REVIEW ARTICLE
Subcutaneous immunotherapy Ansley M. Roche, MD and Sarah K. Wise, MD, MSCR, FAAOA
Background: Allergic rhinitis, asthma, and Hymenoptera sensitivity affect approximately 20%, 9%, and 0.66% to 3.3% of adults in the United States, respectively. Various environmental control measures and pharmacologic options are available for symptomatic treatment of allergic rhinitis and allergic asthma. However, allergen-specific immunotherapy is the only form of treatment that alters the natural history of allergic disease. Methods: A literature review was performed. Information from systematic reviews, meta-analyses, and practice parameters were closely examined and summarized, and they are included in this primer. Results: There is evidence that supports the use of subcutaneous immunotherapy (SCIT) for the treatment of perennial and seasonal allergic rhinitis, asthma, and Hymenoptera sensitivity. Efficacy of SCIT has been established in the
A
llergic rhinitis, asthma, and Hymenoptera sensitivity affect approximately 20%,1 9%,2 and 0.66% to 3.3%3 of adults in the United States, respectively. Of the 9% of patients with asthma, approximately 63% have allergic asthma.2 Itchy nose, nasal congestion, and rhinorrhea are classic for allergic rhinitis. Asthma is a chronic inflammatory condition of the airway. Hymenoptera sensitivity is a hypersensitivity reaction to the venom of insects in the order Hymenoptera (ie, yellow jackets, wasps, bees, ants). These disease processes are type I hypersensitivity reactions, which are immunoglobulin E (IgE)-mediated. Environmental control measures, such as using dust mite covers and acaricides, animal avoidance, closing household windows during active pollen seasons, and cleaning one’s clothes of pollen after spending time outside, may all be used to decrease exposure to environmental allergens. Pharmacotherapy such as oral or topical antihistamines, antileukotrienes, cromolyn, and nasal or inhaled steroids are agents that may
Department of Otolaryngology–Head and Neck Surgery, Emory University, Atlanta, GA Correspondence to: Sarah K. Wise, MD, MSCR, AAOA, Department of Otolaryngology–Head and Neck Surgery, Emory University, 550 Peachtree St. NE, MOT 9th Floor, Atlanta GA 30308; e-mail: [email protected] Potential conflict of interest: None provided. Received: 26 June 2014; Revised: 2 July 2014; Accepted: 2 July 2014 DOI: 10.1002/alr.21382 View this article online at wileyonlinelibrary.com.
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adult and pediatric populations. Adverse reactions occur in up to 71% of patients. However, the rate of serious or fatal side effects is very rare. Conclusion: SCIT is safe and effective in the treatment of allergic rhinitis, allergic asthma, and Hymenoptera sensitivity. Adverse reactions occur but, in general, SCIT is well tolerated, and the vast majority of reactions are mild and very C 2014 ARS-AAOA, LLC. rarely fatal.
Key Words: immunotherapy; allergic rhinitis; asthma; Hymenoptera; SCIT; efficacy; safety; rhinoconjunctivitis; extracts How to Cite this Article: Roche AM, Wise SK. Subcutaneous immunotherapy. Int Forum Allergy Rhinol. 2014;4:S51–S54.
also be used in the treatment of these conditions. These medications provide symptomatic relief, but they do not alter the course of disease. Immunotherapy is offered to patients who have minimal improvement with avoidance measures and pharmacotherapy. Immunotherapy alters the body’s immune reaction to causative allergens on a cellular level. Despite the possibly fatal, though rare, side effects of subcutaneous immunotherapy (SCIT), SCIT is considered a safe and effective treatment for allergic rhinitis, allergic asthma, and hymenoptera sensitivity.
Diagnosis Considered the only hope for “cure” in the treatment of allergy, immunotherapy modulates the body’s immune system and enables it to tolerate exposure to known allergens. By providing exposure to an allergen in a controlled manner, the severity of the allergic response is ideally reduced. Prior to initiation of immunotherapy, the existence of an allergy must be confirmed. There are several methods to determine allergy sensitization. Skin testing options include intradermal dilutional testing (IDT), modified quantitative testing (MQT), and skin-prick testing. In vitro serologic testing include the classic radioallergosorbent test (RAST; no longer routinely performed in its originally described methodology), modified RAST techniques, enzymelinked immunosorbent assays (ELISA), ImmunoCAP methods, and others. Allergy testing confirms the suspicion of
Roche and Wise
allergy and identifies the offending allergens. Most importantly when considering SCIT, allergy testing determines the degree of sensitivity to an allergy and helps to determine a safe initial starting dose for immunotherapy, commonly referred to as “quantitative” skin testing. Once the existence of allergy is confirmed, either with skin testing or in vitro serologic testing, immunotherapy can be initiated.
Indications and contraindications SCIT and sublingual immunotherapy (SLIT) are the 2 main multiallergen treatment options currently performed in the United States. In patients with allergic rhinitis and allergic asthma with symptoms following allergen exposure and positive allergen testing, immunotherapy is indicated for patients with poorly controlled symptoms with pharmacotherapy and avoidance measures, patients with coexisting allergic rhinitis and asthma, or patients who have adverse effects of medication or desire avoidance of long-term pharmacotherapy.4 SCIT is also indicated for possible prevention of asthma in children,4, 5 as well as in the treatment of Hymenoptera sensitivity—a condition characterized by a history of a systemic reaction to a Hymenoptera sting and specific IgE antibodies to Hymenoptera venom.4 Contraindications of immunotherapy are relative and include medical conditions that impair a patient’s ability to survive a systemic allergic reaction, such as poorly controlled asthma, concomitant use of β-blocker medication, and significant cardiovascular disease.4
Dosing, escalation, and maintenance SCIT involves initial exposure to a dilute concentration of antigen, as determined by the safe starting dose or “endpoint” from quantitative testing. This is followed by the escalation phase, in which the dose is gradually increased on a regular schedule to a therapeutic dose that controls symptoms without causing unacceptable reactions.6 A maintenance phase is then reached and is continued for 3 to 5 years. Preparation of testing vials and treatment vials must be precise, and the preparer should not be distracted while making vials. SCIT should be administered in an office setting that is equipped to handle any adverse reactions to immunotherapy. Patients should be observed for 20 to 30 minutes after receiving their injection, as this is the most common period of time in which postinjection reactions will occur. As an added safety measure, it is advocated that SCIT patients receive a prescription for an epinephrine autoinjector. The patient, close family members, and coworkers should be instructed in the proper use of the epinephrine autoinjector and the signs and symptoms of impending anaphylaxis so that the epinephrine autoinjector is appropriately used in a timely fashion when necessary. Initial dosing of immunotherapy is dependent on the method of allergy testing. In order of precision, IDT, in vitro serologic testing, IDT with extrapolation, MQT or blended techniques, and skin prick testing can all be used
to estimate the starting dose of immunotherapy. In IDTbased immunotherapy, the same extract that is used for testing is also used for treatment. IDT-based immunotherapy also determines a patient’s level of sensitivity to each antigen. Escalation of therapy depends on several factors including local and systemic reactions to injections, seasonal changes and allergen load, changes in health, and patient compliance. Discussion of specific SCIT escalation protocols is beyond the scope of this primer. However, most SCIT escalation protocols will have specific instructions for measuring local reactions, both early and late, and determining whether to advance the SCIT dose according to the scheduled escalation, hold the dose at the same level, or decrease the dose. Similarly, it is very important to have regular immunotherapy doses on a specified schedule. If a patient misses some injections, the treatment dose may be reduced or the vial may be restarted. If a patient consistently misses the weekly injection, immunotherapy may be ineffective. Once the escalation phase reaches a dose that provides maximal benefit with acceptable risk, the maintenance phase is initiated. Maintenance dosing, duration of the maintenance phase, and therefore the cumulative dose of treatment, depend on factors related to patient compliance, side effects of escalation, and the specific allergen. Effective dose ranges have been suggested for some allergens based upon doses used in placebo-controlled studies. Effective maintenance dose ranges are known for house dust mite antigens Dermatophagoides pteronyssinus and Dermatophagoides farinae, cat, dog, pooid grasses, and short ragweed.4 It is felt by some clinicians that there is a correlation between the cumulative dose and efficacy. Therefore, rapid escalation and delivery of the highest tolerable maintenance dose may provide more effective immunotherapy. A low-dose treatment method (Rinkel method), created in the 1920s, is of historical importance but is no longer used after it was shown to be no more effective in alleviating allergic symptoms than placebo.7 Though duration of treatment depends on several factors, the World Allergy Organization (WAO) indicates that the efficacy of immunotherapy for more than 3 to 5 years has not been demonstrated.8 In the event that immunotherapy is stopped, it can be restarted at a dose that depends on how long the patient has been off of immunotherapy. After completion of the maintenance phase, there are persistent immunologic changes that impart long-term benefits of immunotherapy.9
Safety The risks and benefits of SCIT should be weighed on a patient-by-patient basis, and initiation of SCIT must account for a patient’s overall health. The risks of immunotherapy range from local pruritus at the site of injection to anaphylaxis and even death. SCIT is typically administered on a weekly basis initially and requires rigorous patient compliance and accountability. Patients should
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be educated prior to initiation of SCIT regarding potential benefits and expectations of immunotherapy. According to the WAO taskforce, “the minimal clinically relevant efficacy should be a least 20% higher than placebo.”7 Therefore, patients should be aware that immunotherapy will not necessarily obviate the need for pharmacotherapy and may not eliminate all symptoms of allergic rhinitis and/or allergic asthma. Given the possible fatal adverse events due to anaphylaxis, the safety of SCIT is an important consideration in creating a treatment plan for a patient with allergies. In a recent systematic review on the safety and efficacy of SCIT, Erekosima et al.10 reviewed 61 randomized control trials that included 3577 subjects and determined that the most common systemic reactions were respiratory and occurred in 71% of patients receiving SCIT vs 88% of control patients. Local reactions were found to be common and occurred in 5% to 58% of patients and 3% to 10% of injections. Most of the reported reactions were mild or unspecified severity, 13 accounts of anaphylaxis were reported, and no deaths were reported in the trials reviewed.10 A 2008 update on safety of specific immunotherapy reported that the likelihood of a fatal reaction to SCIT is 1 in 2 million to 2.5 million doses administered. Of the fatalities reviewed, 61% occurred as part of the buildup phase of immunotherapy.11 The subcutaneous use of aqueous allergen extracts is U.S. Food and Drug Administration (FDA)-approved in the United States, but sublingual administration of aqueous allergen extracts is not. Of note, the FDA approved sublingual tablets containing grass and short ragweed extracts in 2014.
Efficacy Despite its potentially fatal, though rare, side effects, SCIT is considered the gold standard in treating allergy. Due to the complexity of creating randomized controlled trials for multiple allergens, a majority of studies investigating the efficacy of SCIT have evaluated only 1 allergen. In those studies, SCIT has been shown to be more effective than the comparator group, with a high level of support for the treatment of the following: asthma symptoms and reduction in the use of asthma medication; rhinitis/rhinoconjunctivitis symptoms; allergic conjunctivitis; and combined nasal, ocular, and bronchial symptom scores. SCIT has also been shown to improve disease-specific quality of life in patients with rhinitis/rhinoconjunctivitis.10 It has also been shown to have preventative properties with regard to asthma in children5 and with the development of new sensitivities in children.12 Additionally, SCIT has been shown to reduce seasonal allergic rhinitis symptoms and medication usage based on a 2007 Cochrane review,13 treat perennial rhinitis,14 and contribute to asthma prevention in adults.15 Hymenoptera sensitivity is identified not only among beekeepers but also in the general population. The rate of Hymenoptera stings ranges from 56.6% to 85.5% in an
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adult life.16 Immunotherapy has been shown to decrease Hymenoptera sensitivity, providing 75% to 93% protection from a systemic reaction for subsequent stings. Several randomized double-blind placebo-controlled studies have demonstrated that venom immunotherapy (whole-body extracts for imported fire ants) is effective in reducing the risk of anaphylaxis to Hymenoptera stings.17 Additionally, a Cochrane review from 2012 found that in 6 randomized controlled trials, 2.7% of patients developed a systemic allergic reaction after treatment with venom immunotherapy compared to 39.8% of untreated patients.18 Patients with atopic dermatitis may benefit from SCIT. The Joint Task Force on Practice Parameters suggests that clinicians may consider SCIT in patients with atopic dermatitis and aeroallergen sensitivity.19 This recommendation is based on several studies, only some of which are randomized controlled trials. In a 2013 systematic review that included 7 randomized controlled trials (1 of which included treatment with SLIT), the data supports a weak recommendation for the use of immunotherapy in atopic dermatitis.20 This “weak” recommendation is based on a lack of high-quality evidence. As in all patients, use of SCIT for the treatment of atopic dermatitis should be considered after a detailed discussion of risks and benefits. There is no evidence that SCIT is effective in the treatment of urticaria, food allergy, and non-IgE–mediated disease.
Immunologic changes Immunologic changes occur with the use of immunotherapy, thereby altering the natural history of allergen sensitivity. Allergic conditions are characterized by an overactive Th2-mediated response to allergens. Allergen exposure leads to T cell changes and activation of Th2 cells, which are triggered by interleukin 4 (IL-4), resulting in a shift from Th1 to Th2 response. Effector cells include eosinophils, mast cells, and basophils. These effector cells contribute to the inflammatory process of allergic rhinitis, asthma, and Hymenoptera sensitivity. Immunotherapy promotes a shift from Th2 to Th1 predominance. Immunotherapy also causes an increase in regulatory T cell (Treg) response, cells that are able to discriminate between self and nonself and potentiate tolerance.21 This leads to an increase in transforming growth factor β (TGF-β) IL-10, and suppression of allergen-specific T-cell responses.22 Immunoglobulin changes have also been noted. There is initially an increase in IgE antibody, followed by a gradual decrease. This leads to a decrease in serum IgE and subsequently a decrease in IgE-dependent dendritic cell and T-cell activation. B cells undergo class switching initially to IgG1 then to IgG4 and IgA2, resulting in high levels of IgG4.23 Allergen-specific IgG4 antibodies are known as “blocking” antibodies, because they demonstrate passive protection from experimental anaphylaxis, and are temporally related to symptom improvement. Elevated IgG4 suppresses IgE-mediated
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degranulation, antigen presentation, and memory B cells.24 Once immunotherapy is discontinued, these levels fall.
dardized allergens should be used due to the variability of biologic activity and potency of nonstandardized allergens.
Standardization Several commonly used allergens are currently standardized, whereas most known allergens are not. Standardization of allergens requires selection of a reference extract and “selection of an assay or procedure to compare the manufactured extract with the reference extract.”4 Nonstandardized extracts may be measured in various units, making cross-comparison of biologic potency difficult as well. Where possible, stan-
Conclusion SCIT is the gold standard for the treatment of pharmacologically-resistant allergic rhinitis and allergic asthma, as well as Hymenoptera sensitivity. Despite the potentially fatal, though rare, side effect of anaphylaxis, SCIT is safe and effective and is approved by the FDA for the treatment of allergic rhinitis, allergic asthma, and Hymenoptera sensitivity.
References 1.
2.
3.
4.
5.
6.
7.
Wallace DV, Dykewicz MS, Bernstein DI, et al.; Joint Task Force on Practice; American Academy of Allergy; Asthma and Immunology; American College of Allergy; Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008;122(2 Suppl):S1– S84. Gergen PJ, Arbes SJ Jr, Calatroni A, Mitchell HE, Zeldin DC. Total IgE levels and asthma prevalence in the US population: results from the National Health and Nutrition Examination Survey 2005–2006. J Allergy Clin Immunol. 2009;124:447–453. Charpin D, Birnbaum J, Lanteaume A, Vervloet D. Prevalence of allergy to hymenoptera stings in different samples of the general population. J Allergy Clin Immunol. 1992;9(3 Pt 1):331–334. Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol. 2007;120(3 Suppl):S25–S85. Niggemann B, Jacobsen L, Dreborg S, et al.; PAT Investigator Group. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy. 2006;61:855– 859. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998;102(4 Pt 1):558–562. Van Metre TE, Adkinson NF Jr, Amodio FJ, et al. A comparative study of the effectiveness of the Rinkel method and the current standard method of
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immunotherapy for ragweed pollen hay fever. J Allergy Clin Immunol. 1980;66:500–513. Canonica GW, Baena-Cagnani CE, Bousquet J, et al. Recommendations for standardization of clinical trials with Allergen Specific Immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce. Allergy. 2007;62:317–324. Des Roches A, Paradis L, Knani J, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy. 1996;51:430–433. Erekosima N, Suarez-Cuerov C, Ramanathan M, et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope. 2014;124:616–627. Windom HH, Lockey RF. An updated on the safety of specific immunotherapy. Curr Opin Allergy Clin Immunol. 2008;8:571–576. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy. 2001;31:1392–1397. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007;(1):CD001936. Passalacqua G, Durham SR; Global Allergy and Asthma European Network. Allergic rhinitis and its impact on asthma update: allergen immunotherapy. J Allergy Clin Immunol. 2007;119:881–891. Polosa R, Al-Delaimy WK, Russo C, Piccillo G, Sarva` M. Greater risk of incident asthma cases in adults with allergic rhinitis and effect of allergen immunotherapy: a retrospective cohort study. Respir Res. 2005:6:153.
16. Brown TC, Tankersley MS. The sting of the honeybee: an allergic perspective. Ann Allergy Asthma Immunol. 2011;107:463–470. 17. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of hymenoptera venom hypersensitivity: a meta-analysis. Clin Ther. 2000;22:351–358. 18. Boyle RJ, Elremeli M, Hockenhull J, et al. Venom immunotherapy for preventing allergic reactions to insect stings. Cochrane Database Syst Rev. 2012;10:CD008838. 19. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131:295–299.e27. 20. Gendelman SR, Lang DM. Specific immunotherapy in the treatment of atopic dermatitis: a systematic review using the GRADE system. Ann Allergy Asthma Immunol. 2013;111:555–561. 21. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133:775–787. 22. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, ¨ Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med. 2008;205:2887–2898. 23. Meiler F, Klunker S, Zimmermann M, Akdis CA, Akdis M. Distinct regulation of IgE, IgG4 and IgA byT regulatory cells and toll-like receptors. Allergy. 2008;63:1455–1463. 24. van Neerven RJ, Wikborg T, Lund G, et al. Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. J Immunol. 1999;163:2944– 2952.
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Subcutaneous immunotherapy Ansley M. Roche, MD and Sarah K. Wise, MD, MSCR, FAAOA
Background: Allergic rhinitis, asthma, and Hymenoptera sensitivity affect approximately 20%, 9%, and 0.66% to 3.3% of adults in the United States, respectively. Various environmental control measures and pharmacologic options are available for symptomatic treatment of allergic rhinitis and allergic asthma. However, allergen-specific immunotherapy is the only form of treatment that alters the natural history of allergic disease. Methods: A literature review was performed. Information from systematic reviews, meta-analyses, and practice parameters were closely examined and summarized, and they are included in this primer. Results: There is evidence that supports the use of subcutaneous immunotherapy (SCIT) for the treatment of perennial and seasonal allergic rhinitis, asthma, and Hymenoptera sensitivity. Efficacy of SCIT has been established in the
A
llergic rhinitis, asthma, and Hymenoptera sensitivity affect approximately 20%,1 9%,2 and 0.66% to 3.3%3 of adults in the United States, respectively. Of the 9% of patients with asthma, approximately 63% have allergic asthma.2 Itchy nose, nasal congestion, and rhinorrhea are classic for allergic rhinitis. Asthma is a chronic inflammatory condition of the airway. Hymenoptera sensitivity is a hypersensitivity reaction to the venom of insects in the order Hymenoptera (ie, yellow jackets, wasps, bees, ants). These disease processes are type I hypersensitivity reactions, which are immunoglobulin E (IgE)-mediated. Environmental control measures, such as using dust mite covers and acaricides, animal avoidance, closing household windows during active pollen seasons, and cleaning one’s clothes of pollen after spending time outside, may all be used to decrease exposure to environmental allergens. Pharmacotherapy such as oral or topical antihistamines, antileukotrienes, cromolyn, and nasal or inhaled steroids are agents that may
Department of Otolaryngology–Head and Neck Surgery, Emory University, Atlanta, GA Correspondence to: Sarah K. Wise, MD, MSCR, AAOA, Department of Otolaryngology–Head and Neck Surgery, Emory University, 550 Peachtree St. NE, MOT 9th Floor, Atlanta GA 30308; e-mail: [email protected] Potential conflict of interest: None provided. Received: 26 June 2014; Revised: 2 July 2014; Accepted: 2 July 2014 DOI: 10.1002/alr.21382 View this article online at wileyonlinelibrary.com.
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adult and pediatric populations. Adverse reactions occur in up to 71% of patients. However, the rate of serious or fatal side effects is very rare. Conclusion: SCIT is safe and effective in the treatment of allergic rhinitis, allergic asthma, and Hymenoptera sensitivity. Adverse reactions occur but, in general, SCIT is well tolerated, and the vast majority of reactions are mild and very C 2014 ARS-AAOA, LLC. rarely fatal.
Key Words: immunotherapy; allergic rhinitis; asthma; Hymenoptera; SCIT; efficacy; safety; rhinoconjunctivitis; extracts How to Cite this Article: Roche AM, Wise SK. Subcutaneous immunotherapy. Int Forum Allergy Rhinol. 2014;4:S51–S54.
also be used in the treatment of these conditions. These medications provide symptomatic relief, but they do not alter the course of disease. Immunotherapy is offered to patients who have minimal improvement with avoidance measures and pharmacotherapy. Immunotherapy alters the body’s immune reaction to causative allergens on a cellular level. Despite the possibly fatal, though rare, side effects of subcutaneous immunotherapy (SCIT), SCIT is considered a safe and effective treatment for allergic rhinitis, allergic asthma, and hymenoptera sensitivity.
Diagnosis Considered the only hope for “cure” in the treatment of allergy, immunotherapy modulates the body’s immune system and enables it to tolerate exposure to known allergens. By providing exposure to an allergen in a controlled manner, the severity of the allergic response is ideally reduced. Prior to initiation of immunotherapy, the existence of an allergy must be confirmed. There are several methods to determine allergy sensitization. Skin testing options include intradermal dilutional testing (IDT), modified quantitative testing (MQT), and skin-prick testing. In vitro serologic testing include the classic radioallergosorbent test (RAST; no longer routinely performed in its originally described methodology), modified RAST techniques, enzymelinked immunosorbent assays (ELISA), ImmunoCAP methods, and others. Allergy testing confirms the suspicion of
Roche and Wise
allergy and identifies the offending allergens. Most importantly when considering SCIT, allergy testing determines the degree of sensitivity to an allergy and helps to determine a safe initial starting dose for immunotherapy, commonly referred to as “quantitative” skin testing. Once the existence of allergy is confirmed, either with skin testing or in vitro serologic testing, immunotherapy can be initiated.
Indications and contraindications SCIT and sublingual immunotherapy (SLIT) are the 2 main multiallergen treatment options currently performed in the United States. In patients with allergic rhinitis and allergic asthma with symptoms following allergen exposure and positive allergen testing, immunotherapy is indicated for patients with poorly controlled symptoms with pharmacotherapy and avoidance measures, patients with coexisting allergic rhinitis and asthma, or patients who have adverse effects of medication or desire avoidance of long-term pharmacotherapy.4 SCIT is also indicated for possible prevention of asthma in children,4, 5 as well as in the treatment of Hymenoptera sensitivity—a condition characterized by a history of a systemic reaction to a Hymenoptera sting and specific IgE antibodies to Hymenoptera venom.4 Contraindications of immunotherapy are relative and include medical conditions that impair a patient’s ability to survive a systemic allergic reaction, such as poorly controlled asthma, concomitant use of β-blocker medication, and significant cardiovascular disease.4
Dosing, escalation, and maintenance SCIT involves initial exposure to a dilute concentration of antigen, as determined by the safe starting dose or “endpoint” from quantitative testing. This is followed by the escalation phase, in which the dose is gradually increased on a regular schedule to a therapeutic dose that controls symptoms without causing unacceptable reactions.6 A maintenance phase is then reached and is continued for 3 to 5 years. Preparation of testing vials and treatment vials must be precise, and the preparer should not be distracted while making vials. SCIT should be administered in an office setting that is equipped to handle any adverse reactions to immunotherapy. Patients should be observed for 20 to 30 minutes after receiving their injection, as this is the most common period of time in which postinjection reactions will occur. As an added safety measure, it is advocated that SCIT patients receive a prescription for an epinephrine autoinjector. The patient, close family members, and coworkers should be instructed in the proper use of the epinephrine autoinjector and the signs and symptoms of impending anaphylaxis so that the epinephrine autoinjector is appropriately used in a timely fashion when necessary. Initial dosing of immunotherapy is dependent on the method of allergy testing. In order of precision, IDT, in vitro serologic testing, IDT with extrapolation, MQT or blended techniques, and skin prick testing can all be used
to estimate the starting dose of immunotherapy. In IDTbased immunotherapy, the same extract that is used for testing is also used for treatment. IDT-based immunotherapy also determines a patient’s level of sensitivity to each antigen. Escalation of therapy depends on several factors including local and systemic reactions to injections, seasonal changes and allergen load, changes in health, and patient compliance. Discussion of specific SCIT escalation protocols is beyond the scope of this primer. However, most SCIT escalation protocols will have specific instructions for measuring local reactions, both early and late, and determining whether to advance the SCIT dose according to the scheduled escalation, hold the dose at the same level, or decrease the dose. Similarly, it is very important to have regular immunotherapy doses on a specified schedule. If a patient misses some injections, the treatment dose may be reduced or the vial may be restarted. If a patient consistently misses the weekly injection, immunotherapy may be ineffective. Once the escalation phase reaches a dose that provides maximal benefit with acceptable risk, the maintenance phase is initiated. Maintenance dosing, duration of the maintenance phase, and therefore the cumulative dose of treatment, depend on factors related to patient compliance, side effects of escalation, and the specific allergen. Effective dose ranges have been suggested for some allergens based upon doses used in placebo-controlled studies. Effective maintenance dose ranges are known for house dust mite antigens Dermatophagoides pteronyssinus and Dermatophagoides farinae, cat, dog, pooid grasses, and short ragweed.4 It is felt by some clinicians that there is a correlation between the cumulative dose and efficacy. Therefore, rapid escalation and delivery of the highest tolerable maintenance dose may provide more effective immunotherapy. A low-dose treatment method (Rinkel method), created in the 1920s, is of historical importance but is no longer used after it was shown to be no more effective in alleviating allergic symptoms than placebo.7 Though duration of treatment depends on several factors, the World Allergy Organization (WAO) indicates that the efficacy of immunotherapy for more than 3 to 5 years has not been demonstrated.8 In the event that immunotherapy is stopped, it can be restarted at a dose that depends on how long the patient has been off of immunotherapy. After completion of the maintenance phase, there are persistent immunologic changes that impart long-term benefits of immunotherapy.9
Safety The risks and benefits of SCIT should be weighed on a patient-by-patient basis, and initiation of SCIT must account for a patient’s overall health. The risks of immunotherapy range from local pruritus at the site of injection to anaphylaxis and even death. SCIT is typically administered on a weekly basis initially and requires rigorous patient compliance and accountability. Patients should
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be educated prior to initiation of SCIT regarding potential benefits and expectations of immunotherapy. According to the WAO taskforce, “the minimal clinically relevant efficacy should be a least 20% higher than placebo.”7 Therefore, patients should be aware that immunotherapy will not necessarily obviate the need for pharmacotherapy and may not eliminate all symptoms of allergic rhinitis and/or allergic asthma. Given the possible fatal adverse events due to anaphylaxis, the safety of SCIT is an important consideration in creating a treatment plan for a patient with allergies. In a recent systematic review on the safety and efficacy of SCIT, Erekosima et al.10 reviewed 61 randomized control trials that included 3577 subjects and determined that the most common systemic reactions were respiratory and occurred in 71% of patients receiving SCIT vs 88% of control patients. Local reactions were found to be common and occurred in 5% to 58% of patients and 3% to 10% of injections. Most of the reported reactions were mild or unspecified severity, 13 accounts of anaphylaxis were reported, and no deaths were reported in the trials reviewed.10 A 2008 update on safety of specific immunotherapy reported that the likelihood of a fatal reaction to SCIT is 1 in 2 million to 2.5 million doses administered. Of the fatalities reviewed, 61% occurred as part of the buildup phase of immunotherapy.11 The subcutaneous use of aqueous allergen extracts is U.S. Food and Drug Administration (FDA)-approved in the United States, but sublingual administration of aqueous allergen extracts is not. Of note, the FDA approved sublingual tablets containing grass and short ragweed extracts in 2014.
Efficacy Despite its potentially fatal, though rare, side effects, SCIT is considered the gold standard in treating allergy. Due to the complexity of creating randomized controlled trials for multiple allergens, a majority of studies investigating the efficacy of SCIT have evaluated only 1 allergen. In those studies, SCIT has been shown to be more effective than the comparator group, with a high level of support for the treatment of the following: asthma symptoms and reduction in the use of asthma medication; rhinitis/rhinoconjunctivitis symptoms; allergic conjunctivitis; and combined nasal, ocular, and bronchial symptom scores. SCIT has also been shown to improve disease-specific quality of life in patients with rhinitis/rhinoconjunctivitis.10 It has also been shown to have preventative properties with regard to asthma in children5 and with the development of new sensitivities in children.12 Additionally, SCIT has been shown to reduce seasonal allergic rhinitis symptoms and medication usage based on a 2007 Cochrane review,13 treat perennial rhinitis,14 and contribute to asthma prevention in adults.15 Hymenoptera sensitivity is identified not only among beekeepers but also in the general population. The rate of Hymenoptera stings ranges from 56.6% to 85.5% in an
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adult life.16 Immunotherapy has been shown to decrease Hymenoptera sensitivity, providing 75% to 93% protection from a systemic reaction for subsequent stings. Several randomized double-blind placebo-controlled studies have demonstrated that venom immunotherapy (whole-body extracts for imported fire ants) is effective in reducing the risk of anaphylaxis to Hymenoptera stings.17 Additionally, a Cochrane review from 2012 found that in 6 randomized controlled trials, 2.7% of patients developed a systemic allergic reaction after treatment with venom immunotherapy compared to 39.8% of untreated patients.18 Patients with atopic dermatitis may benefit from SCIT. The Joint Task Force on Practice Parameters suggests that clinicians may consider SCIT in patients with atopic dermatitis and aeroallergen sensitivity.19 This recommendation is based on several studies, only some of which are randomized controlled trials. In a 2013 systematic review that included 7 randomized controlled trials (1 of which included treatment with SLIT), the data supports a weak recommendation for the use of immunotherapy in atopic dermatitis.20 This “weak” recommendation is based on a lack of high-quality evidence. As in all patients, use of SCIT for the treatment of atopic dermatitis should be considered after a detailed discussion of risks and benefits. There is no evidence that SCIT is effective in the treatment of urticaria, food allergy, and non-IgE–mediated disease.
Immunologic changes Immunologic changes occur with the use of immunotherapy, thereby altering the natural history of allergen sensitivity. Allergic conditions are characterized by an overactive Th2-mediated response to allergens. Allergen exposure leads to T cell changes and activation of Th2 cells, which are triggered by interleukin 4 (IL-4), resulting in a shift from Th1 to Th2 response. Effector cells include eosinophils, mast cells, and basophils. These effector cells contribute to the inflammatory process of allergic rhinitis, asthma, and Hymenoptera sensitivity. Immunotherapy promotes a shift from Th2 to Th1 predominance. Immunotherapy also causes an increase in regulatory T cell (Treg) response, cells that are able to discriminate between self and nonself and potentiate tolerance.21 This leads to an increase in transforming growth factor β (TGF-β) IL-10, and suppression of allergen-specific T-cell responses.22 Immunoglobulin changes have also been noted. There is initially an increase in IgE antibody, followed by a gradual decrease. This leads to a decrease in serum IgE and subsequently a decrease in IgE-dependent dendritic cell and T-cell activation. B cells undergo class switching initially to IgG1 then to IgG4 and IgA2, resulting in high levels of IgG4.23 Allergen-specific IgG4 antibodies are known as “blocking” antibodies, because they demonstrate passive protection from experimental anaphylaxis, and are temporally related to symptom improvement. Elevated IgG4 suppresses IgE-mediated
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degranulation, antigen presentation, and memory B cells.24 Once immunotherapy is discontinued, these levels fall.
dardized allergens should be used due to the variability of biologic activity and potency of nonstandardized allergens.
Standardization Several commonly used allergens are currently standardized, whereas most known allergens are not. Standardization of allergens requires selection of a reference extract and “selection of an assay or procedure to compare the manufactured extract with the reference extract.”4 Nonstandardized extracts may be measured in various units, making cross-comparison of biologic potency difficult as well. Where possible, stan-
Conclusion SCIT is the gold standard for the treatment of pharmacologically-resistant allergic rhinitis and allergic asthma, as well as Hymenoptera sensitivity. Despite the potentially fatal, though rare, side effect of anaphylaxis, SCIT is safe and effective and is approved by the FDA for the treatment of allergic rhinitis, allergic asthma, and Hymenoptera sensitivity.
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