Allergen immunotherapy: A practice parameter second update


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Allergen immunotherapy: A practice parameter second update

  1. 1. Allergen immunotherapy: A practice parameter second update Supplement Editor: Linda Cox, MD Co-editors: James T. Li, MD, Harold Nelson, MD, and Richard Lockey, MD These parameters were developed by the Joint Task Force on parameters by the AAAAI or the ACAAI should be directed to the Practice Parameters, representing the American Academy of Executive Offices of the AAAAI, the ACAAI, and the Joint Council Allergy, Asthma and Immunology; the American College of Allergy, of Allergy, Asthma and Immunology. These parameters are not Asthma and Immunology; and the Joint Council of Allergy, Asthma designed for use by pharmaceutical companies in drug promotion. and Immunology. Published practice parameters of the Joint Task Force The American Academy of Allergy, Asthma and Immunology on Practice Parameters for Allergy and Immunology (AAAAI) and the American College of Allergy, Asthma and include the following: Immunology (ACAAI) have jointly accepted responsibility for establishing the ‘‘Allergen immunotherapy: a practice parameter 1. Practice parameters for the diagnosis and treatment second update.’’ This is a complete and comprehensive document at of asthma. J Allergy Clin Immunol 1995;96(suppl): the current time. The medical environment is a changing S707-S870. environment, and not all recommendations will be appropriate for 2. Practice parameters for allergy diagnostic testing. all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served Ann Allergy 1995;75:543-625. on the Joint Task Force, is authorized to provide an official AAAAI 3. Practice parameters for the diagnosis and management or ACAAI interpretation of these practice parameters. Any request of immunodeficiency. Ann Allergy 1996;76:282-94. for information about or an interpretation of these practice 4. Practice parameters for allergen immunotherapy. J Allergy Clin Immunol 1996;98:1001-11. 5. Disease management of atopic dermatitis: a practice Disclosure of potential conflict of interest: L. Cox has consulting arrangements parameter. Ann Allergy 1997;79:197-211. with Allergy Therapeutics, Genentech/Novartis, and Greer Laboratories and 6. The diagnosis and management of anaphylaxis. is on the speakers’ bureau for Genentech/Novartis, GlaxoSmithKline, and AstraZeneca. R. Lockey has received grant support from Greer Laboratories; J Allergy Clin Immunol 1998;101(suppl):S465-S528. served as chairman of an advisory committee for ALK-Abello for over´ 7. Algorithm for the diagnosis and management of 7 years; and has served as an expert witness for allergen immunotherapy asthma: a practice parameter update. Ann Allergy death for both plaintiff and defendant. H. Nelson has consulting arrange- 1998;81:415-20. ments with Genentech/Novartis, Curalogic, GlaxoSmithKline, Inflazyme 8. Diagnosis and management of rhinitis: parameter Pharmaceuticals, Dey Laboratories, Dynavax Technologies, Altana, and Schering-Plough; has received grant support from Dey Laboratories, documents of the Joint Task Force on Practice IVAX, MediciNova, Wyeth, Sepracor, Genentech, Schering-Plough, No- parameters in Allergy, Asthma and Immunology. vartis, AstraZeneca, SkyPharma, Altana, and Roche; and is on the speakers’ Ann Allergy 1998;81(suppl):S463-S518. bureau for GlaxoSmithKline and AstraZeneca. D. Bernstein has consulting 9. Parameters for the diagnosis and management of arrangements with ALK-Abello and has received grant support from ´ Dynavax and ALK-Abello. J. Blessing-Moore has received grant support ´ sinusitis. J Allergy Clin Immunol 1998;102(suppl): from Novartis-Genentech and AstraZeneca and is on the speakers’ bureau S107-S144. for Schering-Plough, Merck, Aventis, Novartis/Genentech, AstraZeneca. 10. Stinging insect hypersensitivity: a practice parameter. D. M. Lang has consulting arrangements with, has received grant support J Allergy Clin Immunol 1999;103:963-80. from, and is on the speakers’ bureau for GlaxoSmithKline, Merck, Astra- 11. Disease management of drug hypersensitivity: a Zeneca, Centocor, Sanofi-Aventis, Schering-Plough, Verus, and Dey. J. Oppenheimer has consulting arrangements with GlaxoSmithKline, Astra- practice parameter. Ann Allergy 1999;83(suppl): Zeneca, Sepracor, and Merck; has received grant support from AstraZeneca, S665–S700. Sepracor, and Merck, Boehringer Ingelheim, Novartis/Genentech, and 12. Diagnosis and management of urticaria: a practice Schering-Plough; and is on the speakers’ bureau for GlaxoSmithKline, parameter. Ann Allergy 2000;85(suppl):S521-S544. AstraZeneca, Sepracor, and Merck. J. M. Portnoy has consulting arrange- ments with Greer and GlaxoSmithKline; has received grant support from 13. Allergen immunotherapy: a practice parameter. Ann Clorox; and is on the speakers’ bureau for Schering-Plough, Merck, Aventis, Allergy 2003;90(suppl):SI-S540. Secpracor, and AstraZeneca. S. A. Tilles has consulting arrangements with 14. Symptom severity assessment of allergic rhinitis: Genentech, Schering-Plough, and GlaxoSmithKline; has received grant sup- part I. Ann Allergy 2003;91:105-14. port from AstraZeneca, Novartis, Medpoint, Apieron, and ALK-Abello; and´ 15. Disease management of atopic dermatitis: an updated is on the speakers’ bureau for GlaxoSmithKline, Pfizer, Genentech, and Alcon. The rest of the authors have declared that they have no conflict of practice parameter. Ann Allergy 2004;93(suppl): interest. S1-S21. Reprint requests: Joint Council of Allergy, Asthma and Immunology, 50 N 16. Stinging insect hypersensitivity: a practice parameter Brockway St, #3-3, Palatine, IL 60067. update. J Allergy Clin Immunol 2004;114:869-86. J Allergy Clin Immunol 2007;120:S25-85. 0091-6749/$32.00 17. The diagnosis and management of anaphylaxis: an Ó 2007 American Academy of Allergy, Asthma & Immunology updated practice parameter. J Allergy Clin Immunol doi:10.1016/j.jaci.2007.06.019 2005;115(suppl):S483-S523. S25
  2. 2. S26 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 18. Practice parameter for the diagnosis and management University of Cincinnati College of Medicine of primary immunodeficiency. Ann Allergy 2005; Cincinnati, Ohio 94(suppl):S1-S63. I. Leonard Bernstein, MD 19. Attaining optimal asthma control: a practice parame- Departments of Medicine and Environmental Health ter. J Allergy Clin Immunol 2005;116(suppl):S3-S11. University of Cincinnati College of Medicine 20. The diagnosis and management of sinusitis: a practice Cincinnati, Ohio parameter update. J Allergy Clin Immunol 2005; David A. Khan, MD 116(suppl):S13-S47. Department of Internal Medicine 21. Food allergy: a practice parameter. Ann Allergy University of Texas Southwestern Medical Center Asthma Immunol 2006;96(suppl 2):S1-S68. Dallas, Tex 22. Contact dermatitis: a practice parameter. Ann Allergy Joann Blessing-Moore, MD Asthma Immunol 2006;97(suppl 2):S1-S38. Departments of Medicine and Pediatrics Stanford University Medical Center These parameters are also available on the internet at Department of Immunology Palo Alto, Calif David M. Lang, MD CONTRIBUTORS Allergy/Immunology Section Division of Medicine The Joint Task Force has made a concerted effort to Allergy and Immunology Fellowship Training Program acknowledge all contributors to this parameter. If any Cleveland Clinic Foundation contributors have been excluded inadvertently, the Task Cleveland, Ohio Force will ensure that appropriate recognition of such Richard A. Nicklas, MD contributions is made subsequently. Department of Medicine The Joint Task Force gratefully acknowledges the George Washington Medical Center American Academy of Allergy, Asthma and Immunology Washington, DC Board of Directors and the American College of Allergy, John Oppenheimer, MD Asthma and Immunology Board of Regents for their Department of Internal Medicine review and support of this document. New Jersey Medical School Pulmonary and Allergy Associates SUPPLEMENT EDITOR Morristown, NJ Jay M. Portnoy, MD Linda Cox, MD Section of Allergy, Asthma & Immunology Department of Medicine The Children’s Mercy Hospital Nova Southeastern University College of Osteopathic Department of Pediatrics Medicine University of Missouri-Kansas City School of Medicine Davie, Fla Kansas City, Mo Diane E. Schuller, MD Department of Pediatrics CO-EDITORS Pennsylvania State University Milton S. Hershey Medical College James T. Li, MD, PhD Hershey, Pa Division of Allergic Diseases Sheldon L. Spector, MD Mayo Clinic Department of Medicine Rochester, Minn UCLA School of Medicine Richard Lockey, MD Los Angeles, Calif Departments of Medicine, Pediatrics, and Public Health Stephen A. Tilles, MD Division of Allergy and Immunology Department of Medicine University of South Florida College of Medicine University of Washington School of Medicine James A. Haley Veterans’ Hospital Redmond, Wash Tampa, Fla Dana V. Wallace, MD Harold Nelson, MD Nova Southeastern University Department of Medicine Davie, Fla National Jewish Medical and Research Center Denver, Colo INVITED REVIEWERS JOINT TASK FORCE REVIEWERS Don Aaronson, MD, Chicago, Ill David Bernstein, MD David Golden, MD, Baltimore, Md Department of Medicine and Environmental Health Moises Calderon, MD, London, United Kingdom (UK)
  3. 3. J ALLERGY CLIN IMMUNOL Cox et al S27 VOLUME 120, NUMBER 3 Stephen Durham, MD, London, UK process consistent with recommendations of the Ira Finegold, MD, New York, NY American College of Medical Quality’s ‘‘Policy on de- Stephen Kemp, Jackson, Miss velopment and use of practice parameters for medical Brian Smart, MD, Glen Ellyn, Ill quality decision-making’’ (Appendix 1).1 Mark L. Vandewalker, MD, Columbia, Mo This document builds on the previous Joint Task Force Richard Weber, MD, Denver, Colo document, ‘‘Allergen immunotherapy: a practice param- David Weldon, MD, College Station, Tex eter’’ published in the Annals of Allergy, Asthma and Immunology in 2003.2 The updated practice parameters draft was prepared by Drs Linda Cox, James Li, Hal REVIEWERS OF ALLERGEN EXTRACT Nelson, and Richard Lockey. The Joint Task Force SECTION reworked the initial draft into a working draft of the document. The project was exclusively funded by the 3 Robert Esch, PhD, Lenoir, NC allergy and immunology societies noted above. Larry Garner, CPT, BA, Spokane, Wash In preparation for the 2003 ‘‘Allergen immunotherapy: Richard Lankow, PhD, Round Rock, Tex a practice parameter’’ and the second update, a compre- Greg Plunkett, PhD, Round Rock, Tex hensive search of the medical literature was conducted with Tom Willoughby, Liberty, Miss various search engines, including PubMed; immunother- The authors and editors gratefully acknowledge Susan apy, allergic rhinitis, asthma, stinging insect allergy, and Grupe for her administrative assistance. related search terms were used. Published clinical studies were rated by category of evidence and used to establish Allergen immunotherapy: A practice parame- the strength of a clinical recommendation (Table I).3 ter second update Laboratory-based studies were not rated. The working draft of ‘‘Allergen immunotherapy: a Preface S27 practice parameter second update’’ was reviewed by a Algorithm and annotations for immunotherapy S28 large number of experts in immunotherapy, allergy, and Immunotherapy glossary S31 immunology. These experts included reviewers appointed Introduction S33 by the ACAAI, AAAAI, and JCAAI. In addition, the draft Summary statements S33 was posted on the ACAAI and AAAAI Web sites with an Mechanisms of immunotherapy S38 invitation for review and comments from members of the Allergen extracts S38 sponsoring organizations. The authors carefully consid- Efficacy of immunotherapy S41 ered all of these comments in preparing the final version. Safety of immunotherapy S43 An annotated algorithm in this document summarizes the Patient selection S46 key decision points for the appropriate use of allergen Allergen selection and handling S48 immunotherapy (Fig 1). Immunotherapy schedules and doses S53 The section on efficacy summarizes the evidence Location of allergen immunotherapy demonstrating that allergen immunotherapy is effective in administration S61 the management of properly selected patients with allergic Special considerations in immunotherapy S63 rhinitis, allergic asthma, and stinging insect hypersensi- Alternative routes of immunotherapy S64 tivity. This document also contains recommendations for Future trends in immunotherapy S66 the safe practice of allergen immunotherapy, including References S67 specific recommendations on the prevention and manage- ment of systemic reactions. Specific recommendations guide the physician in PREFACE selecting those patients for whom allergen immunotherapy is appropriate. Aeroallergen immunotherapy should be This document was developed by the Joint Task Force considered for patients who have symptoms of allergic on Practice Parameters, which represents the American rhinitis or asthma with natural exposure to allergens and Academy of Allergy, Asthma and Immunology (AAAAI); who demonstrate specific IgE antibodies to the relevant the American College of Allergy, Asthma and Immunol- allergen or allergens. Symptoms of allergic conjunctivitis ogy (ACAAI); and the Joint Council of Allergy, Asthma (eg, itchy watery eyes) are often considered part of allergic and Immunology (JCAAI). rhinitis or are included in the diagnosis of rhinoconjuncti- The objective of ‘‘Allergen immunotherapy: A practice vitis. Particularly good candidates for immunotherapy are parameter second update’’ is to optimize the practice of patients whose symptoms are not controlled adequately by allergen immunotherapy for patients with allergic rhinitis, medications and avoidance measures, those in whom it is allergic asthma, and Hymenoptera sensitivity. This pa- important to avoid the potential adverse effects of medi- rameter is intended to establish guidelines for the safe and cations, and those who wish to reduce the long-term use of effective use of allergen immunotherapy, while reducing medications. Immunotherapy is recommended for patients unnecessary variation in immunotherapy practice. These with a history of systemic reaction to Hymenoptera stings guidelines have undergone an extensive peer-review and specific IgE antibodies to Hymenoptera venom.
  4. 4. S28 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 TABLE I. Classification of evidence and volume-to-volume dilution (eg, 1:100 vol/vol dilution of recommendations* a maintenance concentrate). Allergen immunotherapy is effective when appropriate Category of evidence Ia Evidence from meta-analysis of randomized doses of the allergens are administered. ‘‘Allergen immu- controlled trials notherapy: A practice parameter’’ recommends that vials of Ib Evidence from at least 1 randomized controlled allergen immunotherapy extracts should be prepared indi- trial vidually for each patient to enhance the individualization IIa Evidence from at least 1 controlled study without of therapy, reduce the risk of allergen cross-contamination, randomization and reduce the risk of error in administration.4,5 This IIb Evidence from at least 1 other type of parameter recommends the use of standardized allergen quasiexperimental study immunotherapy prescription and administration forms to III Evidence from nonexperimental descriptive improve the safety, uniformity, and standardization of studies, such as comparative studies, allergen immunotherapy practice.4,5 The suggested forms correlation studies, and case-control studies IV Evidence from expert committee are found in the Appendix (Appendices 7, 8, 11, 12, and reports or opinions, clinical experience 14) and in the members’ section of the of respected authorities, or both Web site. The routine use of these standardized forms LB Evidence from laboratory-based studies should improve the quality of immunotherapy practice. NR Not rated Members’ feedback comments on the recommended Strength of recommendation allergen extract dilution dating in the 2003 ‘‘Allergen A Directly based on category I evidence immunotherapy: A practice parameter’’ led to an allergen B Directly based on category II evidence immunotherapy extract dilution stability study designed or extrapolated from category I evidence by the AAAAI Immunotherapy and Allergy Diagnostics C Directly based on category III evidence or Committee and funded by the AAAAI Board of Directors. extrapolated from category I or II evidence The study was designed to investigate the effect of time, D Directly based on category IV evidence or temperature, and dilution of standardized allergen extract extrapolated from category I, II, or III evidence potency, and the results of this study were considered in NR Not rated this update. *Adapted with permission from Shekelle PG, Woolf SH, Eccles M, This document was approved by the sponsoring orga- Grimshaw J. Clinical guidelines: developing guidelines. BMJ nizations and represents an evidence-based, broadly ac- 1999;318:593-6.3 cepted consensus opinion. These clinical guidelines are designed to assist clinicians by providing a framework for The selection of allergens for immunotherapy is based the evaluation and treatment of patients and are not intended on clinical history, the presence of specific IgE antibodies, to replace a clinician’s judgment or establish a protocol for and allergen exposure. This parameter offers suggestions all patients. Not all recommendations will be appropriate and recommendations derived from known patterns of for all patients. Because this document incorporates the allergen cross-reactivity. Recognizing that the immuno- efforts of many participants, no individual, including therapy terminology used to describe extract dilutions is anyone who served on the Joint Task Force, is authorized sometimes ambiguous, the 2003 ‘‘Allergen immunother- to provide an official AAAAI or ACAAI interpretation apy: a practice parameter’’ established standardized ter- of these guidelines. Recognizing the dynamic nature of minology for describing allergen immunotherapy extract clinical practice and practice parameters, the recommen- dilutions. These parameters also provided specific recom- dations in this document should be considered applicable mendations for immunotherapy maintenance doses for for 3 years after publication. Requests for information some standardized allergens and a suggested dosing range about or an interpretation of these practice parameters for nonstandardized allergen extracts. The therapeutic should be directed to the Executive Offices of the AAAAI, preparations for allergen immunotherapy are extracted ACAAI, and JCAAI. These parameters are not designed from source materials, such as pollen, mold cultures, and for use by pharmaceutical companies in drug promotion. pelt, hence the traditional term allergen extract. The terms allergen extract or extract refer to solutions of proteins or glycoproteins extracted from source material not yet incor- ALGORITHM AND ANNOTATIONS FOR porated into a therapeutic allergen immunotherapy extract. IMMUNOTHERAPY The term maintenance concentrate should be used to iden- tify the allergen immunotherapy extract that contains a ther- Fig 1 provides an algorithm for the appropriate use of apeutic effective dose for each of its individual constituents allergen immunotherapy. Given below are annotations (see the Immunotherapy schedules and doses section). for use with the algorithm. The term manufacturer’s extract refers to the allergy extract purchased from the manufacturer. The terms Box 1 stock, full-strength, and concentrate are ambiguous and Immunotherapy is effective in the management of should not be used. All dilutions should be referenced allergic asthma, allergic rhinitis/conjunctivitis, and to the maintenance concentrate and should be noted as a stinging insect hypersensitivity. Allergen immunotherapy
  5. 5. J ALLERGY CLIN IMMUNOL Cox et al S29 VOLUME 120, NUMBER 3 FIG 1. Algorithm for allergen immunotherapy.
  6. 6. S30 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 might prevent the development of asthma in individuals immunotherapy injection is administered. In general, with allergic rhinitis.6-9 Evaluation of a patient with sus- patients with stinging insect hypersensitivity who are at pected allergic rhinitis, allergic rhinoconjunctivitis, aller- risk for anaphylaxis should receive venom immunother- gic asthma, or stinging insect allergy includes a detailed apy (VIT). history, an appropriate physical examination, and selected laboratory tests. A definitive diagnosis of allergic asthma, Box 6 allergic conjunctivitis, allergic rhinitis, or stinging insect After careful consideration of appropriate management hypersensitivity depends on the results of allergy testing options, the physician and patient might decide not to (immediate hypersensitivity skin tests or in vitro tests for proceed with immunotherapy. specific IgE antibody).10 Box 7 Box 2 Before immunotherapy is started, patients should un- Immediate hypersensitivity skin testing is generally the derstand its benefits, risks, and costs. Counseling should preferred method of testing for specific IgE antibodies, also include the expected onset of efficacy and duration of although in vitro testing for specific IgE antibodies is use- treatment, as well as the risk of anaphylaxis and impor- ful under certain circumstances. Immunotherapy should tance of adhering to the immunotherapy schedule. be considered when positive test results for specific IgE antibodies correlate with suspected triggers and patient Box 8 exposure. The physician prescribing immunotherapy should be trained and experienced in prescribing and administering Box 3 immunotherapy. The prescribing physician must select the Immunotherapy should not be given to patients with appropriate allergen extracts on the basis of that particular negative test results for specific IgE antibodies or those patient’s clinical history and allergen exposure history and with positive test results for specific IgE antibodies that do the results of tests for specific IgE antibodies. The quality not correlate with suspected triggers, clinical symptoms, of the allergen extracts available is an important consid- or exposure. This means that the presence of specific IgE eration. When preparing mixtures of allergen extracts, the antibodies alone does not necessarily indicate clinical prescribing physician must take into account the cross- sensitivity. There is no evidence from well-designed reactivity of allergen extracts and the potential for allergen studies that immunotherapy for any allergen is effective degradation caused by proteolytic enzymes. The prescrib- in the absence of specific IgE antibodies. ing physician must specify the starting immunotherapy dose, the target maintenance dose, and the immunotherapy Box 4 schedule (see the Immunotherapy schedules and doses Management of complex medical conditions, such as section). In general, the starting immunotherapy dose is allergic asthma, allergic rhinitis/conjunctivitis, and sting- 1000-fold to 10,000-fold less than the maintenance dose. ing insect hypersensitivity, should include the careful For highly sensitive patients, the starting dose might be evaluation of management options. Each of the 3 major lower. The maintenance dose is generally 1000 to 4000 management approaches (allergen immunotherapy, aller- arbitrary units (AU; eg, for dust mite) or bioequivalent gen exposure reduction, and pharmacotherapy) has ben- allergy units (BAU; eg, for grass) for standardized allergen efits, risks, and costs. Furthermore, the management plan extracts. For nonstandardized extracts, a suggested main- must be individualized, with careful consideration given tenance dose is 3000 to 5000 protein nitrogen units (PNU) to patient preference. Disease severity and response (or or 0.5 mL of a 1:100 wt/vol dilution of manufacturer’s lack of response) to previous treatment are important extract. If the major allergen concentration of the extract is factors. known, a range between 5 and 20 mg of major allergen is the recommended maintenance dose for inhalant allergens Box 5 and 100 mg for Hymenoptera venom. Immunotherapy The physician and patient should discuss the benefits, treatment can be divided into 2 periods, which are com- risks, and costs of the appropriate management options monly referred to as the build-up and maintenance phases. and agree on a management plan. On the basis of clinical The immunotherapy build-up schedule (also referred to considerations and patient preference, allergen immuno- as up-dosing, induction, or the dose-increase phase) en- therapy might or might not be recommended. Patients with tails administration of gradually increasing doses during allergic rhinitis/conjunctivitis or allergic asthma whose a period of approximately 14 to 28 weeks. In conventional symptoms are not well controlled by medications or schedules a single dose increase is given on each visit, and avoidance measures or require high medication doses, the visit frequency can vary from 1 to 3 times a week. multiple medications, or both to maintain control of their Accelerated schedules, such as rush or cluster immuno- allergic disease might be good candidates for immuno- therapy, entail administration of several injections at in- therapy. Patients who experience adverse effects of med- creasing doses on a single visit. Accelerated schedules ications or who wish to avoid or reduce the long-term use offer the advantage of achieving the therapeutic dose ear- of medications are good candidates for immunotherapy. lier but might be associated with increased risk of systemic However, asthma must be controlled at the time the reaction in some patients.
  7. 7. J ALLERGY CLIN IMMUNOL Cox et al S31 VOLUME 120, NUMBER 3 Box 9 and medication use, the medical history since the previous Immunotherapy should be administered in a setting that visit, and an evaluation of the clinical response to immu- permits the prompt recognition and management of adverse notherapy. The immunotherapy schedule and doses, reactions. The preferred location for such administration is reaction history, and patient compliance should also be the prescribing physician’s office. However, patients can evaluated. The physician can at this time make adjust- receive immunotherapy injections at another health care ments to the immunotherapy schedule or dose, as clini- facility if the physician and staff at that location are trained cally indicated. and equipped to recognize and manage immunotherapy There are no specific markers that will predict who will reactions, in particular anaphylaxis. Patients should wait at remain in clinical remission after discontinuing effective the physician’s office for at least 30 minutes after the allergen immunotherapy. Some patients might sustain immunotherapy injection or injections so that reactions lasting remission of their allergic symptoms after dis- can be recognized and treated promptly, if they occur. continuing allergen immunotherapy,13 but others might In general, immunotherapy injections should be with- experience a recurrence of their symptoms after discontin- held if the patient presents with an acute asthma exacer- uation of allergen immunotherapy.14 As with the decision bation. For patients with asthma, consider measuring peak to initiate allergen immunotherapy, the decision to discon- expiratory flow rate before administering an immunother- tinue treatment should be individualized, taking into ac- apy injection and withholding an immunotherapy injec- count factors such as the severity of the patient’s illness tion if the peak expiratory flow rate is considered low for before treatment, the treatment benefit sustained, and the that patient. Some physicians recommend providing cer- inconvenience immunotherapy represents to a specific pa- tain patients with epinephrine for self-administration in tient and the potential effect a clinical relapse might have case of severe late reactions to immunotherapy injections. on the patient. Ultimately, the duration of immunotherapy should be individualized on the basis of the patient’s clin- Box 10 ical response, disease severity, immunotherapy reaction Injections of allergen immunotherapy extract can cause history, and patient preference. local or systemic reactions. Most severe reactions develop within 30 minutes after the immunotherapy injection, but reactions can occur after this time. IMMUNOTHERAPY GLOSSARY Box 11 For more information on immunotherapy definitions, Local reactions can be managed with local treatment see the article by Kao.15 (eg, cool compresses or topical corticosteroids) or anti- The allergen immunotherapy extract is defined as the histamines. Systemic reactions can be mild or severe mixture of the manufacturer’s allergen extract or extracts (anaphylaxis). Epinephrine is the treatment of choice in that is used for allergen immunotherapy. Allergen extracts anaphylaxis, preferably when administered intramus- used to prepare the allergen immunotherapy extract can be cularly,11 although subcutaneous administration is complex mixtures containing multiple allergenic and non- acceptable.12 allergenic macromolecules (proteins, glycoproteins, and Antihistamines and systemic corticosteroids are sec- polysaccharides) and low-molecular-weight compounds ondary medications that might help to modify systemic (pigments and salts; see the Allergen selection and han- reactions but should never replace epinephrine in the dling section). Other terms used to describe the allergen treatment of anaphylaxis. Intravenous saline or sup- immunotherapy extract include allergen product,16 plemental oxygen might be required in severe cases. allergy serum, allergen vaccine,17 and allergen solution. For additional details, see the practice parameters for Allergen immunotherapy is defined as the repeated anaphylaxis.12 administration of specific allergens to patients with IgE- The immunotherapy dose and schedule, as well as the mediated conditions for the purpose of providing protec- benefits and risks of continuing immunotherapy, should tion against the allergic symptoms and inflammatory be evaluated after any immunotherapy-induced systemic reactions associated with natural exposure to these aller- reaction. After a severe systemic reaction, careful evalu- gens.18 Other terms that have been used for allergen im- ation by the prescribing physician is recommended. For munotherapy include hyposensitization, allergen-specific some patients, the immunotherapy maintenance dose desensitization, and the lay terms allergy shots or allergy might need to be reduced because of repeated systemic injections.15 reactions to immunotherapy injections. The decision to Anaphylaxis is an immediate systemic reaction often continue immunotherapy should be re-evaluated after occurring within minutes and occasionally as long as an severe or repeated systemic reactions to allergen immu- hour or longer after exposure to an allergen. It can be notherapy extracts. IgE mediated, as can occur with allergen immunotherapy, or non–IgE mediated, as occurs with radiocontrast media. Box 12 It is caused by the rapid release of vasoactive mediators Patients receiving maintenance immunotherapy should from tissue mast cells and peripheral blood basophils. have follow-up visits at least every 6 to 12 months. The build-up phase involves receiving injections with Periodic visits should include a reassessment of symptoms increasing amounts of the allergen. The frequency of
  8. 8. S32 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 TABLE II. Allergen immunotherapy dose-calculation table 1 d Express weight per volume as a fraction: N or 1:N. d Calculate concentration of individual allergens in mixtures. If a mixture is made of equal amounts of N individual allergens to make a total concentration (C), the final concentration of an individual allergen (Ca) can be calculated by using the following equation: 1 C Ca 5 C 3 N 5 N or C:N. For example, if a mixture of equal amounts of 5 (N) allergens has a total concentration (C) of 100,000 BAU/mL, then the final concentration of each individual allergen (Ca) is: Ca 5 N 5 100;000 5 20; 000 BAU=mL C 5 Likewise, if C 5 1:10 (wt/vol), then: Ca 5 N 5 1=10 5 0:1 5 0:02 or 50 or 1:50. C 5 5 1 d Dilution of individual allergen: If an initial volume, Vi (in milliliters), of an individual antigen with concentration, Ci, is added to an allergen extract to make a final volume of Vf (in milliliters), the final allergen concentration (Ca) in the allergen extract mixture will Vi be: Ca 5 Ci 3 Vf . d Final concentration of an allergen in a mixture of mixtures is determined by multiplying the initial concentration by the dilution factors from each mixing step. For example, consider a mixture containing equal amounts of 5 (N) allergens with a total concentration (C) of 100,000 BAU/mL (first dilu- tion). If an initial volume (Vi) of 0.5 mL of this mixture is further mixed with other components and diluent to make a final allergen extract mixture volume (Vf) of 5.0 mL (second dilution), the final concentration of an individual allergen (Ca) will be: 1 Vi 1 0:5 100;000 Ca 5 C 3 N 3 Vf 5 100; 000 3 5 3 5:0 5 50 5 2000 BAU=mL |{z} |{z} Mixture dilution Allergen extract dilution Likewise, if C 5 1:10 (wt/vol), then: Ca 5 10 3 1 3 5:0 5 500 or 1:500. 1 5 0:5 1 injections during this phase generally ranges from 1 to 3 Hyposensitization is a term formerly used interchange- times a week, although more rapid build-up schedules ably with allergen immunotherapy. It was introduced to are sometimes used. The duration of this phase depends distinguish allergen immunotherapy from classical desen- on the frequency of the injections but generally ranges sitization. Hyposensitization denotes a state of incomplete from 3 to 6 months (at a frequency of 2 times and 1 time desensitization because complete desensitization is rarely per week, respectively). accomplished with allergen immunotherapy. Cluster immunotherapy is an accelerated build-up Immunomodulation is a term that denotes a wide variety schedule that entails administering several injections at in- of drug or immunologic interventions that alter normal or creasing doses (generally 2-3 per visit) sequentially in abnormal immune responses by deletion of specific T a single day of treatment on nonconsecutive days. The cells, B cells, or both; immune deviation; induction of maintenance dose is generally achieved more rapidly than peripheral/central tolerance; or modification of various with a conventional (single injection per visit) build-up inflammatory pathways (eg, chemotaxis, adhesions, or schedule (generally within 4 to 8 weeks). intracytoplasmic signaling). Desensitization is the rapid administration of incremen- Immunotherapy is a treatment modality that appeared tal doses of allergens or medications by which effector soon after adaptive immune responses were discovered cells are rendered less reactive or nonreactive to an IgE- and has gradually evolved to encompass any intervention medicated immune response. Desensitization can involve that might benefit immune-induced aberrant conditions by IgE-mediated or other immune mechanisms. The positive a variety of immunologic transformations. Early defini- skin test response to the allergens might diminish or actu- tions of the term immunotherapy included active and pas- ally convert to a negative response in some cases after this sive immunization for the purpose of improving a host’s procedure. Tolerance to medications can be achieved defenses against microorganisms. Allergen immunother- through desensitization. apy was originally conceived as a form of active immuni- The dose is the actual amount of allergen administered zation, the purpose of which was to alter the host’s in the injection. The volume and concentration can vary abnormal immune responses and not augment the host’s such that the same delivered dose can be given by changing defenses against microorganisms. The modern rubric of the volume and concentration (ie, 0.05 mL of a 1:1 vol/vol immunotherapy includes all methods used to overcome ab- allergen would equal 0.5 mL of a 1:10 vol/vol allergen). normal immune responses by means of induction of clonal The dose can be calculated by using the following formula: deletion, anergy, immune tolerance, or immune deviation. concentration of allergen multiplied by volume of admin- The maintenance concentrate is a preparation that istered dose (see Table II for a dose-calculation table). contains individual or mixtures of manufacturer’s aller- The effective therapeutic dose or maintenance dose is gen extracts intended for allergen immunotherapy treat- the dose that provides therapeutic efficacy without signif- ment. A maintenance concentrate can be composed of icant adverse local or systemic reactions. The effective a concentrated dose of a single allergen or a combination therapeutic dose might not be the initially calculated pro- of concentrated allergens to prepare an individual jected effective dose (eg, cat, 1000 BAU, [highest tolerated patient’s customized allergen immunotherapy extract dose] vs 2000 BAU [projected effective dose]). mixture. Subsequent dilutions can be prepared from the
  9. 9. J ALLERGY CLIN IMMUNOL Cox et al S33 VOLUME 120, NUMBER 3 maintenance concentrate for the build-up phase or if the INTRODUCTION patient cannot tolerate the maintenance concentrate. The maintenance dose (or effective therapeutic dose) is Immunity has been defined as protection against certain the dose that provides therapeutic efficacy without signif- diseases. The initial immunotherapeutic interventions, icant adverse local or systemic reactions. The effective which included the use of preventive vaccines and xen- therapeutic dose may not be the initially calculated pro- ogenic antisera by Jenner, Pasteur, Koch, and von jected effective dose. Behring, were effective for disease prevention. These The maintenance goal (or projected effective dose) is initial efforts in immune modulation served as a model for the allergen dose projected to provide therapeutic efficacy. later developments in the field of allergen immunotherapy. The maintenance goal is based on published studies, but a From its humble empiric emergence in 1900, when projected effective dose has not been established for aller- ragweed injections were proposed as therapy for autumnal gens. Not all patients will tolerate the projected effective hay fever, allergen immunotherapy has progressed in both dose, and some patients experience therapeutic efficacy theory and practice from the passive immunologic ap- at lower doses. proach to the active immunologic procedures pioneered The maintenance phase begins when the effective ther- by Noon19 and Freeman.20,21 Advances in allergen immu- apeutic dose is reached. Once the maintenance dose is notherapy have depended on the improved understanding reached, the intervals between the allergy injections are of IgE-mediated immunologic mechanisms, the character- increased. The dose generally is the same with each injec- ization of specific antigens and allergens, and the stan- tion, although modifications can be made based on several dardization of allergen extracts. Proof of the efficacy of variables (ie, new vials or a persistent large local reaction allergen immunotherapy has accumulated rapidly during causing discomfort). The intervals between maintenance the past 10 years. Numerous well-designed controlled immunotherapy injections generally ranges from 4 to 8 studies have demonstrated that allergen immunotherapy weeks for venom and every 2 to 4 weeks for inhalant aller- is efficacious in the treatment of allergic rhinitis, allergic gens but can be advanced as tolerated if clinical efficacy is asthma, and stinging insect hypersensitivity. Some studies maintained. have suggested that allergen immunotherapy might pre- A major allergen is an antigen that binds to the IgE sera vent the development of asthma in individuals with aller- from 50% or more of a clinically allergic group of patients. gic rhinitis.6-9 Such allergens are defined either by means of immuno- Effective subcutaneous allergen immunotherapy ap- blotting or crossed allergoimmunoelectrophoresis. pears to correlate with administration of an optimal For a definition of projected effective dose, see mainte- maintenance dose in the range of 5 to 20 mg of major nance goal. allergen for inhalant allergens,22-26 and it should be differ- Rush immunotherapy is an accelerated immunotherapy entiated from unproved methods, such as neutralization- build-up schedule that entails administering incremental provocation therapy and low-dose subcutaneous regimens doses of allergen at intervals varying between 15 and 60 based on the Rinkel technique, which have been found minutes over 1 to 3 days until the target therapeutic dose to ineffective in a double-blind placebo-controlled is achieved. Rush immunotherapy schedules for inhalant study.27,28 allergens can be associated with a greater risk of systemic reactions, particularly in high-risk patients (eg, those with markedly positive prick/puncture test responses), and SUMMARY STATEMENTS premedication with antihistamines and corticosteroids appears to reduce the risk associated with rush immuno- Mechanisms of immunotherapy therapy. However, rush protocols for administration of Summary Statement 1: Immunologic changes during Hymenoptera VIT have not been associated with a similar immunotherapy are complex. D high incidence of systemic reactions. Summary Statement 2: Successful immunotherapy is Off the board into one syringe is a phrase that describes a associated with a change toward a TH1 CD41 cytokine method of allergen immunotherapy preparation and admin- profile. A istration that involves specifically mixing the patient’s Summary Statement 3: Allergen immunotherapy is also allergen immunotherapy injection in a single syringe, which associated with immunologic tolerance, defined as a is not recommended. This syringe might be inserted into relative decrease in allergen-specific responsiveness and more than one allergen extract vial, and this poses a risk of by the generation of CD41CD251 regulatory T lympho- cross-contamination of the allergen extracts and might dull cytes. A the needle with repeated penetration of the rubber stopper. Summary Statement 4: Efficacy from immunotherapy Shared specific patient vials is a method of allergen im- is not dependent on reduction in specific IgE levels. A munotherapy preparation and administration in which the Summary Statement 5: Increases in allergen-specific allergy immunotherapy extract is withdrawn from a shared IgG antibody titers are not predictive of the duration and vial (eg, mixed vespids or dust mite mix). This is some- degree of efficacy of immunotherapy. However, altera- times referred to as off the board, but it is distinct from tions in the allergen-specific IgG specificity with immu- the method of off the board into one syringe in that the notherapy might play a role in determining clinical syringe enters only one allergen extract vial. efficacy. A
  10. 10. S34 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 Allergen extracts Summary Statement 14: Although there is a low risk of Summary Statement 6: When possible, standardized severe systemic reactions with appropriately administered extracts should be used to prepare the allergen immuno- allergen immunotherapy, life-threatening and fatal reac- therapy extract treatment sets. A tions do occur. C Summary Statement 7: Nonstandardized extracts might Summary Statement 15: An assessment of the patient’s vary widely in biologic activity and, regardless of a current health status should be made before administration particular wt/vol or PNU potency, should not be consid- of the allergy immunotherapy injection to determine ered equipotent. B whether there were any recent health changes that might Summary Statement 8: In choosing the components for require modifying or withholding that patient’s immuno- a clinically relevant allergen immunotherapy extract, the therapy treatment. Risk factors for severe immunotherapy physician should be familiar with local and regional reactions include symptomatic asthma and injections aerobiology and indoor and outdoor allergens, paying administered during periods of symptom exacerbation. special attention to potential allergens in the patient’s own Before the administration of the allergy injection, the environment. D patient should be evaluated for the presence of asthma or Cross-reactivity of allergen extract. Summary allergy symptom exacerbation. One might also consider Statement 9: Knowledge of allergen cross-reactivity is an objective measure of airway function (eg, peak flow) important in the selection of allergens for immunotherapy for the asthmatic patient before allergy injections. B because limiting the number of allergens in a treatment Timing of anaphylactic reactions to immunotherapy vial is necessary to attain optimal therapeutic doses for the injections. Summary Statement 16: Because most systemic individual patient. B reactions that result from allergen immunotherapy occur within 30 minutes after an injection, patients should remain in Efficacy of immunotherapy the physician’s office at least 30 minutes after an injection. C Allergic rhinitis, allergic asthma, and stinging insect b-Adrenergic blocking agents. Summary Statement hypersensitivity. Summary Statement 10: Immunotherapy 17: b-Adrenergic blocking agents might make allergen is effective for treatment of allergic rhinitis, allergic con- immunotherapy–related systemic reactions more difficult junctivitis, allergic asthma, and stinging insect hypersensi- to treat and delay the recovery. Therefore a cautious tivity. Therefore immunotherapy merits consideration in attitude should be adopted toward the concomitant use of patients with these disorders as a possible treatment option. A b-blocker agents and inhalant allergen immunotherapy. Food allergy, urticaria, and atopic dermatitis. However, immunotherapy is indicated in patients with Summary Statement 11: Clinical studies do not support life-threatening stinging insect hypersensitivity who also the use of allergen immunotherapy for food hypersensi- require b-blocker medications because the risk of the tivity or chronic urticaria, angioedema, or both at this time. stinging insect hypersensitivity is greater than the risk of Therefore allergen immunotherapy for patients with food an immunotherapy-related systemic reaction. C hypersensitivity or chronic urticaria, angioedema, or both Contraindications. Summary Statement 18: Medical is not recommended. D conditions that reduce the patient’s ability to survive the Summary Statement 11b: There are limited data indi- systemic allergic reaction or the resultant treatment are cating that immunotherapy might be effective for atopic relative contraindications for allergen immunotherapy. dermatitis when this condition is associated with aero- Examples include severe asthma uncontrolled by phar- allergen sensitivity. C macotherapy and significant cardiovascular disease. C Summary Statement 11c: The potential for benefit in Reducing the risk of anaphylaxis to immunotherapy symptoms related to oral allergy syndrome with inhalant injections. Summary Statement 19: Allergen immuno- immunotherapy directed at the cross-reacting pollens has therapy should be administered in a setting where proce- been observed in some studies but not in others. For this dures that can reduce the risk of anaphylaxis are in place reason, more investigation is required to substantiate that a and where the prompt recognition and treatment of benefit in oral allergy symptoms will occur with allergen anaphylaxis is ensured. C immunotherapy. C Measures of efficacy. Summary Statement 12: Clinical Patient selection parameters, such as symptoms and medication use, might Clinical indications. Summary Statement 20: Allergen be useful measures of the efficacy of immunotherapy in a immunotherapy should be considered for patients who have clinical setting; however, repetitive skin testing of patients demonstrable evidence of specific IgE antibodies to clini- receiving immunotherapy is not recommended. A cally relevant allergens. The decision to begin allergen immunotherapy depends on the degree to which symptoms Safety of immunotherapy can be reduced by avoidance and medication, the amount Reaction rates. Summary Statement 13: Published and type of medication required to control symptoms, and studies indicate that individual local reactions do not the adverse effects of medications. A appear to be predictive of subsequent systemic reactions. Special precautions in patients with asthma. Summary However, some patients with greater frequency of large Statement 21: Allergen immunotherapy in asthmatic local reactions might be at an increased risk for future patients should not be initiated unless the patient’s asthma systemic reactions. C is stable with pharmacotherapy. C
  11. 11. J ALLERGY CLIN IMMUNOL Cox et al S35 VOLUME 120, NUMBER 3 Clinical indications for VIT. Summary Statement 22: Allergen immunotherapy extract handling VIT should be strongly considered if the patient has had a STORAGE systemic reaction to a Hymenoptera sting, especially if Summary Statement 33a: Allergen immunotherapy such a reaction was associated with respiratory symptoms, extracts should be stored at 48C to reduce the rate of cardiovascular symptoms, or both and if the patient has potency loss. B demonstrable evidence of specific IgE antibodies. A Summary statement 33b: Extract manufacturers con- Summary Statement 23: Patients selected for immuno- duct stability studies with standardized extracts that therapy should be cooperative and compliant. D expose them to various shipping conditions. It is the responsibility of each supplier or manufacturer to ship Allergen selection and handling extracts under validated conditions that are shown not to Clinical evaluation. Summary Statement 24: The se- adversely affect the product’s potency or safety. C lection of the components of an allergen immunotherapy STORING DILUTE EXTRACTS extract that are most likely to be effective should be based Summary Statement 34a: More dilute concentrations of on a careful history of relevant symptoms with knowledge allergen immunotherapy extracts (diluted greater than of possible environmental exposures and correlation with 1:10 vol/vol) are more sensitive to the effects of temper- positive test results for specific IgE antibodies. A ature and lose potency more rapidly than more concen- Clinical correlation. Summary Statement 25: The trated allergen immunotherapy extracts. The expiration allergen immunotherapy extract should contain only clin- date for more dilute concentrations should reflect this ically relevant allergens. A shorter shelf life. B Skin tests and in vitro IgE antibody tests. Summary Summary Statement 34b: In determining the allergen Statement 26: Skin testing has been the primary diagnostic immunotherapy extract expiration date, consideration tool in clinical studies of allergen immunotherapy. must be given to the fact that the rate of potency loss Therefore in most patients, skin testing should be used over time is influenced by a number of factors separately to determine whether the patient has specific IgE anti- and collectively, including (1) storage temperature, (2) bodies. Appropriately interpreted in vitro tests for specific presence of stabilizers and bactericidal agents, (3) con- IgE antibodies can also be used. A centration, (4) presence of proteolytic enzymes, and (5) Specific allergens. Summary Statement 27: Immuno- volume of the storage vial. B therapy is effective for pollen, mold, animal allergens, cockroach, dust mite, and Hymenoptera hypersensitivity. Immunotherapy schedules and doses Therefore immunotherapy should be considered as part of Summary Statement 35: A customized individual the management program in patients who have symptoms allergen immunotherapy extract should be prepared from related to exposure to these allergens, supported by the a manufacturer’s extract or extracts in accordance to the presence of specific IgE antibodies. A patient’s clinical history and allergy test results and might Principles of mixing. Summary Statement 28: be based on single or multiple allergens. D Consideration of the following principles is necessary Maintenance concentrate. Summary Statement 36: when mixing allergen extract: (1) cross-reactivity of The highest-concentration allergy immunotherapy vial allergens, (2) optimization of the dose of each constituent, (eg, 1:1 vol/vol vial) that is used for the projected effective and (3) enzymatic degradation of allergens. B dose is called the maintenance concentrate vial. The Mixing cross-reactive extracts. Summary Statement maintenance dose is the dose that provides therapeutic 29: The selection of allergens for immunotherapy should efficacy without significant adverse local or systemic be based (in part) on the cross-reactivity of clinically reactions and might not always reach the initially calcu- relevant allergens. Many botanically related pollens con- lated projected effective dose. This reinforces that allergy tain allergens that are cross-reactive. When pollens are immunotherapy must be individualized. D substantially cross-reactive, selection of a single pollen Recommended doses. Summary Statement 37: The within the cross-reactive genus or subfamily might suffice. maintenance concentrate should be formulated to deliver When pollen allergens are not substantially cross-reactive, a dose considered to be therapeutically effective for each of testing for and treatment with multiple locally prevalent its constituent components. The projected effective dose is pollens might be necessary. B referred to as the maintenance goal. Some individuals Dose selection. Summary Statement 30: The efficacy of unable to tolerate the projected effective dose will expe- immunotherapy depends on achieving an optimal thera- rience clinical benefits at a lower dose. The effective peutic dose of each of the constituents in the allergen therapeutic dose is referred to as the maintenance dose. A immunotherapy extract. A Effect of dilution on dose. Summary Statement 38: Proteolytic enzymes and mixing. Summary Statement Dilution limits the number of antigens that can be added to 31: Separation of extracts with high proteolytic enzyme a maintenance concentrate if a therapeutic dose is to be activities, such as mold/fungi and cockroach, from other delivered. A extracts, such as pollens, is recommended. B Dilutions of the maintenance concentrate. Summary Summary Statement 32: Allergen immunotherapy Statement 39: Serial dilutions of the maintenance concen- extract preparation should be performed by individuals trate should be made in preparation for the build-up phase experienced and trained in handling allergenic products. D of immunotherapy. D
  12. 12. S36 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 Labeling dilutions. Summary Statement 40: A consis- Premedication with cluster and rush immunotherapy. tent uniform labeling system for dilutions from the Summary Statement 51: Premedication should be given maintenance concentrate might reduce errors in adminis- before cluster and rush immunotherapy with aeroallergens tration and therefore is recommended. D to reduce the rate of systemic reactions. A Individualized treatment vials. Summary Statement 41: Maintenance schedules. Summary Statement 52: Once Administration of an incorrect injection is a potential risk a patient reaches a maintenance dose, the interval between of allergen immunotherapy. An incorrect injection is an injections often can be progressively increased as tolerated injection given to the wrong patient or a correct patient up to an interval of up to 4 weeks for inhalant allergens and receiving an injection of an incorrect dose. up to 8 weeks for venom. Some individuals might tolerate A customized individual maintenance concentrate of longer intervals between maintenance dose injections. A the allergen immunotherapy extract and serial dilutions, Continuing care whether a single extract or a mixture of extracts, prepared TIME COURSE OF IMPROVEMENT and labeled with the patient’s name and birth date might Summary Statement 53: Clinical improvement can be reduce the risk of incorrect (ie, wrong patient) injection. demonstrated very shortly after the patient reaches a The mixing of antigens in a syringe is not recommended maintenance dose. A because of the potential for cross-contamination of FOLLOW-UP VISITS extracts. C Summary Statement 54: Patients should be evaluated at Starting doses. Summary Statement 42: The starting least every 6 to 12 months while they receive immuno- dose for build-up is usually a 1000- or 10,000-fold dilution therapy. D of the maintenance concentrate, although a lower starting DURATION OF TREATMENT dose might be advisable for highly sensitive patients. D Summary Statement 55a: At present, there are no Summary Statement 43: The frequency of allergen specific tests or clinical markers that will distinguish immunotherapy administration during the build-up phase between patients who will relapse and those who will is usually 1 to 2 injections per week. D remain in long-term clinical remission after discontinuing Dose adjustments for systemic reactions. Summary effective inhalant allergen immunotherapy, and the dura- Statement 44: The dose of allergen immunotherapy extract tion of treatment should be determined by the physician should be appropriately reduced after a systemic reaction and patient after considering the benefits and risks asso- if immunotherapy is continued. D ciated with discontinuing or continuing immunotherapy. D Reductions during periods of exacerbation of symp- Summary Statement 55b: Although there are no specific toms. Summary Statement 45: Immunotherapy given tests to distinguish which patients will relapse after during periods when the patient is exposed to increased discontinuing VIT, there are clinical features that are levels of allergen to which they are sensitive might be associated with a higher chance of relapse, notably a history associated with an increased risk of a systemic reaction. of very severe reaction to a sting, a systemic reaction during Consider not increasing or even reducing the immuno- VIT (to a sting or a venom injection), honeybee venom therapy dose in highly sensitive patients during the time allergy, and treatment duration of less than 5 years. C period when they are exposed to increased levels of Summary Statement 55c: The patient’s response to allergen, especially if they are experiencing an exacerba- immunotherapy should be evaluated on a regular basis. A tion of their symptoms. C decision about continuation of effective immunotherapy Dose adjustments for late injections. Summary should generally be made after the initial period of up to Statement 46: It is customary to reduce the dose of 5 years of treatment. D allergen immunotherapy extract when the interval be- Summary Statement 55d: The severity of disease, tween injections is prolonged. D benefits sustained from treatment, and convenience of Cluster schedules. Summary Statement 47: With clus- treatment are all factors that should be considered in ter immunotherapy, 2 or more injections are administered determining whether to continue or stop immunotherapy per visit to achieve a maintenance dose more rapidly than for any individual patient. D with conventional schedules. C Summary Statement 55e: Some patients might experience Rush schedules. Summary Statement 48: Rush sched- sustained clinical remission of their allergic disease after ules can achieve a maintenance dose more quickly than discontinuing immunotherapy, but others might relapse. B weekly schedules. A DOCUMENTATION AND RECORD KEEPING Systemic reactions and rush schedules. Summary Summary Statement 56: The allergen immunotherapy Statement 49: Rush schedules are associated with an extract contents, informed consent for immunotherapy, and increased risk of systemic reactions. However, rush pro- administration of extracts should be carefully documented. D tocols for administration of Hymenoptera VIT have not INJECTION TECHNIQUES been associated with a similarly high incidence of sys- Summary Statement 57: Allergen immunotherapy ex- temic reactions. A tract injections should be administered with a 1-mL syringe Premedication and weekly immunotherapy. Summary with a 26- to 27-gauge half-inch nonremovable needle. D Statement 50: Premedication might reduce the frequency Summary Statement 58: The injection should be ad- of systemic reactions caused by conventional immuno- ministered subcutaneously in the posterior portion of the therapy. A middle third of the upper arm. D
  13. 13. J ALLERGY CLIN IMMUNOL Cox et al S37 VOLUME 120, NUMBER 3 Location of allergen immunotherapy reaction with a different extract might be greater with administration nonstandardized extracts and with extracts that contain mixtures of allergens. D Physician’s office. Summary Statement 59: The pre- ferred location for administration of allergen immuno- Summary Statement 68: Immunotherapy with a differ- therapy is in the office of the physician who prepared the ent extract should be conducted cautiously. If there is inadequate information to support continuing with the patient’s allergen immunotherapy extract. D Summary Statement 60: Patients at high risk of systemic previous immunotherapy program, re-evaluation might be reactions, where possible, should receive immunotherapy necessary, and a new schedule and allergen immunother- apy extract might need to be prepared. D in the office of the physician who prepared the patient’s allergen immunotherapy extract. D Special considerations in immunotherapy Other locations. Summary Statement 61: Regardless of the location, allergen immunotherapy should be adminis- Allergen immunotherapy in children. Summary tered under the supervision of an appropriately trained Statement 69: Immunotherapy for children is effective physician and personnel. D and often well tolerated. Therefore immunotherapy should Home administration. Summary Statement 62: In rare be considered (along with pharmacotherapy and allergen and exceptional cases, when allergen immunotherapy avoidance) in the management of children with allergic cannot be administered in a medical facility and withhold- rhinitis, allergic asthma, and stinging insect hypersensi- ing this therapy would result in a serious detriment to the tivity. It might prevent the new onset of allergen sensitiv- patients’ health (eg, VIT for a patient living in a remote ities or progression to asthma. A area), very careful consideration of potential benefits and Summary Statement 70: Children under 5 years of age risks of at-home administration of allergen immunother- can have difficulty cooperating with an immunotherapy apy should be made on an individual patient basis. If this program. Therefore the physician who evaluates the approach is used, informed consent should be obtained patient must consider the benefits and risks of immuno- from the patient, and the person administering the injection therapy and individualize treatment in patients under the to the patient must be educated about how to administer age of 5 years. A immunotherapy and recognize and treat anaphylaxis. D Pregnancy. Summary Statement 71: Allergen immu- Summary Statement 63: If a patient receiving immuno- notherapy can be continued but is usually not initiated in therapy transfers from one physician to another, a decision the pregnant patient. C must be made by the physician to whom the patient has Immunotherapy in the elderly patient. Summary transferred as to whether to continue immunotherapy. If Statement 72: Comorbid medical conditions and certain immunotherapy is continued, a decision must then be medication use might increase the risk from immunother- made about whether to continue an unchanged immuno- apy in elderly patients. Therefore special consideration therapy program initiated by the previous physician or to must be given to the benefits and risks of immunotherapy prepare a new immunotherapy program. D in this patient population. D Summary Statement 64: If a patient transfers from one Immunotherapy in patients with immunodeficiency physician to another and continues on an immunotherapy and autoimmune disorders. Summary Statement 73: program without changes to either the schedule or allergen Immunotherapy can be considered in patients with immu- immunotherapy extract, the risk of a systemic reaction is nodeficiency and autoimmune disorders. D not substantially increased. D Summary Statement 65: A full, clear, and detailed Alternative routes of immunotherapy documentation of the patient’s schedule must accompany Sublingual and oral immunotherapy. Summary a patient when he or she transfers responsibility for his or Statement 74: Optimal high-dose sublingual swallow her immunotherapy program from one physician to and oral immunotherapies are under clinical investigation another. In addition, a record of previous response to in the United States. Studies of oral immunotherapy have and compliance with this program should be communi- demonstrated conflicting results. High-dose sublingual cated to the patient’s new physician. D immunotherapy has been found to be effective in many Summary Statement 66: An allergen immunotherapy studies of adults and children with allergic rhinitis and extract must be considered different from a clinical stand- asthma, but a consistent relationship among allergen dose, point if there is any change in the constituents of the treatment duration, and clinical efficacy has not been extract. These include changes in the lot, manufacturer, established. However, there is no US Food and Drug allergen extract type (eg, aqueous, glycerinated, standard- Administration (FDA)–approved formulation for sub- ized, and nonstandardized), and/or components or relative lingual or oral immunotherapy in the United States. amounts in the mixture. D Therefore sublingual and oral immunotherapy should be Summary Statement 67: There is an increased risk of a considered investigational at this time. A systemic reaction in a patient who transfers from one Summary Statement 75: Intranasal immunotherapy is physician to another if the immunotherapy extract is undergoing evaluation in children and adults with allergic changed because of the significant variability in content rhinitis, but there is no FDA-approved formulation for this and potency of allergen extracts. The risk of a systemic modality in the United States. B
  14. 14. S38 Cox et al J ALLERGY CLIN IMMUNOL SEPTEMBER 2007 Immunotherapy techniques that are not recommended. develops before decreases in their IgE antibody levels occur Summary Statement 76: Low-dose immunotherapy, en- or in other patients whose IgE antibody levels never zyme-potentiated immunotherapy, and immunotherapy decrease, thereby demonstrating that efficacy is not depen- (parenteral or sublingual) based on provocation-neutrali- dent on reductions in specific IgE levels.42,43 Immunother- zation testing are not recommended. D apy does diminish the seasonal increase in specific IgE levels.44 Despite the persistence of significant levels of spe- cific IgE antibody levels, immunotherapy usually causes a MECHANISMS OF IMMUNOTHERAPY reduction in release of mediators, such as histamine, from ba- sophils and mast cells, a phenomenon most relevant to the Summary Statement 1: Immunologic changes during immediate phase of allergic reactions. Suppression of late- immunotherapy are complex. D phase inflammatory responses in the skin and respiratory Summary Statement 2: Successful immunotherapy is tract generally also occur with allergen immunotherapy.45-48 associated with a change toward a TH1 CD41 cytokine An increase in serum allergen-specific IgA and IgG profile. A levels, particularly of the IgG4 isotype, has also been Summary Statement 3: Allergen immunotherapy is also associated with immunotherapy. The properties of aller- associated with immunologic tolerance, which is defined gen-specific IgA have yet to be determined, and there is a as a relative decrease in allergen-specific responsiveness, weak correlation between the increase in allergen-specific and by the generation of CD41CD251 regulatory T lym- IgG levels and immunotherapy’s clinical efficacy.30,49,50 phocytes. A Immunotherapy might alter the affinity and specificity Summary Statement 4: Efficacy from immunotherapy of allergen-specific IgG.51,52 During the initial phase of ul- is not dependent on reduction in specific IgE levels. A trarush VIT, a change in IgG specificity (ie, a change in the Summary Statement 5: Increases in allergen-specific IgG set of epitopes dominantly recognized by IgG on wasp antibody titers are not predictive of the duration and degree venom antigens) occurred concomitantly with early clini- of efficacy of immunotherapy. However, alterations in the cal tolerance and was seen within 12 hours of ultrarush allergen-specific IgG specificity with immunotherapy VIT (P < .001).51 VIT resulted in a change in IgG specific- might play a role in determining clinical efficacy. A ity to the major bee venom allergen, phospholipase A2, to a The immunologic changes associated with immuno- specificity similar to that seen in healthy nonallergic indi- therapy are complex, and the exact mechanism or mech- viduals.52 This change in IgG specificity preceded the in- anisms responsible for its’ clinical efficacy are continually crease in IgG titers and was sustained for up to 6 months.52 being elucidated. Data support the concept that successful Allergen-specific IgG induced from immunotherapy immunotherapy is associated with a change to a TH1 CD41 can block IgE-dependent histamine release and subse- cytokine profile.29-34 Data indicate that increased produc- quent IgE-mediated antigen presentation to T cells.53 This tion of IL-12, a strong inducer of TH1 responses, contrib- effect might be dependent on IgE, allergen concentration, utes to this shift.33 Clinically successful immunotherapy and CD23, the low-affinity receptor for IgE. has been reported to be associated with immunologic tol- Whereas serum immunoreactive specific IgG levels are erance, which is defined as a relative decrease in antigen- not predictive, it is possible that functional assays of IgG, specific responsiveness, immune deviation, or anergy. For such as detection of IgG-associated serum inhibitory example, lymphoproliferative responses to allergen are activity for IgE-facilitated allergen presentation, basophil reduced with immunotherapy.32 Successful immunother- histamine release, or both, might be more closely associ- apy results in generation of a population of T regulatory ated with the clinical response to immunotherapy, al- cells, which are CD41CD251 T lymphocytes producing though this remains to be tested in larger clinical trials.37,53 IL-10, TGF-b, or both.35-39 Regulatory T-cell release has The relationship between these immunologic changes been described in allergen immunotherapy with Hyme- and immunotherapy efficacy is not completely understood. noptera venom,35 grass pollen extract,37 and house dust mites.38 IL-10 reduces B-cell antigen-specific IgE and increases IgG4 levels; reduces proinflammatory cytokine ALLERGEN EXTRACTS release from mast cells, eosinophils, and T cells; and elicits tolerance in T cells by means of selective inhibi- Summary Statement 6: When possible, standardized tion of the CD28 costimulatory pathway.36,37 extracts should be used to prepare the allergen immuno- Allergen immunotherapy has been shown to block both therapy extract treatment sets. A the immediate and late-phase allergic response.40 Allergen Allergen extracts are commercially available for most immunotherapy has been shown to decrease the recruit- of the commonly recognized allergens. Allergen extract ment of mast cells, basophils, and eosinophils in the potency variability and product composition inconsis- skin, nose, eye, and bronchial mucosa after provocation tency has several potential consequences. Diagnostic or natural exposure to allergens.41 allergy skin testing and allergen immunotherapy efficacy In patients receiving immunotherapy, initially there is an and safety are dependent on the quality of the allergen increase in specific IgE antibody levels, followed by a extracts. When possible, standardized extracts should gradual decrease to a level that is still higher than that present be used to prepare allergen immunotherapy treatment before treatment. Clinical improvement in many patients sets.2,18,54-56 The advantage of standardized extracts is that
  15. 15. J ALLERGY CLIN IMMUNOL Cox et al S39 VOLUME 120, NUMBER 3 the biologic activity is more consistent, and therefore the Nonstandardized extracts can also be labeled in PNU, risk of an adverse reaction caused by extract potency where 1 PNU equals 0.01 g of protein nitrogen. Neither variability should be diminished. method confers any direct or comparative information United States–licensed extracts can be obtained in aque- about an extract’s biologic potency. Nonstandardized ous, glycerinated, lyophilized, and acetone-precipitated extracts can have a wide range of potencies. Extracts and alum-precipitated formulations. Some commonly with a particular wt/vol or PNU potency can have widely used allergens are standardized. These include extracts varying biologic activities.62-64 Therefore they should not for cat hair, cat pelt, Dermatophagoides pteronyssinus, be considered equipotent. Dermatophagoides farinae, short ragweed, Bermuda grass, Summary Statement 8: In choosing the components for Kentucky bluegrass, perennial rye grass, orchard grass, a clinically relevant allergen immunotherapy extract, the timothy grass, meadow fescue, red top, sweet vernal physician should be familiar with local and regional grass, and Hymenoptera venoms (yellow jacket, honey- aerobiology and indoor and outdoor allergens, paying bee, wasp, yellow hornet, and white-faced hornet). special attention to potential allergens in the patient’s own However, most allergen extracts are not yet standardized. environment. D Allergen standardization comprises 2 components: (1) Because North America is botanically and ecologically selection of a reference extract and (2) selection of an diverse, it is not possible to devise a common list of assay or procedure to compare the manufactured extract appropriate allergen extracts for each practice location. with the reference extract. Allergen standardization in The major clinically relevant aeroallergens of North the United States is based on assessment of the potency America are listed in Table III. Furthermore, nonrelevant of allergen extracts by using quantitative skin tests and allergens in such mixtures could act as sensitizers rather reported as BAU values. The quantitative test method is than as tolerogens.65,66 The physician must therefore called the intradermal dilution for 50 mL sum of erythema select only those aeroallergens for testing and treatment (ID50EAL) system for determining BAU values.57 The that are clinically relevant in a particular geographic area. ID50EAL method entails preparing a series of 3-fold dilu- The clinical relevance of an aeroallergen depends on tions of a candidate reference extract and injecting 0.05 mL certain key properties: (1) its intrinsic allergenicity, (2) its intradermally to 15 to 20 ‘‘highly sensitive’’ allergic aerodynamic properties, (3) whether it is produced in large subjects. The dilution that results in an erythema with the enough quantities to be sampled, (4) whether it is suffi- sum of the longest diameter and midpoint (orthogonal) ciently buoyant to be carried long distances, and (5) diameter equaling 50 mm is considered the end point whether the plant releasing the pollen is widely and (D50). The mean D50 is calculated, and the potency of abundantly prevalent in the region. The primary allergens the extract is assigned. used for immunotherapy are derived from plant (grasses, Most standardized extracts are labeled in BAU. Short trees, and weeds), arthropod (house dust mites), fungus, ragweed potency units were originally based on the animal (cat, dog), insect (cockroach), and Hymenoptera content of the major allergen Amb a 1. Ragweed potency venom source materials. is reported in FDA units and BAU. One FDA unit of Amb a 1 equals 1 mg of Amb a 1, and 350 units of Amb a 1/mL Cross-reactivity of allergen extract is equivalent to 100,000 BAU/mL. Cat extracts were also Summary Statement 9: Knowledge of allergen cross- originally standardized based on the content of major reactivity is important in the selection of allergens for allergen (Fel d 1), with 100,000 arbitrary units (AU) per immunotherapy because limiting the number of allergens milliliter containing between 10 to 19.9 FDA units of Fel d in a treatment vial is necessary to attain optimal therapeu- 1 per milliliter (1 FDA unit of Fel d 1 equals 2 to 4 mg of tic doses for the individual patient. B Fel d 1).55,58,59 Subsequently, ID50EAL testing suggested Cumulative data, both in vitro and in vivo, concerning that 100,000 AU/mL was equal to 10,000 BAU/mL.60 cross-reactivity offer a practical advantage in the selection Approximately 22% of individuals with cat allergy have of several categories of pollen allergens for immunother- specific IgE antibodies to cat albumin.61 Cat pelt extracts apy. However, because cross-reactivity is variable for have a greater amount of albumin than cat hair extracts.60 many grass and weed pollens, their intrinsic allergenicity, Dust mites were originally standardized in AU by prevalence, and aerobiologic characteristics within a spe- means of inhibition radioimmunoassay (RIA), and subse- cific region should be considered. A summary of cross-re- quent ID50EAL testing indicated that the AU was bioequi- activity patterns of the clinically relevant North American valent to the BAU, and the original AU nomenclature was aeroallergens can be found in Fig 2. Because many tem- kept. Dust mite extracts are still labeled in AU. perate pasture grasses (subfamily Pooideae; eg, fescue, Summary Statement 7: Nonstandardized extracts can rye, timothy, blue, and orchard), which are widely distrib- vary widely in biologic activity and, regardless of a uted throughout the United States, share major allergens,67 particular wt/vol or PNU potency, should not be consid- inclusion of a representative member (eg, perennial rye, ered equipotent. B meadow fescue, or timothy) generally provides efficacy Nonstandardized extracts are labeled as wt/vol, which against the entire group.68-75 Grasses in other subfamilies expresses weight in grams per volume in milliliters; that is, (eg, Bermuda, Bahia, and Johnson) show greater diversity a potency of 1:100 indicates that 1 g of dry allergen (eg, and should be evaluated separately.76-78 Bermuda and ragweed) was added to 100 ml of a buffer for extraction. Johnson grasses are increasingly important in the South,