use of specif ic sublingual drops have been proposed and may be used of f -label, these products and f ormulations have not been systematically studied in a rigorous manner in US populations. Use of such products or f ormulations is without recommendation f or any current particular indication in the US populations and is not endorsed. (Strength of Recommendation: Strong; Evidence: D: Directly based on category IV evidence or extrapolated recommendation f rom category I, II, or III evidence.) At present there are no U.S. Food and Drug Administration (FDA)-approved sublingual antigen extract drop preparations. Several meta-analyses and systematic reviews have examined outcomes with subcutaneous antigen extract drop immunotherapy (Fortescue, et al., 2020; Calderon, et al., 2011; DiBona, et al., 2010; Calamita, et al., 2006; Wilson, et al., 2004; update Radulovic, et al., 2010). Other studies have evaluated the comparative clinical ef f ectiveness of this immunotherapy compared with subcutaneous immunotherapy, placebo and other interventions f or the treatment of allergic rhino-conjunctivitis and/or asthma (Chelladurai and Lin, 2014; de Bot, et al., 2013). Study authors noted randomized controlled trials with head-to-head direct comparisons of subcutaneous immunotherapy and sublingual antigen extract drop immunotherapy are needed to strengthen the evidence base. Indirect comparisons of treatment options have many limitations and must be taken into consideration f or clinical decision making. Liu et al. (2019) conducted a multi-center, double-blind, randomized placebo-controlled trial with f our parallel groups to evaluate the efficacy and saf ety of sublingual immunotherapy (SLIT) with Dermatophagoides f arinae (D. f arina) drops on patients with house dust mites (HDM) induced atopic dermatitis (AD). The study included patients (n=239) aged 18–60 years, a severity score of atopic dermatitis between 10 and 40 on the scoring atopic dermatitis (SOCRAD) scale, and a positive skin prick test results to D. f arinae stimulation. Patients were randomly divided into f our groups: placebo (n=60), high-dose sublingual D. f arinae drops (n=60), medium-dose sublingual D. f arinae drops (n=60) and low-dose sublingual D. f arinae drops (n=59). Treatment was conducted by two phases: up-dosing phase (1st–10th weeks) and maintenance phase (11th–36th Medical Coverage Policy: 0070 weeks). In up-doing phase, patients received low to high dose of sublingual D. f arinae drops or placebo treatment. In the maintenance phase, patients took a high dose of sublingual D. f arinae drops or placebo daily. The primary outcome assessed the therapeutic efficacy and saf ety of SLIT drops. Patients were assigned to receive relevant treatment f or 36 weeks with f ollow-ups at f our, 10, 16, 24 and 36 weeks. The therapeutic ef f icacy of SLIT with D. f arinae drops was assessed using the SCORAD scale, the use of concomitant drugs to relieve clinical symptoms in maintenance phase, the dermatology lif e quality index (DLQI) and the skin lesion area. The saf ety was evaluated by adverse events (AE) and general clinical laboratory evaluations. 48 cases withdrew before the end of study. There were no signif icant differences in withdraw rates between the placebo group and D. f arinae Drops groups. There was significant decreases in scoring atopic dermatitis and total medication score in the medium-dose and high-dose D. f arinae drops groups. At the sixth visit, the skin lesion area showed a statistically signif icant dif f erence between high- dose/medium-dose D. f arinae drops group and placebo group (p<0.05). Most adverse events were minimal, and no lif e-threatening adverse drug reactions occurred. Author noted limitations included short term f ollow-up and children were not included as test subjects. The authors concluded that the study demonstrated the beneficial effect of SLIT with high or medium dose D. f arinae drops on AD, and the treatment was well tolerated. However, f urther studies should include a longer time f rames and a more suitable D. f arina drops dosage. Pf aar et al. (2019) conducted a parallel-group, multicenter, double-blind, randomized placebo- controlled trial to investigate the ef f icacy and saf ety of sublingual high-dose liquid birch pollen extract (40,000 allergy units native [AUN]/mL) in adults with birch pollen allergy. The study included adult patients (n=406) aged 18-65 years with moderate-to-severe birch pollen-induced allergic rhinoconjunctivitis with or without mild-to-moderate controlled asthma. Patients were randomized into the active treatment group (n=208) or the placebo group (n=198). Treatment was started three to six months bef ore the birch pollen season and continued co-seasonally during the pollen season f ollowed by an open-label saf ety extension period over six months that included 343 patients treated exclusively with the active product (n=169/active treatment group and n=174/placebo group). The primary outcome measured the dif f erence in mean combined symptom and medication score (CSMS) between the active and placebo treatment groups. The CSMS is the European Academy of Allergy and Clinical Immunology (EAACI) recommended end point f or pivotal studies. Primary outcome analysis was carried out in the intention-to-treat (ITT) population (n=357), with 179 patients in the active treatment group and 178 patients in the placebo group. The Secondary outcomes assessed quality-of -lif e, immunologic parameters, and saf ety. Thirty-two patients were lost to f ollow-up primarily due to the development of adverse events (AEs). Primary ef f icacy results demonstrated a signif icant (p<0.0001) and clinically relevant (32%) reduction in the combined symptom and medication score compared with placebo af ter three to six months of sublingual allergen immunotherapy (SLIT) in the intention to treat (ITT) population. Signif icantly better rhinoconjunctivitis quality-of-lif e scores (p<0.0001) and the patient’s own overall assessment of his or her health status, including the visual analog scale score (Euro Quality of Lif e Visual Analogue Scale; p=0.0025), were also demonstrated. In total, a good saf ety profile of SLIT was observed. The local and systemic treatment-emergent adverse events (TEAEs) in the double blind period of the study totaled 342 local reactions in 165 (40.6%) patients and 83.0% of all reactions were mild. Four (1.9%) patients of the active treatment group experienced at least one severe local reaction. Local and systemic adverse reactions were mainly of mild intensity and well controlled in the open label extension, 123 of 343 patients reported a local reaction, 88 of whom belonged to the f ormer placebo group. Most local reactions were of mild-to-moderate intensity (> 97%). Regarding clinical and laboratory saf ety parameters, no saf ety issues were observed. On behalf of the Agency f or Healthcare Research and Quality, Lin et al. (2013) and colleagues reported results of a comparative effectiveness review of 60 studies comparing sublingual antigen extract drop therapy to placebo or another intervention f or the treatment of allergic Medical Coverage Policy: 0070 rhinoconjunctivitis and/or asthma. Authors note overall quality of evidence is assessed to be low to moderate due in part to limitations with the description of allocation concealment in some studies, moderate statistical heterogeneity and possible publication bias. Large def initive trials are required as well as head-to-head comparative studies with currently available anti-allergic drugs. Further studies evaluating the mechanisms of sublingual antigen extract drop immunotherapy preparations are needed as is a need to develop and validate standard instruments, such as questionnaires with adequate psychometrical properties. There is need f or f urther large rigorously designed studies that examine long-term ef f ectiveness af ter discontinuation of treatment and establish the cost-effectiveness of sublingual antigen extract drop immunotherapy preparations. In a Cochrane review, Wilson et al. (2004; update Radulovic, et al., 2010), conducted a systematic review and meta-analysis of sublingual antigen extract drop immunotherapy f or the treatment for allergic rhinitis. The authors identif ied 22 randomized controlled trials involving 979 patients. Only two of the studies compared injection therapy with sublingual extract drop therapy. The studies reported similar improvements in symptoms and medication requirements. The authors f ound heterogeneity in the f indings, due to varying methods used to administer sublingual extract drop therapy and dif ferent clinical response scoring systems. Overall, sublingual antigen extract drop immunotherapy was f ollowed by a signif icant reduction in mean symptom scores (p=0.002) and medication use (p=0.0003) when compared to placebo therapy. There were no signif icant variations in response to the use of dif ferent allergens in the studies. The authors noted total amount of allergen delivered may be a determinant of success, but the increasing time duration of sublingual extract drop therapy did not clearly increase ef f icacy. Sublingual extract drop therapy did not appear to be ef f ective in studies limited to allergic children; however, the numbers of children in such studies were too small to draw def initive conclusions. The subgroup analyses did not suggest a benef it of treatment in any particular patient or disease group. The updated review of 2010 resulted in no change to the conclusions.