Summary Of Evidence

A literature search was conducted using the following key words: allergens; allergen immunotherapy; practice guidelines; practice parameters; meta-analysis; systematic review; allergic rhinitis; seasonal allergic rhinitis; allergic conjunctivitis; allergic asthma; inhalant allergies; routes of immunotherapy administration; subcutaneous immunotherapy; allergen-specific immunotherapy, atopic dermatitis; acute and chronic urticaria; skin rash; food allergies; stinging insect allergy; Hymenoptera; anaphylaxis.

Evidence-Based Guidelines

A Joint Task Force represented by the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology (JCAAI) has provided an updated practice parameter for allergen immunotherapy.¹ Also, the European Academy of Allergy and Clinical Immunology (EAACI) and the AAAAI provided an updated, comprehensive consensus report which includes the mechanisms of allergy immunotherapy and its use in clinical practice.⁶ In addition, the AAAAI and the ACAAI have provided a practice parameter update for stinging insect hypersensitivity.²

Allergen immunotherapy is defined as the repeated administration of specific allergens to individuals with IgE-mediated conditions to provide protection against allergic symptoms and inflammatory reactions associated with natural exposure to these allergens. Immunotherapy is effective for pollen, animal allergens, dust mites, mold/fungi, and Hymenoptera hypersensitivity. Allergen immunotherapy should be considered for patients who have discernable evidence of specific IgE antibodies to these allergens.¹

The decision to begin allergen immunotherapy may depend on a number of factors, including but not limited to, patient's preference/acceptability, adherence, medication requirements, response to avoidance methods, and the adverse effects of medications. The severity and duration of symptoms should also be considered when evaluating the need for allergen immunotherapy. Patient assessments should include a detailed clinical history, an applicable physical evaluation, and particular laboratory tests. Allergy testing results provide a conclusive diagnosis (e.g., immediate hypersensitivity skin tests, in vitro tests for serum specific IgE). When tests outcomes are positive for select IgE antibodies that align with likely triggers and patient exposure, immunotherapy is recommended; however, the manifestation of specific IgE antibodies alone does not infer the need for immunotherapy; the presence of IgE antibodies to an allergen must correlate with the patient’s history.¹

Many well-designed controlled trials show that allergen immunotherapy is effective for individuals with symptoms of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity.^2-9 Also, randomized trials demonstrate that allergen immunotherapy inhibits the development of asthma in individuals with allergic rhinitis.¹⁵ Several studies have also shown that aeroallergen immunotherapy may be beneficial for individuals with atopic dermatitis resulting from aeroallergen sensitization to dust mites.^1,9-11

Venom immunotherapy (VIT) is recommended for individuals with a history of a systemic reaction to Hymenoptera stings who demonstrate Hymenoptera-specific IgE antibodies and exhibit large local reactions (LLRs). In this regard, measurements of serum tryptase levels are recommended in individuals with a history of moderate to severe anaphylactic reactions to stings. Studies have shown that greater serum tryptase levels are correlated with recurrent and severe systemic responses (including deadly reactions) to VIT injections, increased failure rates in VIT, and increased relapse rates with discontinuation of VIT. While venom extracts are available for honeybees, yellow jackets, white-faced hornets, yellow hornets, and wasps, there is currently no venom extract available for fire ants. However, literature supports the use of whole-body extract (WBE) to be used as a reagent for diagnostic testing and immunotherapy for fire ant sting allergy.^1,2,9

The provider prescribing immunotherapy should be trained and experienced in prescribing and administering immunotherapy. The prescribing provider must choose the applicable allergen extracts based on the patient’s medical history, allergen exposure history, and the presence of specific IgE antibodies. The prescription must indicate the initial dose, the target maintenance dose, and the immunotherapy schedule.^1,2

Immunotherapy treatments are generally separated into two phases; the build-up phase and the maintenance phase. The build-up phase (also referred to as updosing, induction, or dose-increase) involves gradually giving greater doses within 8-28 weeks. Usually a single dose increase is administered per visit and visits generally vary from 1-3 times per week. Accelerated timetables, also referred to as rush or cluster immunotherapy, involve giving several injections at increasing doses on a single visit. While accelerated timetables provide a means of reaching the therapeutic dose sooner, a greater risk of a systemic reaction is possible in some individuals.^1,9

The maintenance phase occurs when the effective therapeutic dose is reached. This dose provides therapeutic efficiency without significant adverse local or systemic consequences. This dose may not be the initial targeted concentration/dose. The maintenance immunotherapy schedule is generally every 4-8 weeks for venoms and every 2-4 weeks for inhalant allergens. Maintenance immunotherapy generally involves follow-up visits every 6-12 months. If clinical improvement is not achieved after 1 year of maintenance immunotherapy, potential reasons for lack of effectiveness should be investigated and if no reasons are discovered, cessation of immunotherapy should be contemplated and other therapy possibilities should be explored. For many patients, the recommended duration of immunotherapy is 3-5 years. However, the duration of immunotherapy should be personalized based on the benefits sustained from therapy, disease severity, immunotherapy reaction, patient preference, and certain antigens in the therapy.^1,2,9

Generally, the initial dose is 1,000 to 10,000-fold less than the maintenance dose. The maintenance dose is usually 500-2,000 allergy units (AU) (e.g., for dust mites) or 1,000-4,000 bioequivalent allergy units (BAU) (e.g., for grass or cat) for standardized allergen extracts. For non-standardized extracts, a recommended dose is 3,000-5,000 protein nitrogen units (PNU) or 0.5 mL of a 1:100 or 1:200 weight/volume dilution of manufacturer’s extract. If the main allergen concentration for the extract is available, a maintenance dose of 5-20 micrograms (µg) of the major allergen is recommended for inhalant allergens and 100 µg for Hymenoptera venoms.^1,2

Desensitization involves the rapid administration of incremental doses of allergens or medications by which effector cells are rendered less reactive or nonreactive to an IgE-mediated immune response. Desensitization can involve IgE-mediated or other immune mechanisms. A positive skin test response to the allergens might lessen or actually convert to a negative response in some situations after desensitization. Tolerance to medications can be achieved through desensitization.

Immunotherapy may have severe unpredictable systemic and local reactions within the first 30 minutes following the injection. It is recommended that immunotherapy be administered in a setting that permits the prompt recognition and management of adverse reactions.⁶ The preferred location for such administration is the prescribing physician's office. However, patients can receive immunotherapy at another health care facility if the physician and staff at that location are trained and equipped to recognize and manage immunotherapy reactions, particularly anaphylaxis. It is recommended that patients wait at the physician's office/medical clinic for at least 30 minutes after the immunotherapy injection. Regardless of the location, allergen immunotherapy should be administered under the direct supervision of an appropriately trained physician, qualified nurse practitioner or physician assistant in a facility with the proper equipment, medications, and personnel to treat anaphylaxis.^1,9

The risk of severe systemic reactions is low with allergen immunotherapy that is administered appropriately; however, life-threatening and fatal reactions do happen. Studies have shown that severe responses following allergen immunotherapy occur in less than 1% of patients receiving conventional immunotherapy, but occur in about 34% of patients receiving rush (e.g., accelerated timetable) immunotherapy.¹

Limitations for Immunotherapy

Immunotherapy injections should be withheld if the patient presents with an acute asthma exacerbation; allergen immunotherapy should not be initiated unless the patient’s asthma is stable with pharmacotherapy as patients with severe or uncontrolled asthma are at a greater risk for systemic reactions to immunotherapy injections. Regarding inhalant and venom allergen immunotherapy, individual evaluations of risk versus benefit must be made for individuals on beta-blockers and angiotensin-converting enzyme (ACE) inhibitor medications.^1,2,9

Home administration of allergen immunotherapy should only be considered in rare and exceptional cases when the benefits of immunotherapy clearly outweigh the risks. Frequent or routine home immunotherapy is not considered appropriate under any circumstances. If this method is utilized, informed consent should be attained from the patient and the individual administering the injection must be trained and equipped to recognize and manage immunotherapy reactions, particularly anaphylaxis.¹

Methods of Immunotherapy not Supported in the Literature

In addition to the subcutaneous route, allergen extracts can be given by various methods. However, there are currently no FDA-approved formulations for a non-injection immunotherapy extract. In this regard, the quality of evidence in the literature does not support the following methods of immunotherapy: Oral and sublingual immunotherapy (SLIT) for food hypersensitivity, multiallergen subcutaneous immunotherapy (SCIT), neutralization-provocation therapy, low-dose subcutaneous therapy based on the Rinkel method, intranasal, intra-bronchial, intralymphatic, and epicutaneous. Further research is needed to clarify the utility and efficacy of these methods.^1,6,12,13

Conditions not Supported in the Literature for Immunotherapy

The quality of evidence in the literature is lacking in support of allergen immunotherapy for food hypersensitivity, cockroach hypersensitivity, chronic urticaria and/or angioedema, and therefore, is not recommended.^1,12,13 The use of therapy formulations, such as allergoids and adjuvants is also not supported in the literature.¹

Analysis of Evidence

Allergen immunotherapy, also known as allergy shots involves the repeated administration of allergen extracts to individuals with IgE-mediated conditions to decrease symptoms and improve quality of life during subsequent natural allergen exposure. Allergen immunotherapy consists of administering increasingly greater doses of specific allergens to individuals who have shown immunologic sensitivity or reaction to a particular allergen through allergy testing.

Multiple evidence-based practice guidelines and appropriate use criteria are available for allergen immunotherapy. Many well-designed controlled studies have shown that immunotherapy is effective for pollen, animal allergens, dust mites, mold/fungi, and Hymenoptera hypersensitivity. Also, aeroallergen immunotherapy is recommended for individuals with atopic dermatitis resulting from aeroallergen sensitization to dust mites. In addition, venom immunotherapy (VIT) is recommended for individuals with a history of a systemic reaction to Hymenoptera stings who demonstrate Hymenoptera-specific IgE antibodies and exhibit large local reactions (LLRs). Measurements of serum tryptase levels are also recommended for these individuals as increased serum tryptase levels are correlated with recurrent and severe systemic responses (including deadly reactions) to VIT injections, increased failure rates in VIT, and increased relapse rates with discontinuation of VIT. Also, the use of whole-body extract (WBE) is recommended for fire ant sting allergy as venom extracts are not currently available for fire ants.

The decision to begin allergen immunotherapy may depend on a number of factors, including but not limited to, patient's preference/acceptability, adherence, medication requirements, response to avoidance methods, and the adverse effects of medications. The severity and duration of symptoms should also be considered when evaluating the need for allergen immunotherapy. Patient assessments should include a detailed clinical history, an applicable physical evaluation, and particular laboratory tests. Evidence-based guidelines recommend immunotherapy when allergy testing results are positive for select IgE antibodies that align with likely triggers and patient exposure. The presence of IgE antibodies alone does not infer the need for immunotherapy; the presence of IgE antibodies to an allergen must correlate with the patient’s history.

Per evidence-based guidelines, the provider prescribing immunotherapy should be trained and experienced in prescribing and administering immunotherapy. The prescribing provider must choose the applicable allergen extracts based on the patient’s medical history, allergen exposure history, and the presence of specific IgE antibodies. The prescription must indicate the initial dose, the target maintenance dose, and the immunotherapy schedule.

Evidence-based guidelines recommend that immunotherapy be administered in a setting that permits the prompt recognition and management of adverse reaction. The preferred location for such administration is the prescribing physician's office. However, patients can receive immunotherapy at another health care facility if the physician and staff at that location are trained and equipped to recognize and manage immunotherapy reactions, particularly anaphylaxis. It is recommended that patients wait at the physician's office/medical clinic for at least 30 minutes after the immunotherapy injection as immunotherapy may have severe unpredictable systemic and local reactions within the first 30 minutes following the injection. Regardless of the location, allergen immunotherapy should be administered under the direct supervision of an appropriately trained physician, qualified nurse practitioner or physician assistant in a facility with the proper equipment, medications, and personnel to treat anaphylaxis.

Evidence-based guidelines support the following limitations for allergen immunotherapy: 1) Patients should not have substantial comorbid conditions that could increase immunotherapy risk (e.g., severe asthma uncontrolled by pharmacotherapy, significant cardiovascular disease); 2) Patients on beta-blockers and/or angiotensin-converting enzyme (ACE) inhibitor medications must have individualized assessments of risk versus benefit prior to receiving inhalant or venom allergen immunotherapy; 3) Patients should be able to cooperate during therapy; and 4) Home administration of allergen immunotherapy should only be considered in rare and exceptional cases when the benefits of immunotherapy clearly outweigh the risks. Frequent or routine home immunotherapy is not considered appropriate under any circumstances.

The quality of evidence in the literature does not support the following methods of immunotherapy: 1) oral and sublingual immunotherapy (SLIT) for food hypersensitivity; 2) multiallergen subcutaneous immunotherapy (SCIT); 3) neutralization-provocation therapy; 4) low-dose subcutaneous therapy based on the Rinkel method; 5) intranasal; 6) intra-bronchial; 7) intralymphatic; and 8) epicutaneous. Further research is needed to clarify the utility and efficacy of these methods. Also, the quality of evidence in the literature is lacking in support of allergen immunotherapy for the following conditions: a) food hypersensitivity; b) cockroach hypersensitivity; and c) chronic urticaria and/or angioedema. In addition, the use of therapy formulations, such as allergoids and adjuvants is also not supported in the literature.