Allergen Immunotherapy (AIT) with Subcutaneous Immunotherapy (SCIT)

Title XVIII of the Social Security Act, §1862 (a)(1)(A) allows coverage and payment for only 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.

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §20.2 Physician Expense for Allergy Treatment, §50.2 Determining Self-Administration of Drug or Biological and §50.4.4.1 Antigens

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, §90 Routine Services and Appliances

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

CMS Internet-Only Manual, Pub. 100-04, Medicare Claims Processing Manual, Chapter 12, §200 Allergy Testing and Immunotherapy

Compliance with the provisions in this LCD may be monitored and addressed through post-payment data analysis and subsequent medical review audits.

History/Background and General Information

Allergen immunotherapy (AIT) involves the administration of an allergen to which the patient is sensitive, for the purpose of modulating the untoward immune response to that allergen and alleviating allergic symptoms. AIT represents the only therapy capable of inducing a state of immune tolerance and, through its inherent disease-modifying properties, provides the potential to affect a sustained clinical benefit with long-lasting clinical remission of the allergic condition. In addition, it offers the possibility of preventing the development of new allergen sensitivities in the allergic patient, inhibiting the progression of allergic rhinitis to asthma, and improving a patient's quality of life and medication requirements. Subcutaneous immunotherapy (SCIT) is the best-established form of this treatment. The indications and efficacy for SCIT with aeroallergens (i.e., inhaled allergens, such as pollens, dust mites, animal dander, etc.) are considered in this LCD. SCIT with other allergens, such as venoms, is not considered in this LCD.

General Guidelines

There are several important considerations that should be addressed to determine if aeroallergen SCIT is appropriate for a specific patient.^1,2 SCIT using preparations of aeroallergens may be indicated in the management of the following disorders: allergic rhinitis and/or allergic conjunctivitis, including seasonal allergic rhinitis and/or conjunctivitis, perennial allergic rhinitis and/or conjunctivitis, and both seasonal and perennial allergic rhinitis and/or conjunctivitis; allergic asthma, including seasonal allergic asthma and perennial allergic asthma; and both allergic rhinitis and/or allergic conjunctivitis and allergic asthma. Clinical studies demonstrate that patients with both asthma and allergic rhinitis derive particular benefit.^3-6

Prior to consideration for AIT, the health care professional should ensure that the patient has maximized environmental control measures and is on an optimal medication regimen. If the patient has not been compliant with medications, the reasons for this should be explored in depth, including documentation to substantiate that the medications are either no longer effective or minimally effective in controlling the symptoms of allergic rhinitis, allergic conjunctivitis, or allergic asthma. SCIT is usually recommended for the treatment of allergic respiratory disease only after a period of pharmacologic management to include intranasal steroids and observation.⁷ Medications are relatively easy for most patients to use, and when effective, they provide relief more rapidly than immunotherapy.⁷

Per consensus published guidelines from a 2020 rhinitis update, it has been suggested that AIT (subcutaneous or sublingual tablets) be offered through shared decision making to patients with moderate/severe allergic rhinitis who (1) are not controlled with allergen avoidance and/or pharmacotherapy or (2) choose immunotherapy as the preferred method of treatment (e.g., due to the desire to avoid the adverse effects or long-term use of pharmacotherapy), and/or (3) desire the potential benefit of immunotherapy to prevent or reduce the severity of comorbid conditions, such as asthma. It is suggested that AIT (subcutaneous or sublingual tablets) be considered for patients with controlled mild and moderate asthma with coexisting allergic rhinitis.⁸

A period of observation also allows the clinician to monitor the patient's disease over time, which is particularly important for adults with new-onset asthma in whom the differential should include other disorders that may present with respiratory symptoms (e.g., other pulmonary conditions [chronic obstructive lung disease, chronic bronchitis, nonallergic asthma], gastroesophageal reflux disease, and cough caused by chronic rhinosinusitis). These conditions should be considered first before initiating SCIT. If current management is suboptimal, it is reasonable to consider a trial of AIT in patients with significant allergic disease, for any of the following reasons: the severity of the patient's condition, its duration (intermittent versus persistent; seasonal versus perennial), and the impact on work, schooling, and quality of life. These are some of the important factors in deciding whether to initiate a course of SCIT. Tangential to these considerations is an understanding of the patient's anticipated goals which highlights the importance of the establishment of a strong patient-physician relationship and the role of shared decision making in this process.^6,8,9

Covered Indications

SCIT using preparations of aeroallergens can be considered reasonable and necessary in the management of the following disorders:

Allergic rhinitis and/or allergic conjunctivitis, including:

• Seasonal allergic rhinitis and/or conjunctivitis
• Perennial allergic rhinitis and/or conjunctivitis
• Both seasonal and perennial allergic rhinitis and/or conjunctivitis

Allergic asthma:

• Seasonal allergic asthma
• Perennial allergic asthma
• Both allergic rhinitis and/or allergic conjunctivitis and allergic asthma

A patient is a candidate for AIT only if it has been established that there is a clinically important allergic component to their disease. For patients with the disorders listed above, clinical relevance is established by the presence of both of the following:

• Symptoms upon natural exposure to the allergen OR inferred when the patient has known exposure to an allergen and a temporal pattern of symptoms that is consistent with occurrence of that allergen, such as rhinitis and conjunctivitis during tree pollen season; AND
• The presence of specific immunoglobulin E (IgE) to that allergen, demonstrated either through allergen skin testing or serum tests for allergen specific IgE.

Clinical Indications for Allergen Immunotherapy

These clinical indications must be met to be considered reasonable and necessary for AIT:

1. Symptoms of allergic rhinitis, allergic conjunctivitis, allergic asthma, or any combination of these disorders after natural exposure to aeroallergens AND
2. Demonstrable evidence of clinically relevant specific IgE AND
3. At least 1 of the following:
4. Poor response to pharmacotherapy, allergen avoidance, or both for a minimum of 28 consecutive days
5. Unacceptable adverse effects of medications
6. Avoidance of long-term pharmacotherapy and its side effect(s)
7. Possible prevention of asthma in patients with allergic rhinitis

Dosing:

The effectiveness of SCIT is dose dependent. The optimal dose or dose range is specific to each type of allergen and varies significantly among allergens. AIT dosing is not adjusted for patient size or age. Children have customarily been given the same dose as adults. Some patients may not tolerate this dose due to repeated large local or systemic reactions. In this situation, the patient's highest tolerated dose becomes their maintenance dose. Most patients placed on immunotherapy are sensitized to multiple allergens when dosed from a mixture of allergens; however, monotherapy may also be reasonable and necessary.^1,10-13

Maintenance Therapy

Time to onset of benefit — The beneficial effects of SCIT for allergic respiratory disease begin during the first year of therapy and continue throughout the period in which the patient receives injections.^1,14-16

Clinical improvement can be demonstrated very shortly after the patient reaches a maintenance dose.^1,17-20

Duration of therapy — There is consensus that an initial course of immunotherapy should consist of 3 to 5 years of maintenance treatment. After this, the clinician and patient should meet to review overall impact on quality of life and based upon these factors, decide if treatment will be continued.^1,16,21,22

A decision about continuation of effective immunotherapy should generally be made after the initial period of 3 to 5 years of treatment. Some patients might experience sustained clinical remission of their allergic disease after discontinuing immunotherapy, but others might relapse. The severity of disease and benefits sustained from treatment are factors that should be considered in determining whether to continue or stop immunotherapy for any individual patient. Patients should be evaluated at least every 6 to 12 months while receiving immunotherapy to assess efficacy, to implement and reinforce its safe administration and to monitor adverse reactions, to assess the patient’s compliance with treatment, to determine whether immunotherapy can be discontinued, and to determine whether adjustments in the immunotherapy dosing schedule or allergen content are necessary.¹

Limitations for Immunotherapy

The following are considered not reasonable and necessary:

• First-line treatment for allergic rhinitis and allergic conjunctivitis in the absence of previous medical treatment and environmental avoidance
• Absence of clinically relevant IgE
• Atopic dermatitis
• Sublingual immunotherapy (SLIT)
• SCIT during pregnancy
• Treatment for food sensitivities
• A presumption of failure can be made when, after 12-24 months of therapy, a person does not experience a noticeable decrease of symptoms, an increase in tolerance to the offending allergen and a reduction in medication usage. Treatment will not be reimbursed after a 2-year period when there is no apparent clinical benefit.
• For those patients who have equivocal testing on IgE specific antibodies but have a strong clinical suspicion of allergic rhinitis and have a positive reaction to nasal allergen challenge, SCIT may be considered on a case-by-case basis as reasonable and necessary.

Provider Requirements

Payment may be made for a reasonable supply of antigens that have been prepared for a particular patient when:

• The antigens are prepared by a physician who is a Doctor of Medicine or Osteopathy; and
• The physician who prepared the antigens has examined the patient and has determined a plan of treatment and a dosage regimen; and because the major risk of AIT is anaphylaxis, SCIT should, therefore, be administered under the supervision of an appropriately trained physician who can recognize early symptoms and signs of anaphylaxis and administer emergency medications where necessary. In addition, SCIT should be administered only in facilities equipped to treat anaphylaxis.
• It may be appropriate to permit patient self-administration at home for the patient with a history of life-threatening anaphylaxis who cannot receive immunotherapy in a health care facility. This requires very careful consideration of potential benefits and risks and should be made on an individual patient basis with appropriate informed consent.

Documentation

Clear and accurate recording of the initial prescription for an AIT extract is essential to ensure that it is mixed in an identical fashion each time it is filled. In addition, these forms allow transmission of information to any clinician who may undertake the allergy care of the patient. It is recommended that the following information be contained in the form:

• Patient information, including name, patient number, birth date, telephone number, and picture (if available), to reduce the risk of an extract being given to the wrong patient.
• Preparation information, including name of person preparing and date of preparation.
• AIT extract content, including (for each allergen) common name or genus and species, extract manufacturer, concentration of manufacturer's extract, volume of manufacturer's extract added, the type of diluent (if any), volume of diluent added, lot number, and expiration date of each individual component.

A literature search was conducted using the following key terms: allergy immunotherapy, sublingual immunotherapy, allergens, allergic rhinitis, asthma, allergic dermatitis, allergy testing, Immunoglobulin E, Immunoglobulin G and blocking antibodies. Additional sources included PubMed^®, UpToDate^® and Hayes Knowledge Center. The literature search included published peer-reviewed literature and published societal guidelines within the last 50 years with greater emphasis placed upon literature from the last 25 years. Retrospective studies involving larger sample sizes were included to gather as much evidence as possible, although randomized controlled clinical trials (RCTs) and prospective RCTs were more useful in the analysis of current evidence. Case reports and case series were excluded due to low-quality of evidence. Published societal guidelines and recommendations were considered in the analysis as supported by the literature. Poster presentations and unpublished reports were not included in the analysis.

AIT was first introduced as a treatment for "hay fever" in 1911 by British physicians who injected grass-allergic patients with a dilute solution of timothy grass pollen. They demonstrated that immunized subjects experienced a meaningful (100-fold) decrement in ocular symptoms upon ocular challenge with timothy pollen extract.²³ The first controlled trials of AIT were performed in the 1950s.²³ In the 1960s, the benefit of AIT was shown to be specific to the allergen used in treatment, and major allergens in specific pollens were identified in the first double-blind, randomized, controlled trials using sham injections.²³ Studies of the mechanisms by which AIT altered the cellular and humoral pathways involved in the allergic diathesis followed. These studies of the interrelationships between a patient's serum IgE, basophil histamine releasability, skin test sensitivity, and clinical symptoms allowed a more precise understanding of the relationships between efficacy and allergen dose. For pollen allergy, it was also demonstrated that a perennial immunization regimen was superior to that of pre-seasonal "desensitization" because of inducing a persistent level of protective "blocking" antibody against pollen allergens. The results of these studies ushered in the modern era of AIT.²⁴

Immediate hypersensitivity to inhaled allergens is very common among children and young adults with asthma and rhinitis. Sensitization to 1 or more of the major indoor allergens (such as dust mite, cat, dog, or cockroach) combined with significant accumulation of relevant allergens in the house has been consistently found to be the strongest risk factor for asthma in population, case control, and prospective studies.^25-29

The evidence supporting a causal relationship between allergen exposure and asthma comes from bronchoprovocation experiments demonstrating that these allergens can induce bronchospasm, eosinophilic airway inflammation, and prolonged increases in bronchial hyperreactivity.^30,31 Perhaps more significantly, moving some asthmatic children or adults from their homes to a different low-allergen residential setting results in major improvements in clinical symptoms and bronchial hyperreactivity.^25,32 This background provides a powerful rationale for recommending that allergic patients should reduce allergen exposure in their houses as part of the management of asthma and allergic rhinitis.³³

Initial Therapy

A previous 2013 Agency for Healthcare Research and Quality meta-analysis reviewed 74 references and concluded that allergen SCIT is effective for reducing symptoms of allergic rhinitis, allergic asthma, and allergic conjunctivitis in adults (high strength of evidence).³⁴ Similarly, allergen immunotherapy (SCIT) was shown to be very effective in adults with asthma.^35,36

The overall efficacy of SCIT in treating allergic disease is supported by an extensive body of evidence.³⁷ The effectiveness of SCIT for the treatment of inhalant allergy (allergic rhinitis/conjunctivitis and allergic asthma) has been demonstrated by placebo-controlled studies for the following allergens: tree pollens (birch and mountain cedar), grass pollens (timothy and grass mixes), weed pollens (ragweed and Russian thistle), animal dander (cat and dog), dust mites (Dermatophagoides pteronyssinus and D. farinae), molds (Alternaria and Cladosporium), and cockroach.^14,15,38-41

Other allergens used in SCIT (other tree, grass, and weed pollens, molds, and animal materials [rodent, horse, etc.]), have not been studied as rigorously, although they are prepared and processed similarly to the well-studied extracts.

Allergic Rhinoconjunctivitis

Several randomized trials have demonstrated that AIT with the following specified allergens is efficacious in treating allergic rhinoconjunctivitis: birch, mountain cedar, grass, ragweed, and Parietaria pollen; cat, dog, Alternaria and Cladosporium molds; cockroach; and dust mites.^{14-16,39,42-50}

A 2007 meta-analysis evaluated 51 randomized trials published between 1950 and 2006 that assessed the efficacy of immunotherapy with pollen vaccines in the treatment of 2871 adults and children with seasonal allergic rhinitis.³⁸ The duration of immunotherapy ranged from 3 days to 3 years, with an average number of 18 injections per subject. Patients receiving immunotherapy experienced a significant reduction (expressed as standard mean difference, or SMD) in both symptom scores SMD -0.73 (95% confidence interval [CI] -0.97 to -0.50) and medication use -0.57 (95% CI -0.82 to -0.33).

Most studies of the effect of immunotherapy on allergic conjunctivitis were performed in patients with concomitant rhinitis. However, one review examined the effects of SCIT on ocular allergy by analyzing 15 studies of varying rigor that documented ocular symptoms.⁵¹ Twelve showed benefits in terms of reduced ocular symptom scores, medication use, or decreased reactivity upon conjunctival provocation challenges.

The magnitude of effect of SCIT on allergic rhinitis was assessed in a study of patients with allergic rhinoconjunctivitis, some of whom also had allergic asthma.⁵² In this study, SCIT was approximately equivalent in efficacy to glucocorticoid nasal sprays. Authors concluded that it is probable that the 2 therapies together are additive and that the combination of a glucocorticoid nasal spray and SCIT represents the most effective medical management of allergic rhinitis available, although SCIT has not been compared with other therapies in head-to-head trials.

Local allergic rhinitis is a term applied to a subset of patients with classic rhinitis symptoms who test negative for allergen specific IgE on skin testing and in vitro immunoassays, but who react to nasal challenge with allergen, especially dust mite, with signs and symptoms similar to those in patients with typical allergic rhinitis and significantly different from controls without rhinitis.^53,54 There is some evidence that such patients produce allergen specific IgE locally in the nasal tissues. A systematic review and meta-analysis that included 4 randomized trials (156 patients) evaluated the effects of AIT (administered with an aluminum-containing adjuvant) on various clinical parameters (symptom scores, medication scores, combined scores, and quality of life) and immunologic changes associated with successful AIT.⁵⁵ Limited by the small number of patients, heterogeneity of study design and scoring methods, and high dropout rate, the analysis provides limited clinical and immunologic data supporting benefit from SCIT; however, further studies are needed. A standardized method of intranasal challenge would also be necessary to identify patients with local allergic rhinitis before AIT could be routinely recommended for this population subset.

Allergic Asthma

Proper selection of patients is crucial for clinical success.^56,57 Asthma triggers vary significantly among individuals, and allergen exposure may be just one of several triggers that are important for a given patient. Thus, patients for whom allergen exposure is clearly an important trigger are more likely to experience meaningful benefit. In contrast, SCIT might not produce clinically meaningful improvement in a patient whose asthma is largely triggered by viral illnesses or irritant exposure (e.g., tobacco smoke), even if they are sensitized to several allergens. Another important factor may be the duration of allergic disease. New-onset allergic asthma may be more responsive to SCIT than longstanding disease.⁵⁶ For example, a school-aged child with new asthma symptoms in response to a pet may benefit more from immunotherapy than a middle-aged patient with lifelong asthma who had increased wheezing after bringing a new animal into the home.

Efficacy studies — Double-blind, placebo-controlled studies of specific allergens (short ragweed, mixed grass, D. pteronyssinus, Cladosporium, cat, or dog) have shown significant benefit in carefully selected patients with allergic asthma.^14,42,58,59

Several meta-analyses support the efficacy of SCIT in allergic asthma.^49,60 One reviewed 88 trials, including 42 trials of immunotherapy for dust mite allergy, 27 for pollen allergy, 10 for animal dander allergy, 2 for Cladosporium mold allergy, and 6 using multiple allergens.⁶⁰ Overall, there was a significant improvement in asthma symptom scores (SMD -0.59, 95% CI -0.83 to -0.35), and it would have been necessary to treat 4 patients (95% CI 3-5) with immunotherapy to avoid 1 deterioration in asthma symptoms. The combined SMD for medication requirements was -0.53 (95% CI -0.80 to -0.27) and showed a significant reduction in medication use following AIT. AIT also significantly reduced allergen-specific bronchial hyperreactivity, with some reduction in nonspecific bronchial hyperreactivity.

A 2017 meta-analysis evaluating the preventative effects of AIT (both subcutaneous and sublingual) included 32 studies of sufficient quality and found evidence of a reduction in the short-term (<2 years) risk of developing asthma among patients with allergic rhinitis (relative risk 0.40, 95% CI 0.30-0.54). The analysis also examined the longer-term risk of asthma development, as well as the ability of immunotherapy to prevent the occurrence of a first allergic disease in sensitized but asymptomatic individuals or to prevent sensitization to new allergens. For these outcome measures, there were consistent trends toward benefit, although the findings were not conclusive (CIs included no effect).⁶¹

Based upon the collective body of evidence, SCIT was added to the National Asthma Education and Prevention Program (NAEPP) guidelines for asthma management in 2007 and is recommended as an adjunct to standard pharmacotherapy.⁶² Practice parameters subsequently delineated optimal target dosing for clinical practice.¹ However, given the heterogeneity of asthma, it remains difficult to predict the degree of improvement in clinical asthma symptoms that will be achieved with SCIT in a given individual patient.

Dosing

The effectiveness of SCIT is dose dependent. The optimal dose or dose range is specific to each type of allergen and varies significantly among allergens. Optimal doses have been determined for many of the major inhalant allergens.¹⁰ Doses of individual standardized allergens that produced clinically effective results in double-blind, placebo-controlled trials are known for the standardized allergens.¹⁰ Data on effective doses of non-standardized extracts are available. It should be noted that the non-standardized pollens are generally in the same range of potency as the standardized pollens. Because of the relatively low content of major allergen in non-standardized extracts of cockroach, fungi, and aqueous preparations of dog dander, it is uncertain whether clinically effective immunotherapy doses can be attained with these extracts. However, there are fully controlled trials showing effective immunotherapy with Alternaria alternata⁶³ and Cladosporium herbarum⁶⁴, as well as unblinded and/or uncontrolled studies reporting favorable patient outcomes with cockroach⁶⁵ and horse dander⁶⁶ immunotherapy using available extracts.

An AIT extract should be prepared so that the maintenance concentration delivers a dose of each allergen that has been demonstrated to be clinically effective (called the maintenance goal). Most patients placed on immunotherapy are sensitized to multiple allergens.^13-15 In the United States (U.S.), the use of immunotherapy solutions containing multiple allergens is the rule, while in many other countries, patients are treated with the single allergen to which the patient shows greatest clinical sensitivity. Both methods have been shown to be effective in randomized, controlled studies.^16-19 However, direct, head-to-head studies comparing the 2 approaches are lacking. In a large, randomized trial of patients receiving grass SCIT, both monosensitized and polysensitized patients benefited to a similar degree from monotherapy with grass pollen extract.¹⁹

Duration of Therapy/Maintenance Therapy

A minimum of 3 years has been identified in several studies as an effective initial treatment period and one that provides some lasting benefit after the injections are discontinued. Several more years of continued relief is typical after SCIT is discontinued, although there is a risk of earlier relapse that is not predictable. In the case of relapse, it is possible to start immunotherapy again.

A prospective controlled trial of 40 asthmatic patients who were treated with standardized dust mite SCIT for 1 to 8 years found that in the 3 years after stopping therapy, the relapse rate was 48% in patients who had completed 3 or more years of treatment, compared with 62% in those who had completed less than 3 years.²¹

Another study of patients with allergic rhinitis and asthma attributable to dust mite allergy found that 3 years on an effective dose and with good adherence of SCIT achieved significant clinical benefit, and only a small additional improvement in rhinitis symptoms was gained from extending therapy to 5 years.²²

In a multiyear double-blind trial, 32 grass-allergic patients who had experienced relief from 3 to 4 years of grass pollen SCIT were randomized to continued immunotherapy or placebo injections and compared with patients who never received SCIT. There was no difference between the 2 immunotherapy groups for at least the next 2 years, and symptom scores were markedly lower than in the control group.¹⁶ In addition, immunologic markers provided strong supportive evidence of the treatment's effect, with an inhibition of late-phase skin test reactivity, and reduction in CD3+ T cell infiltration into the tissue and IL-4 messenger RNA expression. This work led to the currently accepted recommendation that SCIT be administered for a minimum of 3 years.¹⁶

Typically, several more years of continued relief is typical after SCIT is discontinued, although there is a risk of earlier relapse that is not predictable. In the case of relapse, it is possible to start immunotherapy again. Reliable biomarkers for determining which patients will experience lasting benefit from SCIT have not been identified. Neither skin tests nor serum immunoglobulin G (IgG) antibodies, local antibody production, or in vitro T cell responses have been demonstrated to predict outcomes after the cessation of treatment.^67,68

Sublingual Immunotherapy

The available studies have provided mixed evidence that liquid SLIT may improve symptoms and reduce medication use in patients with allergic rhinitis or rhinoconjunctivitis compared with placebo treatment. However, benefits over placebo treatment were not found in all studies, and questions remain regarding durability of benefits due to limited follow-up. Due to the lack of a U.S. Food and Drug Administration (FDA) approved liquid for SLIT, questions remain regarding standardization of the extracts, dosing, and patient selection. Additional large, well-designed clinical studies with long-term follow-up are needed to optimize patient selection criteria and treatment parameters in order to support this service as reasonable and necessary.^69-73

In the studies noted above, the low-quality body of evidence was also largely limited by heterogeneity in liquid SLIT preparations (e.g., type of allergen extract, number of allergen extracts, and dose), timing of treatment initiation, treatment duration, patients being sensitized to single or multiple allergens, variations in acceptable medication use outside of liquid SLIT, differences in pollen dispersal over allergy seasons and across geographical regions, lack of standardized criteria for symptom and medication use scores, and a paucity of evidence regarding patient-centered outcomes, including satisfaction and health-related quality of life measures. Overall quality was based on the balance of benefits and harms and was assessed taking into consideration the quality of individual studies; the precision, directness, and consistency of data; and the applicability of the data to general practice.

SLIT is excluded from Medicare Coverage; see NCD 110.9 Antigens Prepared for Sublingual Administration.

Societal Guidelines

According to the American Academy of Allergy, Asthma and Immunology (AAAAI), societal guidelines favor AIT for allergic rhinitis, allergic conjunctivitis, and allergic asthma. Conclusions from the workgroup showed that randomized, prospective, single- or double-blind, placebo-controlled studies demonstrate the effectiveness of specific immunotherapy in the treatment of allergic rhinitis. Prospective, randomized, double-blind, placebo-controlled studies demonstrate the effectiveness of specific immunotherapy in the treatment of allergic asthma. AIT is an effective form of treatment for many allergic patients, provided they have undergone an appropriate allergy evaluation. The expected response to AIT is antigen specific and depends on the proper identification and selection of component allergens based on the patient’s history, exposure, and diagnostic test results. Aeroallergen immunotherapy should be considered for patients who have symptoms of allergic rhinitis, rhinoconjunctivitis, and/ or asthma after natural exposure to allergens and who demonstrate specific IgE antibodies to relevant allergens.¹

According to the 2019 Allergic Rhinitis and its Impact on Asthma (ARIA) project from the European Academy of Allergy and Immunology, the authors concluded that the use of AIT was effective in the treatment of allergic rhinitis and/or asthma using SCIT. Studies using prescription databases have recently found that the efficacy demonstrated in double-blind, placebo-controlled, randomized clinical trials (DB-PC-RCT) translates into real life.⁷⁴

Finally, according to societal guidelines, immunotherapy should not be given to patients with negative test results for specific IgE antibodies or those with positive test results for specific IgE antibodies that do not correlate with suspected triggers, clinical symptoms, or exposure. This means that the presence of specific IgE antibodies alone does not necessarily indicate clinical sensitivity. There is no evidence from well-designed studies that immunotherapy for any allergen is effective in the absence of specific IgE antibodies. These parameters were developed by the Joint Task Force on Practice Parameters, representing the AAAAI; the American College of Allergy, Asthma and Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing this position statement.¹

Health Care Disparities

Health care disparities were considered in the formulation of this LCD. According to the AAAAI, health care disparities exist in the treatment of patients with allergic rhinitis and allergic asthma. Groups that have been economically marginalized have a higher rate of asthma-related health care utilization such as emergency room visits, hospitalizations, and readmission. Similarly, allergic rhinitis has a high prevalence in the general population but is underdiagnosed in under-resourced patients. Differential sensitization and exposure to mold, cockroach, and mouse allergens are linked to the urban built environment and low SES, and predominantly affects Black and Latino populations, contributing to disease in these groups. As a result of reduced recognition and treatment of allergic rhinitis, as highlighted by the AAAAI Work Group Report of the Committee on the Underserved, disparate outcomes for Black and Latino patients exist. In addition, AIT in these patients was either less likely to be prescribed or prematurely discontinued.⁷⁵

SCIT for allergic disease involves the gradual administration of increasing amounts of allergen to induce protective immunologic responses. Immunotherapy is the only means of altering the abnormal immune response that underlies allergic disease in a semipermanent manner. SCIT is the most established form of this treatment. As most practiced, SCIT involves 1 or more injections per visit, administered at regularly scheduled intervals over a period of 3 to 5 years.⁷⁶

SCIT is effective in the treatment of allergic rhinitis, allergic conjunctivitis, and allergic asthma, in both children and adults. Patients should have symptoms of allergic rhinitis, allergic conjunctivitis, allergic asthma, or any combination of these disorders after natural exposure to aeroallergens with demonstrable evidence of clinically relevant specific IgE on allergy testing. Based upon the literature, SCIT would be reasonable and necessary for those patients who exhibit a poor or inadequate response to pharmacotherapy and allergen avoidance, experience unacceptable adverse effects of medications or for the possible prevention of asthma in patients with allergic rhinitis.⁷⁶

Societal guidelines and the literature support SCIT as reasonable and necessary for patients who have IgE antibodies to specific allergens and demonstrate correlation with suspected triggers, clinical symptoms, and exposure. In general, for the absence of clinical symptoms or in the absence of IgE antibodies to those specific allergens, SCIT would not be considered reasonable and necessary.

Allergic rhinitis and/or allergic conjunctivitis – In adults and children with moderate-to-severe allergic rhinitis and/or allergic conjunctivitis, SCIT is reasonable and necessary for those who fulfill the criteria noted above (Grade 2A).⁷⁹ The evidence reviewed suggests that the magnitude of effect for SCIT is approximately equivalent to that of glucocorticoid nasal sprays, and together may be additive.

Allergic asthma – In adults and children with mild-to-moderate allergic asthma, with or without rhinitis, SCIT is recommended for those who fulfill the criteria above (Grade 2B).⁷⁹ Patients with clear allergen-induced exacerbations or new-onset disease are most likely to experience clinically meaningful improvement.

The allergens that are known to be effective in SCIT include several tree, grass, and weed pollens; cat and dog dander; dust mites; certain molds; and cockroach. Beneficial effects are usually seen within the first year of treatment.

Contraindications – Severe or very labile asthma is a relative contraindication to SCIT, as patients with unstable asthma are at risk for severe bronchospasm during systemic reactions, and the risk is felt to outweigh the benefit in many cases. SCIT is not usually initiated during pregnancy, although it may be continued, without increasing the doses given, in women who were tolerating and benefiting from the therapy prior to becoming pregnant.

A course of immunotherapy usually consists of 3 to 5 years of treatment. After this time, the clinician and patient should review the overall impact of treatment on quality of life and based upon these factors, decide if treatment will be continued. SCIT can help prevent the progression of allergic disease and may be particularly valuable in helping patients with allergic rhinitis/conjunctivitis avoid the development of allergic asthma.

Types of allergen preparations – An AIT extract is a solution of 1 or more allergens that is used for SCIT. In the U.S., most allergens are commercially available as aqueous or glycerinated solutions.

Standardized extracts – Standardized extracts are more consistent in their potency and are thus preferred when available over non-standardized extracts; however, the literature supports both modalities as reasonable and necessary in the preparation of AIT.

Dosing – The effectiveness of SCIT is dose-dependent. The optimal dose or dose range is specific to each type of allergen and varies significantly among allergens. Optimal doses have been determined for many of the major inhalant allergens. Immunotherapy practice parameters provide recommended doses for maintenance immunotherapy with various standardized and non-standardized allergens. Doses are not adjusted for the age or size of the patient.

Single versus multiple allergens – In the U.S., it is common to administer SCIT with a mixture of several allergens, although this is not the practice in much of the rest of the world, and the 2 approaches have not been compared directly.

Liquid SLIT may be a promising alternative to subcutaneous injections in patients with allergic rhinitis; however, the development of standardized allergen extracts and dosing schedules that are approved by the FDA is necessary for the widespread use of liquid SLIT in the U.S. Additional well-designed studies with long-term follow-up are required to establish treatment durability in adult patients with allergic rhinitis. Future studies should assess patient-centered outcomes (e.g., patient satisfaction and quality of life) and address the paucity of evidence regarding the efficacy and safety of liquid SLIT in pediatric populations. Comparisons of the efficacy and safety of liquid products versus dissolvable tablets and standard immunotherapy are also warranted. Until further studies are conducted that address the aforementioned concerns, the evidence supporting the use of SLIT remain uncertain. Therefore, SLIT is not considered reasonable and necessary (see NCD 110.9 Antigens Prepared for Sublingual Administration).

AIT is effective for the treatment of allergic rhinitis. SCIT should be considered for patients with allergic rhinitis who have specific IgE antibodies to clinically relevant allergens, and its use depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, the adverse effects of medications, and patient preference.^1,77

Expert consensus is that there is no absolute lower or upper age limit for initiation of AIT, that AIT can be continued but generally not be initiated in pregnancy, and that SCIT can be considered in patients with immunodeficiency and autoimmune disorders.¹ In general, the clinical indications for AIT for allergic rhinitis and asthma are similar for adults and children. Studies of children receiving AIT have demonstrated significant improvement in symptom control for asthma and allergic rhinitis, a reduction in airway responsiveness to cat and house dust mite allergens, and reduction in pharmacy, outpatient, and total health care costs.¹

When clinically indicated, the decision to initiate AIT depends on several factors, including but not limited to patient’s preference/acceptability, adherence, medication requirements, response to avoidance measures, and the adverse effects of medications. SCIT should be administered in a setting where procedures that can reduce the risk of anaphylaxis are in place and where the prompt recognition and treatment of anaphylaxis is ensured.¹ The first dose of SCIT is administered in a clinical setting under medical supervision but, thereafter, may be administered by the patient at home or in the clinician’s office. Clinical and physiological improvement can be demonstrated shortly after the patient reaches a maintenance dose. Patients should be evaluated at least every 12 months while receiving AIT. While many patients experience sustained clinical remission of their allergic disease after discontinuing AIT, others may relapse.¹

A decision about continuation of effective AIT should generally be made after the initial period of 3 to 5 years of treatment.⁷⁸ For an individual patient, the decision to continue or discontinue treatment should be based on the severity of disease and the benefits sustained from treatment.

N/A

NCD 110.9 Antigens Prepared for Sublingual Administration

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