Allergen immunotherapy: A practice parameter third update

Transcript

1 Task force report Allergen immunotherapy: A practice parameter third update s: Linda Cox, MD, Harold Nelson, MD, and Richard Lockey, MD Chief Editor Workgroup Contributor s: Christopher Calabria, MD, Thomas Chacko, MD, Ira Finegold, MD, Michael Nelson, MD, PhD, and Richard Weber, MD s: David I. Bernstein, MD, Joann Blessing-Moore, MD, David A. Khan, MD, David M. Lang, MD, Task Force Reviewer Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher Randolph, MD, Diane E. Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, and Dana Wallace, MD These parameters were developed by the Joint Task Force on Keywords: Allergy immunotherapy, subcutaneous immunotherapy, Practice Parameters, representing the American Academy of sublingual immunotherapy, allergic rhinitis, asthma, Hymenoptera, Allergy, Asthma & Immunology (AAAAI); the American Col- b -blockers, angioten- atopic dermatitis, anaphylaxis, epinephrine, lege of Allergy, Asthma & Immunology (ACAAI); and the Joint sin-converting enzyme inhibitor, epicutaneous immunotherapy, in- Council of Allergy, Asthma & Immunology. The American tralymphatic immunotherapy, nasal immunotherapy Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology have jointly accepted responsibility for establishing ‘‘Allergen immunotherapy: A practice parameter third update.’’ This is a complete and com- Disclosure of potential conflict of interest: L. Cox is a consultant for Genentech/Novartis, prehensive document at the current time. The medical environ- Hollister-Stier, and Stallergenes; is a speaker for Novartis; has received research ment is a changing environment, and not all recommendations support from Stallergenes; is on the Board of Directors for the American Board of Allergy and Immunology; and is on the US Food and Drug Administration (FDA)’s will be appropriate for all patients. Because this document Allergenic Product Advisory Committee. H. Nelson is a consultant for Merck and incorporated the efforts of many participants, no single individ- Planet Biopharmaceuticals, is a Data and Safety Monitoring Board member of DBV ual, including those who served on the Joint Task Force, is  Technologies, and has received research support from ALK-Abell o. M. Nelson has re- authorized to provide an official AAAAI or ACAAI interpretation ceived research support from the Department of Defense, is a speaker for the American College of Allergy, Asthma & Immunology (ACAAI), and is a member of the FDA’s of these practice parameters. Any request for information about or Advisory Committee on Allergic Products. R. Weber is on the speakers’ bureau for As- an interpretation of these practice parameters by the AAAAI or traZeneca and Genentech, has received research support from Novartis and Glaxo- the ACAAI should be directed to the Executive Offices of the SmithKline, and is Committee Chair of the ACAAI. D. I. Bernstein is a consultant AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & and on the advisory board for ALK America, is on the advisory board for Merck, Immunology. These parameters are not designed for use by and has received research support from Merck and Schering-Plough. J. Blessing- Moore is a speaker for Merck-Schering/AstraZeneca, Novartis, TEVA, and Meda pharmaceutical companies in drug promotion. A current list of Alcon and has received research support from Meda. D. A. Khan is a speaker for As- published practice parameters of the Joint Task Force on Practice traZeneca and Merck, has received research support from the Vanberg Family Foun- Parameters for Allergy and Immunology can be found in Table E1 dation and the Sellars Family Foundation, is Conjoint Board Review Chair for the in this article’s Online Repository at . www.jacionline.org ACAAI, and is a past president of the Texas Allergy, Asthma and Immunology Society. D. M. Lang is a speaker and consultant for GlaxoSmithKline; is a speaker for Astra- Zeneca, Merck, TEVA, Sanofi-Aventis, and Genentech/Novartis; and has received re- search support from Genentech/Novartis. R. A. Nicklas is a fellow for the ACAAI. J. CONTRIBUTORS Oppenheimer is a consultant and has provided lectures for AstraZeneca, Merck, and The Joint Task Force has made a concerted effort to acknowl- GlaxoSmithKline; and has received research support from AstraZeneca, Merck, Glax- edge all contributors to this parameter. If any contributors have oSmithKline, and Genentech. J. M. Portnoy is a speaker for Phadia, Merck, and CSL been excluded inadvertently, the Task Force will ensure that Behring; has received research support from the US Department of Housing and Urban Development; and is a board member of the ACAAI board of regents. S. L. Spector has appropriate recognition of such contributions is made subse- received research support from Genentech, GlaxoSmithKline, Schering-Plough, quently. The Joint Task Force gratefully acknowledges the Aventis, Novartis, Pharmaxis, Boehringer Ingelheim, AstraZeneca, Johnson & John- AAAAI Board of Directors and the ACAAI Board of Regents son, Xyzal, Alcon, Centocor, Sepracor, UCB, Amgen, Capnia, and IVAX. S. Tilles for their review and support of this document. is a speaker for Alcon; is on the advisory board for ALK, Ista, Merck, and Stallergenes; has received research support from Alcon, Amgen, Amphastar, Astellas, Boehringer The authors and editors gratefully acknowledge Susan Grupe Ingelheim, Ception, Genentech, Icagen, MAP Pharma, MEDA, Merck, Novartis, Rox- and Jessica Karle for their administrative assistance. Allergy Watch ; and is a ane, and Sepracor; is Associate Editor of Annals of Allergy and task force member for the Joint Task Force for Practice Parameters. D. Wallace is a speaker and advisor for Alcon, is a speaker for Merck and Sanofi-Aventis, and is CHIEF EDITORS President-Elect of the ACAAI. The rest of the authors have declared that they have no conflict of interest. Linda Cox, MD Received for publication September 18, 2010; accepted for publication September 23, Department of Medicine Nova Southeastern University 2010. College of Osteopathic Medicine Available online December 3, 2010. Davie, Florida Reprint requests: Joint Council of Allergy, Asthma & Immunology, 50 N Brockway St, . #3-3, Palatine, IL 60067. E-mail: [email protected] Richard Lockey, MD 0091-6749/$36.00 Division of Allergy and Immunology Ó 2010 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2010.09.034 Department of Internal Medicine S1

2 COXETAL S2 J ALLERGY CLIN IMMUNOL JANUARY 2011 University of Missouri–Kansas City School of Medicine University of South Florida College of Medicine and James A. Kansas City, Missouri Haley Veterans’ Hospital Tampa, Florida Christopher Randolph, MD Yale University Harold Nelson, MD New Haven, Connecticut Department of Medicine National Jewish Health Diane E. Schuller, MD Denver, Colorado Department of Pediatrics Pennsylvania State University Milton S. Hershey Medical College WORK GROUP MEMBERS Hershey, Pennsylvania Christopher Calabria, MD Glen Burnie, Maryland Sheldon L. Spector, MD Department of Medicine Thomas Chacko, MD UCLA School of Medicine Roswell, Georgia Los Angeles, California Ira Finegold, MD Stephen A. Tilles, MD New York, New York Department of Medicine University of Washington School of Medicine Michael Nelson, MD, PhD Redmond, Washington Washington, DC Dana V. Wallace, MD Richard Weber, MD Department of Medicine Denver, Colorado Nova Southeastern University Davie, Florida JOINT TASK FORCE REVIEWERS David Bernstein, MD INVITED REVIEWERS Department of Medicine and Environmental Health Don Aaronson, MD, JD, MPH University of Cincinnati College of Medicine Chicago, Illinois Cincinnati, Ohio Desiree Larenas-Linnemann, MD David A. Khan, MD Mexico city, Mexico Department of Internal Medicine University of Texas Southwestern Medical Center Bryan Leatherman, MD Dallas, Texas Gulfport, Mississippi Joann Blessing-Moore, MD Sandra Y. Lin, MD Departments of Medicine and Pediatrics Johns Hopkins Department of Otolaryngology–Head & Neck Stanford University Medical Center Surgery Department of Immunology Baltimore, Maryland Palo Alto, California Oral and sublingual immunotherapy for food hypersensitivity David M. Lang, MD Wesley Burkes, MD Allergy/Immunology Section Duke University Division of Medicine Allergy and Immunology Fellowship Raleigh, North Carolina Training Program Venom hypersensitivity Cleveland Clinic Foundation David Golden, MD Cleveland, Ohio Baltimore, Maryland Richard A. Nicklas, MD Theodore M. Freeman, MD Department of Medicine Helotes, Texas George Washington Medical Center Allergen extract section Washington, DC Derek Constable, PhD John Oppenheimer, MD Spokane, Washington Department of Internal Medicine New Jersey Medical School Robert Esch, PhD Pulmonary and Allergy Associates Lenoir, North Carolina Morristown, New Jersey Larry Garner, CPT, BA Jay M. Portnoy, MD Spokane, Washington Section of Allergy, Asthma & Immunology The Children’s Mercy Hospital Richard Lankow, PhD Department of Pediatrics Round Rock, Texas

3 S3 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 Extract Manufacturers were invited through their organization, Greg Plunkett, PhD the Allergenic Products Manufacturing Association, to review Round Rock, Texas and comment on the allergen extract section. All of these in- Ronald Rabin, MD vited reviewers who contributed to the document are acknowl- Rockville, Maryland edged for their efforts within the particular section that they reviewed. In addition, the draft was posted on the ACAAI and AAAAI ASSIGNED REVIEWERS Web sites with an invitation for members to review and comment. Paul Greenberger, MD The authors carefully considered all of these comments in Northwestern University Feinberg School of Medicine preparing the final version. Chicago, Illinois An annotated algorithm in this document summarizes the key decision points for the appropriate use of allergen immunotherapy Bryan Martin, DO (Fig 1 ). The section on efficacy summarizes the evidence demon- Ohio State University strating that allergen immunotherapy is effective in the manage- Columbus, Ohio ment of properly selected patients with aeroallergen and stinging insect hypersensitivity. This document also contains rec- ommendations for optimizing the efficacy and safety of allergen PREFACE immunotherapy, including specific recommendations on preven- This document was developed by the Joint Task Force on tion and management of adverse reactions and a uniform classifi- Practice Parameters, which represents the American Academy of cation system for grading systemic reactions. Allergy, Asthma & Immunology (AAAAI); the American Col- Specific recommendations guide the physician in selecting lege of Allergy, Asthma & Immunology (ACAAI); and the Joint those patients for whom allergen immunotherapy is appropri- Council of Allergy, Asthma & Immunology (JCAAI). ate. Aeroallergen immunotherapy should be considered for The objective of ‘‘Allergen immunotherapy: a practice param- patients who have symptoms of allergic rhinitis/conjunctivitis eter third update’’ is to optimize the practice of allergen immu- or asthma with natural exposure to allergens and who demon- notherapy for patients with allergic diseases. This parameter is strate specific IgE antibodies to the relevant allergen or intended to establish guidelines for the safe and effective use of allergens. There is also some evidence that patients with atopic allergen immunotherapy while reducing unnecessary variation in dermatitis with aeroallergen sensitivity might benefit from immunotherapy practice. These guidelines have undergone an immunotherapy. extensive peer-review process consistent with recommendations Candidates for immunotherapy are patients whose symptoms of the American College of Medical Quality ‘‘Policy on devel- are not controlled adequately by medications and avoidance opment and use of practice parameters for medical quality 1 measures or those experiencing unacceptable adverse effects of decision-making.’’ medications or who wish to reduce the long-term use of medi- This document builds on the previous Joint Task Force cations. Immunotherapy is recommended for patients with a document ‘‘Allergen immunotherapy: a practice parameter history of a systemic reaction to Hymenoptera stings who second update’’ published in the Journal of Allergy and Clinical 2 demonstrate Hymenoptera-specific IgE antibodies. There is ev- Immunology in 2007. The updated practice parameter draft idence that venom immunotherapy (VIT) might be effective in was prepared by a work group that included 3 of the editors reducing large local reactions (LLRs) that might cause significant from the second update, Linda Cox, MD; Hal Nelson, MD; and morbidity and impair quality of life. Richard Lockey, MD, and other workgroup members as follows: The focus of this parameter is on allergen immunotherapy Christopher Calabria, MD; Thomas Chacko, MD; Ira Finegold, practice in the United States. Although several studies have MD; Michael Nelson, MD, PhD; and Richard Weber, MD. demonstrated the efficacy of sublingual immunotherapy (SLIT), In preparation for the third update, the workgroup performed a there is no FDA-approved formulation for SLIT, and this treat- comprehensive search of the medical literature, which was ment route is considered investigational in the United States. Oral conducted with various search engines, including PubMed; immunotherapy and SLIT for food hypersensitivity are also immunotherapy, allergic rhinitis, asthma, stinging insect allergy, considered investigational. and related search terms were used. In addition to the published This document was approved by the sponsoring organizations literature from the comprehensive search, information from and represents an evidence-based, broadly accepted consensus articles known to the authors was considered. Published clinical opinion. These clinical guidelines are designed to assist clinicians studies were rated by category of evidence and used to establish 3 by providing a framework for the evaluation and treatment of Table I ). the strength of a clinical recommendation ( Laboratory- patients and are not intended to replace a clinician’s judgment or based studies were not rated. establish a protocol for all patients. Not all recommendations will The working draft of ‘‘Allergen immunotherapy: a practice be appropriate for all patients. Because this document incorpo- parameter third update’’ was reviewed by a large number of rates the efforts of many participants, no individual, including individuals. Reviewers include persons appointed by the anyone who served on the Joint Task Force, is authorized to pro- AAAAI, ACAAI, and invited experts. Invited reviewers in- vide an official AAAAI or ACAAI interpretation of these guide- cluded those with known expertise in specific areas (eg, oral lines. Recognizing the dynamic nature of clinical practice and immunotherapy or immunotherapy mechanisms), the US Food practice parameters, the recommendations in this document and Drug Administration’s (FDA) Center for Biologics Evalu- should be considered applicable for up to 5 years after publica- ation and Research, and the American Academy of Otolaryngic tion. Requests for information about or an interpretation of these Allergy, who formally endorsed the previous practice parameter 4 practice parameters should be directed to the Executive Offices of update. The scientific representatives of the US Allergen

4 COXETAL J ALLERGY CLIN IMMUNOL S4 JANUARY 2011 Classification of evidence and recommendations TABLE I. Category of evidence Evidence from meta-analysis of randomized controlled trials Ia Ib Evidence from at least 1 randomized controlled trial IIa Evidence from at least 1 controlled study without randomization IIb Evidence from at least 1 other type of quasiexperimental study III Evidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case-control studies Evidence from expert committee reports or opinions, clinical experience of respected authorities, or both IV Evidence from laboratory-based studies LB NR Not rated Strength of recommendation A Directly based on category I evidence B Directly based on category II evidence or extrapolated from category I evidence C Directly based on category III evidence or extrapolated from category I or II evidence D Directly based on category IV evidence or extrapolated from category I, II, or III evidence Not rated NR Adapted with permission from Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ 1999;318:593-6. the AAAAI, ACAAI and JCAAI. These parameters are d Special considerations not designed for use by pharmaceutical companies in drug Pregnancy B : The summary statement that states ‘‘aller- promotion. gen immunotherapy can be continued but usually is not initiated in the pregnant patient’’ is unchanged from the previous update. However, the text accompa- KEY HIGHLIGHTS OF THE UPDATE: NEW nying the summary statement includes a review of DEVELOPMENTS OR MODIFICATIONS literature on the safety of immunotherapy in pregnancy. The update also suggests that discontinuation of immunotherapy should be considered if the pregnancy d New indications for allergen immunotherapy : occurs during the build-up phase and the patient is B Atopic dermatitis in subjects with aeroallergen sensiti- receiving a dose unlikely to be therapeutic (Summary zation (Summary Statement 8) . Statement 20) . VIT: patients who experience recurrent bothersome B (Summary Statement 11). LLRs B : The summary statement Patients with HIV infection stating that the ‘‘immunotherapy can be considered in is recommended in pa- Measurement of baseline tryptase d patients with immunodeficiency and autoimmune disor- tients with moderate or severe anaphylactic reactions to ders’’ is unchanged from the previous update. However, stings. Increased serum tryptase levels are associated with the text accompanying the summary statement includes more frequent and severe systemic reactions to VIT injec- discussion of the published literature and case reports tions, greater failure rates during VIT, and greater relapse on patients with HIV and allergen immunotherapy rates (including fatal reactions) if VIT is discontinued (Summary Statement 21) . (Summary Statement 10b). d Patient age and initiation of allergen immunotherapy : : The current update includes several sum- d Local reactions The update states there is no specific upper or lower age mary statements on local reactions, including discussions limit for initiating allergen immunotherapy. The update regarding: stresses the importance of appropriate indications, the ab- relationship with systemic reactions (predictive value of B sence of significant comorbid conditions, and the patients’ a single local reaction or incidence of systemic reac- ability to comply/cooperate with allergen immunotherapy. tions in patients with frequent large local reactions); B influence of glycerin and allergen content on local reac- B Pediatrics : There is no specific lower limit for immuno- (Summary State- therapy if indications are present tions; and . ments 17 and 18) B possible prevention with antihistamines and leukotriene receptor antagonists ( Summary Statements 27-30) . B : There is no specific summary statement on Elderly immunotherapy in the elderly patient in the current d Systemic reactions, wait period after immunotherapy, update. The previous update recommended that the and delayed systemic reactions : The update includes new risk/benefit assessment be carefully evaluated in the summary statements on delayed systemic reactions, defined elderly population because they might have comorbid as occurring 30 minutes after the injection, and biphasic re- medical conditions that could increase immunotherapy actions. Delayed-onset systemic reactions might account for up to 50% of reactions. Delayed systemic reactions can occur risk. The current update recognizes that some of these conditions can occur more frequently in older subjects, without any preceding symptoms or can be part of a biphasic but they can also be present in younger subjects. The reaction. Several large studies demonstrate that life- current update states that the risk/benefit assessment threatening anaphylactic reactions after 30 minutes are must be evaluated in every situation, but there is no rare. The recommendation that a patient should remain in absolute upper age limit for initiation of immunother- the physician’s office/medical clinic for 30 minutes after apy . (Summary Statement 19) the injection is unchanged from the previous update. It is

5 J ALLERGY CLIN IMMUNOL COX ET AL S5 VOLUME 127, NUMBER 1 FIG 1. Algorithm for immunotherapy. ( Continued. )

6 COXETAL S6 J ALLERGY CLIN IMMUNOL JANUARY 2011 ). Continued ( FIG 1. inhibitors were associated with more severe reactions recommended that at the onset of immunotherapy, patients from VIT. This update recommends that ACE inhibitor dis- should be counseled on the possibility of immediate and de- continuation be considered for patients receiving VIT. layed systemic reactions during risk communication; an ac- However, concurrent administration of VIT and an ACE in- tion plan for such an event should be discussed. The decision hibitor is warranted in selected cases in which there is no to prescribe epinephrine autoinjectors to patients receiving equally efficacious alternative and the risk/benefit assess- immunotherapy should be at the physician’s discretion ment is favorable. . (Summary Statements 40-41) (Summary Statements 33-36) . -Blocker medications d : The current update includes a dis- b : The update includes Premedication and immunotherapy d b -blockers, noting that it is not cussion of cardioselective 3 summary statements on premedication during accelerated known whether there is less risk associated with immunother- (rush and cluster) and conventional build-up schedules. The apy but that there have been some severe cases of anaphylaxis specific medications used in immunotherapy premedication from other causes reported in patients receiving cardioselec- regimens are discussed and include antihistamines, leuko- tive b -blockers (Summary Statements 37-39 and 41) . triene receptor antagonists, omalizumab, and combination d Angiotensin-converting enzyme (ACE) inhibitor medi- . (Summary Statements 56-58) pretreatment. cations : The update includes a new summary statement d Rush VIT and premedication : Because the risk of a on ACE inhibitors, noting that there is some conflicting systemic reaction from flying Hymenoptera rush VIT is information in the published literature regarding immuno- relatively low, the recommendation that routine premedica- therapy risk in patients taking ACE inhibitors who tion is usually not necessary is unchanged from the previous receive immunotherapy. Two retrospective studies found update. The previous update suggested that imported fire ant no increased frequency of systemic reactions in patients rush immunotherapy had a similarly low risk. However, taking ACE inhibitors receiving VIT or inhalant immuno- there are currently some conflicting data about the risk of therapy. However, a few case reports and a prospective imported fire rush immunotherapy, and premedication might study of 962 patients who received VIT found that ACE . (Summary Statements 55 and 57) be considered

7 S7 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 efficacy of allergen immunotherapy has accumulated rapidly d Aspiration before the immunotherapy injection : The up- during the past 30 years. Numerous well-designed controlled date includes a discussion of the debate regarding the need studies demonstrate that allergen immunotherapy is efficacious for aspiration before the immunotherapy injection (Sum- in the treatment of allergic rhinitis, allergic conjunctivitis, aller- mary Statement 61) . gic asthma, and stinging insect hypersensitivity. Randomized Cockroach immunotherapy : The update includes a new d controlled studies showed that allergen immunotherapy prevents summary statement noting that there are limited data on 8-11 the development of asthma in subjects with allergic rhinitis. the efficacy of cockroach immunotherapy (Summary There is some evidence of immunotherapy’s efficacy in the Statement 71) . treatment of patients with atopic dermatitis with aeroallergen d Multiallergen immunotherapy : A new summary state- 12-16 sensitization. ment stating that there have been few studies that have in- Allergen immunotherapy is effective when appropriate doses vestigated the efficacy of multiallergen subcutaneous of allergens are administered. Effective subcutaneous allergen immunotherapy (SCIT) and that these studies have pro- immunotherapy appears to correlate with administration of an duced conflicting results has been included in this update optimal maintenance dose in the range of 5 to 20 m g of major . (Summary Statement 72) 17-22 allergen for inhalant allergens. It should be differentiated d Allergen extract preparation : The update includes discus- from unproved methods, such as neutralization-provocation sion of the United States Pharmacopeia (USP) 797 allergen 23 therapy and low-dose subcutaneous regimens based on the extract preparation guidelines, as well as the allergen extract 24,25 Rinkel technique, which have been found to be ineffective preparation guidelines developed by the AAAAI/ACAAI/ in double-blind, placebo-controlled trials. The selection of al- JCAAI, which was included in the previous update. The lergens for immunotherapy is based on clinical history, the USP 797 guidelines were finalized after the previous param- presence of specific IgE antibodies, and allergen exposure. eter was published, and there are some differences between This parameter offers suggestions and recommendations de- the 2 guidelines, one of which is that the USP 797 guidelines rived from known patterns of allergen cross-reactivity. Recog- recommend that the preparer should wear a protective cap, nizing that the immunotherapy terminology used to describe face mask, and gown during the extract preparation process extract dilutions is sometimes ambiguous, the 2003 ‘‘Allergen . (Summary Statement 77) immunotherapy: a practice parameter’’ established standardized d Probable effective dosing for US-licensed standardized terminology for describing allergen immunotherapy extract di- and nonstandardized extracts table : The update includes lutions, which is included in this and the 2007 update. These a column presenting the range of major allergen content parameters also provided specific recommendations for immu- in US-licensed extracts, as well changes in the recommen- notherapy maintenance doses for some standardized allergens (Summary State- ded dosing for nonstandardized extracts and a suggested dosing range for nonstandardized allergen . ment 81) extracts. Noninjection routes of immunotherapy d : Compared with The therapeutic preparations for allergen immunotherapy are the previous update, this section includes an expanded dis- extracted from source materials, such as pollen, mold cultures, cussion of SLIT, a summary statement on oral immunother- al- and pelt, hence the traditional term allergen extract. The terms apy for food hypersensitivity, and summary statements on or extract refer to solutions of proteins or glycopro- lergen extract epicutaneous and intralymphatic immunotherapy (Sum- teins extracted from source material not yet incorporated into a mary Statements 92-99) . therapeutic allergen immunotherapy extract. The term manufac- : This section includes summary state- Novel formulations d turer’s extract refers to the allergen extract purchased from the ments on allergoids and adjuvants, the immunostimulatory concentrate manufacturer. The terms , and full strength , stock oligonucleotide sequence of DNA containing a CpG motif are ambiguous and should not be used. The term maintenance (CpG), and 3-deacylated monophospholipid A (MPL; concentrate should be used to identify the allergen immunother- ). Summary Statements 100-101 apy extract that contains a therapeutic effective dose for each of its individual constituents. All dilutions should be referenced to the maintenance concentrate and should be noted as a volume- to-volume dilution (eg, 1:100 vol/vol dilution of a maintenance INTRODUCTION concentrate). Immunity has been defined as protection against certain This parameter reinforces the 2 previous allergen immunother- diseases. The initial immunotherapeutic interventions, which apy practice parameters’ recommendations that vials of allergen included the use of preventive vaccines and xenogeneic antisera immunotherapy extracts should be prepared individually for by Jenner, Pasteur, Koch, and von Behring, were effective for each patient and documented with standardized allergen immuno- disease prevention. These initial efforts in immune modulation therapy prescription and administration forms. Individualized pa- served as a model for later developments in allergen immuno- tient vials will allow for customized treatment specific to the therapy. From its empiric emergence in the early 1900s, when patient’s identified allergen sensitivities and reduce the risk of al- grass pollen inoculation was proposed as therapy for hay fever, lergen cross-contamination and patient identification errors in ad- allergen immunotherapy has progressed in both theory and 26,27 ministration. practice from the passive immunologic approach to the active Standardized prescription and administration 5 6,7 immunologic procedures pioneered by Noon forms will improve the safety, uniformity, and standardization and Freeman. of allergen immunotherapy practice. The suggested forms are Advances in allergen immunotherapy have depended on the im- found in this article’s Online Repository at www.jacionline.org proved understanding of IgE-mediated immunologic mecha- and on the AAAAI, ACAAI, and JCAAI Web sites ( www.aaaai. nisms, the characterization of specific antigens and allergens, ). The routine use of these www.jcaai.org , and org , www.acaai.org and the standardization of allergen extracts. Proof of the

8 COXETAL S8 J ALLERGY CLIN IMMUNOL JANUARY 2011 patient’s preference, allergen immunotherapy might or might standardized forms should improve the quality of immunotherapy not be recommended. Patients with allergic rhinitis/conjunctivitis practice. or allergic asthma whose symptoms are not well controlled by medications or avoidance measures or require high medication ALGORITHM AND ANNOTATIONS FOR doses, multiple medications, or both to maintain control of their IMMUNOTHERAPY allergic disease might be good candidates for immunotherapy. Pa- Fig 1 provides an algorithm for the appropriate use of allergen tients who experience adverse effects of medications or who wish immunotherapy. Given below are annotations for use with the to avoid or reduce the long-term use of medications are appropri- algorithm. ate candidates for immunotherapy. However, asthma must be con- trolled at the time the immunotherapy injection is administered. Patients with aeroallergen-induced atopic dermatitis might bene- Box 1 fit from immunotherapy. In general, patients with flying insect or Immunotherapy is effective in the management of allergic imported fire ant hypersensitivity who are at risk for anaphylaxis asthma, allergic rhinitis/conjunctivitis, and stinging insect hyper- should receive VIT or whole-body extract, respectively. VIT has sensitivity. There is some evidence it might be effective in the also been shown to decrease LLRs to stinging insects. treatment of atopic dermatitis in patients with aeroallergen sensi- tivity. Allergen immunotherapy might prevent the development of asthma in subjects with allergic rhinitis. Evaluation of a patient Box 6 with suspected allergic rhinitis, allergic conjunctivitis, allergic After careful consideration of appropriate management op- asthma, or stinging insect allergy includes a detailed history, an tions, the physician and patient might decide not to proceed with appropriate physical examination, and selected laboratory tests. immunotherapy. A definitive diagnosis depends on the results of allergy testing (immediate hypersensitivity skin tests or in vitro tests for serum specific IgE). Box 7 Before immunotherapy is started, patients should understand its benefits, risks, and costs. Counseling should also include the Box 2 expected onset of efficacy and duration of treatment, as well as the Immediate hypersensitivity skin testing is generally the pre- risk of anaphylaxis and importance of adhering to the immuno- ferred method of testing for specific IgE antibodies, although therapy schedule. testing for serum specific IgE antibodies is useful under certain circumstances. Immunotherapy should be considered when pos- itive test results for specific IgE antibodies correlate with Box 8 suspected triggers and patient exposure. The physician prescribing immunotherapy should be trained and experienced in prescribing and administering immunother- apy. The prescribing physician must select the appropriate aller- Box 3 gen extracts based on that particular patient’s clinical history and Immunotherapy should not be given to patients with negative allergen exposure history and the results of tests for specific IgE test results for specific IgE antibodies or those with positive test antibodies. The quality of the allergen extracts available is an im- results for specific IgE antibodies that do not correlate with portant consideration. When preparing mixtures of allergen ex- suspected triggers, clinical symptoms, or exposure. This means tracts, the prescribing physician must take into account the that the presence of specific IgE antibodies alone does not cross-reactivity of allergen extracts and the potential for allergen necessarily indicate clinical sensitivity. There is no evidence degradation caused by proteolytic enzymes. The prescribing phy- from well-designed studies that immunotherapy for any allergen sician must specify the starting immunotherapy dose, the target is effective in the absence of specific IgE antibodies. maintenance dose, and the immunotherapy schedule. In general, the starting immunotherapy dose is 1,000- to 10,000-fold less than the maintenance dose. For highly sensitive patients, the start- Box 4 ing dose might be lower. The maintenance dose is generally 500 to The management of allergic asthma, allergic rhinitis/conjunc- 2000 allergy units (AU; eg, for dust mite) or 1000 to 4000 bioequi- tivitis, and stinging insect hypersensitivity should include the valent allergy units (BAU; eg, for grass or cat) for standardized al- evaluation of different treatment options. Each of the 3 major lergen extracts. For nonstandardized extracts, a suggested management approaches (allergen immunotherapy, allergen ex- maintenance dose is 3000 to 5000 protein nitrogen units (PNU) posure reduction, and pharmacotherapy) has benefits, risks, and or 0.5 mL of a 1:100 or 1:200 wt/vol dilution of manufacturer’s costs. Furthermore, the management plan must be individualized, extract. If the major allergen concentration of the extract is known, with careful consideration given to the patient’s preference. Dis- a range between 5 and 20 m g of major allergen is the recommen- ease severity and response (or lack of response) to previous treat- ded maintenance dose for inhalant allergens and 100 m g for Hy- ment are important factors. menoptera venom. Immunotherapy treatment can be divided into 2 periods, which are commonly referred to as the build-up and maintenance phases. Box 5 The immunotherapy build-up schedule (also called updosing, The physician and patient should discuss the benefits, risks, and induction, or the dose-increase phase) entails administration of costs of the appropriate management options and agree on a gradually increasing doses during a period of approximately 8 to management plan. Based on clinical considerations and the

9 S9 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 28 weeks.Inconventionalschedulesa singledoseincreaseisgiven Box 12 on each visit, and the visit frequency can vary from 1 to 3 times a Patients receiving maintenance immunotherapy should have week. Accelerated schedules, such as rush or cluster immuno- follow-up visits at least every 6 to 12 months. Periodic visits therapy, entail administration of several injections at increasing should include a reassessment of symptoms and medication use, doses on a single visit. Accelerated schedules offer the advantage the medical history since the previous visit, and an evaluation of of achieving the therapeutic dose earlier but might be associated the clinical response to immunotherapy. The immunotherapy with increased risk of a systemic reaction in some patients. schedule and dose, reaction history, and patient compliance should also be evaluated. The physician can at this time make adjustments to the immunotherapy schedule or dose, as clinically indicated. Box 9 There are no specific markers that will predict who will remain Immunotherapy should be administered in a setting that in clinical remission after discontinuing effective allergen immu- permits the prompt recognition and management of adverse notherapy. Some patients might sustain lasting remission of their reactions. The preferred location for such administration is the allergic symptoms after discontinuing allergen immunotherapy, prescribing physician’s office. However, patients can receive im- but others might experience a recurrence of their symptoms. As munotherapy injections at another health care facility if the phy- with the decision to initiate allergen immunotherapy, the decision sician and staff at that location are trained and equipped to to discontinue treatment should be individualized, taking into recognize and manage immunotherapy reactions, particularly an- account factors such as the severity of the patient’s illness before aphylaxis. Patients should wait at the physician’s office/medical treatment, the treatment benefit sustained, the inconvenience im- clinic for at least 30 minutes after the immunotherapy injection munotherapy represents to a specific patient, and the potential ef- or injections so that reactions can be recognized and treated fect a clinical relapse might have on the patient. Ultimately, the promptly if they occur. duration of immunotherapy should be individualized based on Immunotherapy injections should be withheld if the patient the patient’s clinical response, disease severity, immunotherapy presents with an acute asthma exacerbation. For patients with reaction history, and preference. asthma, consider measuring the peak expiratory flow rate before administering an immunotherapy injection and withholding an immunotherapy injection if the peak expiratory flow rate is IMMUNOTHERAPY GLOSSARY considered low for that patient. For more information on immunotherapy definitions, see the 29 article by Kao. allergen immunotherapy extract The is defined as the mixture Box 10 of the manufacturer’s allergen extract or extracts that is used Injections of allergen immunotherapy extract can cause local for allergen immunotherapy. Allergen extracts used to prepare or systemic reactions. Most serious systemic reactions develop the allergen immunotherapy extract can be complex mixtures within 30 minutes after the immunotherapy injection. However, containing multiple allergenic and nonallergenic macromolecules immunotherapy-induced systemic reactions can occur after 30 (proteins, glycoproteins, and polysaccharides) and low- minutes. Patients should be counseled on the possibility of molecular-weight compounds. Other terms used to describe the 30 immediate and delayed systemic reactions during risk communi- allergen immunotherapy extract include allergen product, al- 31 cation; an action plan for such an event should be discussed. In the lergy serum, allergen vaccine, and allergen solution. event of a delayed systemic reaction, the patient should be Allergen immunotherapy is defined as the repeated administra- counseled on appropriate treatment based on his or her symptoms. tion of specific allergens to patients with IgE-mediated conditions for the purpose of providing protection against the allergic symp- toms and inflammatory reactions associated with natural expo- 2 sure to these allergens. Box 11 Other terms that have been used for allergen immunotherapy include hyposensitization, allergen- Local reactions can be managed with local treatment (eg, cool specific desensitization, and the lay terms allergy shots or allergy compresses or topical corticosteroids) or antihistamines. Sys- 29 injections. temic reactions can be mild or severe. Epinephrine is the treatment of choice in patients with anaphylaxis. is an immediate systemic reaction often occurring Anaphylaxis Antihistamines and systemic corticosteroids are secondary within minutes and occasionally as long as an hour or longer after medications that might help to modify systemic reactions but exposure to an allergen. It can be IgE mediated, as can occur with should never replace epinephrine in the treatment of anaphylaxis. allergen immunotherapy, or non–IgE mediated, as occurs with Intravenous saline or supplemental oxygen might be required in radiocontrast media. It is caused by the rapid release of vasoac- severe cases. For additional details on anaphylaxis management tive mediators from tissue mast cells and peripheral blood see, ‘‘The diagnosis and management of anaphylaxis practice basophils. 28 parameter: 2010 update.’’ The build-up phase involves receiving injections with increas- ing amounts of the allergen. The frequency of injections during The immunotherapy dose and schedule, as well as the benefits this phase generally ranges from 1 to 3 times a week, although and risks of continuing immunotherapy, should be evaluated after more rapid build-up schedules are sometimes used. The duration any immunotherapy-induced systemic reaction. For some pa- of this phase depends on the frequency of the injections but gener- tients, the immunotherapy maintenance dose might need to be ally ranges from 3 to 6 months (at a frequency of 2 times and 1 time reduced. After systemic reactions to immunotherapy, the pre- per week, respectively). Other terms used to describe the build-up scribing physician can re-evaluate the risk/benefit ratio of phase include updosing, induction or the dose-increase phase. continued immunotherapy.

10 COXETAL S10 J ALLERGY CLIN IMMUNOL JANUARY 2011 TABLE II. Calculations for making extract dilutions* is a term formerly used interchangeably Hyposensitization with allergen immunotherapy. It was introduced to distinguish al- All dilutions can be calculated by using the following formula: lergen immunotherapy from classical desensitization. Hyposensi- V2 3 C2, V1 3 C1 5 tization denotes a state of incomplete desensitization because where V1 5 Final volume you want to prepare complete desensitization is rarely accomplished with allergen Concentration (wt/vol or PNU) of extract you want to prepare 5 C1 immunotherapy. 5 Volume of extract you will need for dilution V2 Immunomodulation is a term that denotes a wide variety of drug Concentration of extract you will use. 5 C2 or immunologic interventions that alter normal or abnormal im- C1)/C2 Example: Solve for V2; (V1 V2. 5 3 mune responses by means of deletion of specific T cells, B cells, To determine the concentration of an item in a mixture: or both; immune deviation; induction of peripheral/central toler- 1. determine which formula you need to use; ance; or modification of various inflammatory pathways (eg, che- 2. choose the numbers/fractions that will be inserted motaxis, adhesions, or intracytoplasmic signaling). into the formula for V1, C1, V2, and C2; is a treatment modality that appeared soon af- Immunotherapy 3. change all wt/vol fractions to a decimal number and insert into the formula (see below); and ter adaptive immune responses were discovered and has gradually 4. multiply first and then divide to get the answer. evolved to encompass any intervention that might benefit To express concentration as a percentage: immune-induced aberrant conditions through a variety of immu- 5 1:10 wt/vol 1/10 5 100 3 10% solution 0.1 nologic transformations. Early definitions of the term immuno- 0.05 3 100 5 5% solution 5 1:20 wt/vol 1/20 therapy included active and passive immunization to improve a 1:40 wt/vol 1/40 0.025 3 100 5 2.5% solution 5 host’s defenses against microorganisms. Allergen immunother- Example: apy was originally conceived as a form of active immunization, 5 Final volume you want to prepare 5 mL V1 the purpose of which was to alter the host’s abnormal immune re- 1:200 5 Concentration you want to prepare C1 sponses and not augment the host’s defenses against microorgan- Unknown Volume of extract you will need for dilution V2 5 isms. The modern rubric of immunotherapy includes all methods Concentration of extract you will use 1:10 5 C2 Add values into formula: used to overcome abnormal immune responses with induction of V2 5 (1/200) 3 5 C2 3 V2 5 C1 3 V1 (1/10) 3 clonal deletion, anergy, immune tolerance, or immune deviation. (0.1) 3 V2 5 (0.005) 3 5 Local reactions to SCIT injections can manifest as redness, 5 5 0.25 5 0.025/0.1 V2 C1)/C2 3 (V1 V2 pruritus, and swelling at the injection site. To determine amount of diluent needed: The is a preparation that contains in- maintenance concentrate mL V1 2 4.75 5 0.25 5 2 V2 dividual extracts or mixtures of manufacturer’s allergen extracts Adapted from the Greer Allergy Compendium. Lenoir (NC): Greer Laboratories; intended for allergen immunotherapy treatment. A maintenance 2005. p. 71. Permission provided by Robert Esch, PhD. concentrate can be composed of a concentrated dose of a single allergen or a combination of concentrated allergens to prepare an individual patient’s customized allergen immunotherapy ex- tract mixture. Subsequent dilutions can be prepared from the is an accelerated build-up schedule Cluster immunotherapy maintenance concentrate for the build-up phase or if the patient that entails administering several injections at increasing doses cannot tolerate the maintenance concentrate. (generally 2-3 per visit) sequentially in a single day of treatment The ) is the maintenance dose effective therapeutic dose (or on nonconsecutive days. The maintenance dose is generally dose that provides therapeutic efficacy without significant adverse achieved more rapidly than with a conventional (single injection local or systemic reactions. The effective therapeutic dose might per visit) build-up schedule (generally within 4-8 weeks). not be the initially calculated projected effective dose. Desensitization is the rapid administration of incremental maintenance goal The (or projected effective dose ) is the aller- doses of allergens or medications by which effector cells are ren- gen dose projected to provide therapeutic efficacy. Not all patients dered less reactive or nonreactive to an IgE-mediated immune re- will tolerate the projected effective dose, and some patients expe- sponse. Desensitization can involve IgE-mediated or other rience therapeutic efficacy at lower doses. immune mechanisms. The positive skin test response to the aller- begins when the effective therapeutic The maintenance phase gens might diminish or actually convert to a negative response in dose is reached. Once the maintenance dose is reached, the inter- some cases after this procedure. Tolerance to medications can be vals between allergy injections are increased. The dose generally achieved through desensitization. is the same with each injection, although modifications can be The dose is the actual amount of allergen administered in the made based on several variables (ie, new vials or a persistent injection. The volume and concentration can vary such that the LLR causing discomfort). The intervals between maintenance im- same delivered dose can be given by changing the volume and munotherapy injections generally range from 4 to 8 weeks for concentration (ie, 0.05 mL of a 1:1 vol/vol allergen would equal venom and every 2 to 4 weeks for inhalant allergens but can be 0.5 mL of a 1:10 vol/vol allergen). The dose can be calculated by advanced as tolerated if clinical efficacy is maintained. using the following formula: Concentration of allergen 3 volume major allergen is an antigen that binds to the IgE sera from A Table II for calculation formula for of administered dose. See 50% or more of a clinically allergic group of patients. Such aller- making extract dilutions. gens are defined either with immunoblotting or crossed is the dose The effective therapeutic dose or maintenance dose allergoimmunoelectrophoresis. that provides therapeutic efficacy without significant adverse lo- , see the definition of projected effective dose For a definition of cal or systemic reactions. The effective therapeutic dose might maintenance goal. not be the initially calculated projected effective dose (eg, 500 Rush immunotherapy is an accelerated immunotherapy build- BAU [highest tolerated dose] vs 2000 BAU [projected effective up schedule that entails administering incremental doses of dose] for cat).

11 S11 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 1 1 population of regulatory T cells, which are CD4 CD25 T lym- allergen at intervals varying between 15 and 60 minutes over 1 to 3 days until the target therapeutic dose is achieved. Rush immuno- phocytes, as an early event, occurring within days or weeks. Reg- ulatory T cells can produce inhibitory cytokines, such as IL-10, therapy schedules for inhalant allergens can be associated with a 32-37 b , or both. greater risk of systemic reactions, particularly in high-risk patients TGF- The presence of such regulatory cytokines in vitro IgE (eg, those with markedly positive prick/puncture or has been described in allergen immunotherapy with Hymenoptera 34 35 32 test responses), and premedication primarily with antihistamines venom, grass pollen, and house dust mite allergen extracts. and corticosteroids appears to reduce the risk associated with Properties of IL-10 include the induction of a decrease in B-cell rush immunotherapy. However, rush protocols for administration antigen–specific IgE production and increases in IgG4 levels; re- of stinging Hymenoptera VIT have not been associated with a sim- duction in proinflammatory cytokine release from mast cells, eo- ilarly high incidence of systemic reactions. sinophils, and T cells; and elicitation of tolerance in T cells by specific immunotherapy , see the definition of For a definition of means of selective inhibition of the CD28 costimulatory pathway. allergen immunotherapy. As a consequence, lymphoproliferative responses to allergen are 38 is an adverse reaction involving organ- systemic reaction A reduced after immunotherapy. specific systems distant from the injection site. Systemic reactions Data also support the concept of a later, more delayed, allergen- can range in severity from mild rhinitis to fatal cardiopulmonary specific immune deviation from a T 1 cytokine pro- 2toaT H H 39-41 arrest. The grading of systemic reactions is based on the organ file. Data indicate that increases in production of IL-12, a system or systems involved and the severity. strong inducer of T 1 responses, might contribute to this later H 42 www. See Table E2 in this article’s Online Repository at shift. for a list of summary statements without accompa- jacionline.org The immunologic response to SCIT is characterized by nying explanations. decreases in the sensitivity of end organs and changes in the humeral and cellular responses to the administered allergens. The response to allergen challenge of the conjunctiva, skin, and 5,43-46 IMMUNOLOGIC RESPONSES TO respiratory mucosa is reduced, including both the immedi- 44-46 ate and delayed responses. With natural allergen exposure, an IMMUNOTHERAPY enhanced sensitivity to allergen known as priming occurs. This Summary Statement 1: The immunologic response to sub- 45 too is reduced by immunotherapy, cutaneous immunotherapy is characterized by decreases in as is the nonspecific sensitiv- 47,48 the sensitivity of end organs and changes in the humoral ity to bronchoconstrictive agents, such as histamine. Eosino- and cellular responses to the administered allergens. A phils and mast cells increase in the respiratory mucosa and Summary Statement 2: Reduction in end-organ response secretions during natural allergen exposure. These infiltrations 49-51 with immunotherapy includes decreased early and late re- are reduced by immunotherapy. sponses of the skin, conjunctiva, nasal mucosa, and bronchi In patients receiving immunotherapy, initially there is an 52 increase in specific IgE antibody levels, followed by a gradual to allergen challenge; decreased allergen-induced eosinophil, basophil, and mast cell infiltration; blunting of mucosal prim- and progressive decrease in IgE levels toward or to less than base- ing; and reduction of nonspecific bronchial sensitivity to his- line levels that might continue to occur over several years. Clini- tamine. A cal improvement occurs before subsequent decreases in IgE Summary Statement 3: Shortly after initiation of immuno- antibody levels, and it is clear that efficacy is not dependent on re- 1 53,54 1 therapy, there is an increase in CD4 ductions in specific IgE levels. Thus decreased levels of spe- CD25 regulatory T 55 associated with im- cific IgE do not explain the clinical response to immunotherapy. b lymphocytes secreting IL-10 and TGF- munologic tolerance, which is defined as a long-lived decrease Despite the persistence of significant levels of specific IgE anti- in allergen-specific T-cell responsiveness. With continued im- body, immunotherapy usually results in a reduction in the release munotherapy, there is some waning of this response, and im- of mediators, such as histamine, from basophils and mast cells, a mune deviation from T phenomenon most relevant to the immediate phase of allergic re- 2toT 1 cytokine response to the H H actions. Suppression of late-phase inflammatory responses in the administered allergen predominates. A skin and respiratory tract generally also occur with allergen Summary Statement 4: Specific IgE levels initially increase 56-58 immunotherapy. and then gradually decrease. Levels of specific IgG1, IgG4, and IgA increase. None of these changes in antibody levels An increase in serum allergen-specific IgA and IgG levels, have been shown to consistently correlate strongly with clini- particularly of the IgG4 isotype, has also been associated with cal improvement. A immunotherapy. Increased levels of allergen-specific IgA have 35 Summary Statement 5: Increases in allergen-specific IgG been found in patients early in the course of immunotherapy. levels are not predictive of the degree or duration of efficacy The properties of allergen-specific IgA include the induction of 59 of immunotherapy. However, functional alterations in IL-10 release from monocytes. Although immunoreactive allergen-specific IgG levels, such as changes in avidity, affinity, allergen-specific IgG levels increase, particularly IgG4 levels, or both for allergen, might play a role in determining clinical the correlation between the increase in allergen-specific IgG efficacy. LB levels and clinical improvement after immunotherapy has not 40,60,61 been consistently demonstrated. It is likely that immuno- Immunologic changes associated with immunotherapy are complex, and the exact mechanism or mechanisms responsible therapy alters either the affinity, specificity, or both of allergen- 62,63 for its clinical efficacy are continually being elucidated. Immu- specific IgG. During the initial phase of ultrarush VIT, a notherapy results in immunologic tolerance, which is denned as a change in IgG specificity (ie, a change in the set of epitopes on relative decrease in antigen-specific responsiveness that might be wasp venom antigens dominantly recognized by IgG) occurred accompanied by immune deviation, T-cell anergy, and/or T-cell concomitantly with early clinical tolerance and was seen within 62 apoptosis. Successful immunotherapy results in generation of a 12 hours of ultrarush VIT ( P < .001). VIT resulted in a change

12 COXETAL S12 J ALLERGY CLIN IMMUNOL JANUARY 2011 patients on immunotherapy. Numbers of cells expressing the cos- in IgG specificity to the major bee venom allergen phospholipase timulatory molecules CD80 and CD86 were reduced at the site of A to a specificity similar to that seen in healthy nonallergic sub- 2 63 the late-phase cutaneous reaction in subjects receiving immuno- jects. This change in IgG specificity preceded the increase in 63 73 therapy. IgG titers and was sustained for up to 6 months. It has not been determined whether these are primary to secondary responses to immunotherapy. Allergen-specific IgG induced after immunotherapy can block IgE-dependent histamine release and also IgE-facilitated antigen 64 presentation to T cells. This latter effect is dependent on aller- gen bound to IgE and the expression of either the low-affinity EFFICACY OF IMMUNOTHERAPY IgE receptor (CD23) on B cells, which then serve as antigen- Allergic rhinitis, allergic asthma, and stinging insect presenting cells, or the high-affinity IgE receptor on dendritic cells, mast cells, and basophils. hypersensitivity Although serum immunoreactive specific IgG levels are not Summary Statement 6: Immunotherapy is effective for the predictive, it is possible that functional assays of IgG, such as treatment of allergic rhinitis, allergic conjunctivitis, allergic detection of IgG-associated serum inhibitory activity for IgE- asthma, and stinging insect hypersensitivity. Therefore immu- facilitated allergen presentation, basophil histamine release, or notherapy merits consideration in patients with these disor- both, might be more closely associated with the clinical response ders as a possible treatment option. A to immunotherapy, although this remains to be tested in larger Many double-blind, placebo-controlled randomized clinical 34,64 clinical trials. trials demonstrate a beneficial effect of immunotherapy under a 74-81 A decrease in allergen-stimulated basophil histamine release variety of conditions. Immunotherapy is effective for the 82 77 treatment of allergic rhinitis has been demonstrated with immunotherapy, but it is not ), al- (including ocular symptoms 65 74,79,81,83,84 78,85 specific to the allergens administered. lergic asthma, Spontaneous in vitro and stinging insect hypersensitivity 86-92 release of histamine was also reduced after 4 months of Its efficacy is and is effective in both adults and children. 66 immunotherapy. confirmed for the treatment of inhalant allergy caused by 18,21,22,47,108-111 93-101 102-107 pollens, Immunotherapy induces an allergen-specific reduction in animal allergens, fungi, dust 121 35,38 17,83,84,112-120 allergen-stimulated proliferation of PBMCs. mites, and cockroaches. There have been no con- This was dem- trolled trials of fire ant whole-body extract, but it does appear to be onstrated after 70 days of SCIT to be induced by the release of 1 122-124 35 1 by CD4 effective in uncontrolled trials. b IL-10 and TGF- The sup- T lymphocytes. A variety of different types CD25 pression of lymphocyte proliferation was accompanied by re- of extracts have been evaluated in these clinical trials, including g , IL-5, and IL-13, indicating a duced release of IFN- aqueous and modified extracts. Outcome measures used to mea- sure the efficacy of immunotherapy include symptom and medi- suppression of both T 1 and T 2 lymphocyte populations. IL- H H cation scores, organ challenge, and immunologic changes in 10 is a general inhibitor of proliferation and cytokine responses in T cells while also inhibiting IgE and enhancing IgG4 produc- cell markers and cytokine profiles. Several studies have also dem- onstrated a significant improvement in quality of life, as measured b , on the other hand, induces an isotype switch to tion. TGF- 20,125-128 by using standardized questionnaires. IgA, levels of which were also increased in the treated patients The magnitude of in this study. The IL-10 response has been shown to occur in the effect depends on the outcome that is used. For dust mite, the the first few weeks of SCITat allergen doses that are not clinically effect size ranges from a 2.7-fold improvement in symptoms to a 37 129 effective. 13.7-fold reduction in bronchial hyperreactivity. There is a suggestion that its secretion is not fully sus- 37,67 tained by the end of a year of immunotherapy. Although many studies demonstrate the efficacy of immuno- therapy, some do not. A review of the studies that do not Other studies of immunotherapy have demonstrated a de- 80 demonstrate efficacy failed to identify a systematic deficiency. crease in the release of IL-4 and IL-13 but an increase in the release of IFN- g from allergen-stimulated peripheral circulating Instead, this review notes that many studies evaluating immuno- 68-70 41 T lymphocytes therapy are only marginally powered to show efficacy, making or nasal mucosa. After 4 years of immu- it likely that some would fail to demonstrate efficacy by chance notherapy, biopsies of the site of the late cutaneous reaction alone, even when it is present (a type II error). Meta-analyses of showed increased cells staining for mRNA for IL-12, a pro- 77,130 42 the efficacy of immunotherapy both for rhinitis moter of T and The number 1 differentiation of T lymphocytes. H 74,79,81,129 of cells with mRNA for IL-12 correlated positively with the asthma have been performed to address the issue of number staining for mRNA for IFN- g and negatively with those power. In one systematic review of 88 trials involving 3,459 asth- staining for mRNA for IL-4 in the same biopsy specimens. matic patients, SCIT resulted in significant reductions in asthma Overall, the results are consistent with an early response to symptoms, medication use, and improvement in bronchial hyper- 74 immunotherapy dominated by the generation of regulatory reactivity. This meta-analysis determined that it would have T lymphocytes that suppress both T been necessary to treat 3 patients (95% CI, 3-5) with immunother- 2 responses but 1 and T H H apy to avoid 1 deterioration in asthma symptom and 4 patients later a waning of this response and, instead, a dominance of im- (95% CI, 3-6) with immunotherapy to avoid 1 patient requiring mune deviation from T 2 toward T 1 responses to the admin- H H increased medication. These meta-analyses strongly support the istered allergen. Many other changes in cells involved in the allergic response efficacy of allergen immunotherapy. Allergen immunotherapy for allergic rhinitis might have have been reported with SCIT. Numbers of B lymphocytes 93,131,132 persistent benefits after immunotherapy is discontinued expressing the low-affinity IgE receptor (CD23) were increased in allergic asthmatic children, and their percentage in peripheral and reduce the risk for the future development of asthma in pa- 71 8,9,91,131-134 blood was reduced by immunotherapy. tients with allergic rhinitis. Allergen immunotherapy Plasmacytoid dendritic a might also prevent the development of new allergen sensitivities cells from allergic patients showed a decreased IFN- response 72 135-138 in monosensitized patients. to Toll-like receptor (TLR) 9 stimulation. This was restored in

13 S13 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 Indications for allergen immunotherapy in patients with allergic rhinitis, allergic conjunctivitis, or asthma TABLE III. Allergen immunotherapy should be considered for patients who have demonstrable evidence of specific IgE antibodies to clinically relevant allergens. The decision to begin allergen immunotherapy might depend on a number of factors, including but not limited to: patient’s preference/acceptability; d d adherence; medication requirements; d response to avoidance measures; d d adverse effects of medications; d coexisting allergic rhinitis and asthma; and possible prevention of asthma in patients with allergic rhinitis d Potential indication : atopic dermatitis, if associated with aeroallergen sensitivity: Indications for allergen immunotherapy in patients with reactions to Hymenoptera stings : d patients with a history of a systemic reaction to a Hymenoptera sting (especially if such a reaction is associated with respiratory symptoms, cardiovascular symptoms, or both) and demonstrable evidence of clinically relevant specific IgE antibodies; d patients older than 16 years with a history of a systemic reaction limited to the skin and demonstrable evidence of clinically relevant specific IgE <_ antibodies (patients 16 years of age who present with a history of only cutaneous symptoms to Hymenoptera stings usually do not require immunotherapy); and d adults and children with a history of a systemic reaction to imported fire ant and demonstrable evidence of clinically relevant specific IgE antibodies. Potential indication : for large local reactions in patients who have frequent and disabling large local reactions. pharmacotherapy. Unacceptable adverse effects of medications PATIENT SELECTION should favor one’s decision to initiate allergen immunotherapy. Clinical indications for allergic rhinitis and allergic Immunotherapy does not appear to be more costly than asthma 139-141 pharmacotherapy over the projected course of treatment. Summary Statement 7: Allergen immunotherapy should be Allergen immunotherapy for allergic rhinitis has been shown to considered for patients who have demonstrable evidence of have persistent benefits after discontinuation and to reduce the specific IgE antibodies to clinically relevant allergens. The de- 8-11,91,131-134 risk for future development of asthma. cision to begin allergen immunotherapy might depend on a Coexisting medical conditions should also be considered in the number of factors, including but not limited to patient’s pref- evaluation of a patient who might be a candidate for allergen erence/acceptability, adherence, medication requirements, immunotherapy. Patients with coexisting allergic rhinitis and response to avoidance measures, and the adverse effects of asthma should be managed with an appropriate regimen of allergen medications. D avoidance measures and pharmacotherapy but might also benefit Randomized, prospective, single- or double-blind, placebo- from allergen immunotherapy. However, the patient’s asthma must controlled studies demonstrate the effectiveness of specific 142,143 77,130 be stable before allergen immunotherapy is administered. immunotherapy in the treatment of allergic rhinitis. Prospec- tive, randomized, double-blind, placebo-controlled studies demonstrate the effectiveness of specific immunotherapy in the 74,79,81,129 treatment of allergic asthma. Atopic Dermatitis Allergen immunotherapy is an effective form of treatment for many allergic patients, pro- Summary Statement 8: There are some data indicating that vided they have undergone an appropriate allergy evaluation. immunotherapy can be effective for atopic dermatitis when The expected response to allergen immunotherapy is antigen this condition is associated with aeroallergen sensitivity. B specific and depends on the proper identification and selection There are some data indicating that immunotherapy might be of component allergens based on the patient’s history, exposure, effective for atopic dermatitis when this condition is associated 12,14,144 and diagnostic test results. with aeroallergen sensitivity. In a systematic review of im- Aeroallergen immunotherapy should be considered for patients munotherapy for atopic dermatitis that included 4 comparable who have symptoms of allergic rhinitis, rhinoconjunctivitis, and/ placebo-controlled studies involving a small number of patients, or asthma after natural exposure to allergens and who demonstrate statistical analysis showed significant improvement in symptoms 12 for in- specific IgE antibodies to relevant allergens (see Table III in patients with atopic dermatitis who received SCIT. One ran- dications for allergen immunotherapy). The severity and duration domized, double-blind study of adults with atopic dermatitis dem- of symptoms should also be considered in assessing the need for onstrated a dose-response effect of dust mite immunotherapy on allergen immunotherapy. Severity of symptoms can be defined atopic dermatitis severity, as measured by using the SCORAD 14 by subjective, as well as objective, parameters. Time lost from .0007). P 5 .0378) and topical corticosteroid use ( P 5 score ( work, emergency department or physician’s office visits, and re- One open-label study of 25 patients with dust mite allergy and sponse to pharmacotherapy are important objective indicators of atopic dermatitis treated with dust mite SCIT demonstrated sero- allergic disease severity. Symptoms interfering with sleep or logic and immunologic changes consistent with tolerance in addi- work or school performance are other factors to be considered. tion to significant reductions in objective and subjective SCORAD 13 The effect of the patient’s symptoms on quality of life and respon- scores. siveness to other forms of therapy, such as allergen avoidance or In addition, one double-blind, placebo-controlled study of 48 medication, should also be factors in the decision to prescribe al- children with atopic dermatitis treated with dust mite SLIT lergen immunotherapy. In addition, allergen immunotherapy reported a significant difference from baseline values in visual should be considered if patients wish to avoid long-term analog scores, SCORAD scores, and medication use only in the

14 COXETAL S14 J ALLERGY CLIN IMMUNOL JANUARY 2011 158 positive venom skin test results (25% to 70%). mild-to-moderate severity group, whereas patients with severe However, even though the risk is small, the reaction can be severe, and disease had only a marginal benefit (see Summary Statements 93- 16 95 for a further discussion of SLIT). VIT is recommended for patients with negative venom skin test results and positive venom-specific serum IgE test results who Summary Statement 9: The potential for benefit in symp- 158 have had severe anaphylaxis to an insect sting. toms related to oral allergy syndrome with inhalant immuno- therapy directed at the cross-reacting pollens has been Some patients who have negative venom-specific IgE test and observed in some studies but not in others. For this reason, skin test results are reported to have had subsequent systemic 155,156,159 more investigation is required to substantiate that a benefit reactions to stinging insects. Controlled studies de- in oral allergy symptoms will occur with allergen immuno- signed to evaluate the efficacy of immunotherapy in these pa- therapy. C tients have not been performed. There are few anecdotal The potential for benefit in symptoms related to oral allergy reports of patients with negative venom skin test results and syndrome with cross-reacting inhalant immunotherapy, which negative venom-specific IgE test results being successfully trea- includes the cross-reacting pollen or pollens, has been observed in ted with VIT if the selected venom is based on the results of a some studies but not in others. One controlled prospective study sting challenge. Generally, there are not sufficient data on the demonstrated the potential to decrease oral allergy syndrome efficacy of immunotherapy in these patients to form conclusive 145 symptoms with SCIT directed against birch tree. recommendations. Another The AAAAI Insect Committee’s modified working guidelines double-blind, double-dummy, placebo-controlled study comparing state that a negativevenom skin test result or in vitro assay result is the effect of SCITwith SLIT demonstrated no significant effect on not a guarantee of safety, and patients with suspected higher risk the severity of apple allergy symptoms with either method com- should be counseled about avoidance strategies, use of epineph- paredwiththeplacebogroup,despiteasignificanteffectonseasonal rine injectors, and the emergency and follow-up care of the acute hay fever symptoms and medication use and a decrease in IgE reac- 159 146 allergic reaction. tivity. More investigation is required to substantiate the conten- The AAAAI Insect Committee also acknowl- tion that benefits in oral symptoms will occur with immunotherapy. edged that the management of patients with a positive history and negative venom skin test results requires clinical judgment and Summary Statement 10a: Immunotherapy should be con- ongoing research. sidered if the patient has had a systemic reaction to a Hyme- Several studies of patients with imported fire ant allergy noptera sting, especially if such a reaction was associated with respiratory symptoms, cardiovascular symptoms, or both and demonstrate the effectiveness of immunotherapy with fire ant 122,123,160 whole-body extracts. if the patient has demonstrable evidence of specific IgE. A Adults and children with a history Systemic reactions to Hymenoptera stings, both flying and species) Solenopsis of systemic reactions to the imported fire ant ( imported fire ants, especially when associated with respiratory who have positive skin test results or venom-specific IgE anti- symptoms, cardiovascular symptoms, or both and positive skin bodies should be treated with allergen immunotherapy, although test results for specific IgE, are an indication for al- in vitro test or children 16 years or younger who have experienced only a cutane- 85,147-150 lergen immunotherapy. ous reaction to an imported fire ant sting might not require In the United States patients immunotherapy. older than 16 years with a systemic reaction limited to the skin Although VIT is fundamentally similar to immunotherapy with are also candidates for allergen immunotherapy. Patients 16 years inhalant allergens, there are a few noteworthy and unique or younger who present only with a cutaneous reaction to Hyme- 151,152 features. Adverse effects are no greater in frequency or severity noptera stings might not require immunotherapy. In addi- than with inhalant allergen immunotherapy (despite the more tion to allergen immunotherapy, patients with Hymenoptera severe nature of the reaction to natural exposure). In contrast to sensitivity should be instructed in how to best avoid insect inhalant rush immunotherapy, rush VIT is not associated with an stings, be prescribed epinephrine, and be taught how and when increased incidence of systemic reactions. The maintenance dose to inject it. and clinical protection can routinely be achieved with 8 weekly Venom skin test results are positive in more than 65% of treatments, and even 2-day rush schedules can be used in most patients with a history of a systemic reaction to a Hymenoptera patients without an increased risk of systemic reactions. Unlike sting compared with 15% of those who have not had this type of a 153 immunotherapy with inhalant allergens, the starting dose can be reaction. In patients with negative venom skin test results who just 1/100 of the maintenance dose. Also, the recommended have a severe systemic reaction, further evaluation for the pres- 154-156 m maintenance dose (100 g of each venom) is expected to be ence of venom-specific serum IgE is recommended. If the achieved, regardless of LLRs or temporary delays caused by venom-specific serum IgE test result is also negative, it is recom- systemic reactions during VIT. In patients who cannot safely mended that the skin tests, venom-specific serum IgE tests, or discontinue -blockers but who have a history of moderate- b both be repeated 3 to 6 months later. Approximately 5% to 10% to-severe sting-induced anaphylaxis, VIT is indicated because the of patients with negative venom skin test results with a history risk of anaphylaxis related to a venom sting is greater than the risk of a systemic reaction have a positive venom-specific serum 153,157 of an immunotherapy-related systemic reaction. IgE test result. There are no published results of the effec- Summary Statement 10b: Measurement of baseline serum tiveness of allergen immunotherapy in patients with negative skin tryptase level is recommended in patients with moderate or test results and positive venom-specific IgE test results who have severe anaphylactic reactions to stings because its predictive experienced systemic reactions resulting from a Hymenoptera value is useful regardless of the decision about VIT. Increased sting. There are data to indicate that these patients might have an- tryptase levels are associated with more frequent and more other episode of anaphylaxis if they are restung. The chance of an- severe anaphylactic reactions to stings, as well as greater fail- other systemic reaction to a sting is relatively small (5% to 10%) ure rates with VIT and greater relapse rates after stopping in adults with negative venom skin test results with a history of VIT. B systemic reactions compared with the risk associated with

15 S15 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 Measurement of baseline serum tryptase levels is recommen- Conditions for which immunotherapy is not ded in patients with moderate or severe anaphylactic reactions to indicated stings. They can be increased in more than 10% of cases and in Summary Urticaria and angioedema. 161 more than 20% of those with marked hypotension. An in- Statement 14: Clinical studies do not support the use of creased level of baseline serum tryptase in patients with allergen immunotherapy for chronic urticaria, angioedema, moderate-to-severe insect sting–induced anaphylaxis is also an or both. Therefore allergen immunotherapy for patients indicator for a possible clonal mast cell disorder, including mas- with chronic urticaria, angioedema, or both is not recom- 162 tocytosis. Measurement of baseline serum tryptase concentra- mended. D tions might also identify patients with a high risk for side effects There is no allergic basis for the vast majority of patients with during vespid VIT. Higher baseline tryptase levels correlated with chronic urticaria or angioedema. There is no evidence supporting a greater frequency of severe systemic reactions during the vespid the efficacy of immunotherapy for subjects with chronic urticaria, 163 VIT build-up phase. Increased baseline serum tryptase levels angioedema, or both. are associated with an increased frequency of systemic reactions to VIT injections, a greater failure rate during VIT, and a greater relapse rate (including fatal reactions) if VIT is Measures of efficacy 162,164,165 discontinued. Summary Statement 15: Clinical parameters, such as Summary Statement 11: Large local reactions (LLRs) to in- symptoms and medication use, might be useful measures of sect stings can cause significant morbidity and impair quality the efficacy of immunotherapy in a clinical setting; however, of life. VIT might significantly reduce the size and duration of repetitive skin testing of patients receiving immunotherapy LLRs and might be considered in patients who have frequent is not recommended. A and disabling LLRs, particularly those with occupational ex- Whether immunotherapy is effective can be determined by 179 posure. B measuring objective and subjective parameters. Objective A 4-year controlled trial designed to examine the efficacy of measures, such as an increase in allergen-specific IgG levels VIT in reducing the size and duration of large local sting reactions and decreased skin test reactivity, as measured by means of demonstrated significant reductions in both parameters in patients skin test titration, are changes generally associated with effective 166 with a history of large local sting reactions. Twenty-nine pa- immunotherapy but, at present, are not practical for routine clin- 115 >_ tients with LLRs confirmed on sting challenge ( 16 cm) were as- ical use. Nonquantitative skin testing or serum specific IgE signed to receive VITor no treatment. There was a 42% reduction antibody testing of patients during immunotherapy is not recom- in size and a 53% reduction in duration of the large local sting re- mended because it has not been demonstrated that skin test reac- 166 actions after 7 to 11 weeks of VIT. There was further improve- tivity (to a single dilution) or specific IgE antibody levels ment after 2 years of treatment that was maintained through 4 correlate closely with a patient’s clinical response. For that rea- years of VIT, with a 60% reduction in size and a 70% reduction son, most allergists rely on subjective assessments, such as a pa- in the duration of the LLRs. tient’s report that he or she is feeling better during a season previously causing symptoms. Although subjective assessments are the most common means by which physicians judge the result Conditions for which immunotherapy is of immunotherapy, they might not be reliable, given the strong investigational placebo-like effect (Hawthorne effect) associated with any Summary Statement 12: Clinical Food hypersensitivity. treatment. trials do not support the use of subcutaneous immunotherapy A more objective means for determining efficacy, which has for food hypersensitivity. A been validated in controlled clinical studies, is the use of clinical Summary Statement 13: The safety and efficacy of oral and symptom scores and the amount of medication required to control sublingual immunotherapy for food hypersensitivity is cur- symptoms, maintain peak flow rates or pulmonary function test rently investigational. NR results within acceptable limits, or both. Successful immunother- The use of allergen immunotherapy for subjects with the apy often results in a reduction in medication use, as well as potential for IgE-mediated reactions (anaphylaxis) to foods improvement in symptoms. Guidelines for allergen immunother- 167-170 should be regarded as investigational at this time. There apy clinical trials recommend that the combined symptom- 180,181 are studies demonstrating efficacy in food hypersensitivity, the medication score be used as the primary outcome measure. 170,171 first using aqueous subcutaneous injections of peanut. Stud- These guidelines also provide examples of scoring systems for 172 173 ies with SLIT with hazelnut and milk and oral immunother- 5 measuring symptoms (eg, a 4-point rating scale, where 0 absent 174 176-178 175,176 apy with peanut, and milk have demonstrated egg, to 3 severe) and medication use (a point system that might vary 5 180,181 increased tolerance to these foods (see Summary Statement 103 with type of medication and duration of use). Sequential for further discussion). measurements of disease-specific quality of life also might be 179,181 In the subcutaneous peanut immunotherapy study there was helpful. increased tolerance to oral peanut challenge in all of the treated patients, but there were repeated systemic reactions in most patients, even during maintenance injections, and the authors Special precautions in patients with asthma concluded that a modified peanut extract is needed for clinical Summary Statement 16: Allergen immunotherapy in asth- 170 application of this method of treatment. matic patients should not be initiated unless the patient’s There are no FDA- asthma is stable with pharmacotherapy. C approved formulations for oral immunotherapy or SLIT, and Patients with severe or uncontrolled asthma are at increased this route of allergen immunotherapy is considered investiga- 142,143,182 risk for systemic reactions to immunotherapy injections. tional at this time.

16 COXETAL J ALLERGY CLIN IMMUNOL S16 JANUARY 2011 TABLE IV. Actions to reduce immunotherapy risk d Assess the patient’s general medical condition at the time of injection (eg, recent asthma exacerbation and increased asthma symptoms). d In addition to assessing asthma symptoms, consider obtaining a PEF for patients with a history of asthma before administration of the injection. The intention of assessing PEF is to alert the provider to the need for a more in-depth assessment of asthma control. If the PEF is substantially reduced compared with the patient’s baseline value, the clinical condition of the patient should be evaluated before administration of the injection. d The patient should not receive his or her immunotherapy injection if his or her asthma is poorly controlled. d Adjust the immunotherapy dose or injection frequency if symptoms of anaphylaxis occur and immunotherapy is continued. Use appropriately diluted initial allergen immunotherapy extract in patients who appear to have increased sensitivity on the basis of history or tests for d specific IgE antibodies. Instruct patients to wait in the physician’s office/medical facility for 30 minutes after an immunotherapy injection. Patients at greater risk of reaction d from allergen immunotherapy (eg, patients who have previously had a systemic reaction) might need to wait longer. Educate the patient on signs and symptoms of systemic reactions and instruct them to report symptoms immediately if in the office/medical facility or to d report any delayed systemic reactions to his or her physician. d Ensure procedures to avoid clerical or nursing errors (eg, careful checking of patient identification). d Recognize that dosage adjustments downward are usually necessary with a newly prepared allergen immunotherapy extract or a patient who has had a significant interruption in the immunotherapy schedule. PEF , Peak expiratory flow rate measurement. Although there is some disagreement about the role of allergen Three surveys found that fatal and near-fatal reactions (NFRs) immunotherapy in children younger than 5 years, there have been from immunotherapy injections were more common in patients 143,183-185 reports of effectiveness of allergen immunotherapy in this age with severe/labile asthma. Thus allergen immunother- 86,91 group. apy should not be initiated in patients with poorly controlled In children with allergic rhinitis, allergen immuno- 8,9,132-134 2 asthma symptoms. therapy might prevent asthma. Assessment of asthma control should be con- However, allergen immu- Table IV ). notherapy for inhalant allergens is usually not considered in sidered at each injection visit ( infants and toddlers because (1) there might be difficulty in com- municating with the child regarding systemic reactions and (2) in- jections can be traumatic to very young children. Therefore each SPECIAL CONSIDERATIONS IN IMMUNOTHERAPY case should be considered individually by weighing the benefits Allergen immunotherapy in children and risks. For children who have had a history of anaphylaxis to Summary Statement 17: Immunotherapy for children is ef- stinging insects or have severe allergic disease, the benefits of al- fective and well tolerated. It has been shown to prevent the lergen immunotherapy might outweigh the risks. new onset of allergen sensitivities in monosensitized patients, Immunotherapy can be initiated in young children less than 5 as well as progression from allergic rhinitis to asthma. There- years of age if indicated. Indications should be based on the fore immunotherapy should be considered along with phar- severity of the disease, risk/benefit ratios, and the ability of the macotherapy and allergen avoidance in the management of physician to correlate the clinical presentation with appropriate children with allergic rhinitis/rhinoconjunctivitis, allergic and obtainable allergy testing. There have been several reports of asthma, and stinging insect hypersensitivity. B efficacy and safety with immunotherapy in children as young as 3 Immunotherapy for children has been shown to be effective and 106,186,187 years. A randomized, double-blind, placebo-controlled study well tolerated, although at least 1 study did not show ef- 188 assessing the efficacy of grass pollen–specific allergen immuno- ficacy. However, this study did not include an important aller- therapy over 2 pollen seasons showed that immunotherapy was gen, cockroach, which has been shown to correlate with asthma 189 effective for childhood seasonal allergic asthma in children aged 3 severity in other studies of inner-city asthmatic children. In 191 to 16 years. The subjects were children sensitized to grass pol- general, the clinical indications for immunotherapy for allergic g of inhaled beclomethasone m len and requiring at least 200 rhinitis and asthma are similar for adults and children ( Table equivalent per day. The primary outcome measure was a com- III). Studies of children receiving allergen immunotherapy have bined asthma symptom-medication score during the second pol- demonstrated significant: len season. Secondary outcome measures included end point 86,88,90,91 d and improvement in symptom control for asthma titration skin prick testing, conjunctival and bronchial provoca- 87 allergic rhinitis ; tion testing to allergen, sputum eosinophilia, exhaled nitric oxide, 90 ; to histamine d increase in PC 20 and adverse events. Of the 39 patients enrolled, 35 provided data. 17,90 to cat and house dust mite allergens ; increase in PC d 20 In the SCIT-treated group there was a substantial reduction in 8,9,132-134,190 d decrease in the risk of asthma ; asthma symptom-medication scores compared with those seen 135,136,138 decrease in the development of new sensitivities d ; in the placebo group ( P 5 .04). There was also a significant de- d modification in the release of mediators in children receiv- P 5 .002), conjunctival ( P 5 .02), and bron- crease in cutaneous ( ing immunotherapy that correlates with decreased clinical 5 .01) reactivity to allergen in the SCIT group compared chial ( P 92 symptoms ; and with that seen in the placebo group. The 2 groups had similar d reduction in pharmacy, outpatient, and total health care levels of airway inflammation, despite a trend toward less inhaled 139,140 costs. steroid use in the active group. No serious adverse events were re- ported, and no subjects withdrew because of adverse events. Summary Statement 18: Immunotherapy can be initiated Another study examined the safety of immunotherapy in 239 in young children. Indications are similar to those of other 192 children less than 5 years of age. age groups. D Immunotherapy was

17 S17 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 retrospective studies suggest that there is no greater risk of prescribed according to the immunotherapy guidelines of the prematurity,fetalabnormality,orotheradversepregnancyoutcome World Health Organization (except for age). In this prospective 195,196 in women who receive immunotherapy during pregnancy. study there was 1 systemic reaction among 6,689 injections in 239 patients, with 18 children younger than 2 years, 29 between One retrospective study of the allergy clinic records of 109 the ages of 2 and 3 years, 33 between the ages of 3 and 4 years, pregnant patients who received immunotherapy and 60 pregnant and 52 between the ages of 4 and 5 years. The systemic reaction patientswhorefusedimmunotherapyrevealedahigherincidenceof occurred in a 3-year-old with severe allergic rhinitis after 1 AU of abortion, prematurity, and toxemia in the group that did not receive 196 mite mix. Generalized urticaria and rhinitis occurred 1.5 hours immunotherapy compared with the immunotherapy group. after the injection and were ‘‘easily’’ treated with epinephrine Another retrospective study of 121 pregnancies in atopic and an antihistamine medication. The authors conclude as fol- patients who had received immunotherapy during pregnancy lows: ‘‘We consider specific immunotherapy in patients less found the incidence of prematurity, toxemia, abortion, neonatal than five years of age to be a safe treatment that should increase death, and congenital malformation was no greater than that for 195 research of its efficacy and preventive effects against asthma and the general population. The incidence of these adverse events new sensitizations.’’ was also similar to that seen in a group of 147 pregnancies in Young children have been thought to present problems unique atopic patients who did receive immunotherapy, except for a to their age with regard to immunotherapy and complications. greater incidence of abortion in the untreated group. Similar 197 However, young children seldom present difficulties in the diag- safety was demonstrated with VIT during pregnancies. nosis of a systemic reaction, and there have been no studies that In addition to improving the pregnant patient’s allergic condi- 193 indicate that children are more at risk to conventional SCIT. tion, 2 studies suggest that allergen immunotherapy might prevent 198,199 allergic sensitization in the child. Summary Statement 19: In patients who otherwise have the One demonstrated an ab- 199 sence of allergen-specific IgE in paired cord blood, indication for specific immunotherapy, there is no absolute and the upper age limit for initiation of immunotherapy. D other demonstrated an inhibitory effect on immediate skin reac- 198 Immunotherapy can be considered in the treatment of patients tivity to grass allergens in some of the offspring. of all ages, and the risk/benefit assessment must be evaluated in Both studies showed similar levels of allergen-specific IgG in 198,199 every situation. Some patients might be taking medications that paired cord blood and maternal blood samples. More re- could make treatment of anaphylaxis with epinephrine more search is needed to elucidate the effect of allergen immunother- difficult, such as -blockers, or might have significant comorbid b apy during pregnancy on the subsequent development of medical conditions, such as hypertension, coronary artery disease, allergen sensitization in the child. cerebrovascular disease, and/or cardiac arrhythmias. Some of Allergen immunotherapy maintenance doses can be continued these conditions can occur more frequently in older subjects. during pregnancy. The initiation of immunotherapy might be However, immunotherapy can provide significant benefits in considered during pregnancy when the clinical indication for the older adult population and should be considered if the immunotherapy is a high-risk medical condition, such as ana- appropriate indications are present and there are no significant phylaxis caused by Hymenoptera hypersensitivity. When a comorbid conditions. A study that compared the clinical efficacy patient receiving immunotherapy reports that she is pregnant, of immunotherapy in 2 age populations (>54 years vs <54 years) the dose of immunotherapy is usually not increased. found a similar reduction in medication use and improvement in The recommended precautions for the prevention of adverse 194 symptoms in the 2 age groups. reactions are important in the pregnant patient because of the on Table IV possible effect on the fetus, as well as the patient (see The patient’s age alone should not preclude the consideration reducing immunotherapy risk). of allergen immunotherapy, and clinical benefits have been There is no evidence of an increased risk of prescribing or reported. continuing allergen immunotherapy for a mother while breast- feeding and no risk for the breast-fed child. Immunotherapy in pregnancy Summary Statement 20a: Allergen immunotherapy can Immunotherapy in patients with immunodeficiency be continued but is usually not initiated in the pregnant patient. C and autoimmune disorders Summary Statement 20b: If pregnancy occurs during the Summary Statement 21: Immunotherapy can be consid- build-up phase and the patient is receiving a dose unlikely ered in patients with immunodeficiency and autoimmune dis- to be therapeutic, discontinuation of immunotherapy should orders. C be considered. D There are no controlled studies about the effectiveness or risks The physician must be aware of the benefits versus potential associated with immunotherapy in patients with immunodefi- risks of immunotherapy in pregnant patients. Allergen immuno- ciency or autoimmune disorders. Concern about the increased risk therapy is usually not initiated during pregnancy because of of immunotherapy in such patients is largely hypothetical. concerns about the potential adverse effects of systemic reactions A review article suggested guidelines for treatment of HIV- and their resultant treatment on the fetus, mother, or both (eg, positive patients who meet the criteria for allergen immunother- 195 spontaneous abortion, premature labor, or fetal hypoxia). apy. Immunotherapy was recommended for pollen and mite If allergy in patients who have early to middle HIV disease, which pregnancy occurs during the build-up phase and the patient is re- is defined as a peripheral CD4 count of 400 or more cells/ m L with ceiving a dose unlikely to be therapeutic, discontinuation of im- no history of opportunistic infections or other AIDS-associated munotherapy should be considered. 200 pathology and no evidence of plasma HIV viremia. There have been no large prospective studies investigating the Close mon- safety of immunotherapy in pregnancy. However, several itoring is recommended monthly for the first 3 months and then

18 COXETAL S18 J ALLERGY CLIN IMMUNOL JANUARY 2011 immunotherapy vials or lots) or changes in the management of quarterly. Cases of allergen immunotherapy in patients with HIV underlying allergic disease or comorbid conditions. controlled with highly active antiretroviral therapy are re- 201,202 Summary Statement 24: The Duration of treatment. ported. In 1 case report, allergen immunotherapy appeared patient’s response to immunotherapy should be evaluated to induce a transient T-cell proliferation and modest increase in on a regular basis. A decision about continuation of effective RNA viral load, which resolved with highly active antiretroviral 201 immunotherapy should generally be made after the initial pe- therapy. In another patient a 3.5-year course of immunotherapy riod of 3 to 5 years of treatment. Some patients might experi- for tree pollen–induced allergic rhinitis was successful in reducing ence sustained clinical remission of their allergic disease after the reported visual analog scale for subjective symptoms and med- 202 discontinuing immunotherapy, but others might relapse. The ication use by almost 90%. During therapy, his CD4 cell count severity of disease, benefits sustained from treatment, and L, and his HIV RNA level re- m remained greater than 350 cells/ convenience of treatment are all factors that should be consid- mained less than 50 copies/mL. His symptoms remained well con- ered in determining whether to continue or stop immunother- trolled 3 years after discontinuation of immunotherapy. apy for any individual patient. D Although concern about the safety of allergen immunotherapy The patient’s response to immunotherapy should be evaluated in patients with autoimmune disorders has been raised in the past, on a regular basis. The severity of disease, benefits obtained from there is no substantive evidence that such treatment is harmful in treatment, and convenience of treatment are all factors that should patients with these diseases. Therefore the benefits and risks of be considered in determining whether to continue or stop immu- allergen immunotherapy in patients with HIV infection, other notherapy for any patient. If allergen immunotherapy is effective, immunodeficiencies, or autoimmune disorders must be assessed treatment might be continued for longer than 3 years, depending on an individual basis. on the patient’s ongoing response to treatment. Some patients experience a prolonged remission after discontinuation, but others might relapse after discontinuation of immunotherapy. FOLLOW-UP CARE AND DURATION OF Therefore the decision to continue or stop immunotherapy must TREATMENT be individualized. Continuing care Summary Statement 25: Although there are no specific tests Time course of improvement. Summary Statement 22: to distinguish which patients will relapse after discontinuing Clinical and physiological improvement can be demonstrated VIT, there are clinical features that are associated with a very shortly after the patient reaches a maintenance dose. A higher chance of relapse, notably a history of a very severe re- Clinical improvement can be demonstrated very shortly after 20,103,111,203 action to a sting, an increased baseline serum tryptase level, a the patient reaches a maintenance dose. One study of systemic reaction during VIT (to a sting or a venom injection), patients with cat allergy who achieved the maintenance dose in 5 honeybee venom allergy, and treatment duration of less than 5 weeks with a cluster schedule reported the results of titrated nasal years. C allergen challenge, titrated skin prick testing, and allergen- There have been few studies designed specifically to look at the specific IgG4 measurement with cat immunotherapy at 5 weeks 22 question of when to discontinue effective allergen immunotherapy were predictive of the response at 1 year. or the duration of immunotherapy efficacy after termination of Improvement might not be observed for several reasons, includ- treatment. The duration of allergen immunotherapy efficacy has ing (1) failure to remove significant allergenic exposures (eg, a cat probably been most extensively studied in Hymenoptera hyper- in the household), (2) exposure to high levels of allergen, (3) sensitivity. Long-term follow-up studies suggest that a 5-year continued exposure to nonallergen triggers (eg, tobacco smoke), (4) immunotherapy treatment course for Hymenoptera hypersensitiv- incomplete identification and treatment of clinically relevant aller- 204-206 ity might be sufficient for most allergic subjects. However, gens, or (5) failure to treat with adequate doses of each allergen. If relapse rates as high as 15% of patients in the 10-year period after clinical improvement is not apparent after 1 year of maintenance 205,206 discontinuing VIT have been reported. Nevertheless, sys- therapy, possible reasons for lack of efficacy should be evaluated. If temic reactions to stings after discontinuing VIT are generally none are found, discontinuation of immunotherapy should be much milder than pretreatment reactions and are rarely severe. considered, and other treatment options should be pursued. There are conflicting data on the optimal duration of VIT. Two Follow-up visits. Summary Statement 23: Patients should studies did not find a difference in relapse rates between the be evaluated at least every 6 to 12 months while they receive patients treated for 3 years compared with those treated for 5 immunotherapy. D 205,207 years, but the limited number of patients who were treated Patients should be evaluated at least every 6 to 12 months while for 3 years or less in one study did not allow for any conclusions receiving immunotherapy: 205 regarding the risk of stopping therapy after 3 years of treatment. d to assess efficacy; Two studies reported better outcomesin terms ofre-sting reactions d to implement and reinforce its safe administration and to in patients who received 4 or more years of VIT compared with monitor adverse reactions; 206,208 those who received shorter treatment courses. d to assess the patient’s compliance with treatment; Change in skin test reactivity does not appear to predict d to determine whether immunotherapy can be discontinued; persistent efficacy after discontinuation because the skin test and response was negative in some of the patients who had a systemic d to determine whether adjustments in the immunotherapy sting reaction. However, no relapses were observed among dosing schedule or allergen content are necessary. 207,209 patients without detectable venom-specific IgE. Some of Patients might need more frequent office visits for evaluation the patients who experienced systemic sting reactions after dis- and management of immunotherapy (eg, treatment of local continuing VIT had experienced systemic reactions during the 209 reactions, systemic reactions, or both or changes in their VIT treatment.

19 S19 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 subsequent systemic reactions. However, some patients with The relapse rate and the frequency of severe reactions are a greater frequency of large local reactions might be at an in- greater in patients who had a history of very severe reactions to creased risk for future systemic reactions. C stings before treatment, those with increased baseline tryptase In a survey of 249 patients undergoing immunotherapy, 71% levels, those who had systemic reactions during VIT (to a sting or 212 reported experiencing a local reaction. a venom injection), those with honeybee allergy, and those who Of the patients experi- had less than 5 years of treatment. encing local reactions, 84.7% reported reactions smaller than the Summary Statement 26: At present, there are no specific palm of the hand, and 81.9% deemed local reactions not to be tests or clinical markers that will distinguish between patients bothersome at all or only slightly bothersome. Ninety-six percent who will relapse and those who will remain in long-term clin- of the local reactors stated they would not stop immunotherapy ical remission after discontinuing effective inhalant allergen because of the local reactions. immunotherapy, and the duration of treatment should be de- Local reactions associated with allergen immunotherapy are termined by the physician and patient after considering the fairly common, with a frequency ranging from 26% to 82% of 213-215 risks and benefits associated with discontinuing or continuing patients and 0.7% to 4% of injections. Two retrospective immunotherapy. D studies compared the effect of not adjusting the immunotherapy The duration of aeroallergen immunotherapy efficacy has not dose based on LLRs on the immunotherapy systemic reaction 210 215,216 been as extensively studied as that for VIT. rate with dose-adjustment protocols. Both studies found Some studies no statistical difference between the dose-adjustment and no- suggest that a 3- to 5-year treatment duration is sufficient for in- dose-adjustment protocols in terms of immunotherapy-induced halant allergen immunotherapy, but others have reported a signif- systemic reactions. Both authors concluded that local reactions icant relapse rate within 3 years of discontinuing allergen immunotherapy. were poor predictors of subsequent systemic reactions at the next injection, and dose reductions for most local reactions are One prospective controlled study was designed to study the immunotherapy relapse rate during the 3-year period after unnecessary. However, a retrospective review of a large, multicenter allergy discontinuation of immunotherapy in 40 asthmatic patients who had been treated with immunotherapy with a standardized dust practice group’s database comparing the frequency of LLRs (de- >_ extract for 12 to 96 (Dermatophagoides pteronyssinus) 25 mm) in patients who had experienced systemic reac- fined as mite 89 tions with age-, sex-, and allergen sensitivity–matched control months. Fifty-five percent of the patients relapsed. The duration subjects who had not had allergen immunotherapy–induced sys- of efficacy was related to the reduction of skin test reactivity at the temic reactions found the rate of LLRs was 4 times higher among 5 .003) and the duration of end of immunotherapy treatment ( P the 258 patients who had experienced a systemic reaction com- immunotherapy treatment. The relapse rate was 62% in the group pared with those who had never experienced a systemic reac- treated for less than 35 months compared with 48% in the group 217 tion. treated for greater than 36 months ( P 5 .04). Prolonged clinical Patients who had experienced systemic reactions had efficacy was demonstrated in a double-blind, placebo-controlled LLRs in 35.2% of visits compared with 8.9% of visits in the study of patients with severe grass pollen–induced allergic rhinitis matched control group without systemic reactions (difference be- 93 who had been treated for 3 to 4 years with immunotherapy. P < .001). Individual LLRs were not predictive of tween groups, future systemic reactions, but LLRs preceded systemic reactions There was a switch to placebo in half the group (16 patients) after in approximately one third of the systemic reactions. These differ- 3 to 4 years of immunotherapy, and efficacy parameters were encessuggestthatsubjectswitha greaterfrequency ofLLRsmight monitored over the next 3 years. Seasonal symptom scores and be at greater risk for systemic reactions. Of note, it was the policy the use of rescue medication remained low for 3 to 4 years after of this practice group to repeat the dose for LLRs between 25 and the discontinuation of immunotherapy, and there was no signifi- 30 mm size and reduce the dose for LLRs between 30 and 50 mm. cant difference between patients who continued and those who A case-cohort study based on a 3-year retrospective chart discontinued immunotherapy. Similar sustained clinical benefits review of patients receiving imported fire ant immunotherapy with accompanying immunologic changes in grass pollen– defined as local reactions larger than the . identified LLRs, ‘‘ specific serum IgG4 levels and IgE-blocking factor were patient’s palm (average adult, 8-10 cm),’’ as a risk factor for a sys- demonstrated 1 year after discontinuation of a 3-year course of temic reaction to imported fire ant immunotherapy (odds ratio, grass pollen tablets in one double-blind, placebo-controlled study 218 211 34.5; 95% CI, 6.52-182). of 257 patients with allergic rhinitis. Currently, there are inadequate diagnostic tools available to Prospective studies investigating the sensitivity and specificity of LLRs and the effect of immunotherapy protocol modifications identify which patients will experience a sustained clinical remission after discontinuing inhalant immunotherapy. Therefore based on them are needed. the duration of treatment should be determined by the physician Summary Statement 28: Local reactions were found to not and patient after considering the benefits and risks associated with predict local reactions at the next injection in a retrospective discontinuing or continuing inhalant immunotherapy. study. C A 12-month study at a single site demonstrated that local A form to document indications for continuation of immuno- 219 reactions did not predict local reactions at the next injection. therapy can be found at www.aaaai.org , www.jcaai.org ,or www. acaai.org . The clinic did not perform routine dose adjustments for local re- actions and did not control for antihistamine use. A total number of 9,678 injections were administered to 360 patients. Small local SAFETY OF IMMUNOTHERAPY reactions (the size of the patient’s palm or less), LLRs (larger than the patient’s palm), and whether a local reaction was followed by Local reactions a local reaction were recorded. At least 1 local reaction was expe- Summary Statement 27: Published studies indicate that rienced by 78.3% of patients, and 7.5% had an LLR. The total individual local reactions do not appear to be predictive of

20 COXETAL S20 J ALLERGY CLIN IMMUNOL JANUARY 2011 local reaction rate was 16.3% per injection, the small local reac- The only other drug class studied for immunotherapy local tion rate was 15.9%, and the LLR rate was 0.4% per injection. reaction prevention are the leukotriene antagonists. A double- Overall, 27% of all local reactions were followed by another local blind, placebo-controlled pilot study of 15 patients that compared reaction, whereas 6% of LLRs were followed by a subsequent the effect of placebo, montelukast, or desloratadine premedica- tion on local reactions with rush VIT demonstrated a significant LLR. The sensitivity and positive predictive value for a local re- delay in the onset and decrease in the size of local reactions in the action predicting a local reaction at the next injection were 26.2% and 27.2%, respectively. The sensitivity, positive predictivevalue, montelukast group compared with the placebo group, whereas there was no difference between the desloratadine and placebo and specificity for an LLR predicting an LLR at the subsequent 226 groups in these parameters. injection were 5.2%, 6.0%, and 99.6%, respectively. This study suggests that local reactions do not predict local reactions at the next immunotherapy injection. Summary Statement 29: Glycerin concentrations of up to Systemic reactions 50% were not associated with significantly higher local reac- Summary Statement 31: Although there is a low risk of se- tion rates. Higher glycerin concentrations are associated with vere systemic reactions with appropriately administered al- injection pain, which correlates with the total amount of glyc- lergen immunotherapy, life-threatening and fatal reactions erin injected. C do occur. A Glycerin is a preservative used in allergen extracts that might The prevalence of severe systemic reactions after allergen have some irritant properties that can produce injection pain. immunotherapy ranges from less than 1% of patients receiving Despite its irritating properties, a 1-year retrospective study at conventional immunotherapy to greater than approximately 34% 182,227-229 a single site demonstrated that higher glycerin concentrations of patients in some studies of rush immunotherapy. (even 50%) were not associated with significantly higher small A review of the SCIT systemic reaction rates reported in studies 220 or LLR rates. published within the past 15 years found that the percentage of Small local reaction (the size of the patient’s systemic reactions per injection with conventional schedules is palm or less) but not LLR (larger than size of the patient’s 230 approximately 0.2%. palm) rates increased with higher allergen concentration, num- ber, and volume. The study also demonstrated that although In a 2006 survey of allergen immunotherapy–induced fatal small local reactions increased with allergen content, LLRs reactions and NFRs sent to physician members of the AAAAI, 220 did not. 273 of 646 respondents reported NFRs during the period of 1990 185 to 2001. The incidence of unconfirmed NFRs was 23 per year Local reaction rates were similar for aeroallergen, flying (5.4 events per million injections). Administration during the Hymenoptera, and imported fire ant injections. Because flying height of the pollen season (46% of respondents) and immuno- Hymenoptera did not contain any glycerin and had comparable local reaction rates, this, along with the aforementioned findings, therapy dosing errors (25% of respondents) were cited as the 2 suggests that the allergen content and the not the glycerin plays a most important contributing factors in the NFRs. The most severe NFR was respiratory failure (10% of NFRs). One patient with an larger role in the cause of local reactions. This study suggests that LLRs are not associated with the glycerin concentration or NFR was receiving a b -blocker, and none were taking concomi- allergen content of immunotherapy extracts. However, a prospec- tant ACE inhibitors. Ninety-three percent of the NFRs occurred tive study demonstrated that pain associated with glycerin in clinics staffed by allergists, and none occurred in medically un- supervised settings. increases in proportion to glycerin concentration and injection 221 volume. In a retrospective analysis of the incidence and characteristics The glycerin concentrations in this study ranged from of nonfatal SCIT-induced systemic reactions in 435,854 injec- 0% to 30%, and the volume injected ranged from 0.1 to 1.0 mL. tions administered to 4,000 patients over a 20-year period (1981- Although clinically important pain was unusual when the injected 2000), there were 115 systemic reactions (5.2% of patients and total dose of glycerin (volume 3 concentration) was less than 0.06% of injections) in the first 10 years and 26 systemic reactions 0.05 mL, the frequency of bothersome pain increased as the total (1.08% of patients and 0.01% of injections) in the second 10 glycerin dose increased. The extract manufacturers’ package in- 231,232 years. sert advises care when administering a volume greater than 0.2 There were significantly less asthma and urticaria re- 232 mL of an extract in 50% glycerin because of the potential discom- actions in the second period. fort and pain it might cause. In a prospective multicenter study there were 53 systemic reactions in 17,526 doses administered to 423 patients (0.3% per 233 injection and 3.7% of patients). All systemic reactions were mild to moderate and responded well to treatment. Five patients Management of LLRs experienced more than 3 systemic reactions (total of 36 reac- Summary Statement 30: Antihistamines have been demon- tions), and the authors noted that 40% of the systemic reactions strated to be beneficial in decreasing local reactions during would have been avoided if patients experiencing the third sys- cluster and rush protocols, whereas leukotriene antagonists temic reaction had been withdrawn. were shown to be effective in a rush protocol. Although com- Inthe previously mentioned AAAAI physician members’ survey monly used, the effect of these medications in reducing local of fatal reactions and NFRs from immunotherapy injections, there reactions during conventional build-up and maintenance im- 143 were 41 fatalities identified in the initial brief survey. munotherapy injections has not been extensively reported. A The esti- Oral antihistamines are effective in decreasing local reactions mated fatality rate was 1 per 2.5 million injections (average of 3.4 222 223-225 during cluster regimens deaths per year), which is similar to 2 previous surveys of AAAAI and rush protocols with VIT. 183,184 physician members. One study that demonstrated a decrease in the frequency of In a subsequent 3-year AAAAI/ACAAI Immunotherapy Safety Surveillance study, data were provided by LLRs with fexofenadine premedication found no additional ben- 225 806 practices representing 1922 SCIT prescribers (>50% response efit with the addition of the H2 antihistamine ranitidine.

21 S21 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 234 withholding that patient’s immunotherapy treatment. The preinjec- There were no fatalities reported in 2008 for the approxi- rate). tion health inquiry might include questions regarding the presence mately 8.1 million injections administered, although respondents of asthma symptom exacerbation, -blocker use, change in health b voluntarily reported 6 SCIT fatalities from 2001 to 2007 that oc- status (including pregnancy), or an adverse reaction to the previous curred in other practices. allergen immunotherapy injection. The preinjection evaluation Therefore although severe systemic reactions to allergen im- might also include a peak flow measurement to assess the airway munotherapy are uncommon, serious systemic reactions (some function of asthmatic patients (an example of a written preinjection fatal) can occur. www.aaaai. questionnaire can be found in the members section of Summary Statement 32: An assessment of the patient’s cur- org). rent health status should be made before administration of the A patient’s asthma must be stable before the allergen immuno- allergy immunotherapy injection to determine whether there therapy injection is administered, and patients with significant wereanyhealth changes that mightrequire modifyingor with- systemic illness generally should not receive an allergy immuno- holding that patient’s immunotherapy treatment. Poorly con- therapy injection. trolled asthma has been identified as a risk factor for a severe immunotherapy-induced reaction. Before the administration of the allergy injection, the patient should be evaluated for Timing of anaphylactic reactions to immunotherapy the presence of asthma symptoms. One might also consider an objective measure of airway function (eg, peak flow) for injections the asthmatic patient before allergy injections. B Summary Statement 33: The majority of safety data on al- In the AAAAI’s survey of physician members on immunother- lergen immunotherapy reactions are in the context of 30 min- apy- and skin testing–induced fatal reactions and NFRs during the utes. Because most serious systemic reactions from allergen period of 1990-2001, 15 of the 17 fatalities occurred in patients immunotherapy occur within 30 minutes after an injection, with asthma, and in 9 patients not optimally controlled asthma patients should remain in the physician’s office/medical clinic was considered the susceptibility factor that contributed to the fa- for at least 30 minutes after the immunotherapy injection. C 143 tal outcome. A review of the literature indicates that most systemic reactions The most severe NFR, respiratory failure, oc- 230,235 occur within 30 minutes after an injection. curred exclusively in asthmatic patients, and 4 (57%) of 7 Although some asthmatic patients had a baseline FEV studies reported up to 50% of systemic reactions occurring after of less than 70% of pre- 1 185 236-238 30 minutes, dicted value. almost all severe systemic reactions (equiva- lent to grade 4 in the World Allergy Organization SCIT Systemic In the most comprehensive evaluation of fatalities associated ) began within 30 minutes after Table V Reaction Grading System, with allergen immunotherapy (1945-1987), there were 40 fatal- 235,236,239 the injection. ities during allergen immunotherapy and 6 fatalities during skin 184 testing. In a review of 14 studies that reported immunotherapy systemic Sufficient information for complete analysis was pro- vided for 30 patients. Ten fatalities occurred during seasonal ex- reaction rates published between 1995-2009, 10 of 12 studies that reported the timing of the system reactions reported the incidence acerbation of the patient’s disease, 4 in patients who had been in terms of greater than or less than 30 minutes (see Table E3 in this symptomatic at the time of the injection, 2 of whom had been re- 230 ceiving ). www.jacionline.org article’s Online Repository at -adrenergic blockers. Of the 24 fatalities associated with b The other 2 immunotherapy, 4 had experienced previous reactions, 11 mani- studiesreportedsystemicreactiontimingasanaverageandarange: fested a high degree of sensitivity, and 4 had been injected with one reported an average time of systemic reactions as 20 minutes newly prepared extracts. (range, 1-60 minutes), and the other reported that 6 reactions oc- In a prospective study of 125 asthmatic patients with mite curredbetween20and55minutes.Fewstudieshaveprovidedcom- allergy that used a 3-day rush immunotherapy protocol, FEV parative safety data on the incidence of systemic reactions in the was 1 182 first 20 minutes versus the 20- to 30-minute time period. identified as a predictor for systemic reactions. In this study In the AAAAI’s fatal reaction and NFR surveys previously dis- 73.3% of the patients with an FEV of less than 80% of predicted 1 cussed, 10 (77%) patients with fatal reactions and 65 (96%) pa- value experienced an asthma reaction during rush immunother- tients with NFRs for whom information on the timing of the apy, whereas only 12.6% of patients with an FEV of greater 1 onset of symptoms was available had symptoms within 30 min- than 80% of predicted value had asthmatic reactions ( P < 143,185 utes of the injection. .0001).The authors noted that if the patients with an FEV The onset of symptoms before the fatal of 1 less than 80% of predicted value had been excluded from the immunotherapy reaction was greater than 30 minutes in 3 pa- study, the systemic reaction rate would have been 19.7% instead tients. In 1 patient the reaction began within 35 minutes after of 36%. These studies suggest that labile asthma, severe asthma, the injection, but treatment was not administered until 45 minutes or both is a risk factor for immunotherapy. after the injection. A second late reaction occurred after the pa- tient had left the clinic early, and it was estimated that treatment In addition to symptomatic asthma and injections administered was initiated at least 50 minutes after the injection. A third late during periods of exacerbation of symptoms, other risk factors for immunotherapy that have been identified include the presence of a reaction occurred in the office of a primary care physician and be- gan 30 to 40 minutes after the injection, but treatment was initi- high degree of hypersensitivity, use of -blockers, injections from b 31 new vials, and dosing errors. With the exception of dosing errors ated 20 minutes after the onset of symptoms. The timing of the reaction was unknown in 4 of the fatal reactions. and a high degree of hypersensitivity, these risk factors can be min- In an earlier AAAAI survey, 17 fatalities associated with imized by performing a preinjection health screen before the ad- allergen immunotherapy were reported for the years 1985- ministration of the allergy immunotherapy injection. This 183 1989. preinjection evaluation might include a health inquiry administered Onset of anaphylaxis occurred within 20 minutes in 11 verbally or as a written questionnaire directed to determinewhether patients, within 20 to 30 minutes in 1 patient, and after more there were any health changes that might require modifying or than 30 minutes in 1 patient. Four patients did not wait after the

22 COXETAL S22 J ALLERGY CLIN IMMUNOL JANUARY 2011 * TABLE V. Subcutaneous systemic reaction grading system Patients might also have a feeling of impending doom, especially in grades 2, 3, or 4. Note: Children with anaphylaxis seldom convey a sense of impending doom, and their behavior changes might be a sign of anaphylaxis, such as becoming very quiet or irritable and cranky. a Scoring includes a suffix that denotes if and when epinephrine is or is not administered in relationship to symptoms/signs of the systemic reaction: , 5 minutes , greater 10 minutes to 20 minutes or less; d z or less; b , greater than 5 minutes to 10 minutes or less; , greater than 20 minutes; c , epinephrine not administered. The final grade of the reaction will not be determined until the event is over, regardless of the medication administered. The final report should include the first iii and a suffix reflecting if and when epinephrine was or symptom(s)/sign(s) and the time of onset after the subcutaneous allergen immunotherapy injection was not administered (eg, Grade2a:rhinitis:10 minutes). Final report: Grade a-d,or z ________________ First symptom_______Time of onset of first symptom______ iv Comments i Each grade is based on the organ system involved and severity. Organ systems are defined as follows: cutaneous, conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular, and other. A reaction from a single organ system, such as cutaneous, conjunctival, or upper respiratory, but not asthma, gastrointestinal, or cardiovascular, is classified as grade 1. Symptom(s)/sign(s) from more than 1 organ system or asthma, gastrointestinal, or cardiovascular are classified as grades 2 or 3. Respiratory failure or hypotension, with or without loss of consciousness, is defined as grade 4 and death as grade 5. The grade is determined by the physician’s clinical judgment. ii This constellation of symptoms can rapidly progress to a more severe reaction. iii Symptoms occurring within the first minutes after the injection might be a sign of severe anaphylaxis. Mild symptoms can progress rapidly to severe anaphylaxis and death. iv If signs or symptoms are not included in the table or the differentiation between a systemic reaction and a vasovagal (vasodepressor) reaction, which can occur with any medical intervention, is difficult, please include comment, as appropriate. *This is the World Allergy Organization Subcutaneous Systemic Reaction Grading System, which has been endorsed by the AAAAI and ACAAI (from Cox L, Larenas-Linnemann D, Lockey RF, et al. J Allergy Clin Immunol 125:569-574, e567; reprinted with permission from Elsevier Inc).

23 S23 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 and a management plan outlined with instructions on when to injection, and the onset of their systemic reaction symptoms is not seek medical care. known. Summary Statement 36: Several large studies demonstrate In a prospective study a total of 20,588 extract injections were that life-threatening anaphylactic reactions after the first 30 administered to 628 patients, resulting in 52 systemic reactions in minutes are rare. Delayed and biphasic immunotherapy- 42 patients, with 38% of the systemic reactions occurring from 30 240 induced systemic reactions can occur outside of a supervised minutes to 6 hours after the allergy vaccine administration. In medical facility. Thus patients should be educated regarding another prospective study 8% of systemic reactions occurred 241 the possible signs and symptoms of systemic reactions and more than 2 hours after injection. to contact their health care professional or seek emergency Most of the extract manufacturers’ package inserts recommend medical attention, as indicated. The decision to prescribe ep- a wait period of either 20 to 30 minutes or 30 minutes after admin- inephrine autoinjectors to patients receiving allergen immu- istration of the immunotherapy injection. The European Acad- notherapy is up to the physician’s discretion and is based on emy of Allergy and Clinical Immunology’s recommended a number of considerations. C observation period after an allergen immunotherapy injection is 30 At the onset of immunotherapy, patients should be counseled 30 minutes. Most of the safety data on allergen immunotherapy on the possibility of immediate and delayed systemic reactions reactions are in the context of 30 minutes, and thus 30 minutes during risk communication; an action plan for such an event continues to be the recommended wait period after the immuno- should be discussed. In the event of a delayed systemic reaction, therapy injection. the patient should be counseled on appropriate treatment based on Patients should remain in the physician’s office/medical clinic their symptoms. They should be instructed to contact their health for at least 30 minutes after receiving an injection, but longer care professional or seek emergency medical attention, as indi- waits are reasonable, as directed by the physician. Some physi- cated. After a delayed systemic reaction, the physician should cians might request that patients considered at increased risk of evaluate the risks and benefits of continuing immunotherapy; a serious systemic reaction outside of the office/medical clinic consider some treatment modifications, such as a longer wait carry injectable epinephrine. These patients should be instructed period; or both. The length of the longer wait time will depend on in the use of epinephrine to treat a systemic reaction that occurs the clinical history of the delayed systemic reaction. Physicians after they have left the physician’s office or other location where might also want to consider prescribing an epinephrine auto- the injection was given. The risks and benefits of continuing aller- injector to treat such future reactions. gen immunotherapy in patients who have had a severe systemic reaction should be carefully considered. Summary Statement 34: Delayed systemic reactions, defined as occurring after the 30-minute wait period, can b -Blockers and ACE inhibitors occur and, in general, are not severe. B Summary Statement 37: Exposure to b -adrenergic block- Delayed systemic reactions, defined as the onset of a systemic ing agents is a risk factor for more serious and treatment- reaction after the 30-minute wait period, have been reported to resistant anaphylaxis. Concomitant use of -blockers and al- b 235-239,242,243 account for 27% to 50% of all systemic reactions. lergen immunotherapy should be carefully considered from an individualized risk/benefit standpoint and incorpo- Although several studies reported no severe delayed reac- 235 236,237 rate the patient’s preferences in the medical decision- tions others or no delayed reactions with hypotension, 239,243 making process. C reported delayed reactions associated with urticaria, 243 238 -blockade can enhance mediator release in the setting of IgE- b wheezing, and stridor and abnormal peak flow readings. 247,248 mediated and non–IgE-mediated anaphylactic reactions ; In a retrospective study that reported 50% of the systemic reac- might intensify pulmonary, cardiovascular, and cutaneous end- tions as delayed, the authors concluded that their findings support . 30 minutes as an optimal wait time for immunotherapy’’ be- ‘‘ organ effects of mediators; and has been associated with increased 236 cause all serious reactions occurred within 30 minutes. mortality in experimental anaphylaxis induced by either immuno- 249,250 logic or nonimmunologic mechanisms. Patients who are re- SummaryStatement 35: Biphasicimmunotherapyreactions, ceiving b -adrenergic blockers might be at heightened risk should defined as resolution of the initial reaction with recurrence at 2 to 24 hours, were reported in up to 23% of patients who expe- they experience a systemic reaction to an allergen immunother- apy injection because epinephrine might be less efficacious; epi- rienced a systemic reaction after allergen immunotherapy in nephrine administration might also paradoxically worsen one study. Biphasic reactions were typically less severe than anaphylaxis through facilitating unopposed the initial reaction. C -adrenergic and va- a 247,251-257 gotonic effects. Biphasic anaphylactic reactions are characterized by complete clinical resolution of initial symptoms followed by onset of late- There are 3 potential elements of risk that can be influenced by 244 phase symptoms, usually within 24 hours. b -blockers in the setting of allergen immunotherapy administra- Biphasic anaphy- tion. Reactions might be (1) more frequent, (2) more severe, and lactic reactions are reported to occur 1% to 20% of the time. (3) refractory to treatment. Two prospective studies report that biphasic reactions occur in 245 246 A prospective cohort study that investigated anaphylactoid 10% and 23% of immunotherapy reactions. Biphasic im- munotherapy reactions occurred more frequently in women reactions from contrast media found no statistically significant increase in risk associated with b -blocker exposure; however, few and were more common in patients who required more than 258 severe reactions occurred in this study. 1 dose of epinephrine during the initial reaction. No specific A case-control study symptoms during the initial reaction predicted a biphasic reac- b –blocker use was a significant risk factor for anaphy- found that tion. Biphasic reactions were typically less severe than the initial lactoid reactions from intravenous radiocontrast media infusions, reaction, and none required additional epinephrine. Patients which were more likely to be severe and refractory to treat- 255 should be counseled on the possibility of a biphasic reaction ment. An expanded case-control study with both retrospective

24 COXETAL S24 J ALLERGY CLIN IMMUNOL JANUARY 2011 -blocker is b administration of venom immunotherapy and a and concurrent subject selection found patients receiving - b warranted. C blockers were almost 8 times more likely to be hospitalized after It is appropriate to regard venom and inhalant allergen immu- an anaphylactoid reaction and had a greater risk for a severe ana- 256 notherapy differently from the standpoint of potential risks and phylactoid reaction with bronchospasm. In this study nonasth- benefits when making management decisions regarding concom- -blockers b matic patients with cardiovascular disorders receiving itant administration of immunotherapy and b -blockers. Manage- were at greater risk for bronchospasm with severe reactions. This b -blockers in patients receiving or ment decisions concerning case-control study generated data from a stimulus associated with who are candidates for allergen immunotherapy are contingent on non–IgE-mediated anaphylaxis, radiocontrast media. In consider- an individualized assessment of possible risks compared with ing the risk for more serious anaphylaxis in patients receiving al- b -blocker for uncomplicated benefits. For patients taking a lergen immunotherapy, it is assumed that the anaphylactogenic hypertension, an equally efficacious alternative antihypertensive stimulus of radiocontrast media is generalizable to the stimulus agent can generally be prescribed, which would permit admin- of allergen immunotherapy administration. istration of allergen immunotherapy without heightened risk. In Two retrospective studies on immunotherapy risk factors with 238,259 238 some situations there might be no equivalent substitute for VIT and inhalant immunotherapy found no increase in b -blockers, such as when a patient requires a b -blocker for -blockers. the frequency of systemic reactions in patients taking b myocardial reinfarction prophylaxis. In such situations the A prospective cohort study of 3,178 patients receiving inhalant management decision should balance the risk associated with immunotherapy and VIT found no increased risk for more fre- continuing b -blocker treatment with the potential untoward -blockers compared b quent systemic reactions in patients taking 260 b -blocker discontinuation. effects resulting from with those who were not. Overall, 87% of reactions in this When managing patients who are candidates for VIT, there is study were categorized as mild and 2 (1%) as severe, and no reac- greater risk from withholding this therapy, and the benefit tions with hypotension were observed. These data provide sup- 85 associated with this intervention might be life-saving. port for the contention that b -blocker exposure does not When increase the frequency of systemic reactions from allergen immu- -blocker with an equally such patients are unable to replace a b notherapy; however, these data do not allow a determination as to efficacious alternative, concomitant administration of VIT and a the additional 2 elements of risk, severe and refractory to treat- b -blocker is indicated. ment, because few severe reactions were observed in this study. Summary Statement 39: Glucagon might be efficacious for -Blockers have important differences in receptor affinity, b the treatment of refractory -blocker–associated anaphy- b receptor selectivity, lipophilicity, and intrinsic sympathomimetic laxis. C 261 agonism. Glucagon can exert salutary effects in the setting of treatment- It is unknown whether these dissimilarities translate -blocker–associated anaphylaxis based on increasing b resistant, into meaningful differences in the setting of -blocker–associated b cyclic AMP levels through noncatecholamine mechanisms and b anaphylaxis. Topical -blockers have markedly less systemic ef- 267 exertion of potent chronotropic and inotropic effects. -blockers but can still promote b fects than orally administered Improve- -adrenergic antagonism. Cardioselective b systemic b -blockers, -blocker–associ- ment of refractory hypotension in patients with b b which mainly affect ated refractory anaphylaxis has been reported after administration receptors, are less likely to promote bron- 1 262 of intravenous glucagon. chospasm than nonselective b b -blockers, which inhibit both 1 adrenoceptors. Unusually, severe anaphylaxis in patients Summary Statement 40: ACE inhibitors have been associ- and b 2 -blockers has been b taking ophthalmic and cardioselective ated with greater risk for more severe reaction from venom 262-266 immunotherapy, as well as field stings. ACE inhibitor discon- described ; for this reason, the absence of increased tinuation should be considered for patients receiving venom -blocker risk in association with either ophthalmic or cardiose- b immunotherapy. Concurrent administration of venom immu- lective b -adrenergic antagonists in patients receiving allergen notherapy and an ACE inhibitor is warranted in selected immunotherapy cannot be assumed. cases in which no equally efficacious alternative for an ACE -blockers for whom inhalant b In patients who are taking inhibitor exists and this is judged to be favorable from an in- allergen immunotherapy is being considered or administered, it is dividualized risk/benefit standpoint and consideration of pa- appropriate to incorporate patients’ values and preferences into tients’ preferences. No evidence exists that angiotensin the decision-making process to determine whether the b -blocker receptor blockers are associated with greater risk for anaphy- should be replaced with an acceptable alternative. Many patients laxis from allergen immunotherapy. C will place a higher value on reducing the risk for severe reaction ACE inhibitors and angiotensin receptor blockers inhibit the from immunotherapy and will prefer discontinuing the b -blocker 268 metabolism of angiotensin, bradykinin, and substance P. if an alternative is available; others might accept this added risk and place a higher value on the benefits of continuing the b - Greater risk for more serious anaphylaxis might exist in patients blocker. The evidence reviewed above implies that a cautious receiving these drugs because of possible compromise in compen- b - attitude should be adopted toward the concomitant use of satory activation of the renin-angiotensin system. In patients tak- blockers and inhalant allergen immunotherapy. In patients taking ing an ACE inhibitor, breakdown of vasoactive kinins generated -blockers for whom an acceptable alternative is not available b during anaphylaxis might be impaired. Bradykinin is a potent va- (eg, secondary cardioprotection), withholding immunotherapy soactive mediator that can contribute to the hypovolemia and hy- 269 is generally the most prudent management option. potension observed in patients with severe anaphylaxis. Summary Statement 38: The balance of possible risks and Anaphylaxis occurred in 2 patients receiving VIT while ACE benefits is not the same for patients with the potential for inhibitors were being taken, did not occur when these drugs were life-threatening stinging insect reactions who are also taking withheld, and then recurred with resumption of ACE inhibitor 270 -blocker a b -blocker. In patients who are unable to replace a b treatment. There have been other cases of unusually severe with an equally efficacious alternative, concomitant anaphylaxis in patients receiving VIT while taking an ACE

25 S25 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 difficult for the patient to report signs and symptoms, especially inhibitor, which did not recur after the ACE inhibitor was discon- 271 early symptoms, suggestive of systemic reactions. tinued. No cases such as this have been reported in association with angiotensin receptor blockers. Two retrospective cohort studies did not find an association between ACE inhibitor use and systemic reactions to either Special precautions in patients with asthma 272 238 inhalant immunotherapy or VIT. These data provide support Summary Statement 43: Allergen immunotherapy in asth- for the contention that ACE inhibitor use is not associated with in- matic patients should not be initiated unless the patient’s creased frequency of systemic reactions to allergen immunother- asthma is stable. C apy; however, greater risk for a more serious reaction might still Patients with severe or uncontrolled asthma are at increased 142,143,182 exist. risk for systemic reactions to immunotherapy injections. A large multicenter study of patients receiving VIT found that Three surveys found that deaths from immunotherapy were ACE inhibitor exposure was associated with a statistically more common in patients with asthma that was symptomatic, 161 143,183,184 significant increase in the risk for more severe anaphylaxis. labile, or both. Thus allergen immunotherapy should In patients with anaphylactic potential to Hymenoptera venom, not be initiated in patients with poorly controlled asthma 2,30 patients receiving VIT, or both, it is prudent to consider ACE in- symptoms. hibitor discontinuation to reduce the risk for severe reactions Summary Statement 44: Medical conditions that reduce the while substituting an equally efficacious non–ACE inhibitor alter- patient’s ability to survive the systemic allergic reaction or the native. For patients who require an ACE inhibitor for an indica- resultant treatment are relative contraindications for allergen tion for which there is no equally effective alternative immunotherapy. Examples include severe asthma uncon- medication available, a management decision by the physician trolled by pharmacotherapy and significant cardiovascular prescribing VIT should be approached cautiously from an indi- disease. C vidualized risk/benefit standpoint, including consideration of pa- Alternatives to allergen immunotherapy should be considered tients’ preferences. It is also important to note that the in patients with any medical condition that reduces the patient’s Hymenoptera venom package insert contains a warning that pa- ability to survive a systemic allergic reaction. Examples include tients who ‘‘ undergo desensitization treatment while under . patients withmarkedly compromised lungfunction (eitherchronic concomitant therapy with ACE inhibitors may have an increased or acute), poorly controlled asthma, unstable angina, recent myo- 273 risk of life-threatening anaphylactic reactions.’’ The stinging cardial infarction, significant arrhythmia, and uncontrolled hyper- 158 insect practice parameter and the ACE inhibitor package in- tension. Under some circumstances, immunotherapy might be serts carry a similar warning about the potential increased risk indicated for high-risk patients, such as those with Hymenoptera of systemic reactions to VIT in patients receiving ACE inhibitors. hypersensitivity and cardiac disease being treated with -blocker b There is no evidence that greater risk for anaphylaxis, for more medications. serious anaphylaxis, or for recalcitrant anaphylaxis is present in association with angiotensin receptor blockers. For this reason, suspension of an angiotensin receptor blocker in patients receiv- Reducing the risk of anaphylaxis to immunotherapy ing VIT is not necessary. injections b -blockers and ACE inhibitors are Summary Statement 41: Summary Statement 45: Allergen immunotherapy should frequently prescribed in combination. Concomitant adminis- be administered in a setting where procedures that can reduce tration of both of these medications in a patient who requires the risk of anaphylaxis are in place and where the prompt rec- venom immunotherapy might be warranted, if favorable, ognition and treatment of anaphylaxis is ensured. C from an individualized assessment of potential risks and ben- The major risk of allergen immunotherapy is anaphylaxis, efits and patients’ preferences. D which in rare cases can be fatal, despite optimal management. b -Blockers and ACE inhibitors are commonly prescribed in 274 Therefore allergen immunotherapy should be administered in a combination for patients with heart failure and for secondary 275 setting where anaphylaxis will be promptly recognized and prevention of myocardial infarction. Each drug has been treated by a physician, qualified physician extender (nurse associated with prolonged survival. Patients receiving both drugs practitioner or physician assistant), or both appropriately trained are at heightened risk from VIT because the potential for anaphy- ). in emergency treatment ( Table VI laxis that is more severe, treatment resistant, or both might be Before allergen immunotherapy is chosen as a treatment, the additive; however, an individualized risk/benefit assessment physician should educate the patient about the benefits and risks favors concomitant administration of VIT along with these of immunotherapy, as well as the methods for minimizing risks. medications because this intervention offers the potential for The patient also should be told that despite appropriate precau- greater benefit than the alternatives of either withholding VIT or tions, reactions can occur without warning signs or symptoms. drug suspension. Informed consent should include a discussion of the potential immunotherapy-induced adverse reactions, and this discussion should be documented in the patient’s medical record. Patient requirements and contraindications Summary Statement 42: Patients selected for immunother- apy should be cooperative and compliant. D Management of immunotherapy-induced systemic Patients who are mentally or physically unable to communicate clearly with the physician and patients who have a history of reactions noncompliance might be poor candidates for immunotherapy. If a Summary Statement 46: Epinephrine is the treatment of patient cannot communicate clearly with the physician, it will be choice for immunotherapy-induced systemic reactions. Risk

26 COXETAL J ALLERGY CLIN IMMUNOL S26 JANUARY 2011 TABLE VI. Recommended equipment and medications to treat immunotherapy systemic reactions Adequate equipment and medications should be immediately available to treat anaphylaxis, should it occur. The following are suggested equipment and medications for the management of immunotherapy systemic reactions. Modifications of this suggested list might be based on anticipated emergency medical services’ response time and physician’s airway management skills: stethoscope and sphygmomanometer; d tourniquet, syringes, hypodermic needles, and intravenous catheters (eg, 14-18 gauge); d d aqueous epinephrine HCL 1:1,000 wt/vol; d equipment to administer oxygen by mask; d intravenous fluid set-up; d antihistamine for injection (second-line agents for anaphylaxis, but H1 and H2 antihistamines work better together than either one alone); d corticosteroids for intramuscular or intravenous injection (second-line agents for anaphylaxis); d equipment to maintain an airway appropriate for the supervising physician’s expertise and skill; and d glucagon kit available for patients receiving b -blockers. For a detailed listing of recommended equipment and medication for treatment of anaphylaxis, see Lieberman P, Nicklas RA, Oppenheimer J, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010;126:477-80, e1-42. recommended equipment and medications to treat anaphylaxis factors for fatal immunotherapy-induced reactions include are listed in Tables IV and VI , respectively. delayed administration of epinephrine. B The physician and health care professional who administers immunotherapy injections should be able to recognize and treat IMMUNOTHERAPY SCHEDULES AND DOSES the early symptoms and signs of anaphylaxis and administer emergency treatment, if necessary. For further discussion of the Starting doses treatment of anaphylaxis, see ‘‘The diagnosis and management of Summary Statement 47: The starting dose for build-up is 28 anaphylaxis practice parameter: 2010 update’’. usually a 1,000-fold or 10,000-fold dilution of the maintenance 276 There Epinephrine is the first-line treatment for anaphylaxis. concentrate, although a lower starting dose might be advis- is no contraindication to epinephrine administration in patients able for highly sensitive patients. D with anaphylaxis. It is important to administer epinephrine early There are 2 phases of allergen immunotherapy administration: in the management of anaphylaxis. Fatalities during anaphylaxis the initial build-up phase, when the dose and concentration of usually result from delayed administration of epinephrine and allergen immunotherapy extract are increased, and the mainte- from severe respiratory complications, cardiovascular complica- nance phase, when the patient receives an effective therapeutic tions, or both. dose over a period of time. If the starting dose is too dilute, an Aqueous epinephrine (1:1000 dilution, 0.2-0.5 mL [0.01 mg/kg unnecessarily large number of injections will be needed, resulting in children; maximum, 0.3-mg dose]) should be administered in a delay in achieving a therapeutically effective dose. On the every 5 minutes, as necessary, to control symptoms and increase other hand, if the starting dose is too concentrated, the patient blood pressure. If the clinician deems it appropriate, the 5-minute might be at increased risk of having a systemic reaction. interval between injections can be liberalized to permit more When choosing the starting dose, most allergists/immunolo- frequent injections. Physicians and other health care professionals gists start at a dilution of the maintenance concentrate that is should know the potential pharmacologic benefits, risks, and appropriate based on the sensitivity of the patient to the allergens routes of administration of epinephrine, as well as the potential in the extract, which, in turn, is based on the history and skin test 28,277-279 reasons for lack of response. reactivity. Studies in children not experiencing anaphylaxis have dem- Common starting dilutions from the maintenance concentrate onstrated that plasma levels of epinephrine reach higher levels are 1:10,000 (vol/vol) or 1:1,000 (vol/vol), although more diluted more rapidly when epinephrine is administered intramuscularly concentrations frequently are used for patients who are highly in the thigh compared with subcutaneous administration in the sensitive, as indicated by history or skin test reactions. 279 arm. Intramuscular injection in the thigh in adults who were not experiencing anaphylaxis produced significantly higher peak plasma epinephrine concentrations more rapidly than epi- Frequency of build-up injections nephrine injected intramuscularly or subcutaneously in the upper Summary Statement 48: The frequency of allergen immu- 278 arm, the pharmacokinetic profile for which was similar. notherapy administration during a conventional build-up phase is generally 1 to 3 injections per week. D Whether the same pharmacokinetic profile is seen in patients A number of schedules are used for the build-up phase of with anaphylaxis is not known. It is also not clear whether the immunotherapy. The most commonly used schedule is for pharmacokinetic profile observed after intramuscular administra- increasing doses of allergen immunotherapy extract to be admin- tion in the thigh is preferred compared with subcutaneous admin- istered 1 to 3 times per week (see Table E4 in this article’s Online istration in the arm for treatment of protracted or biphasic anaphylaxis. There are no studies evaluating outcomes in for an example of a conven- www.jacionline.org Repository at tional immunotherapy schedule). This weekly schedule is recom- immunotherapy-induced anaphylaxis that compared sites of epi- mended in most of the allergen extract package inserts. With this nephrine administration, particularly in this circumstance, when schedule, a typical patient can expect to reach a maintenance dose the antigen is introduced into the arm. in 3 to 6 months, depending on the starting dilution and the occur- Appropriate personnel, equipment, and medications should be rence of reactions. It is acceptable for patients to receive injec- immediately available to treat anaphylaxis, should it occur. tions more frequently. The interval between injections is Suggested actions to reduce the risk of anaphylaxis and

27 S27 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 235 injections. empiric but might be as short as 1 day without any increase in the There was no direct correlation between pollen 280 counts and the occurrence of systemic reactions. They did note occurrence of systemic reactions if there is a need to achieve a a correlation between the number of systemic reactions and maintenance dose (eg, allergy season is approaching) or for prac- mean monthly mold counts from August to October. The second tical reasons (eg, patient’s schedule). Alternatively, accelerated prospective study conducted from 1976 to 1989 and involving treatment schedules, such as rush or cluster regimens, can be 513,368 injections did not note an increase in systemic reactions used that more rapidly achieve maintenance dosing. These cluster during the grass and ragweed seasons among patients receiving and rush dosing schedules are discussed in Summary Statements 237 grass or ragweed immunotherapy. 52 through 55. Therefore although some Allergen immunotherapy extracts used during the build-up highly sensitive patients might experience systemic reactions dur- phase usually consist of three or four 10-fold dilutions of the ing their pollen season, most patients do well without dose maintenance concentrate. The volume generally is increased at a adjustment. rate that depends on several factors, including (1) the patient’s sensitivity to the extract, (2) the history of prior reactions, and (3) the concentration being delivered (with smaller percentage in- Dose adjustments for late injections crements being given at higher concentrations). Summary Statement 51: There is no retrospective or pro- In the case of VIT, the aim is to achieve a uniform maintenance spective published evidence to support modification of doses g of each venom; to this end, patients might be dose of 100 m of allergen immunotherapy because of treatment gaps during expected to tolerate relatively large local reactions that might not the build-up or maintenance immunotherapy phases. How- be considered acceptable with inhalant immunotherapy.Dose ever, it is customary to reduce the dose of allergen immuno- adjustments for systemic reactions therapy extract when the interval between injections is Summary Statement 49: The dose of allergen immunother- prolonged. D apy extract should be appropriately reduced after a systemic There are no evidence-based guidelines on dose adjustments reaction if immunotherapy is continued. D for missed immunotherapy doses. During the build-up phase, it is It is customary to either reduce the dose if a systemic reaction customary to repeat or even reduce the dose of allergen immu- has occurred or consider discontinuation of immunotherapy, notherapy extract if there has been a substantial time interval especially if the reaction has been severe. Although there are no between injections. This might depend on (1) the concentration of evidence-based guidelines on dose adjustment after a systemic allergen immunotherapy extract that is to be administered, (2) reaction, many allergists/immunologists reduce the dose to one whether there is a previous history of systemic reactions, and (3) that was previously tolerated or an even lower dose if the reaction the degree of variation from the prescribed interval of time, with was severe. Once the patient tolerates a reduced dose, a cautious longer intervals since the last injection leading to greater reduc- increase in subsequent doses can be attempted. It is important for tions in the dose to be administered. See Table E5 in this article’s the physician who prescribed the allergen immunotherapy extract www.jacionline.org for an example of an Online Repository at to review the course of immunotherapy to determine whether the immunotherapy dose-adjustment schedule for unscheduled gaps risk/benefit assessment justifies continuation of immunotherapy. If in allergen immunotherapy injection intervals. there are recurrent systemic reactions at the maintenance dose, one A pilot observational study of 16 missed-dose adjustment management consideration would be to decrease the maintenance protocols illustrated the wide variation of missed-dose adjust- 281 dose provided the dose is still high enough to benefit the patient. ments used. In this study half the protocols calculated the late interval from the date of the last dose received, whereas the other half calculated the late interval from the date of the missed sched- Reductions during periods of exacerbation of uled dose. The author noted that a stepwise reduction (with the late interval beginning with the date of the missed dose) begin- symptoms ning at 3 weeks late for build-up (reduce 1 dose per week late) Summary Statement 50: Immunotherapy given during pe- and 1 week late for maintenance fell within the interquartile riods when the patient is exposed to increased levels of aller- ranges of all protocols. gens to which they are highly sensitive might be associated with an increased risk of a systemic reaction. However, although survey data have noted this to be a risk factor for severe reactions, several published studies have not found an Cluster schedules association between pollen seasons and systemic reactions. C Summary Statement 52: With cluster immunotherapy, 2 or Injections administered during periods when a patient is more injections are administered per visit to achieve a mainte- exposed to increased levels of allergen to which they are highly nance dose more rapidly than with conventional schedules. C sensitive might be associated with an increased risk of a systemic Cluster schedules are designed to accelerate the build-up phase reaction, especially if the patient is experiencing a significant of immunotherapy. Cluster immunotherapy usually is character- exacerbation of symptoms and, in particular, asthma symptoms. ized by visits for administration of allergen immunotherapy Therefore it is reasonable to consider not increasing or even extract 1 or 2 times per week with a schedule that contains fewer reducing the dose of the allergen immunotherapy extract during total injections than are used with conventional immunotherapy. seasons when the patient is exposed to increased levels of allergen With cluster immunotherapy, 2 or more injections are given per 18,22 to which they are highly sensitive, especially if their symptoms visit on nonconsecutive days. The injections are typically are poorly controlled. given at 30-minute intervals, but longer intervals have also been However 2 large studies did not demonstrate an increase in used in some protocols. This schedule can permit a patient to systemic reactions during the pollen season. The first was a reach a maintenance dose in as brief a period of time as 4 weeks. prospective study of 4,578 patients who received 346,251 Controlled studies have shown symptomatic improvement shortly

28 COXETAL S28 J ALLERGY CLIN IMMUNOL JANUARY 2011 immunotherapy schedules ranged from 15% to 100% of patients after reaching maintenance doses by using cluster sched- 22,113,282,283 who did not receive premedication to 3% to 79% of premedicated ules. See Table E6 in this article’s Online Repository 286 patients in 1 review. at www.jacionline.org for an example of a cluster build-up In one double-blind, placebo-controlled schedule. study comparing the effect of premedication before rush immuno- Summary Statement 53: Studies with single allergens using therapy, systemic reactions were experienced by 27% by pre- 229 a cluster schedule demonstrated a similar or increased fre- medicated versus 73% of placebo-premedicated patients. quency of systemic reactions compared with immunotherapy Most reactions to rush immunotherapy are not severe, and the 292 with conventional schedules. A most common systemic reaction is usually flushing. 113,128,283-285 The cluster schedule is associated with the same Systemic reactions with rush schedules have been reported to or 222 an increased occur up to 2 hours after the final injection. For that reason, frequency of systemic reactions compared with subjects receiving rush immunotherapy should remain under a immunotherapy administered with more conventional schedules. physician’s supervision for a longer waiting period than the usual Most studies comparing the safety of cluster schedules with con- 286,287 30 minutes recommended for conventional schedules (eg, 1.5-3 ventional schedules use single allergens. In a review article hours after allergen immunotherapy extract administration during that analyzed 29 studies using a cluster schedule with venom or rush immunotherapy). aeroallergens, the authors conclude that the optimal tolerance of Rush protocols foradministration offlying Hymenopteravenom cluster schedules is associated with: (1) use of premedication (an- have generally not been associated with a similarly high incidence tihistamine), (2) use of a depot preparation, (3) use of no more than 293,295-297 of systemic reactions. 4 administrations per cluster, (4) use of a total of 4 to 6 clusters, There has been some conflicting 287 and (5) administration of 1 to 2 clusters per week. data on the safety of rush immunotherapy with imported fire ant The review venom. One study demonstrated no significant difference between also notes that the twice-a-week cluster might be associated the premedicated and placebo-premedicated group during a 2-day with less adverse effects than the once-a-week cluster based on 124 rush protocol. the significant difference in systemic reaction rates in 2 separate In another study conducted at the same medical grass pollen cluster studies with virtually identical protocols, ex- center, 24% of patients experienced a systemic reaction during a 298 cept for the frequency of clusters. In the once-a-week cluster the 1-day rush protocol that did not include premedication. systemic reaction rate was 33% in the premedicated group versus 222 79% in the group without premedication. The systemic reaction Premedication and immunotherapy-induced rate in the twice-a-week cluster was 18% in the premedicated 128 group versus 22% in the placebo group. systemic reactions Sum- Premedication and weekly immunotherapy. The occurrence of both local and systemic reactions to mary Statement 56: Premedication might reduce the cluster immunotherapy might be reduced with antihistamine 222 premedication. frequency of systemic reactions caused by conventional immu- notherapy. A There is concern that antihistamines might mask a minor reaction that would otherwise alert a physician to an impending Rush schedules systemic reaction if taken before an immunotherapy injection Summary Statement 54: Rush schedules can achieve a during a conventional build-up. However, one randomized con- maintenance dose more quickly than weekly schedules. A trolled study demonstrated that premedication reduced the fre- Rush schedules are more rapid than cluster immunotherapy. An quency of severe systemic reactions caused by conventional early study used a schedule that permitted patients to achieve a immunotherapy and increased the proportion of patients who maintenance dose in 6 days; however, patients were required to 299 288 achieved the target maintenance dose. remain in the hospital. As experience with accelerated forms of immunotherapy was acquired, schedules were developed to reach analysis of a study designed to investigate oma- In the post hoc 182,229,289-291 a maintenance dose more rapidly. lizumab’s effect on the tolerability of cluster immunotherapy in patients with moderate-to-severe asthma, there was a similar inci- The most accelerated schedule that has been described for dence of systemic reactions in the patients who received antihis- inhalant allergens involves administering 7 injections over the 292 tamine premedication compared with those who did not; however, course of 4 hours. Ultrarush immunotherapy schedules have use of antihistamines was not randomized but rather based on the been described for stinging insect hypersensitivity to achieve a 300 293-295 physician’s discretion. maintenance dose in as little as 3.5 to 4 hours. The advan- Thus patients might still experience systemic reactions despite antihistamine premedication treat- tage of a cluster or rush schedule is that it permits patients to attain ment. Because many patients might take an antihistamine as a therapeutically effective maintenance dose more rapidly than with a conventional schedule. Controlled studies have shown part of their overall allergy management, it is important to deter- mine whether they have taken it on the day that they receive an symptomatic improvement shortly after reaching maintenance 103,203 allergen immunotherapy extract injection for consistency in inter- doses by using rush schedules. pretation of reactions. It also might be desirable that they consis- Summary Statement 55: Rush schedules with inhalant al- tently either take their antihistamine or avoid it on days when they lergens are associated with an increased risk of systemic reac- receive immunotherapy. Other attempts to reduce the occurrence tions. However, rush protocols for administration of stinging of systemic reactions, such as the addition of epinephrine to the Hymenoptera venom have not been associated with a simi- allergen immunotherapy extract or use of concomitant corticoste- larly high incidence of systemic reactions. A roids, are not justified and might delay the onset of a systemic re- The advantage of rush immunotherapy is that the therapeutic action beyond the waiting time when the patient is in the maintenance dose is achieved with fewer office visits in a shorter physician’s office, thus increasing the risk (see summary state- period of time. However, there is an increased risk of local and ments 57 and 58 for further discussion on premedication). systemic reactions. The systemic reaction rate with rush

29 S29 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 there were no statistically significant differences in systemic Premedication with accelerated immunotherapy reaction rates between the premedication group (3.6%) and the schedules. Summary Statement 57: Premedication before 124 placebo group (6.7%). However, a recent 1-day imported fire cluster and rush immunotherapy with aeroallergens might ant rush protocol involving 37 patients performed without pre- reduce the rate of systemic reactions. Combination therapy medication reported higher systemic reaction rates (24.3%) than is effective in reducing systemic and local reactions during the 2-day regimen, with most reactions involving urticaria and accelerated immunotherapy build-up protocols. A 298 pruritus. Oral antihistamines. Oral antihistamines have been shown Because the risk of a systemic reaction from rush immuno- to be effective in decreasing local and systemic reactions during 223-225 therapy with the flying Hymenoptera venoms is relatively low, rush VIT protocols. Premedication with a nonsedating routine premedication is usually unnecessary. Further studies are antihistamine (loratadine) 2 hours before the first injection of needed to clarify the risk of fire ant rush immunotherapy, and each visit reduced both the number and severity of systemic premedication might be considered. reactions during cluster immunotherapy with birch or grass 222 pollen extract. Although rush VIT–induced systemic reaction 293,295-297 rates are typically low, some studies have demon- Omalizumab in combination with immunotherapy strated that the addition of antihistamines decreased the fre- Summary Statement 58: Omalizumab pretreatment has 225 quency of systemic reactions compared with placebo. been shown to improve the safety and tolerability of cluster Antihistamines also decreased the frequency of LLRs over the and rush immunotherapy schedules in patients with moderate first 4 weeks of treatment compared with placebo, although persistent asthma and allergic rhinitis, respectively. Addition- the addition of ranitidine to terfenadine did not provide addi- ally, omalizumab used in combination with immunotherapy 225 tional benefit compared with terfenadine alone. Two has been shown to be effective in improving symptom scores additional rush VIT studies demonstrated that antihistamine pre- compared with immunotherapy alone. A treatment decreased LLRs and cutaneous symptoms of pruritus, Omalizumab used in combination with immunotherapy 2 urticaria, and angioedema but did not decrease the frequency of weeks before and during the grass season was compared with 223,224 respiratory, gastrointestinal, or cardiovascular reactions. immunotherapy alone. The combination therapy improved symp- Finally, a retrospective study reported that premedication with tom load and asthma control, with more patients reporting good or 304 terfenadine during rush VIT might improve efficacy because excellent efficacy. Additionally, omalizumab added to standard the treatment group had fewer systemic reactions to field stings maintenance doses of birch and grass immunotherapy resulted in 301 and sting challenges over an average of 3 years. However, this decreased rescue medication use and symptomatic days com- 302 305 finding was not confirmed on prospective study. pared with omalizumab or immunotherapy alone. The effect of antihistamines in decreasing local and systemic In addition to symptom improvement, omalizumab has also reactions when using conventional schedules has been less been shown to reduce systemic reactions to rush immunotherapy. documented. Antihistamine pretreatment was demonstrated to The use of omalizumab 9 weeks before and in conjunction with decrease the frequency of severe systemic reactions in a study ragweed rush immunotherapy improved symptom severity scores 299 using a conventional build-up schedule. The effect of oral during the ragweed season compared with immunotherapy alone. antihistamines on LLRs in this study was not reported, although Furthermore, omalizumab pretreatment resulted in a 5-fold 306 the antihistamine group more frequently attained the target decrease in the risk of anaphylaxis during rush immunotherapy. maintenance dose. No other study has reported the effect of Additionally, a prospective study examined the effect of 16 weeks antihistamines on LLRs or systemic reactions during conven- of treatment with omalizumab or placebo on the incidence of sys- tional build-up or maintenance injections with inhalant temic reactions during cluster immunotherapy in 248 subjects 300 allergens. For VIT, pretreatment with antihistamines did not with asthma. Eligible subjects were required to have perennial reduce LLR rates during conventional monthly maintenance asthma that was not well controlled despite inhaled corticoste- injections after they decreased LLRs during the initial rush roids and to be sensitive to cat, dog, and/or house dust mite. After 224,225 protocol. 13 weeks of pretreatment with omalizumab or placebo, subjects A pilot study demonstrates that Leukotriene antagonists. received immunotherapy to 1, 2, or 3 allergens (cat, dog, and premedication with montelukast delays the onset and decreases dust mite) through a 4-week cluster regimen, which overlapped the size of local reactions during rush VIT, but no controlled with continued omalizumab/placebo treatment for 3 weeks. studies have investigated the effect of leukotriene antagonists on This was followed by 7 weeks of maintenance injections during 226 the incidence of systemic reactions. which the omalizumab or placebo was not given. Compared Combination pretreatment. Combination pretreatment with placebo, omalizumab pretreatment reduced the rate of sys- with ketotifen, methylprednisolone, and theophylline used during temic reactions during cluster immunotherapy from 26.2% to a 3-day rush treatment with pollen immunotherapy decreased the 13.5%. There were no systemic reactions during maintenance 303 frequency of systemic reactions. Premedication with predni- therapy. sone, an H histamine receptor antagonist, and an H2 histamine There have been a few case reports regarding patients with bee 1 receptor antagonist before rush immunotherapy with inhalant al- venom allergy who were unable to tolerate VIT because of lergens reduced the risk of a systemic reaction from approxi- anaphylaxis but were subsequently able to tolerate VIT with 229 307,308 mately 73% to 27% of patients. The number of local omalizumab. There is also evidence that omalizumab might reactions were also decreased, as was the size of the erythema improve the tolerability of VIT in patients with mastocyto- 309,310 and but not the wheal. sis. Although not specifically approved as a pretreatment During a 2-day imported fire ant rush protocol evaluating the for allergen immunotherapy, the use of omalizumab in these sce- effect of combination therapy with antihistamines and steroids, narios might be beneficial for high-risk patients. It should be

30 COXETAL S30 J ALLERGY CLIN IMMUNOL JANUARY 2011 The syringe can be aspirated as an extra safety step to check for noted that omalizumab has been associated with anaphylaxis in 311,312 blood return before injecting. It has been debated whether syringe 0.09% to 0.2% of patients. aspiration is a necessary step. The Centers for Disease Control and Prevention’s ‘‘General recommendations on immunization recommendations of the Advisory Committee on Immunization Maintenance schedules Practices’’ does not support or recommend aspiration, stating Summary Statement 59: Once a patient reaches a mainte- that ‘‘aspiration before injection of vaccines or toxoids (ie, pulling nance dose, the interval between injections often can be pro- back on the syringe plunger after needle insertion, before injec- gressively increased, as tolerated, up to an interval of 4 tion) is not required because no large blood vessels exists at the weeks for inhalant allergens and up to 8 weeks for venom. 320 recommended injection sites.’’ Some subjects might tolerate longer intervals between main- tenance dose injections. A A retrospective study reported no episodes of blood aspiration Once a patient who is receiving inhalant allergen immunother- were noted by ‘‘ . experienced allergy nurses’’ who were asked if apy reaches a maintenance dose, an interval of 2 to 4 weeks they ‘‘had ever seen blood in the syringe after aspiration’’ during between injections is recommended, provided clinical improve- the previous 3 years in 25,285 immunotherapy injections and 321 ment is maintained. Some subjects might tolerate longer intervals 3,540 immunizations. To avoid recall bias, a subsequent 1-year between maintenance dose injections. prospective study in the clinic was performed and again demon- The interval between flying Hymenoptera venom injections can strated that no episodes of blood while aspirating during immuno- be safely increased up to 8 weeks or even 3 months in some patients therapy were noted in 6,642 immunotherapy injections or 683 immunizations. The author concluded that aspiration before im- without loss of efficacy. Although studies have demonstrated 313-315 effectiveness at 3-month intervals, munotherapy injection is not required. Others have challenged 6-month intervals be- these findings and shared their own anecdotal experiences with tween injections resulted in an increase in reactions to field 316 the aspiration of blood into the syringe during immunother- stings. For imported fire ant immunotherapy, there are no studies 322,323 apy. demonstrating efficacy beyond standard maintenance injection in- These authors state that although rare, the benefit of as- tervals. In other patients, greater efficacy, fewer reactions, or both pirating for blood still outweighs the potential risks. might occur with shorter intervals between injections. Therefore If blood is present in the aspirate, the syringe should be the interval between allergen immunotherapy injections should removed and discarded in an appropriate container (‘‘sharps’’ be individualized to provide the greatest efficacy and safety for box). Another dose of the allergen extract should be drawn into a each patient. new syringe, and a different site should be chosen for the injection. In theory, removal of the syringe when blood is present reduces the likelihood of intravenous administration, which could lead to a systemic reaction. The plunger should be depressed at a Injection techniques rate that does not result in wheal formation or excessive pain. Summary Statement 60: Allergen immunotherapy extract Mild pressure should then be applied to the injection site for about injections should be given with a calibrated small-volume 1 minute immediately after removal of the needle. This reduces syringe with a 26- to 27-gauge ½- or 3/8-inch nonremovable the chance of leakage of the allergen extract, which theoretically needle. C could result in a local reaction. Immunotherapy should be administered with a 26- to 27-gauge syringe with a ½- or 3/8-inch nonremovable needle. Syringes specifically designed for immunotherapy are available from LOCATION OF ALLERGEN IMMUNOTHERAPY medical supply companies. Although recent Occupational Safety ADMINISTRATION and Health Administration guidelines mandate the use of safety needles with allergy injections, recent publications indicate a Supervising medical personnel potential increase in accidental needle sticks with the use of safety Summary Statement 62: Regardless of the location, aller- 317-319 needles compared with standard syringes. gen immunotherapy should be administered under the direct supervision of an appropriately trained physician, qualified Antigens from different vials should not be combined in a physician extender (nurse practitioner or physician assistant), single syringe. or both in a facility with the appropriate equipment, medica- Summary Statement 61: The injection should be given sub- tions, and personnel to treat anaphylaxis. D cutaneously in the lateral or posterior portion of the arm. D The physician and personnel administering immunotherapy Immunotherapy should be given subcutaneously. Subcutane- should be aware of the technical aspects of this procedure and ous injections result in formation of a reservoir of allergen have available appropriately trained personnel, resuscitative immunotherapy extract that is slowly absorbed. Absorption that is equipment/medicines, and storage facilities for allergen immu- too rapid, such as after an intramuscular injection, could lead to a notherapy extract. Physicians and other health care professionals systemic reaction. The skin should be pinched and lifted off of the should be able to recognize early signs and symptoms of muscles to avoid intramuscular or intravenous injection and to anaphylaxis and administer emergency medications as necessary. increase access to the subcutaneous tissues. The physician and staff should be aware of situations that might Each immunotherapy injection should be given in the posterior place the patient at greater risk for systemic reactions portion of the middle third of the arm at the junction of the deltoid (eg, concomitant medications that can interfere with emergency and triceps muscles. This location tends to have a greater amount treatment, such as b -blockers; acute illness; and asthma exacer- of subcutaneous tissue than adjacent areas. The skin should be bations at the time of allergen immunotherapy extract injection). wiped with an alcohol swab before giving the immunotherapy Appropriate adjustment of dose should be made, as clinically injection. This does not sterilize the area, but it does remove gross indicated. The physician whose office prepared the patient’s contamination from the skin surface.

31 S31 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 be administered in a medical facility and withholding this allergen immunotherapy extract should provide adequately la- therapy would result in a serious detriment to the patient’s beled allergen immunotherapy extract vials, detailed directions health (eg, VIT for a patient living in a remote area), careful regarding the dosage schedule for build-up and maintenance, consideration of potential benefits and risks of at-home ad- and instructions on adjustments that might be necessary under ministration of allergen immunotherapy should be made on the following circumstances: an individual basis. If this approach is used, informed consent d when providing patients with new vials; should be obtained from the patient, and the person adminis- d during seasonal exposure to allergens that are in the pa- tering the injection to the patient must be educated about how tient’s allergen immunotherapy extract to which the patient to administer immunotherapy and recognize and treat ana- is very sensitive; phylaxis. D if the patient has missed injections; and d Allergen immunotherapy should be administered in a medical d when reactions occur to the allergen immunotherapy extract. facility with trained staff and medical equipment capable of Any systemic reaction to allergen immunotherapy should be recognizing and treating anaphylaxis. Under rare circumstances, treated immediately with epinephrine, and the physician whose when the benefit of allergen immunotherapy clearly outweighs office prepared the allergen immunotherapy extract should be the risk of withholding immunotherapy (eg, patients with a informed. This might require a return to the allergist/immunol- history of venom-induced anaphylaxis living in a remote region), ogist’s office for treatment and re-evaluation. at-home administration of allergen immunotherapy can be con- sidered on an individual basis. In this instance there should be a discussion with the patient, with careful consideration of the Prescribing physician’s office potential benefits and risks involved in home administration and Summary Statement 63: The preferred location for admin- alternatives. Informed consent should be obtained from the istration of allergen immunotherapy is in the office of the phy- patient and appropriate family members after this discussion. sician who prepared the patient’s allergen immunotherapy Under these circumstances, another adult person should be extract. D trained to administer the injection and to treat anaphylaxis, The preferred location of allergen immunotherapy adminis- should it occur. It should be noted, however, that the package tration is in the office of the physician who prepared the insert approved by the FDA that accompanies all allergen patient’s allergen immunotherapy extract. The physician’s office extracts, including venom, implies that allergy injections should should have the expertise, personnel, and procedures in place for be administered in a clinical setting under the supervision of a the safe and effective administration of immunotherapy. How- physician. Intuitively, the risk from administering allergenic ever, in many cases it might be necessary to administer the extracts outside a clinical setting would appear to be greater. allergen immunotherapy extract in another physician’s office. Recognition and treatment of anaphylaxis might be delayed or Allergen immunotherapy should be administered with the less effective than in a clinical setting in which personnel, same care wherever it is administered. A physician or qualified medications, supplies, and equipment are more optimal to physician extender (nurse practitioner or physician’s assistant) ). Home ad- promptly recognize and treat anaphylaxis ( Table VI should be present and immediately available and be prepared ministration should only be considered in the rare circumstance to treat anaphylaxis when immunotherapy injections are admin- when the benefit of immunotherapy clearly outweighs the risks. istered. Regular practice drills with the office staff for handling Frequent or routine prescription of home immunotherapy is not systemic reactions to immunotherapy reactions should be appropriate under any circumstances. considered. Summary Statement 64: Patients at high risk of systemic reactions, where possible, should receive immunotherapy in Transferring allergen immunotherapy care the office of the physician who prepared the patient’s allergen Summary Statement 66: If a patient receiving immunother- immunotherapy extract. D apy transfers from one physician to another, a decision must Patients at high risk of systemic reactions (highly sensitive, be made by the physician to whom the patient has transferred severe symptoms, comorbid conditions, and history of recurrent as to whether to continue immunotherapy. D systemic reactions), where possible, should receive immunother- Summary Statement 67: If immunotherapy is continued, a 324 apy in the allergist/immunologist’s office. The allergist/immu- decision must then be made about whether to continue un- nologist who prepared the patient’s allergen immunotherapy changed the immunotherapy program initiated by the previ- extract and his or her support staff should have the experience ous physician or to start a new immunotherapy program. and procedures in place for the administration of allergen immu- Patients can continue to receive the immunotherapy extract 185 notherapy to such patients. The early signs of an allergic reac- prepared by the patient’s previous physician if this is accept- tion are more likely to be recognized and early treatment initiated, able to the transferring and accepting physicians. D which will decrease the possibility of a serious outcome. Modifi- Patients may transfer from one physician (previous physician) cations in the patient’s immunotherapy schedule, total treatment to another (current physician) while receiving allergen immuno- program, or both might be more frequently necessary in these therapy. When this occurs, a decision must be made by the high-risk patients. current physician about whether to continue immunotherapy and, if so, what allergen immunotherapy extract and schedule should be used: the one that the patient received from the previous physician (ie, an unchanged immunotherapy program) or one to Outside medical facilities be prepared by the current physician (ie, a new immunotherapy Summary Statement 65: In rare Home administration. program). and exceptional cases when allergen immunotherapy cannot

32 COXETAL S32 J ALLERGY CLIN IMMUNOL JANUARY 2011 reactions might be greater with nonstandardized extracts because The current physician might choose to prepare a new allergen of this potential variability in the composition and/or potency. immunotherapy extract formulation based on the immunotherapy If the allergen immunotherapy extract is to be changed, the prescription or allergy test results from the previous physician, if patient might need to be retested for allergen-specific IgE and the records provide adequate details. If there is inadequate started on an immunotherapy schedule and immunotherapy information in the immunotherapy prescription documentation extract formulation that is appropriate. In this situation the to continue the previous immunotherapy program, re-evaluation starting dose should be comparable with the initial dose that might be necessary, and a new schedule and allergen immuno- would be used if the patient had not previously been receiving therapy extract formulation might be prescribed. immunotherapy. If the information that accompanies the patient is SummaryStatement68:Adetaileddocumentationofthepa- thorough, the current physician can prepare an allergen immu- tient’s schedule and allergen extract content must accompany notherapy extract identical or almost identical to that provided by a patient when he or she transfers responsibility for immuno- the previous physician. In such a case all that might be required is therapy care from one physician to another. In addition, a rec- a decrease in the dose from the patient’s previous injection if there ord of previous response to and compliance with this program has not been too long an interval since the last injection. For lot should be communicated to the patient’s new physician. D changes from the same manufacturer, the physician can consider If the patient transfers from one physician to another and decreasing the dose by 50% to 90% of the previous dose. For continues on the previous immunotherapy program without changes in manufacturer and nonstandardized extracts, a greater changing either the schedule or allergen immunotherapy extract, decrease in dose might be necessary. he or she is not at substantially increased risk of having systemic reactions as long as there is a clear and detailed documentation of the patient’s previous schedule and the contents of the allergen ALLERGEN EXTRACT SELECTION AND HANDLING immunotherapy extract. The patient’s immunotherapy adminis- tration documentation must accompany the patient who transfers Specific allergens responsibility for the immunotherapy program from one physi- Summary Statement 70: Immunotherapy is effective for cian to another. This should include a record of any reactions to pollen, animal allergens, dust mite, mold/fungi, and Hyme- immunotherapy and how they were managed, as well as the pa- noptera hypersensitivity. Therefore immunotherapy should tient’s response to immunotherapy. Under these circumstances, be considered as part of the management program in patients immunotherapy can be continued with the allergen immunother- who have symptoms related to exposure to these allergens, as apy extract that the patient was previously receiving if (1) the supported by the presence of specific IgE antibodies. A previous physician is willing and able to continue to provide Pollen. Pollen extracts have been shown to be safe and 74,130 the patient with the allergen immunotherapy extract, (2) the effective in many controlled clinical trials. It seems reason- patient has shown significant improvement on this immunother- able to extrapolate information about pollen extracts that have apy program, (3) the contents of the allergen immunotherapy been studied to those that have not been subjected to rigorous in- extract are appropriate for the area in which the patient is now vestigation and to assume that the latter are also safe and effective. living, and (4) all extracts are well identified and the records are Less information is available with respect to mixtures of pollen clear (see Tables E7-E15 in this article’s Online Repository at extracts. However, those studies that have been conducted with for documentation guidelines and examples www.jacionline.org mixtures have demonstrated clinical effectiveness (see Summary 82,91 of allergen immunotherapy prescription and administration Statement 72). forms). Mold/fungi. Several studies with Alternaria and Cladospo- Summary Statement 69: An allergen immunotherapy ex- rium species suggestthatallergen immunotherapy withfungimight 102-107 tract must be considered different if there is any change. be effective. However, the allergen content of most commer- 325,326 There is potentially an increased risk of a systemic reaction cially available mold extracts is variable but generally low. if the immunotherapy extract is changed because of the possi- Extracts for some potentially clinically important fungi are not 327 ble variability in the composition and potency of allergen ex- available. For example, there are no commercially available tracts. If the allergen immunotherapy extract is changed, the extracts for many fungal ascospores, even though they frequently patient might need to be retested for specific IgE sensitivity are the dominant type of airborne bioparticulate during certain and started on an immunotherapy formulation and schedule seasons. Another example is the lack of basidiospore (mushroom) that is based on this re-evaluation. D extracts, especially given the evidence that such exposures can be An allergen immunotherapy extract must be considered dif- associated with epidemics of asthma in the late fall. It is important ferent from a clinical standpoint if there is any change in the that the practicing physician distinguishes between molds that are constituents of the allergen immunotherapy extract. These in- Aspergillus and predominantly found indoors (eg, Penicillium clude changes in the lot, manufacturer, extract type (eg, aqueous, genera) and many other molds that are found either exclusively glycerinated, standardized, and nonstandardized), and component outdoors or both indoors and outdoors and be able to assess the allergens and their respective concentrations in the allergen potential clinical effect of each. immunotherapy extract. There is potentially an increased risk of Thereisevidencethat proteolyticenzymespresentinsomemold a systemic reaction if the allergen immunotherapy extract is extracts could digest other antigens, such as pollens or dust mites, 328-330 changed and the patient’s dose is not modified. This increased risk whencombinedinamixture. Forthisreason,itisdesirableto might be due to the significant variability in content and potency separate pollen and other extracts from extracts with high proteo- of extracts and the variability in methods used by physicians to lytic activity when using mixtures (see Summary Statement 84). prepare the patient’s immunotherapy extract. For example, the Animal dander. Although the best treatment for animal strength of a given concentration of nonstandardized extracts allergy is avoidance, this is not always possible. Exposure to both might vary significantly from lot to lot. The risk of systemic dog and cat allergen has been shown to be ubiquitous and can

33 S33 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 There are no placebo-controlled trials evaluating the efficacy of occur even without an animal in the home, making avoidance 331 cockroach immunotherapy for allergic rhinitis or asthma. One even more difficult. controlled trial demonstrated significant reductions in symptom Because immunotherapy has been shown to be effective for 18,22,47,108-110,332,333 21,47 scores and medication use in asthmatic patients with cockroach cat and dog, the decision to include dog or 121 hypersensitivity compared with untreated control subjects. cat allergen in an allergen immunotherapy extract should be con- sidered in those circumstances in which there is exposure. How- This suggests that cockroach immunotherapy might be effective. ever, the major allergen content of cat extracts is relatively low, relatively low Although commercially available extracts are ‘‘ . 338 requiring larger amounts to be given than for pollens or house in potency, immunotherapeutic doses should be achievable.’’ dust mite. The major allergen content of most dog extracts is too Immunotherapy can be considered in conjunction with aggres- low to allow effective dosing, even with undiluted manufacturers’ sive avoidance measures, particularly in patients living in the extracts.However, inonestudyusing anextract containingapprox- inner city who have perennial allergic symptoms and specific IgE g/mL Can f 1 (Hollister-StierLaboratories, Spokane, imately 161 m antibodies to cockroach allergens. If immunotherapy with cock- Wash), there was a significant dose response of immunologic pa- roach extract is prescribed, only glycerinated extracts should be 21 rameters similar to that demonstrated with other allergens. used. The most common species of cockroach identified in dwellings Dust mites. Crude house dust extract is generally an inap- are the German cockroach, , and the American Blatella germanica propriate substitute for house dust mite extract because the Periplaneta americana. cockroach, Allergens derived from B ger- protein content is not restricted to dust mite allergens, nor does P amer- include Bla g 2, Bla g 4, and Bla g 5 and that for manica it necessarily guarantee inclusion of dust mite proteins. Immu- is Per a 1. Partial cross-reactivity between cockroach icana notherapy with standardized dust mite is generally more effective allergens exists, but each regionally relevant species should be than that with crude house dust allergens. The house dust mites 339 represented in the immunotherapy extract. Dermatophagoides farinae and Dermatophagoides pteronyssinus contain 2 major allergen groups that are immunologically cross- reactive: Der p 1 and Der f 1 and Der p 2 and Der f 2. Sixty percent or more of mite-sensitive patients react to these 2 major allergen Multiallergen immunotherapy dust mite groups. Allergens from other species of mites (eg, Blo- Summary Statement 72: There are few studies that have in- Euroglyphus mayne i) partially cross-react with mia tropicalis and vestigated the efficacy of multiallergen subcutaneous immu- 334,335 species. allergens from Dermatophagoides notherapy. These studies have produced conflicting results, Only 50% of the with some demonstrating significant clinical improvement D pteronys- projected amounts of each of the 2 house dust mites ( compared with placebo and others showing no benefit over sinus and D farinae ) needs to be included when preparing an al- optimal pharmacotherapy and environmental control mea- lergen immunotherapy extract based on the high degree of cross- sures. Thus it is important to treat the patients only with rel- allergenicity between the major allergens in these 2 species. Im- 17,112,115,116,118 evant allergens. B munotherapy for dust mites is effective and should The vast majority of clinical immunotherapy trials have been be considered in conjunction with avoidance measures in patients 74,130 with single allergens. who have symptoms consistent with dust mite allergy and specific The limited number of studies investi- IgE antibodies for dust mite allergens. gating the efficacy of multiallergen immunotherapy have pro- The addition of dust mite immunotherapy after a year of duced conflicting results. In general, multiallergen trials have 47,82,90,340 pharmacologic treatment and house dust mite avoidance provided demonstrated efficacy, although some failed to provide 9,109,341,342 additional clinical benefits in a double-blind, placebo-controlled results specific to the multiallergens. study of patients with dust mite allergy with mild-to moderate A review of the immunotherapy literature identified 13 studies 112 asthma. that used 2 or more unrelated allergen extracts: 11 subcutaneous, After an observational year of pharmacologic treat- 343 2 sublingual, and 1 with both. ment and allergen avoidance, patients were randomized to receive Four of the 7 studies that used 2 dust mite SCITor placebo for 3 years. There was a significant de- non–cross-reacting allergens reported superior efficacy compared crease in rescue bronchodilator use, an increase in morning and with placebo and comparable efficacy when compared with evening peak expiratory flow rates, and reduction in skin test re- single-allergen extract treatment. However, the other 3 studies activity in the immunotherapy group compared with values in the did not report the results between single and multiple allergens placebo group. A similar improvement in asthma symptoms has separately. In the 5 studies that used multiple allergens, the prac- 336 been demonstrated with dust mite SLIT. tice most commonly used by US allergists, 3 demonstrated effi- 82,100,344 95,188 cacy, and 2 did not. Dust mite hypersensitivity should particularly be considered in patients who have perennial symptoms exacerbated by dusty The considerable heterogeneity of these clinical trials makes environments. comparison difficult, and the failure of some studies to provide Randomized, double-blind, pla- Hymenoptera venom. results specific to each allergen makes it difficult to evaluate the cebo-controlled studies show that immunotherapy with Hyme- efficacy of multiallergen immunotherapy. Further research on the noptera venom is effective in dramatically reducing the risk of efficacy of multiallergen immunotherapy is needed. It is also anaphylaxis to honeybee, yellow jacket, hornet, and wasp important to treat the patients only with relevant allergens. 85,158,337 stings. Efficacy has also been demonstrated with immu- 122,123 notherapy using whole-body extracts of imported fire ants. Basis of allergen extract selection Summary Statement 73: The selection of the components of an allergen immunotherapy extract should be based on a Cockroach careful history in correlation with positive allergy skin test re- Summary Statement 71: There are limited data on the effi- sults or serum specific IgE antibodies. The allergen cacy of cockroach immunotherapy. B

34 COXETAL S34 J ALLERGY CLIN IMMUNOL JANUARY 2011 without establishing the possible clinical relevance of these aller- immunotherapy extract should contain only clinically rele- gens, might dilute the content of other allergens in the allergen vant allergens. In choosing the components for a clinically rel- immunotherapy extract and make allergen immunotherapy less evant allergen immunotherapy extract, the physician should effective. be familiar with local and regional aerobiology and indoor Inclusion of allergens to which the patient does not have and outdoor allergens, paying special attention to potential al- demonstrable specific IgE (ie, nonrelevant allergens) might result lergens in the patient’s own environment. D 348,349 in new sensitization rather than induction of tolerance. A careful history, noting environmental exposures and an The understanding of the local and regional aerobiology of suspected physician should therefore select those aeroallergens for testing allergens, such as pollen, mold/fungi, animal dander, dust mite, and treatment that are clinically relevant. and cockroach, is required in the selection of the components for a As is the case in interpreting positive immediate hypersensi- clinically relevant allergen immunotherapy extract. Although the tivity skin test results, there must be a clinical correlation with the relationship between day-to-day outdoor pollen and fungi expo- in vitro demonstration of allergen-specific IgE levels and a clini- sure and the development of clinical symptoms is not always cal history of an allergic disease. There is no evidence to support clear, symptoms that occur during periods of increased exposure the administration of immunotherapy based solely on results of to allergens, in association with positive allergy skin test results or serum specific IgE testing, as is being done by both commercial serum specific IgE antibodies, provide good evidence that such laboratories and some physician’s offices. This is promoting the exposures are relevant. Because North America is botanically and remote practice of allergy, which is not recommended. ecologically diverse, it is not possible to devise a common list of There are no data to support allergen immunotherapy as a appropriate allergen extracts for each practice location. Only treatment for non–IgE-mediated symptoms of rhinitis or asthma. clinically relevant allergens should be included in the allergen immunotherapy treatment. The clinical relevance of an aeroallergen depends on certain Skin tests and serum specific IgE antibody tests key properties: (1) its intrinsic allergenicity, (2) its aerodynamic Summary Statement 74: Skin testing has been the primary properties, (3) whether it is produced in large enough quantities to diagnostic tool in clinical studies of allergen immunotherapy. be sampled, (4) whether it is sufficiently buoyant to be carried Therefore in most patients skin testing should be used to de- long distances, and (5) whether the plant releasing the pollen is termine whether the patient has serum specific IgE anti- widely and abundantly prevalent in the region. The primary bodies. Appropriately interpreted serum specific IgE allergens used for immunotherapy are derived from plant antibodies can also be used. C (grasses, trees, and weeds), arthropod (house dust mites), fungus, The use of standardized allergens has greatly increased the animal (cat and dog), insect (cockroach), and Hymenoptera consistency of skin test results for these antigens. Controlled venom source materials. Information concerning regional and studies in which the clinical history has correlated with skin test local aerobiology is available on various Web sites or through the results have demonstrated the efficacy of immunotherapy for 17,21,22,47,82,99,103,104,109,121 . National Allergy Bureau at http://www.aaaai.org/nab relevant allergens. Skin testing can A patient’s lifestyle can produce exposure to a wide variety of also provide the physician with useful information about the ap- aeroallergens from different regions, necessitating inclusion in propriate starting dose of selected allergens. On rare occasions, the extract of multiple allergens from different geographic areas. systemic reactions can occur after skin testing in a highly sensi- 237,350,351 Determination of the significance of indoor allergens for a partic- tive subject. In addition, skin tests might be difficult to ular patient might be difficult to determine. Historical factors, perform in patients with dermatographism or atopic dermatitis. such as the presence of a furry animal in the home or a history Serum specific IgE tests are particularly useful in such patients. of insect infestation, might be helpful. Animals in the home Studies indicate that skin testing might be more sensitive than 352-357 were associated with much higher dander levels, cockroach sight- tests in detecting allergen-specific IgE. in vitro Based on ings correlated with significant cockroach allergen in the home, nasal/bronchial challenge test results, skin tests have greater sen- 356-358 and dampness in houses has been a risk factor for respiratory sitivity than serum specific IgE measurement. The compa- symptoms, including asthma. However, some studies have dem- rability of skin tests and serum specific IgE antibodies depends on onstrated significant indoor levels of cat and dog allergen in the allergen being tested. For these reasons, skin testing is prefer- 331 households without pets able as a method for selection of allergens for inclusion in and significant levels of murine aller- 346 345 immunotherapy and determining the starting dose for an immuno- gen in suburban of asthmatic children. and inner-city homes therapy program. Among the skin testing techniques available, a In the National Cooperative Inner-City Asthma Study, 33% of the properly applied percutaneous (prick/puncture) test consistently homes had detectable rat allergen (Rat n 1), and a correlation be- produces reproducible results. Generally, skin prick testing is sen- tween rat allergen sensitization and increased asthma morbidity in 347 sitive enough to detect clinically relevant IgE antibodies when po- inner-city children was found. Fur-bearing pets and the soles of 354 359 tent extracts, such as grass shoes are also conduits by which molds and other ‘‘outdoor’’ al- and cat, are used. lergens can enter the home. Intradermal/intracutaneous skin testing might be required for Several commercial immunoassays to measure the presence of some allergen extracts. It is appropriate in some patients to use indoor allergens (eg, dust mite, cat, cockroach, and dog) in settled serum specific IgE tests as an alternative to skin tests in the house dust samples are available and might provide useful diagnosis of allergic rhinitis, allergic rhinoconjunctivitis, allergic estimates of indoor allergen exposure. asthma, atopic dermatitis, and stinging insect hypersensitivity. The omission of clinically relevant allergens from an allergic Serum specific IgE tests can also be used to define the allergens patient’s allergen immunotherapy extract contributes to the de- that should be used in allergen immunotherapy. creased effectiveness of allergen immunotherapy. Conversely, in- In the case of Hymenoptera venom, immunotherapy can be clusion of all allergens to which IgE antibodies are present, started even without a live sting challenge in patients with

35 S35 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 372 system for determining BAU values. in vitro EAL method en- The ID test results. How- negative skin test results and positive 50 ever, there are no published results of the effectiveness of Hyme- tails preparing a series of 3-fold dilutions of a candidate reference extract and injecting 0.05 mL intradermally to 15 to 20 ‘‘highly noptera VIT in patients with negative skin test results and positive serum venom-specific IgE antibody results. sensitive’’ allergic subjects. The dilution that results in an erythema with the sum of the longest diameter and midpoint (orthogonal) diameter equaling 50 mm is considered the end point (D Allergen extract selection ). The mean D is calculated, and the potency of the extract 50 50 is assigned. Summary Statement 75: Nonstandardized extracts can Standardized extracts are available with biologic potencies of vary widely in biologic activity and composition, regardless 10,000 and 100,000 BAU for grasses; 5,000 and 10,000 BAU for of a particular weight/volume or PNU potency, and should cat allergen; 5,000, 10,000, and 30,000 AU for dust mite; and not be considered equipotent. B 100,000 AU or 1:10 and 1:20 wt/vol for short ragweed, with the An allergen extract is a solution of elutable materials derived Amb a 1 concentration listed in FDA units on the label of the from allergen source materials, such as pollens or molds. They weight/volume extracts. consist of complex mixtures of proteins and glycoproteins to Cat and short ragweed extracts were originally standardized which antibodies can bind. Cockroach and animal dander contain 360,361 based on the estimate of major allergen content: Fel d 1 and Amb a between 10 and 20 antigens, house dust mites between 20 362 363-365 1, respectively. The concentrations of Fel d 1 and Amb a 1 were and 40 antigens, and pollens between 30 and 50 antigens, 366 shown to correlate with the overall biological activity of the cat and a fungal extract can contain as many as 80 antigens. and short ragweed extracts, as determined by means of quanti- Nonstandardized extracts are labeled as weight/volume, which 367,373 tative skin testing. expresses weight in grams per volume in milliliters; that is, a potency of 1:100 indicates that 1 gram of dry allergen (eg, Short ragweed extract is sold as weight/volume or AU per ragweed) was added to 100 mL of a buffer for extraction. milliliter, with the Amb a 1 content reported in FDA units: 1 FDA Nonstandardized extracts can also be labeled in PNU, where unit of Amb a 1 equals 1 m g of Amb a 1, and 350 units of Amb a 1/ 1 PNU equals 0.01 g of protein nitrogen. Neither method confers mL is approximately equivalent to 100,000 AU/mL. Cat extracts any direct or comparative information about an extract’s biologic are available as 5,000 and 10,000 BAL/mL, which contain 10 to potency. Nonstandardized extracts can have a wide range of po- 19.9 FDA units of Fel d 1/mL: 1 FDA unit of Fel d 1 equals 2 to 4 371,373,374 tencies. Extracts labeled with a particular weight/volume or m g of Fel d 1. Approximately 22% of subjects with cat 367-369 375 PNU potency can have widely varying biologic activities. allergy have specific IgE antibodies to cat albumin. Cat pelt ex- 376 tracts have a greater amount of albumin than cat hair extracts. Therefore they should not be considered equipotent. Nonstandardized manufacturer’s extracts usually are available Dust mites were originally standardized in AU by means of the at concentrations of between 1:10 and 1:50 wt/vol or 20,000 and RASTassay. Subsequent ID EAL testing indicates that the AU is 50 bioequivalentto the BAU, and therefore theoriginal AU nomencla- 100,000 PNU. 377 Summary Statement 76: When possible, standardized ex- turewas retained. Thus dust mite extracts are still labeled in AU. tracts should be used to prepare the allergen immunotherapy extract treatment sets. A Allergen extracts are commercially available for most of the Allergen extract preparation commonly recognized allergens. Allergen extract potency varia- Summary Statement 77: Allergen immunotherapy extract bility and product composition inconsistency have several poten- preparation should be performed by persons experienced tial consequences. Diagnostic allergy skin testing and allergen and trained in handling allergenic products. A customized al- immunotherapy efficacy and safety are dependenton the quality of lergen immunotherapy extract should be prepared from a the allergen extracts. When possible, standardized extracts should manufacturer’s extract or extracts in accordance to the pa- 2,370,371 be used to prepare allergen immunotherapy treatment sets. tient’s clinical history and allergy test results and might con- tain single or multiple allergens. D The advantage of standardized extracts is that the biologic activity Allergen immunotherapy extracts carry the risk for anaphy- is more consistent, and therefore the risk of an adverse reaction laxis. Compounding personnel should be appropriately trained caused by extract potency variability should be diminished. health professionals, including, but not limited to, registered US-licensed extracts can be obtained in aqueous, glycerinated, nurses, licensed practical nurses, medical technicians, medical lyophilized, and acetone- and alum-precipitated formulations. assistants, physician assistants, advanced practice nurses, and Some commonly used allergens are standardized. These include physicians. The compounding personnel should use the allergen D farinae , D pteronyssinus extracts for cat hair, cat pelt, , short extract preparation guidelines, the revised USP 797 pharmaceu- ragweed, Bermuda grass, Kentucky bluegrass, perennial rye 2,378 ). Tables VII and VIII tical compounding guidelines, or both ( grass, orchard grass, timothy grass, meadow fescue, red top, sweet vernal grass, and Hymenoptera venoms (yellow jacket, The physician is responsible for providing general oversight and honeybee, wasp, yellow hornet, and white-faced hornet). How- supervision of compounding, as well ensuring that the com- ever, most allergen extracts are not yet standardized. Allergen pounding personnel are appropriately trained in the allergen ex- standardization comprises 2 components: (1) selection of a refer- tract preparation guidelines. These guidelines recommend that ence extract and (2) selection of an assay or procedure to compare compounding personnel complete a media-fill test, which is a the manufactured extract with the reference extract. Allergen procedure used to assess the quality of the aseptic technique. standardization in the United States is based on assessment of The USP 797 guidelines require compounding personnel to per- 379 the potency of allergen extracts by using quantitative skin tests form and pass a media-fill test on at least an annual basis. and reported as BAU values. The quantitative test method is called Both guidelines also recommend that compounding personnel the intradermal dilution for 50 mL sum of erythema (ID take and pass a written test. The test is available online at EAL) 50

36 COXETAL S36 J ALLERGY CLIN IMMUNOL JANUARY 2011 Allergen immunotherapy extract preparation guidelines TABLE VII. Qualifications of extract preparation personnel 1. : Compounding personnel must pass a written test on aseptic technique and extract preparation. d Compounding personnel must be trained in preparation of allergenic products. d d Compounding personnel must annually pass a media-fill test, as described in Addendum A. d Compounding personnel who fail written or media-fill tests would be reinstructed and re-evaluated. d Compounding personnel must be able to demonstrate understanding of antiseptic hand cleaning and disinfection of mixing surfaces. Compounding personnel must be able to correctly identify, measure, and mix ingredients. d d Compounding personnel should be appropriately trained health professionals, including, but not limited to, registered nurses, licensed practical nurses, medical technicians, medical assistants, physicians’ assistants, advanced practice nurses, and physicians. : A physician with training and expertise in allergen immunotherapy is responsible for ensuring that compounding personnel are 2. Physician responsibility instructed and trained in preparation of immunotherapy with aseptic techniques as defined below and that they meet the requirements of these guidelines. Evidence of such compliance shall be documented and maintained in personnel files. The physician is responsible for providing general oversight and supervision of compounding. 3. : Allergen extract dilutions must be bacteriostatic, meaning that they must contain phenol concentrations of at least 0.25%, or if the phenol Bacteriostasis concentration is less than 0.25%, the extract must have a glycerin concentration of at least 20%. 4. Dilutions prepared in accordance with manufacturer’s instructions : Allergen extracts must be diluted in accordance with the antigen manufacturer’s instructions. 5. Potency : The manufacturer’s expiration dates must be followed. Beyond-use dates for allergy extract dilutions should be based on the best available clinical data. : Cross-reactivity of antigens: Separation of aqueous extracts with high proteolytic enzyme 6. Mixing of extracts with high and low proteolytic enzymes activities from other extracts is recommended. C to reduce the rate of potency loss or according to the manufacturer’s directions. Extracts beyond the expiration : Extracts should be stored at 4 7. 8 Storage date of the manufacturer are to be discarded. Storage must be in a designated refrigerator for medications and not used for food or specimens. 8. Subcutaneous injection : Allergen extracts can only be administered intradermally or through subcutaneous injection unless FDA-approved package inserts or accepted standards of clinical practice permit another route of administration. Aseptic technique 9. : Preparation of allergy immunotherapy shall follow aseptic manipulations defined as follows: d The physician must designate a specific site, such as a countertop, in an area of the practice facility where personnel traffic is restricted and activities that might contribute to microbial contamination (eg, eating, food preparation, and placement of used diagnostic devices and materials and soiled linens) are prohibited. d The extract preparation area must be sanitized with 70% isopropanol that does not contain added ingredients, such as dyes and glycerin. d Extract preparation personnel must thoroughly wash hands to wrists with detergent or soap and potable water. Substitution of hand washing by mean of treatment with sanitizing agents containing alcohol, 70% isopropanol, or both is acceptable. d Necks of ampules to be opened and stoppers of vials to be needle punctured must be sanitized with isopropanol. d Direct contact contamination of sterile needles, syringes, and other drug-administration devices and sites on containers of manufactured sterile drug products from which drugs are administered must be avoided. Sources of direct contact contamination include but are not limited to touch by personnel and nonsterile objects, human secretions, blood, and exposure to other nonsterile materials. After mixing is complete, visual inspection is to be performed for physical integrity of the vial. d : Immunotherapy vials are to be clearly labeled with the patient’s name and the beyond-use date of the vial. Labeling 10. Mixing log : A mixing log is to be kept with information on the patient’s name, extract used for mixing, mixing date, and expiration date and lot numbers. 11. 12. Policy and procedure manual : Practices preparing allergy extracts must maintain a policy and procedure manual for the procedures to be followed in mixing, diluting, or reconstituting of sterile products and for the training of personnel in the standards described above. Addendum A. Example of a media-fill test procedure This or an equivalent test is performed at least annually by each person authorized to compound allergen immunotherapy extracts under conditions that closely simulate the most challenging or stressful conditions encountered during compounding of allergen immunotherapy extracts. Once begun, this test is completed without interruption. A double-concentrated medium, such as from Valiteq, is transferred in ten 0.5-mL increments with a sterile syringe to a sterile 10-mL vial. Five milliliters of Cto35 sterile water (preservative free) is added. This is the ‘‘concentrate.’’ The vial is incubated within a range of 20 C for 14 days. Failure is indicated by 8 8 visible turbidity in the medium on or before 14 days. (see Summary Statement 89 for further discussion of allergen www.JCAAI.org along with an allergen extract preparation extract dilution expiration dates). Allergen immunotherapy ex- http://www. handbook that can be used to prepare for the test ( tracts are prepared by using sterile manufacturer’s extracts and ). jcaai.org sterile diluents containing antibacterial constituents (usually phe- Policies, procedures, and processes intended for conventional nol). There are no reports of infections associated with allergen drugs and medications might be inappropriate for allergenic pro- 380-382 immunotherapy injections. ducts. For example, substitution with differing lots, manufacturers, or dose formulations might be routine for conventional drugs and Extracts obtained from extract-manufacturing companies medications but could lead to anaphylactic reactions with allergenic should be called the manufacturer’s extract. Vials of manufac- products because of significant differences in the composition, turer’s extract contain individual or limited mixtures of allergens potency, or both of the new extract. that can be used alone as a concentrated dose of single allergen or Prepared allergenic products usually have expiration dates of 3 combined with other concentrated allergens to prepare an individ- to 12 months from the date of preparation but should not extend ual patient’s customized allergen mixture, designated as the pa- beyond the shortest expiration date of the individual components tient’s maintenance concentrate.

37 S37 J ALLERGY CLIN IMMUNOL COX ET AL VOLUME 127, NUMBER 1 378,379 TABLE VIII. USP Chapter 797 sterile compounding standards for allergy vaccine preparation Allergen extracts as compounding sterile preparations (CSPs) are single- and multiple-dose intradermal or subcutaneous injections that are prepared by specially trained physicians and personnel under their direct supervision. Allergen extracts as CSPs are not subject to the personnel, environmental, and storage requirements for all CSP Microbial Contamination Risk Levels in this chapter only when all of the following criteria are met: 1. Before beginning compounding activities, personnel perform a thorough hand-cleansing procedure by removing debris from under fingernails (using a nail cleaner under running warm water), followed by vigorous hand and arm washing to the elbows for at least 30 seconds with either nonantimicrobial or antimicrobial soap and water. 2. Compounding personnel wear hair covers, facial hair covers, gowns, and face masks. 3. Compounding personnel perform antiseptic hand cleansing with an alcohol-based surgical hand scrub with persistent activity. 4. Compounding personnel wear powder-free sterile gloves that are compatible with sterile 70% isopropyl alcohol before beginning compounding manipulations. 5. Compounding personnel disinfect their gloves intermittently with sterile 70% isopropyl alcohol when preparing multiple allergenic extract as CSPs. 6. Ampule necks and vial stoppers on packages of manufactured sterile ingredients are disinfected by careful wiping with sterile 70% isopropyl alcohol swabs to ensure that the critical sites are wet for at least 10 seconds and allowed to dry before they are used to compound allergen extract as CSPs. 7. The label of each multidose vial of allergen extract as CSPs lists the name of one specific patient, a beyond-use date, and a storage temperature range that is assigned based on the manufacturer’s recommendations or peer-reviewed publications. 8. Single-dose allergen extract as CSPs shall not be stored for subsequent additional use. A copy of the complete USP Chapter _77 guidelines can be accessed at http://www.usp.org/USPNF/pf/generalChapter797.html. 383 even desirable to include both in the same mixture. The main factor that limits how concentrated an allergen immu- Such a practice might result in the addition of too much of a given aller- notherapy extract can be is the tendency of highly concentrated antigen solutions to develop precipitates. This is an unpredictable gen, which could lead to an adverse reaction, as well as the unnec- and poorly understood phenomenon. Although there is no evidence essary dilution of other allergens, with a resultant reduction in efficacy. A knowledge of each allergen’s classification according that such precipitates adversely affect the extract, the FDA does not permit a manufacturer to ship an extract that has a precipitate. to species and the fact that there is immunologic cross-reactivity within allergens of the same genus or subfamily allows one to se- lect components of the allergen immunotherapy extract that are maximally effective. In general, the patterns of allergenic cross- Principles of mixing allergen immunotherapy reactivities among pollens follow their taxonomic relationships Summary Statement 78: Consideration of the following (see Fig E5 in this article’s Online Repository at www. principles is necessary when mixing allergen extracts: jacionline.org for patterns of allergen cross-reactivity). (1) cross-reactivity of allergens, (2) optimization of the dose of in vivo Cumulative data, both in vitro and , concerning cross- each constituent, and (3) enzymatic degradation of allergens. B reactivity offer a practical advantage in the selection of several Once the relevant allergen or allergens for each patient are categories of pollen allergens for immunotherapy. However, identified, a mixture that contains these allergens can be formu- because cross-reactivity is variable for many grass and weed lated. Standardized extracts should be used, when available, and pollens, their intrinsic allergenicity, prevalence, and aerobiologic can be mixed with nonstandardized extracts. Several factors need 384,385 characteristics within a specific region should be considered. to be considered when combining extracts, including (1) cross- reactivity of allergens, (2) the need to include the optimal dose for Because many temperate pasture grasses (subfamily Pooideae; eg, each constituent, and (3) potential interaction between different fescue, rye, timothy, blue, and orchard, which are widely types of allergens, when mixed, that could lead to degradation of distributed throughout the United States) share major allergens, in- allergen extract components because of proteolytic enzymes. clusion of a representative member (eg, perennial rye, meadow fescue, or timothy) generally provides efficacy against the entire 386-393 group. Grasses in other subfamilies (eg, Bermuda, Bahia, and Johnson) show greater diversity and should be evaluated Cross-reactivity of allergen extract 394-396 separately. Bermuda and Johnson grasses are important in Summary Statement 79: The selection of allergens for im- the South, and Bahia has become an important allergenic grass munotherapy should be based in part on the cross-reactivity of clinically relevant allergens. Knowledge of allergen in the lower southern states. Because it is uncertain whether palms, cross-reactivity is important in the selection of allergens for sedges, and cattails have the ability to trigger allergy symptoms, immunotherapy with these allergens is generally not immunotherapy because limiting the number of allergens in recommended. a treatment vial might be necessary to attain optimal thera- Although cross-reactivity among tree pollens is not as pro- peutic doses of each of the components. Many botanically related pollens contain allergens that are cross-reactive. nounced as that among grass or ragweed pollens, it does occur. When pollens are substantially cross-reactive, selection of a Pollen from members of the cypress family (Cupressaceous; eg, 383,397-399 juniper, cedar, and cypress) strongly cross-react. single pollen within the cross-reactive genus or subfamily There- fore pollen from one member of this family should be adequate for might suffice. When pollen allergens are not substantially cross-reactive, testing for and treatment with multiple locally skin testing and immunotherapy. The closely related birch family prevalent pollens might be necessary. B (Betulaceae; eg, birch, alder, hazel, hornbeam, and hop horn- Allergenic cross-reactivity is the recognition by the patient’s beam) and oak (Fagaceae; eg, beech, oak, and chestnut) have 400,401 immune system of different extracts’ constituents as the same strong cross-allergenicity. Significant cross-reactivity be- or similar. When one allergen elicits the same immunologic re- tween Betulaceae pollens and oak of the Fagaceae family has 386 sponses as another cross-reacting allergen, it is not necessary or been demonstrated with percutaneous skin testing. RAST

38 COXETAL S38 J ALLERGY CLIN IMMUNOL JANUARY 2011 Hong Kong, and parts of Australia, and anaphylaxis has been re- inhibition studies have shown cross-inhibition between oaks and 402 418-420 ported in Europe. species. Fagales other IgE immunoblot inhibition experiments Commercial venom extracts are available have demonstrated that the Fagales for some Hymenoptera species, except the fire ant, for which only species might be strongly in- 403 whole-body extract is available. hibited by birch species. The use of one of the locally prevalent 404 members (eg, birch and alder) should be adequate. Ash and European olive trees are strongly cross-reactive; the extract that is the most prevalent in the region and best correlates Dose selection 405,406 with symptoms could be used. Maple and box elder trees Summary Statement 80: The efficacy of immunotherapy depends on achieving an optimal therapeutic dose of each of are found throughout the United States, except for the arid south- the constituents in the allergen immunotherapy extract. A ), box elders Acer west. Although in the same genus as maple (ie, The maintenance dose of allergen immunotherapy must be appear different and should be considered separately. Oaks and 17-22,97,421 elms (eg, Chinese, Siberian, some American) are prevalent in adequate. Low maintenance doses are generally not ef- eastern and central states but have a more limited distribution fective (eg, dilutions of 1:1,000,000, 1:100,000, and 1:10,000 vol/ west of the continental divide. The distribution of other trees is vol). A consideration when mixing extract is the need to deliver an variable enough to require botanical observation in a given locale. optimal therapeutically effective dose of each of the constituents There is strong cross-reactivity between major allergens of in the allergen immunotherapy extract. Failure to do so will re- common ragweed species (eg, short, giant, false, and western). duce the efficacy of immunotherapy. This might occur because However, southern and slender ragweed do not cross-react as of a dilution effect; that is, as one mixes multiple extracts, the con- 385,407 well, and there are allergenic differences between major centration of each in the final mixture will be decreased. Summary Statement 81: The maintenance concentrate and minor allergens of short and giant ragweed that might be clin- 408 should be formulated to deliver a dose considered to be ther- ically significant. apeutically effective for each of its constituent components. Weeds other than ragweed, such as marsh elders, sages, and The maintenance concentrate vial is the highest- mugwort, have an abundant distribution, predominantly in the concentration allergy immunotherapy vial (eg, 1:1 vol/vol western states. These weeds and sages ( Artemisia species) must vial). The projected effective dose is called the maintenance be treated separately from the ragweeds. Sages are strongly goal. Some subjects unable to tolerate the projected effective cross-reactive, and a single member can provide adequate cover- 409 dose will experience clinical benefits at a lower dose. The age of the group. Similarly, Chenopod-Amaranth families have maintenance dose is the dose that provides therapeutic effi- wide ranges in the western regions but are present throughout 410 cacy without significant adverse local or systemic reactions North America. Current information on the cross-reactivity 411,412 and might not always reach the initially calculated projected of these families is limited. Skin testing suggests strong effective dose. This reinforces that allergy immunotherapy cross-reactivity across Chenopod and Amaranth family bound- aries. The Amaranth family also seems to have strong cross- must be individualized. A 413 The highest concentration of an allergen extract mixture that is reactivity by means of RAST inhibition and immunodiffusion. projected to be used as the therapeutic effective dose is called the The use of a single Amaranth extract should be sufficient to cover maintenance concentrate. The maintenance concentrate (if a this family. Similarly, species (eg, saltbushes and scales) Atriplex 414,415 mixture of extracts) should either be obtained from the manufac- show near identity, and use of a single member is adequate. turer as a customized mixture or should be prepared by the Among other subfamily Chenopod members, Russian thistle ap- physician under sterile conditions by adding an appropriate pears to have the most cross-allergenicity. volume of the individual manufacturer’s extracts. The mainte- D pteronyssinus The most prevalent house dust mites, D and nance concentrate should be formulated to deliver a full projected , are ubiquitous except in arid or semiarid climates and re- farinae therapeutic dose of each of its constituent components. However, D pteronyssinus gions of higher altitudes. are mem- D farinae and some patients might not tolerate the targeted therapeutic dose be- bers of the same family and genus. They have allergens with cause of local reactions, systemic reactions, or both, and their extensive cross-reacting epitopes, as well as unique allergenic ep- maintenance dose would be lower (eg, 500 BAU [highest toler- itopes. Generally, are considered D farinae and D pteronyssinus ated dose] vs 2000 BAU [projected effective dose] for cat). individually. Establishing the practical importance of various al- Such patients might need weaker dilutions of their maintenance lergenic fungi involves many of the same problems encountered concentrate. Subjects who have systemic reactions with doses in treating pollen allergy. In general, the genera of Deuteromyce- that are less than the projected effective dose should be main- tes occur in all but the coldest regions. For clinical purposes, tained on the highest tolerated dose, providing this dose is effec- Clado- molds often are characterized as outdoor (eg, Alternaria , tive. The highest tolerated effective therapeutic dose is called the , and sporium Drechslera [Helminthosporium] species) or indoor maintenance dose. The maintenance dose of immunotherapy for a (eg, Aspergillus and Penicillium species). particular patient must be individualized. Immunotherapy with standardized extracts of cat hair (Fel d Nonetheless, the original projected maintenance concentration 1 only) or pelt (Fel d 1 plus cat albumin) is available for cat of the allergen immunotherapy extract is still referred to as the allergy. Although German cockroaches are most likely to occur in American homes, an extract representing an equal mixture of maintenance concentrate, and the specific patient’s therapeutic dose is called the maintenance dose. The consistent use of this no- German and American cockroaches might be appropriate for 416,417 menclature system is essential because errors in choosing the cor- immunotherapy. Flying Hymenoptera insects occur rect vial are a reason for systemic reactions, especially when the throughout the United States. On the other hand, the imported patient transfers from one physician to another. A new office fire ant is found only in the Gulf Coast states, Texas, and some might be unfamiliar with the nomenclature system used by the other southern and western states. Likewise, it appears that im- previous physician. Therefore it is important that standard ported fire ants have become endemic in parts of mainland China,

39 S39 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 Probable effective dose range for standardized and nonstandardized US- licensed allergen extracts TABLE IX. Labeled potency Probable effective Range of estimated major allergen or concentration dose range Allergenic extract content in US-licensed extracts 3,000, 5,000, 10,000, Dust mites: 10,000 AU/mL 500-2,000 AU D farinae g/mL Der p 1, Der f 1 * and 30,000 AU/mL 20-160 m and D pteronyssinus 2-180 m g/mL Der p 2, Der f 2 * g/mL Der p 1, Der f 1 78-206 m 13-147 g/mL Der p 2, Der f 2 m 5,000 and 10,000 BAU/mL Cat hair 10,000 BAU/mL 1,000-4,000 BAU m * à 20-50 g/mL Fel d 1 30-100 m g/mL cat albumin § 5,000-10,000 BAU/mL 1,000-4,000 BAU 10,000 BAU/mL Cat pelt 20-50 m * à g/mL Fel d 1 m 400-2,000 § g/mL cat albumin Grass, standardized 100,000 BAU/mL 1,000-4,000 BAU 100,000 BAU/mL 425-1,100 g/mL Phl p 5 * m 506-2,346 g/mL group 1 k m Bermuda 10,000 BAU/mL 300-1,500 BAU 10,000 BAU/mL * g/mL m 141-422 Cyn d 1 1:10 wt/vol g of Amb a 1 m 6-12 1:10, 1:20 wt/vol, 100,000 AU/mL Short ragweed or 1,000-4,000 AU 300 m g/mL Amb a 1 à Concentration of Amb a 1 is on the label of wt/vol extracts 15 1:100 wt/vol Nonstandardized g/mL Can f 1 m 80-400 g of Can f 1 m { g/mL dog albumin m 10-20 AP Dog 0.5 to 10 15 1:10 and 1:20 wt/vol Nonstandardized extract, dog m m g/mL Can f 1 g of Can f 1 m <12-1,500 g/mL dog albumin { 1:10 to 1:40 wt/vol or 0.5 mL of 1:100 NA Nonstandardized extracts: pollen or 1:200 wt/vol 10,000-40,000 PNU/mL NA Nonstandardized extracts: 1:10 to 1:40 wt/vol or Highest tolerated dose mold/fungi, cockroach 10,000-40,000 PNU/mL 50-200 g/mL of venom protein m 100-300 g of each venom m single venom Hymenoptera venom g/mL 100 m in mixed 300 m g/mL vespid extract 0.5 mL of a 1:100 wt/vol 1:10 to 1:20 wt/vol Imported fire ant NA to 0.5 mL of a whole-body extract 1:10 wt/vol extract , Information not available. NA  *ALK-Abell o ELISA. Indoor Biotechnology ELISA. à FDA radial immunodiffusion assay. §Greer Radial Immunodiffusion assay. k Greer ELISA. Hollister-Stier ELISA using Innovative Research, Inc, reagents. { 18,20,21,24,25,97 very low doses usually are ineffective. terminology be adopted by all physicians who prescribe allergen Although ad- ministration of a higher maintenance dose of immunotherapy in- immunotherapy. creases the likelihood of clinical effectiveness, it also increases The therapeutically effective doses used in controlled clinical the risk of systemic reactions. In particular, highly sensitive pa- studies are the basis of the recommended dosage range of tients might be at increased risk of a systemic reaction to immu- Tables IX and X . For allergens standardized extracts presented in notherapy injections with higher maintenance doses. that have not been standardized, the effective dose must be esti- The concept of highest tolerated dose does not apply for VIT, mated and individualized. It is important to keep a separate record of the contents of each extract, including final dilutions of each of and all patients are expected to achievethe full recommended dose for the necessary degree of protection. There are conflicting data the constituents. Although early improvement in symptoms has been documented with these doses, long-term benefit appears to over whether lower doses (50 mg) are less effective, but there are 421 be related not only to the individual maintenance dose but also also data showing that 200 mg is more reliably effective. In the 99,135 the duration of treatment. case of VIT, patients are expected to tolerate LLRs to achieve the full dose, even though with inhalant immunotherapy the dose can Because a full dose-response curve has not been determined for be reduced for such LLRs to minimize the patient’s discomfort. most allergens, it is possible (and supported by expert opinion) The allergist/immunologist might need to prepare more than that therapeutic response can occur with doses lower than those 1 maintenance concentrate to provide a therapeutic dose of each that have been shown to be effective in controlled studies. In of the allergens for the polysensitized patient. general, however, low doses are less likely to be effective, and

40 COXETAL S40 J ALLERGY CLIN IMMUNOL JANUARY 2011 Basis for allergen extract dosing recommendations TABLE X. g of the major allergen per Major allergen content m : Multiple studies demonstrate that the efficacious dose for allergen immunotherapy is between 5 and 20 injection. Two extracts licensed in the United States are standardized based on major allergen content (measured by means of radial immunodiffusion): short ragweed (Amb a 1) and cat (Fel d 1). Patients might also have IgE sensitivity to multiple allergens in the extracts. Currently, only the Amb a 1 and Fel d 1 FDA-issued radial immunodiffusion test reagents are standardized and used by all US manufacturers for short ragweed and cat hair and pelt extracts. The house dust mite, grass pollen, and dog hair major allergen assays are not standardized by the FDA and are either purchased or used internally by individual manufacturers. Nonstandardized extracts : The labeled concentrations for the nonstandardized extracts have no established standards for biologic potency. Nonstandardized extracts are labeled on the basis of PNU values or the weight of the source material extracted with a given volume of extracting fluid (wt/vol). There are no dose-response studies with nonstandardized extracts. When analyzed, the nonstandardized pollen extracts demonstrate potency that is similar to that of grass and ragweed, although with a wider range. A target dose of 0.5 mL of a 1:100 or 1:200 wt/vol of nonstandardized extract is reasonable. Cockroach and mold/fungi extracts are generally of low potency and vary considerably in composition. Only glycerinated cockroach or mold/fungi extracts should be used, and they should be used at higher doses than the nonstandardized pollens. Dust mites : There are no dose-response studies with US-licensed dust mite extracts, and dosing recommendations in AUs are extrapolated from published 17,118 475 and alum-precipitated extracts. One study, designed to investigate the effect of 3 doses of an alum-precipitated D European studies that use aqueous 17 The authors suggested that the optimal extract (0.7, 7, and 21 g of Der p 1), found a dose-response effect on efficacy and side effects. m pteronyssinus maintenance dose is 7 m g of Der p 1. Corresponding doses are based on specific allergen measurements of US commercially available standardized extracts provided by manufacturers. Appropriate dose reductions would need to be made when combining antigens that have a strong degree of cross-reactivity, such D pteronyssinus and D farinae . as 370,374,476 : The major cat allergen Fel d 1 is reported in FDA units (Fel d 1 U) with 1 Fel d 1 U equal to approximately 2 to 4 m g of Fel d 1. Cat hair and pelt The amount of Fel d 1 in 10,000 BAU/mL ranges from 10 U to 19.9 U/mL. One study demonstrates clinical efficacy of a maintenance dose of 4.56 FDA 332,333 In a study , titrated skin test results, and allergen-specific IgE and IgG. units of Fel d 1 (or highest tolerated) dose in terms of decreased cat extract PD 20  m o, Round that investigated the efficacy in terms of immunologic changes of 3 doses of a US-licensed cat extract (0.6, 3, and 15 g of Fel d 1 from ALK-Abell 1 /IL-4 only in the group treated with 15 m g of Fed Rock, Tex) there was significant effect on titrated skin prick tests, allergen-specific IgG4 levels, and CD4 18 g dose group did demonstrate a significant change in titrated skin test response and an increase in cat-specific IgG4 levels. 1, although the 3- m : There have been no dose-response studies with US-licensed standardized grass extracts. Recommended doses are extrapolated from published Grass 99 20,128 477 alum-precipitated, and calcium phosphate–precipitated grass pollen extracts. One of these studies European studies that have used aqueous, 20 The efficacy was greater in the compared a dose of 2 g with 20 m g of major timothy grass allergen (Phl p 5) and found clinical efficacy at both doses. m dose of 20 m g of Phl p 5, but the systemic reaction rate was also higher in the high-dose group. The package inserts for US-licensed grass pollen extracts contain a table to convert the nonstandardized units (wt/vol and PNU) for which there have been studies that have demonstrated efficacy into BAUs. Appropriate dose reductions would need to be made when combining antigens that have a strong degree of cross-reactivity, such as the Northern pasture grasses (subfamily Pooideae; eg, perennial rye, meadow fescue, or timothy). Bermuda grass : Bermuda grass has an assigned potency of 10,000 BAU, which is 10-fold less than the other standardized grasses. However, the major  m m g/mL, and allergen content of Bermuda grass according to one extract manufacturer (ALK-Abell g/mL of Cyn d 1 with a range of 141 to 422 o) was 348 478 It has been speculated that the apparent discrepancy in assigned potency to this is similar to the major allergen content of the other standardized grasses. EAL testing) undertaken in a nonendemic area for Bermuda grass. Bermuda grass extract was the result of standardization (ID 50 Short ragweed : Short ragweed is reported in FDA units, with 1 U of Amb a 1 equaling 1 m g of Amb a 1. The potency units for short ragweed extracts were g of Amb a 1, and 350 Amb a 1 U/mL m originally assigned based on their Amb a 1 content. Subsequent data suggest that 1 U of Amb a 1 is equivalent to 1 376 The package insert of the short ragweed 100,000 AU/mL extract states the optimal immunotherapy dose is approximately equivalent to 100,000 AU/mL. is 2,000 AU, with a range of 1,000 to 4,000 AU. One open study of patients with ragweed-induced allergic rhinitis demonstrates a significant improvement 479 g of Amb a 1 for 3 to 5 years compared with an untreated matched control group. m in ragweed nasal challenge in patients treated with a mean dose of 6 97 m g Amb a 1) demonstrates efficacy as measured by nasal challenge at 12 and 24 m g Amb a 1. A ragweed dose-response study (0.6, 12.4, and 24.8 The efficacy of the 24- g dose was not significantly better than that of the 12- m g dose, and the authors concluded that the optimal dose for ragweed extract is m greater than 0.6 m g but not more than 12.4 m g of Amb a 1. Dog hair or pelt extracts : Dog hair or pelt extracts are not standardized, and potency is reported as wt/vol or PNU per milliliter. One dose-response study with g of Can f 1) in terms of immunologic a US-licensed dog hair extract investigated the efficacy of 3 doses (AP dog hair; Hollister-Stier; 0.6, 3, and 15 m 21 g dose also demonstrated significant efficacy, although not as great as the m The 3- m g of Can f 1 to be most efficacious. changes and found the dose of 15 m m g/mL. Subsequent lots assayed ranged between 80.4 and 396.3 m g/mL Can f 1 (110 15- g dose. The extract used in the dosing study was assayed at 160 m g/mL Can f 1 [SD, 52.3 lots; mean of 170.8 g/mL]); information provided by the extract manufacturer, Hollister-Stier, by using references calibrated m back to Indoor Biotechnologies ST-CF1 standard to maintain consistency with original clinical trial recommendations. 158 However, Hymenoptera venom : The recommended maintenance dose for stinging Hymenoptera venom immunotherapy is 100 m g of each insect venom. g there is some controversy about the optimum maintenance dose. Initial studies used 100 m g as the maintenance dose. One investigator has used the 50- m 147 although some believe that this dose offers a lesser degree of protection. Increasing maintenance dose in patients with yellow jacket allergy successfully, the maintenance dose up to 200 m g per dose has been effective in achieving protection in some patients who have experienced sting reactions while 421 (see ‘‘Stinging insect hypersensitivity: a practice parameter update II’’ for a more detailed discussion of m g maintenance dose of VIT. receiving a 100- venom and imported fire ant immunotherapy dosing). Imported fire ant : The optimal dose for fire ant whole-body extract immunotherapy is less well defined. Most reports have recommended 0.5 mL of a 1:100 extract, although there are some recommendations for and Solenopsis richteri wt/vol extract with either Solenopsis invicta or a mixture of Solenopsis invicta 122,123,152,298 a dose as high as 0.5 mL of a 1:10 wt/vol extract. dander, and dust mite, have demonstrated a significant loss of Proteolytic enzymes and mixing potency with some of these extracts. Separation of extracts Summary Statement 82: Studies designed to investigate the with high proteolytic enzyme activities from other extracts is effect of combining extracts with high proteolytic activity, recommended. It might be necessary to prepare 2 or more vials such as cockroach and mold/fungi, with extracts such as pollen,

41 S41 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 storage at higher temperatures (eg, room temperature) can result to provide allergen immunotherapy containing an optimal dose 425 in rapid deterioration. of each component while avoiding allergen extract combina- tions that might result in degradation of some or all of the com- Summary Statement 84: Extract manufacturers conduct ponents. B stability studies with standardized extracts that expose them Many allergen extracts contain mixtures of proteins and to various shipping conditions. It is the responsibility of glycoproteins. Proteolytic enzymes can degrade other allergenic each supplier or manufacturer to ship extracts under vali- proteins. There have been reports of interactions between extracts dated conditions that are shown not to adversely affect the 328-330,422,423 when mixed together. product’s potency or safety. C Extracts such as Alternaria Extract manufacturers conduct stability studies with standard- species have been shown to reduce the IgE-binding activity of ized extracts that expose them to various shipping conditions timothy grass extract when mixed together. Studies designed to (personal communication, Robert Esch, PhD, Greer, Lenoir, NC). investigate the effect of combining mold/fungi extracts with pol- These studies include actual shipments made by their carriers to len extracts have demonstrated a significant loss of potency of places like Phoenix in the summer and Alaska in the winter. One grass pollen, cat, birch, white oak, box elder, dog, and some 329,330,422,423 study that evaluated the potency of standardized timothy grass weeds. Cockroach had a similar deleterious effect 422,424 extracts mailed round trip between San Antonio, Texas, and on pollen extract potency. The evidence on mixing cock- Phoenix, Arizona, during August produced no significant reduc- roach extract with dust mite and ragweed extracts is conflict- 329,330,422 tions in relative potencies (in vivo) or skin test reactivity (in vitro) ing. Short ragweed appeared resistant to the effects of 426 330 in 3 sensitive patients. the proteolytic enzymes in one study, but another study found The results of these studies are on file short ragweed Amb a 1 was susceptible to proteases present in under each manufacturer’s product licenses. Each study is spe- cific to each manufacturer because the packaging (eg, use of insu- Penicillium and Alternaria species extracts at relatively low 329 lation) varies from company to company. It is the responsibility of (10%) glycerin levels. each supplier or manufacturer to ship allergen extracts under val- Dust mite extracts do not appear to have a deleterious effect on 329,330,422,424 idated conditions that have been shown not to adversely affect the pollen extracts. These studies suggest that pollen, 328 product’s potency or safety. dust mite, and cat extracts can be mixed together. The effect Summary Statement Allergen extract expiration dates. of the combination of high proteolytic-containing extracts on 85: In determining the allergen immunotherapy extract expi- each other or the extent of self-degradation of allergenic proteins ration date, consideration must be given to the fact that the has not been extensively studied, and the clinical relevance of the rate of potency loss over time is influenced by several factors changes is also unclear. separately and collectively, including (1) storage temperature, Because such interactions between extracts have not been fully (2) presence of stabilizers and bactericidal agents, (3) concen- delineated, consideration should be given to keeping extracts that tration, (4) presence of proteolytic enzymes, and (5) volume of tend to have high proteolytic enzyme activities, such as fungi and the storage vial. D cockroach extracts, separate from those extracts susceptible to 328 The potency of concentrated allergen immunotherapy extracts their action, such as pollen. (1:1 vol/vol up to 1:10 vol/vol) when kept at 4 C is relatively 8 It is not recommended to mix venoms together (eg, wasps or constant and allows the extract to be used until the expiration date honeybee with yellow jacket), even though yellow jacket and that is present on the label. Less concentrated allergen immuno- hornet venom are available premixed as a mixed-vespid extract. therapy extracts are more sensitive to the effects of temperature Preparing allergen immunotherapy extracts that contain an and might not maintain their potency until the listed expiration optimal dose of each allergen extract, a determinant of efficacy, 425,427 date. which does not contain allergen extract combinations that result in degradation of some of all or all of the components, might The mixing of other allergens might decrease the loss of require preparation of 2 or more vials. potency with time because the additional allergens might prevent Therefore 2 or more injections might be needed to be given at adherence of proteins to the vial’s glass wall. Thus highly concen- each patient’s visit depending on whether all of the relevant ex- trated extracts are more stable than diluted ones. Extracts are pre- tracts can be mixed into a single vial and still deliver an optimal pared as aqueous, glycerinated, freeze-dried, and alum dose of each allergen. formulations. Aqueous and glycerin diluents are compatible for mixing standardized with nonstandardized products. Lyophiliza- tion is used to maintain the strength of the dry powder, but once the allergen immunotherapy extract is reconstituted, stabilizing Allergen immunotherapy extract handling agents, such as human serum albumin (0.03%) or 50% glycerin, Storage. Summary Statement 83: Allergen immunother- 427 are needed to maintain potency. C to reduce the Cto8 8 8 apy extracts should be stored at 4 Phenol is a preservative added rate of potency loss. B to extracts to prevent growth of microorganisms. 428,429 Because the efficacy and safety of immunotherapy depend on Phenol can denature proteins in allergen extracts. Human the use of allergen immunotherapy extracts with reasonably serum albumin might protect against the deleterious effect of phe- 428 predictable biologic activity, it is important that they be stored nol on allergen extracts. Human serum albumin might also pre- vent the loss of potency within storage vials by preventing under conditions that preserve such activity. The potency of allergen immunotherapy extracts is affected by several factors, absorption of allergen on the inner surface of the glass vial. Glyc- including the passage of time, temperature, concentration, num- erin is also a preservative. At a concentration of 50%, glycerin ap- ber of allergens in a vial, volume of the storage vial, and presence pears to prevent loss of allergenic potency, possibly through of stabilizers and preservatives. Allergen immunotherapy ex- inhibition of the activity of proteolytic and glycosidic enzymes tracts, including reconstituted lyophilized extracts, should be that are present in certain extracts. However, it might cause dis- 221 8 stored at 4 8 C to minimize the rate of potency loss because Cto8 comfort when injected.

42 COXETAL S42 J ALLERGY CLIN IMMUNOL JANUARY 2011 labels, the authors cited several other reasons why patient- There are few studies that have investigated the potency of specific vials might reduce incorrect injection errors. One reason dilutions of allergen extract mixtures over time. Expiration was that they can be prepared in a confined laboratory setting, dates for allergen extract dilutions are somewhat empiric and which might provide substantially fewer distractions than a situ- not strongly evidence based. A study undertaken by the ation in which a nurse is trying to concentrate on drawing up the AAAAI’s Immunotherapy and Allergy Diagnostic committee injection correctly while in the room with the patient. designed to study the stability of a mixture of standardized ex- With individually prepared vials, the specific components are tracts in 4 conditions of storage (with and without intermittent mixed once, whereas the mixing would be repeated on every room temperature exposure and diluted in normal saline or hu- injection visit if the allergen extract were withdrawn from man serum albumin) found that short ragweed at 1:10 vol/vol different stock solutions, as it in the mixing of antigens in the dilution, as measured by means of radial immunodiffusion, 430 syringe (also referred to as ‘‘off-the-board’’). In addition, the was stable in all conditions of storage over 12 months. mixing of antigens in a syringe is not recommended because of Dust mite and cat at 1:10 and 1:100 vol/vol dilutions were the potential for cross-contamination of extracts. This procedure also stable in all conditions of storage over 12 months, as mea- might pose an increased risk for dosing error if the nurse is sured by using an ELISA assay with an mAb for Der p 1, Der f drawing up the injections from multiple solutions of different 1, and Fel d 1. composition or dilution with similar labels (eg, mold mix I 1:10 The expiration date of any dilution should not exceed the and mold mix II 1:100). expiration date of the earliest expiring constituent that is added to Some allergists/immunologists prefer to administer immuno- the mixture. therapy doses drawn directly from a stock dilution of an individ- ual allergen extract or mixture of allergens and inject the extract Customized individualized allergen immunotherapy into the patient (shared- patient vials). If shared-patient vials are used, it is essential that policies and procedures are developed to extracts verify that the correct allergen and correct dose is administered to Summary Statement 86: Administration of an incorrect the correct patient. Data are not available to determine whether injection is a potential risk of allergen immunotherapy. treatment errors are more common with this method of An incorrect injection is an injection given to the wrong administration. patient or a correct patient receiving an injection of an in- If the allergen immunotherapy is administered from vials correct dose. A customized individual maintenance concen- without specific patient identifiers, measures to reduce the like- trate of the allergen immunotherapy extract and serial lihood of a wrong injection error that might result from similar dilutions, whether a single extract or a mixture of extracts, labels (eg, weed mix I 1:10 and weed mix II 1:100) should be prepared and labeled with the patient’s name and birth implemented. date might reduce the risk of incorrect (ie, wrong patient) To improve the safety of using medications, the Joint Com- injection. D . mission recommends that an ‘‘ [organization] identifies and at a Summary Statement 87: The mixing of antigens in a syringe minimum, annually reviews a list of look-alike/sound-alike is not recommended because of the potential for treatment er- medications used by the [organization] and takes action to rors and cross-contamination of extracts. C 27 prevent errors involving the interchange of these medications.’’ Individually prepared and labeled vials are recommended because they have several potential advantages over shared vials (ie, vials of allergen extract used for multiple patients). These potential advantages include being able to prepare labels with Allergen extract dilution labeling and nomenclature specific patient identifiers, less distractions during mixing, and Summary Statement 88: Serial dilutions of the mainte- less frequent mixing. nance concentrate should be made in preparation for the Labels on patient-specific vials can provide at least 2 patient build-up phase of immunotherapy. D identifiers (eg, birth date and patient name), which would be In preparation for the build-up phase of immunotherapy, serial consistent with the recommendations of the Joint Commission dilutions should be produced from each maintenance concen- National for Patient Safety Goals: ‘‘Goal 1: Improve the accuracy trate. Typically, these are 10-fold dilutions, although other of patient identification. Use at least two patient identifiers when dilutions occasionally are used. These dilutions should be labeled 27 providing care, treatment or services.’’ in terms of volume/volume to indicate that they are dilutions Acceptable identifiers derived from the maintenance concentrate. For example, serial include the patient’s name, birth date, assigned identification 27 10-fold dilutions from the maintenance concentrate would be number, telephone number, or other person-specific identifier. labeled as 1:10 (vol/vol) or 1:100 (vol/vol). Alternatively, the vial The risk of errors of administration might be reduced because dilutions can be labeled in actual units (eg, 1,000 BAU or 100 the individually prepared allergen immunotherapy vials labeled BAU), but this system can be complicated if allergens with with the patient’s name and birth date will allow the person ad- different potency units are used (eg, weight/volume, BAU, AU, ministering the extract and the patient an opportunity to verify or PNU), and this can make it difficult to easily interpret the vial the name/birth date on the label before administering the 26,27 label. injection. Instructions on how to prepare various allergen extract dilu- In a survey endorsed by the AAAAI and JCAAI of 1,717 . If the final volume of the diluted al- tions are shown in Table XI allergists, 57% of the 476 respondents reported at least 1 wrong- lergen immunotherapy extract to be produced is 10 mL, then one patient injection, and 74% of the 473 respondents reported at least 26 tenth of that final volume, or 1.0 mL, should be removed from the 1 wrong-dose injection in the previous 5 years. The incorrect in- more concentrated allergen immunotherapy extract and added to jections resulted in 1 death, 29 hospital admissions, and 59 emer- a new bottle containing 9.0 mL of diluent. gency department visits. In addition to patient identifiers on vial

43 S43 J ALLERGY CLIN IMMUNOL COX ET AL VOLUME 127, NUMBER 1 Procedure for dilutions from the maintenance concentrate (1:1 vol/vol) TABLE XI. Dilution from maintenance concentrate vaccine Final volume (mL) Final concentration Diluent volume (mL) Extract volume (mL) 1.0 0.0 1.0 1:1 (vol/vol) 1:1 (vol/vol) 1:1 (vol/vol) 2.0 8.0 10.0 1:5 (vol/vol) 1:1 (vol/vol) 1.0 9.0 10.0 1:10 (vol/vol) 1:100 (vol/vol) 1:10 (vol/vol) 1.0 9.0 10.0 1:100 (vol/vol) 10.0 9.0 1.0 1:1000 (vol/vol) All dilutions are expressed as vol/vol from the maintenance concentrate. Suggested nomenclature for labeling dilutions from the maintenance concentrate TABLE XII. Dilution from maintenance concentrate Vol/vol label No. Color Maintenance concentrate 1:1 1 Red 10-fold 1:10 2 Yellow 100-fold 1:100 3 Blue 1,000-fold 1:1000 4 Green 5 Silver 10,000-fold 1:10,000 concentrated extracts, the number of the maintenance concentrate Effect of dilution on dose would vary from patient to patient depending on the number of Summary Statement 89: Dilution limits the number of dilutions made. If a color-coding system is used, it should be antigens that can be added to a maintenance concentrate if consistent (eg, the highest concentration should be red, the next a therapeutic dose is to be delivered. A highest yellow, followed by blue, green, and silver in that order; The more antigens that are added to the maintenance concen- Figs 2 and 3 ). trate, the more there is the potential to dilute other antigens in the Regardless of the labeling system used for indicating dilutions allergen immunotherapy extract, thereby limiting the ability to from the maintenance concentrate, the specific contents of each deliver a therapeutic effective dose for any given allergen. allergen immunotherapy extract should be listed separately. The If the appropriate concentration of each allergen extract is volume and concentration of each of its constituents should be added, then adding additional allergens to the maintenance listed on the immunotherapy prescription form. concentration will have no effect on the concentration of the Consistency is essential as a basis for adoption of a standardized other allergens, as long as the additional allergens are replacing system. Some allergists/immunologists, however, have found it diluent. For example, if the desired maintenance concentration for helpful to use letters for designating different component mixtures cat is 2,000 BAU/mL, 2 mL of the manufacturer’s extract (10,000 of extracts (eg, trees [T], grasses [G], and molds [M]; see Table E9 BAU/mL for cat) can be added to 8 mL of diluent or 8 mL of other in this article’s Online Repository at www.jacionline.org ). allergens, and the final concentration of cat will be 2,000 BAU/ mL in both mixtures. Once the diluent is all replaced, addition of further allergens will result in undesirable dilution of all aller- Documentation and record keeping gens in the maintenance mixture. Summary Statement 91: The allergen immunotherapy Summary Statement 90: A consistent uniform labeling extract contents, informed consent for immunotherapy, and system for dilutions from the maintenance concentrate administration of extracts should be documented. D might reduce errors in administration and therefore is An immunotherapy injection should not be given unless recommended. D adequate documentation is available in the patient’s medical rec- During the build-up phase of immunotherapy, several dilutions ord. This also means that patients who receive injections in a of the patient’s maintenance concentrate are needed. Use of one health care facility other than the office of the prescribing physi- labeling system to indicate dilutions might help to avoid adminis- cian must have appropriate documentation. The recommended tration errors ( Table XII). In addition to the labeled dilution from documentation for informed consent to allergy immunotherapy, the maintenance concentrate (volume/volume), a numbering sys- examples of prescription and administration forms, and other sim- tem, a color-coding system, or an alphabetical system should be ilar sample documents can be found in this article’s Online Re- used. If this uniform labeling system is used, it is essential that . These forms, along with pository at www.jacionline.org it be used in the same way by all physicians to reduce potential examples of immunotherapy consent and instruction forms, can administration errors by staff unfamiliar with the labeling system. http://www.aaaai.org also be found at and http://www.acaai.org . If the current labeling system is different, the transition toward the uniform labeling system should be gradually phased in to reduce potential errors, and the staff involved with preparation and ad- ministration of allergen immunotherapy should be involved NONINJECTION ROUTES OF IMMUNOTHERAPY with the planning of this transition. Summary Statement 92: Allergen extracts can be adminis- If a numbering system is used, the highest concentration should tered through several routes in addition to the subcutaneous be numbered 1. This is necessary to provide consistency in route. Currently, there are no FDA-approved formulations labeling because if larger numbers are used to indicate more for a noninjection immunotherapy extract. A

44 COXETAL S44 J ALLERGY CLIN IMMUNOL JANUARY 2011 Example of color-coded vials of allergen immunotherapy maintenance. FIG 2. Example of labels for allergen immunotherapy maintenance concentrate and dilutions. FIG 3. 431 Favorable results have been reported with intranasal, intra- pollen extract containing 15 to 25 g of group 5 allergen for a m 432 433-435 436 437 bronchial, intralymphatic, and ep- oral, sublingual, monthly cumulative dose 22.5 to 37.5 times the monthly mainte- 438 icutaneous administration. With intranasal and intrabronchial nance dose proved effectiveby means ofinjection. Doses one third allergen administration, local symptoms were decreased by use ofthe effectivedosewere not superior toplacebo in 2of these stud- 211,433 of pretreatment with sodium cromoglycate. Despite reported clin- ies. The grass pollen extract in these studies was adminis- ical successes, both approaches have been largely abandoned. In- tered as early as 4 months before the pollen season or as late as 446 tralymphatic and epicutaneous administration are newly the first day of the grass pollen season. As opposed to the clear described approaches, which will be discussed in a later section. dose responses in these studies, other studies with various aller- Administration of pollen allergen extracts through the oral route gens administered by means of SLIT report both positive and neg- reduces symptoms caused by natural pollen exposure, but the ativeresults with doses ranging from 2 to 375 times the cumulative 447 dose required is much greater compared with that required monthly doses used by means ofinjection. Thus the appropriate through the subcutaneous route; gastrointestinal side effects are dose for SLITwith most inhalant allergens is not established. Also frequent. The oral approach has been largely abandoned for inhal- not established is the relative efficacy of SLIT versus SCIT be- ant allergens but has been pursued for treatment of food allergy in cause the few comparative studies available are underpowered. 174,176,439,440 children. Studies of SLIT have shown that it can reduce new sensitiza- Presently, immunotherapy for inhalant al- 448,449 tion, methacholine sensitivity, and the onset of asthma. lergens through the oral route is limited to sublingual administra- Im- tion, with subsequent swallowing of the extract (SLIT). provement in allergic rhinitis persists for at least 1 year after 211,446 The efficacy and safety of SLIT for aeroallergen-induced discontinuation of 3 years of SLITwith grass pollen extract. allergic rhinitis with or without asthma is currently under SLIT improves mild-to-moderate atopic dermatitis caused by 16 investigation in the United States. Clinical trials evaluating the house dust mite sensitivity and increases the tolerance to hazel- safety and efficacy of oral immunotherapy and SLIT for food nuts in allergic subjects, some of whom have had anaphylactic 172,450 hypersensitivity are also being conducted in the United States. reactions. Summary Statement 93: Randomized controlled clinical trials with dust mite and pollen sublingual immunotherapy have demonstrated significant improvement in symptoms Adverse reactions to SLIT and medication use in patients with allergic rhinitis and Summary Statement 94: Local reactions, primarily oral- asthma. A mucosal, are common with sublingual immunotherapy. Sys- Several meta-analyses conclude that SLIT is effective in the temic reactions can occur, and a few have been reported in 443,444 441,442 treatment of allergic rhinitis in and allergic asthma subjects who were unable to tolerate subcutaneous immuno- therapy. A few reported cases have been of a severity to be cat- adults and children. Although these meta-analyses are criticized egorized as anaphylaxis. A because of discrepancies, inconsistencies, and lack of robust- 445 Local reactions to SLITare common. In a study of 316 subjects ness, they conclude that SLIT is effective, as confirmed by sev- receiving grass tablets without build-up, oral pruritus was eral studies, each with hundreds of subjects. These large studies reported by 46%, and edema of the mouth was reported by have been conducted primarily in grass-sensitive subjects with al- 451 211,433,446 18%. lergic rhinitis. Most of these local symptoms were reported to be mild Two studies used daily doses of grass

45 S45 COX ET AL J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 1 immunotherapy, with 56.6% citing ‘‘unpleasant’’ as the reason. to moderate in severity and did not persist with continued treat- The use of this approach to immunotherapy has essentially stop- ment; fewer than 4% of subjects discontinued the study because ped since the introduction of SLIT, and no recent clinical trials of of side effects. Local reactions are no more common when there 447 either intranasal or intrabronchial immunotherapy are available. is no initial build-up in dosing. There are no deaths reported with SLIT; however, systemic reactions occur, and a few have 452-455 been of a severity to be categorized as anaphylaxis. Notable are 2 subjects who did not tolerate SCITwho had anaphylactic re- Intralymphatic 456 actions with the first dose of SLIT. Other authors also report Summary Statement 97: A 3-injection course of intralym- systemic reactions to SLIT in patients who had not tolerated phatic immunotherapy was as effective as a 3-year course of 457 SCIT. conventional subcutaneous immunotherapy in a noncon- Summary Statement 95: Clinical trials evaluating the trolled study. NR safety and efficacy of sublingual immunotherapy for patients A noncontrolled study was conducted with 165 patients with with ragweed- and grass pollen–induced allergic rhinitis. grass pollen allergy, comparing 3 injections of grass allergen Currently, there are no FDA-approved formulations for sub- extract into the inguinal lymph nodes at 4-week intervals with 3 437 lingual immunotherapy. A years of conventional SCIT. The total extract dose was more It was estimated in 2009 that 45% of specific immunotherapy in than 1,000-fold less with the intralymphatic injections. Systemic 458 Europe was administered as SLIT. In the United States SLIT is reactions were less frequent, but nasal tolerance to allergen in- used much less commonly. A survey of 828 US practicing aller- creased more rapidly with intralymphatic injections. After 3 gists in 2007 revealed that 66% had tried SLIT, but only a quarter years, there were no clinical differences in outcomes between 459 of them reported extensive experience. The respondents report the 2 treatments. that the major limiting factors for the use of SLIT in the United States were the lack of allergy extracts approved by the FDA for sublingual administration (61.7%) and the lack of knowledge Epicutaneous of effective doses (27.5%). Because there are no approved ex- Summary Statement 98: Epicutaneous immunotherapy re- tracts for SLIT, no billing codes exist. Another problem for the sulted in significantly higher treatment success in a placebo- use of SLIT in the United States is that most double-blind, pla- controlled study. However, there were no significant differ- cebo-controlled studies demonstrating efficacy used a single al- ences in the primary outcome and nasal provocation test lergen extract. A preliminary study comparing timothy grass scores between the groups. NR monotherapy with the same dose of timothy grass administered A placebo-controlled trial has been reported of application in combination with 9 other pollen extracts suggests that efficacy of grass pollen extract in the form of a patch applied once might be seriously reduced with administration of multiple aller- 438 weekly for 12 weeks and left in place for 48 hours each time. 460 gen extracts sublingually. The typical allergen extract for use in Treatment was initiated 4 weeks before and continued through 461 the United States contains 8 unique allergen extracts. Until the 2006 grass pollen season. Subjects receiving active treat- these limitations are overcome, the administration of allergen im- ment reported fewer symptoms than the placebo-treated subjects munotherapy through the sublingual route must be considered as for both the 2006 and 2007 grass pollen seasons. However, there ‘‘investigational’’ in the United States. were no significant differences in the primary outcome, nasal provocation scores, between the placebo and treatment groups. The major adverse effect was an eczematous reaction at the ap- Intranasal immunotherapy plication sites. Summary Statement 96: Randomized controlled studies have demonstrated that nasal immunotherapy with dust mite and pollen extracts is effective in reducing symptoms Oral immunotherapy and SLIT for food and medication use. Local adverse reactions are common with this approach and are the most frequently cited reason hypersensitivity for discontinuation of treatment in one large prospective Summary Statement 99: Several clinical trials with oral study. The use of this approach has decreased considerably and sublingual immunotherapy demonstrate an increased tol- since the introduction of SLIT. C erance to oral food challenge in subjects with food hypersen- Randomized placebo-controlled studies demonstrate that in- sitivity while receiving therapy. Oral and sublingual food tranasal administration of allergen extracts improves symptoms immunotherapy is investigational. NR 431,462-466 of allergic rhinitis both to pollens At present, the only treatment for food hypersensitivity is and house dust 467 avoidance, but clinical trials suggest that tolerance can be mites. Allergic symptoms caused by the topical administration achieved with oral immunotherapy and SLIT. There was dimin- of allergens are greatly reduced by premedication with topical ished IgE reactivity associated with increased IgG4 reactivity to cromolyn sodium. A study of 3 unrelated weed extracts demon- 466 the major kiwi allergen Act c 1 in Western blots after 5 years of strates efficacy for this multiallergen mixture. A 3-year study continuous treatment in a case of a woman with kiwi-associated Parietaria judaica reports persistent benefits for up to 12 with 465 469 anaphylaxis treated with a kiwi-pulp SLIT extract. months after conclusion of nasal immunotherapy. Local reac- The patient tions are fairly common with this approach and are the most com- tolerated resumption of SLIT after 4 months of interrupted treat- ment, which suggests that this treatment can produce a persistent mon reason for discontinuation of treatment in a 3-year state of tolerance. Clinical trials with SLIT demonstrate an in- prospective study of 2,774 children investigating compliance 172,450 468 creased tolerance to oral food challenge with hazelnut with nasal immunotherapy, SCIT, and SLIT. By the end of 173 the first year, 43.9% of the children discontinued nasal and milk.

46 COXETAL S46 J ALLERGY CLIN IMMUNOL JANUARY 2011 phase 2 trial of 25 adults with ragweed-induced allergic rhinitis A study examining the safety of peanut oral immunotherapy in randomized to receive 6 increasing doses of TOLAMBA (0.06, 28 patients with peanut allergy found that most adverse reactions m 0.3, 1.2, 3.0, 6.0, and 12 g) or placebo before the ragweed season occurred during the initial escalation day, with upper respiratory demonstrated a significant reduction in total nasal symptom tract (79%) and abdominal (68%) symptoms being the most 440 scores during the peak season in the TOLAMBA group compared common adverse reactions. The probability of adverse reac- with the placebo-treated patients in both the first and second rag- tions after the build-up phase dose was 46%, 29% of which weed season with no ‘‘pattern of vaccine-associated systemic re- were upper respiratory tract symptoms and 24% of which were 472 actions or clinically significant laboratory abnormalities.’’ skin symptoms. Fifty-one percent of subjects experienced some . easily controlled by the oral ad- mild side effects, which were ‘‘ However, there was no difference in the primary outcome (ie, al- ministration of antihistamines or sodium cromolyn’’ in a study of bumin levels in nasal lavage fluid after nasal allergen provoca- 59 patients with food allergy treated with oral immunotherapy for tion). The development of a CpG ragweed vaccine was 470 18 months. discontinued by the company after interim analysis of a subse- 174 175,176 176,177 quent large trial indicated that neither the placebo nor CpG groups egg, oral Clinical trials with peanut, and milk showed symptoms during the ragweed season, making it impossi- immunotherapy demonstrate an increased tolerance to treated 473 ble to assess the therapeutic efficacy of the CpG vaccine. food. In an open-label peanut oral immunotherapy trial, 27 (93%) children with peanut allergy were able to tolerate the MPL, the other adjuvant used in allergen immunotherapy, is a 174 target total peanut dose of 3.9 g after 4 to 22 months. TLR4 agonist derived from the LPS of Salmonella minnesota , Treat- which induces T ment was associated with a significant reduction in titrated 1 cytokines in human and animal studies. H skin prick test responses, basophil activation, and other hu- MPL is used in an allergen vaccine product composed of a moral and cellular changes associated with immunologic tyrosine-absorbed (delays absorption) glutaraldehyde-modified tolerance. allergoid (Pollinex Quattro; Allergy Therapeutics Ltd, West Sus- sex, England), which is administered as 4 injections given at 1- to 2-week intervals and ending 2 to 4 weeks before the start of the NOVEL FORMULATIONS: ALLERGOIDS AND season. The highest and cumulative doses were equivalent to 24 474 m g of group 1 grass pollen allergen, respectively. and 60 The ADJUVANTS treatment resulted in significant reductions in symptoms and Summary Statement 100: Allergoids are modified allergen combined symptom-medication scores in a double-blind, extracts processed in a way that reduces the extract’s allerge- placebo-controlled, multicenter study of 141 patients with tree- nicity while preserving its antigenicity. B or grass pollen–induced allergic rhinitis with no difference in Allergoids are chemically modified extracts that reduce IgE- systemic adverse events between the active and placebo binding capacity. These extracts potentially reduce the allerge- 474 groups. nicity of the allergens but retain antigenicity. However, one study comparing the tolerability of a standardized grass pollen extract with an allergoid reported a higher percentage of systemic reactions in the allergoid group during rush build-up and the AUTHORS’ NOTE 96 maintenance phase. Allergoids are used, on average, in 20% of Examples of allergen immunotherapy prescription and admin- SCIT treatments prescribed in Europe, but the use varies in differ- istration forms, immunotherapy labels, conventional and cluster 458 ent countries. There are no FDA-approved allergoids in the build-up schedules, immunotherapy dose adjustments for un- United States. scheduled gaps in allergen immunotherapy injection intervals, Summary Statement 101: Adjuvants might enhance the ef- summaries of documentation guidelines, systemic reaction fectiveness ofallergen immunotherapy by shifting theimmune reporting sheets, and patterns of allergen cross-reactivity can be response toward T 1 production. The 2 adjuvants most exten- found in the tables and figures in this article’s Online Repository H sively studied with allergen immunotherapy are an immunos- at www.jacionline.org . Some of these forms, along with examples timulatory oligonucleotide sequence of DNA containing a of immunotherapy instruction and consent forms, preinjection CpG motif (CpG) and 3-deacylated monophospholipid health questionnaires, and indications for beginning and continu- A (MPL). Clinical trials with these adjuvants, in combination ing immunotherapy forms, the allergen extraction preparation with ragweed (CPG and MPL) and grasses (MPL), demon- , www.acaai.org www.aaaai.org , guidelines, can also be found at strate significant improvement in allergic rhinitis symptoms or www.jcaai.org . with 4 to 6 injections administered preseasonally. Neither of these adjuvants are available as FDA-approved allergen REFERENCES extracts. NR 1. American College of Medical Quality’s policy on development and use of prac- Efforts to develop safer and more effective allergen immuno- tice parameters for medical quality decision-making. Available at: http://www. therapy extracts have resulted in several modifications to the acmq.orq/profess/PDFs/policy5.pdf . Accessed September 26, 2006. NR 2. Cox L, Li J, Lockey R, Nelson H. Allergen immunotherapy: a practice parameter allergen extracts. Adjuvants enhance the effectiveness of allergen second update. 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