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.
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 one 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 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 for food hypersensitivity, 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
Evidence Submitted for Reconsideration
Cox et al1 provides a practice parameter (third update) for allergen immunotherapy. This guideline indicates that few studies have examined the effectiveness of multiallergen subcutaneous immunotherapy. These studies have conflicting outcomes, with some showing substantial clinical improvement compared with placebo and others demonstrating no benefit over optimal pharmacotherapy and environmental control measures. While it is important to treat patients with relevant allergens, the multiallergen studies have shown effectiveness overall, although some did not provide outcomes specific to the multiallergens. Furthermore, this practice is commonly utilized by U.S. allergists.
Nelson16 provides a review of the literature regarding differences in the method of providing subcutaneous allergy immunotherapy in patients with multiple allergies for European and U.S. allergists. This is considered a significant issue as evidence shows that polysensitization is more common than monosensitization.
In the U.S., the above referenced practice parameter (third update), published in 2011 by Cox et al1, for allergen immunotherapy is the most current guideline for multiallergen subcutaneous immunotherapy. This guideline recommends providing subcutaneous allergy immunotherapy “with a mixture consisting of all the allergen extracts to which the patient has evident clinical sensitivity.”16(p583)
In 2018, the EAACI Taskforce provided a guideline on allergen immunotherapy for allergic rhinoconjunctivitis. This guideline includes a recommendation “that a polyallergic patient whose sensitivities are to homologous or related allergens (such as northern grasses or birch/alder/hazel) be given a single representative extract or a mixture of two of the related extracts. Where the extracts are not homologous, they recommend separate allergen immunotherapy preparations for the one or at the most two of the clinically most important allergens with, if two, doses be given 30 – 60 minutes apart in separate locations.”16(p583)
The literature indicates that methods of providing allergy immunotherapy in polyallergic patients are different in the U.S. and Europe. “The U.S. practice parameter’s recommendation that only clinically relevant allergen extracts be included in a multiallergen subcutaneous immunotherapy mixture probably represents the consensus of most practicing U.S. allergists.”16(p584) Allergists in the U.S. seem satisfied with the multiallergen approach, "because empirically it appears to be working well.”16(p588)
Nelson17 provides a review of the literature regarding multiallergen immunotherapy for allergic rhinitis and asthma. Literature was reviewed for studies concurrently using two or more different allergen extracts in subcutaneous or sublingual immunotherapy (this summary focuses on subcutaneous administration). The author concludes, “The findings of the current review strongly suggest that the simultaneous delivery of multiple unrelated allergens can be clinically effective with the proper identification of relevant allergens, and treatment with adequate doses for a sufficient period of time is essential.”17(p768)
Burks et al6 provides a consensus report from the EAACI and the AAAAI for allergy immunotherapy. This consensus report represents a comprehensive review of the literature for allergy immunotherapy and includes the mechanisms of allergy immunotherapy and the utilization of this therapy in clinical practice, variations in methods between Europe and the U.S., and addresses specific unmet clinical needs in allergy immunotherapy with select therapeutic approaches.
The report indicates that European practices generally provide single-allergen subcutaneous immunotherapy. Though, subcutaneous immunotherapy is commonly provided with multiple allergens in the U.S., which is supported by some older studies.6
Wise et al18 provides an international consensus statement on allergy and rhinology for allergic rhinitis based on a review of the literature. Regarding single-allergen versus multiple-allergen allergen immunotherapy, the authors state, “It is the common practice among U.S. allergists to include in their treatment multiple allergen extracts to which the patient is sensitized.”18(p128) Whereas, “European guidelines recommend treating with the single most troublesome allergen identified clinically, or if more than 1 extract is to be given they should be given at separate sites with at least 30 minutes in between administration.”18(p128)
Wood et al19 provides a report of four pilot studies: “(1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults.”19(p2) (This summary will focus on the study for subcutaneous immunotherapy as SLIT is nationally non-covered by Medicare; antigens must be administered by injection to be considered for coverage).
An open-label, pilot study was conducted utilizing German cockroach allergen extract administered by subcutaneous injection to evaluate the safety of this therapy in cockroach-sensitive individuals. “The objective of this protocol was to assess whether treatment with cockroach SCIT using the per-protocol allergen extract doses is safe. The primary outcome measure was the rate of related adverse events and serious adverse events in the course of treatment.”19(p9) The study included ten study participants (average age of 37.5 years) with cockroach sensitivity. Seven of the participants had asthma and six had allergic rhinitis.
The study participants were given increased doses of subcutaneous cockroach extract twice per week for 11 weeks until they reached the maintenance dose of 0.6 mL of a 1:20 concentration of extract. Study participants were then monitored for 15 weeks as they were given weekly injections at the maintenance dose. Blood was collected each month for evaluation of cockroach-specific IgE levels and other biomarkers of allergen immunotherapy.19
The average cockroach skin prick test wheal was 6.75 mm (range, 3–9 mm), and the average cockroach IgE level was 3.8 kU/L (range, 0.9–24.9 kU/L). Three adverse events occurred for localized injection-site reactions and were considered moderate in severity. An additional 147 adverse events occurred for minor injection-site reactions or symptoms that were consistent with the study participants’ underlying allergic rhinitis and were considered mild in severity and likely related to the treatment. Study results showed that changes from baseline in cockroach-specific IgE levels (1.78-fold increase, P=.02), IgG4 levels (12.95-fold increase, P<.001), and facilitated allergen binding activity (43% inhibition of B-cell binding, P<.001) were detected. Five study participants showed at least a 3-fold increase in cockroach IgE levels, while all of the study participants had at least a 2-fold increase in cockroach IgG4 levels.19
The authors stated that “The SCIT trial was designed as an early safety study but also as a proof of concept that consistent, allergen immunotherapy-related immunologic changes can be induced with German cockroach extract. Findings with regard to safety were reassuring because no severe reactions were seen. Mild reactions to SCIT were common, but they did not affect dosing.”19(p6)
The quality of evidence provided is insufficient to support allergen immunotherapy for cockroach hypersensitivity. Further research is needed to clarify the utility and efficacy of allergen immunotherapy for cockroach sensitivity.