The Journal of Allergy and Clinical Immunology
Volume 120, Issue 3, Supplement , Pages S25-S85, September 2007

Allergen immunotherapy: A practice parameter second update

Article Outline

These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology.

The American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) have jointly accepted responsibility for establishing the “Allergen immunotherapy: a practice parameter second update.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or the ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

 

Published practice parameters of the Joint Task Force on Practice Parameters for Allergy and Immunology include the following:

1.Practice parameters for the diagnosis and treatment of asthma. J Allergy Clin Immunol 1995;96(suppl):S707-S870.

2.Practice parameters for allergy diagnostic testing. Ann Allergy 1995;75:543-625.

3.Practice parameters for the diagnosis and management of immunodeficiency. Ann Allergy 1996;76:282-94.

4.Practice parameters for allergen immunotherapy. J Allergy Clin Immunol 1996;98:1001-11.

5.Disease management of atopic dermatitis: a practice parameter. Ann Allergy 1997;79:197-211.

6.The diagnosis and management of anaphylaxis. J Allergy Clin Immunol 1998;101(suppl):S465-S528.

7.Algorithm for the diagnosis and management of asthma: a practice parameter update. Ann Allergy 1998;81:415-20.

8.Diagnosis and management of rhinitis: parameter documents of the Joint Task Force on Practice parameters in Allergy, Asthma and Immunology. Ann Allergy 1998;81(suppl):S463-S518.

9.Parameters for the diagnosis and management of sinusitis. J Allergy Clin Immunol 1998;102(suppl):S107-S144.

10.Stinging insect hypersensitivity: a practice parameter. J Allergy Clin Immunol 1999;103:963-80.

11.Disease management of drug hypersensitivity: a practice parameter. Ann Allergy 1999;83(suppl):S665–S700.

12.Diagnosis and management of urticaria: a practice parameter. Ann Allergy 2000;85(suppl):S521-S544.

13.Allergen immunotherapy: a practice parameter. Ann Allergy 2003;90(suppl):SI-S540.

14.Symptom severity assessment of allergic rhinitis: part I. Ann Allergy 2003;91:105-14.

15.Disease management of atopic dermatitis: an updated practice parameter. Ann Allergy 2004;93(suppl):S1-S21.

16.Stinging insect hypersensitivity: a practice parameter update. J Allergy Clin Immunol 2004;114:869-86.

17.The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 2005;115(suppl):S483-S523.

18.Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy 2005;94(suppl):S1-S63.

19.Attaining optimal asthma control: a practice parameter. J Allergy Clin Immunol 2005;116(suppl):S3-S11.

20.The diagnosis and management of sinusitis: a practice parameter update. J Allergy Clin Immunol 2005;116(suppl):S13-S47.

21.Food allergy: a practice parameter. Ann Allergy Asthma Immunol 2006;96(suppl 2):S1-S68.

22.Contact dermatitis: a practice parameter. Ann Allergy Asthma Immunol 2006;97(suppl 2):S1-S38.

These parameters are also available on the internet at http://www.jcaai.org.

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Contributors 

The Joint Task Force has made a concerted effort to acknowledge all contributors to this parameter. If any contributors have been excluded inadvertently, the Task Force will ensure that appropriate recognition of such contributions is made subsequently.

The Joint Task Force gratefully acknowledges the American Academy of Allergy, Asthma and Immunology Board of Directors and the American College of Allergy, Asthma and Immunology Board of Regents for their review and support of this document.

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Supplement Editor 

Linda Cox, MD

Department of Medicine

Nova Southeastern University College of Osteopathic Medicine

Davie, Fla

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Co-editors 

James T. Li, MD, PhD

Division of Allergic Diseases

Mayo Clinic

Rochester, Minn

Richard Lockey, MD

Departments of Medicine, Pediatrics, and Public Health

Division of Allergy and Immunology

University of South Florida College of Medicine

James A. Haley Veterans' Hospital

Tampa, Fla

Harold Nelson, MD

Department of Medicine

National Jewish Medical and Research Center

Denver, Colo

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Joint Task Force reviewers 

David Bernstein, MD

Department of Medicine and Environmental Health

University of Cincinnati College of Medicine

Cincinnati, Ohio

I. Leonard Bernstein, MD

Departments of Medicine and Environmental Health

University of Cincinnati College of Medicine

Cincinnati, Ohio

David A. Khan, MD

Department of Internal Medicine

University of Texas Southwestern Medical Center

Dallas, Tex

Joann Blessing-Moore, MD

Departments of Medicine and Pediatrics

Stanford University Medical Center

Department of Immunology

Palo Alto, Calif

David M. Lang, MD

Allergy/Immunology Section

Division of Medicine

Allergy and Immunology Fellowship Training Program

Cleveland Clinic Foundation

Cleveland, Ohio

Richard A. Nicklas, MD

Department of Medicine

George Washington Medical Center

Washington, DC

John Oppenheimer, MD

Department of Internal Medicine

New Jersey Medical School

Pulmonary and Allergy Associates

Morristown, NJ

Jay M. Portnoy, MD

Section of Allergy, Asthma & Immunology

The Children's Mercy Hospital

Department of Pediatrics

University of Missouri-Kansas City School of Medicine

Kansas City, Mo

Diane E. Schuller, MD

Department of Pediatrics

Pennsylvania State University Milton S. Hershey Medical College

Hershey, Pa

Sheldon L. Spector, MD

Department of Medicine

UCLA School of Medicine

Los Angeles, Calif

Stephen A. Tilles, MD

Department of Medicine

University of Washington School of Medicine

Redmond, Wash

Dana V. Wallace, MD

Nova Southeastern University

Davie, Fla

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Invited reviewers 

Don Aaronson, MD, Chicago, Ill

David Golden, MD, Baltimore, Md

Moises Calderon, MD, London, United Kingdom (UK)

Stephen Durham, MD, London, UK

Ira Finegold, MD, New York, NY

Stephen Kemp, Jackson, Miss

Brian Smart, MD, Glen Ellyn, Ill

Mark L. Vandewalker, MD, Columbia, Mo

Richard Weber, MD, Denver, Colo

David Weldon, MD, College Station, Tex

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Reviewers of allergen extract section 

Robert Esch, PhD, Lenoir, NC

Larry Garner, CPT, BA, Spokane, Wash

Richard Lankow, PhD, Round Rock, Tex

Greg Plunkett, PhD, Round Rock, Tex

Tom Willoughby, Liberty, Miss

The authors and editors gratefully acknowledge Susan Grupe for her administrative assistance.

Allergen immunotherapy: A practice parameter second update


PrefaceS27

Algorithm and annotations for immunotherapyS28

Immunotherapy glossaryS31

IntroductionS33

Summary statementsS33

Mechanisms of immunotherapyS38

Allergen extractsS38

Efficacy of immunotherapyS41

Safety of immunotherapyS43

Patient selectionS46

Allergen selection and handlingS48

Immunotherapy schedules and dosesS53

Location of allergen immunotherapy administrationS61

Special considerations in immunotherapyS63

Alternative routes of immunotherapyS64

Future trends in immunotherapyS66

ReferencesS67

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Preface 

This document was developed by the Joint Task Force on Practice Parameters, which represents the American Academy of Allergy, Asthma and Immunology (AAAAI); the American College of Allergy, Asthma and Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology (JCAAI).

The objective of “Allergen immunotherapy: A practice parameter second update” is to optimize the practice of allergen immunotherapy for patients with allergic rhinitis, allergic asthma, and Hymenoptera sensitivity. This parameter is intended to establish guidelines for the safe and effective use of allergen immunotherapy, while reducing unnecessary variation in immunotherapy practice. These guidelines have undergone an extensive peer-review process consistent with recommendations of the American College of Medical Quality's “Policy on development and use of practice parameters for medical quality decision-making” (Appendix 1).1

This document builds on the previous Joint Task Force document, “Allergen immunotherapy: a practice parameter” published in the Annals of Allergy, Asthma and Immunology in 2003.2 The updated practice parameters draft was prepared by Drs Linda Cox, James Li, Hal Nelson, and Richard Lockey. The Joint Task Force reworked the initial draft into a working draft of the document. The project was exclusively funded by the 3 allergy and immunology societies noted above.

In preparation for the 2003 “Allergen immunotherapy: a practice parameter” and the second update, a comprehensive search of the medical literature was conducted with various search engines, including PubMed; immunotherapy, allergic rhinitis, asthma, stinging insect allergy, and related search terms were used. Published clinical studies were rated by category of evidence and used to establish the strength of a clinical recommendation (Table I).3 Laboratory-based studies were not rated.

Table I. Classification of evidence and recommendations∗
Category of evidence
IaEvidence from meta-analysis of randomized controlled trials
IbEvidence from at least 1 randomized controlled trial
IIaEvidence from at least 1 controlled study without randomization
IIbEvidence from at least 1 other type of quasiexperimental study
IIIEvidence from nonexperimental descriptive studies, such as comparative studies, correlation studies, and case-control studies
IVEvidence from expert committee reports or opinions, clinical experience of respected authorities, or both
LBEvidence from laboratory-based studies
NRNot rated
Strength of recommendation
ADirectly based on category I evidence
BDirectly based on category II evidence or extrapolated from category I evidence
CDirectly based on category III evidence or extrapolated from category I or II evidence
DDirectly based on category IV evidence or extrapolated from category I, II, or III evidence
NRNot rated

∗Adapted with permission from Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ 1999;318:593-6.3

The working draft of “Allergen immunotherapy: a practice parameter second update” was reviewed by a large number of experts in immunotherapy, allergy, and immunology. These experts included reviewers appointed by the ACAAI, AAAAI, and JCAAI. In addition, the draft was posted on the ACAAI and AAAAI Web sites with an invitation for review and comments from members of the sponsoring organizations. The authors carefully considered all of these comments in preparing the final version. An annotated algorithm in this document summarizes the key decision points for the appropriate use of allergen immunotherapy (Fig 1).

The section on efficacy summarizes the evidence demonstrating that allergen immunotherapy is effective in the management of properly selected patients with allergic rhinitis, allergic asthma, and stinging insect hypersensitivity. This document also contains recommendations for the safe practice of allergen immunotherapy, including specific recommendations on the prevention and management of systemic reactions.

Specific recommendations guide the physician in selecting those patients for whom allergen immunotherapy is appropriate. Aeroallergen immunotherapy should be considered for patients who have symptoms of allergic rhinitis or asthma with natural exposure to allergens and who demonstrate specific IgE antibodies to the relevant allergen or allergens. Symptoms of allergic conjunctivitis (eg, itchy watery eyes) are often considered part of allergic rhinitis or are included in the diagnosis of rhinoconjunctivitis. Particularly good candidates for immunotherapy are patients whose symptoms are not controlled adequately by medications and avoidance measures, those in whom it is important to avoid the potential adverse effects of medications, and those who wish to reduce the long-term use of medications. Immunotherapy is recommended for patients with a history of systemic reaction to Hymenoptera stings and specific IgE antibodies to Hymenoptera venom.

The selection of allergens for immunotherapy is based on clinical history, the presence of specific IgE antibodies, and allergen exposure. This parameter offers suggestions and recommendations derived from known patterns of allergen cross-reactivity. Recognizing that the immunotherapy terminology used to describe extract dilutions is sometimes ambiguous, the 2003 “Allergen immunotherapy: a practice parameter” established standardized terminology for describing allergen immunotherapy extract dilutions. These parameters also provided specific recommendations for immunotherapy maintenance doses for some standardized allergens and a suggested dosing range for nonstandardized allergen extracts. The therapeutic preparations for allergen immunotherapy are extracted from source materials, such as pollen, mold cultures, and pelt, hence the traditional term allergen extract. The terms allergen extract or extract refer to solutions of proteins or glycoproteins extracted from source material not yet incorporated into a therapeutic allergen immunotherapy extract. The term maintenance concentrate should be used to identify the allergen immunotherapy extract that contains a therapeutic effective dose for each of its individual constituents (see the Immunotherapy schedules and doses section).

The term manufacturer's extract refers to the allergy extract purchased from the manufacturer. The terms stock, full-strength, and concentrate are ambiguous and should not be used. 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 concentrate).

Allergen immunotherapy is effective when appropriate doses of the allergens are administered. “Allergen immunotherapy: A practice parameter” recommends that vials of allergen immunotherapy extracts should be prepared individually for each patient to enhance the individualization of therapy, reduce the risk of allergen cross-contamination, and reduce the risk of error in administration.4, 5 This parameter recommends the use of standardized allergen immunotherapy prescription and administration forms to improve the safety, uniformity, and standardization of allergen immunotherapy practice.4, 5 The suggested forms are found in the Appendix (Appendix 7, Appendix 8, Appendix 11, Appendix 12, Appendix 14) and in the members' section of the www.aaaai.org Web site. The routine use of these standardized forms should improve the quality of immunotherapy practice.

Members' feedback comments on the recommended allergen extract dilution dating in the 2003 “Allergen immunotherapy: A practice parameter” led to an allergen immunotherapy extract dilution stability study designed by the AAAAI Immunotherapy and Allergy Diagnostics Committee and funded by the AAAAI Board of Directors. The study was designed to investigate the effect of time, temperature, and dilution of standardized allergen extract potency, and the results of this study were considered in this update.

This document was approved by the sponsoring organizations and represents an evidence-based, broadly accepted consensus opinion. These clinical guidelines are designed to assist clinicians by providing a framework for the evaluation and treatment of patients and are not intended to replace a clinician's judgment or establish a protocol for all patients. Not all recommendations will be appropriate for all patients. Because this document incorporates the efforts of many participants, no individual, including anyone who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these guidelines. Recognizing the dynamic nature of clinical practice and practice parameters, the recommendations in this document should be considered applicable for 3 years after publication. Requests for information about or an interpretation of these practice parameters should be directed to the Executive Offices of the AAAAI, ACAAI, and JCAAI. These parameters are not designed for use by pharmaceutical companies in drug promotion.

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Algorithm and annotations for immunotherapy 

Fig 1 provides an algorithm for the appropriate use of allergen immunotherapy. Given below are annotations for use with the algorithm.

Box 1 

Immunotherapy is effective in the management of allergic asthma, allergic rhinitis/conjunctivitis, and stinging insect hypersensitivity. Allergen immunotherapy might prevent the development of asthma in individuals with allergic rhinitis.6, 7, 8, 9 Evaluation of a patient with suspected allergic rhinitis, allergic rhinoconjunctivitis, allergic asthma, or stinging insect allergy includes a detailed history, an appropriate physical examination, and selected laboratory tests. A definitive diagnosis of allergic asthma, allergic conjunctivitis, allergic rhinitis, or stinging insect hypersensitivity depends on the results of allergy testing (immediate hypersensitivity skin tests or in vitro tests for specific IgE antibody).10

Box 2 

Immediate hypersensitivity skin testing is generally the preferred method of testing for specific IgE antibodies, although in vitro testing for specific IgE antibodies is useful under certain circumstances. Immunotherapy should be considered when positive test results for specific IgE antibodies correlate with suspected triggers and patient exposure.

Box 3 

Immunotherapy should not be given to patients with negative test results for specific IgE antibodies or those with positive test results for specific IgE antibodies that do not correlate with suspected triggers, clinical symptoms, or exposure. This means that the presence of specific IgE antibodies alone does not necessarily indicate clinical sensitivity. There is no evidence from well-designed studies that immunotherapy for any allergen is effective in the absence of specific IgE antibodies.

Box 4 

Management of complex medical conditions, such as allergic asthma, allergic rhinitis/conjunctivitis, and stinging insect hypersensitivity, should include the careful evaluation of management options. Each of the 3 major management approaches (allergen immunotherapy, allergen exposure reduction, and pharmacotherapy) has benefits, risks, and costs. Furthermore, the management plan must be individualized, with careful consideration given to patient preference. Disease severity and response (or lack of response) to previous treatment are important factors.

Box 5 

The physician and patient should discuss the benefits, risks, and costs of the appropriate management options and agree on a management plan. On the basis of clinical considerations and patient preference, allergen immunotherapy might or might not be recommended. Patients with allergic rhinitis/conjunctivitis or allergic asthma whose symptoms are not well controlled by medications or avoidance measures or require high medication doses, multiple medications, or both to maintain control of their allergic disease might be good candidates for immunotherapy. Patients who experience adverse effects of medications or who wish to avoid or reduce the long-term use of medications are good candidates for immunotherapy. However, asthma must be controlled at the time the immunotherapy injection is administered. In general, patients with stinging insect hypersensitivity who are at risk for anaphylaxis should receive venom immunotherapy (VIT).

Box 6 

After careful consideration of appropriate management options, the physician and patient might decide not to proceed with immunotherapy.

Box 7 

Before immunotherapy is started, patients should understand its benefits, risks, and costs. Counseling should also include the expected onset of efficacy and duration of treatment, as well as the risk of anaphylaxis and importance of adhering to the immunotherapy schedule.

Box 8 

The physician prescribing immunotherapy should be trained and experienced in prescribing and administering immunotherapy. The prescribing physician must select the appropriate allergen extracts on the basis of that particular patient's clinical history and allergen exposure history and the results of tests for specific IgE antibodies. The quality of the allergen extracts available is an important consideration. When preparing mixtures of allergen extracts, the prescribing physician must take into account the cross-reactivity of allergen extracts and the potential for allergen degradation caused by proteolytic enzymes. The prescribing physician must specify the starting immunotherapy dose, the target maintenance dose, and the immunotherapy schedule (see the Immunotherapy schedules and doses section). In general, the starting immunotherapy dose is 1000-fold to 10,000-fold less than the maintenance dose. For highly sensitive patients, the starting dose might be lower. The maintenance dose is generally 1000 to 4000 arbitrary units (AU; eg, for dust mite) or bioequivalent allergy units (BAU; eg, for grass) for standardized allergen extracts. For nonstandardized extracts, a suggested maintenance dose is 3000 to 5000 protein nitrogen units (PNU) or 0.5 mL of a 1:100 wt/vol dilution of manufacturer's extract. If the major allergen concentration of the extract is known, a range between 5 and 20 μg of major allergen is the recommended maintenance dose for inhalant allergens and 100 μg for Hymenoptera venom. Immunotherapy treatment can be divided into 2 periods, which are commonly referred to as the build-up and maintenance phases.

The immunotherapy build-up schedule (also referred to as up-dosing, induction, or the dose-increase phase) entails administration of gradually increasing doses during a period of approximately 14 to 28 weeks. In conventional schedules a single dose increase is given on each visit, and the visit frequency can vary from 1 to 3 times a week. Accelerated schedules, such as rush or cluster immunotherapy, entail administration of several injections at increasing doses on a single visit. Accelerated schedules offer the advantage of achieving the therapeutic dose earlier but might be associated with increased risk of systemic reaction in some patients.

Box 9 

Immunotherapy should be administered in a setting that permits the prompt recognition and management of adverse reactions. The preferred location for such administration is the prescribing physician's office. However, patients can receive immunotherapy injections at another health care facility if the physician and staff at that location are trained and equipped to recognize and manage immunotherapy reactions, in particular anaphylaxis. Patients should wait at the physician's office for at least 30 minutes after the immunotherapy injection or injections so that reactions can be recognized and treated promptly, if they occur.

In general, immunotherapy injections should be withheld if the patient presents with an acute asthma exacerbation. For patients with asthma, consider measuring peak expiratory flow rate before administering an immunotherapy injection and withholding an immunotherapy injection if the peak expiratory flow rate is considered low for that patient. Some physicians recommend providing certain patients with epinephrine for self-administration in case of severe late reactions to immunotherapy injections.

Box 10 

Injections of allergen immunotherapy extract can cause local or systemic reactions. Most severe reactions develop within 30 minutes after the immunotherapy injection, but reactions can occur after this time.

Box 11 

Local reactions can be managed with local treatment (eg, cool compresses or topical corticosteroids) or antihistamines. Systemic reactions can be mild or severe (anaphylaxis). Epinephrine is the treatment of choice in anaphylaxis, preferably when administered intramuscularly,11 although subcutaneous administration is acceptable.12

Antihistamines and systemic corticosteroids are secondary medications that might help to modify systemic reactions but should never replace epinephrine in the treatment of anaphylaxis. Intravenous saline or supplemental oxygen might be required in severe cases. For additional details, see the practice parameters for anaphylaxis.12

The immunotherapy dose and schedule, as well as the benefits and risks of continuing immunotherapy, should be evaluated after any immunotherapy-induced systemic reaction. After a severe systemic reaction, careful evaluation by the prescribing physician is recommended. For some patients, the immunotherapy maintenance dose might need to be reduced because of repeated systemic reactions to immunotherapy injections. The decision to continue immunotherapy should be re-evaluated after severe or repeated systemic reactions to allergen immunotherapy extracts.

Box 12 

Patients receiving maintenance immunotherapy should have follow-up visits at least every 6 to 12 months. Periodic visits should include a reassessment of symptoms and medication use, the medical history since the previous visit, and an evaluation of the clinical response to immunotherapy. The immunotherapy schedule and doses, 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.

There are no specific markers that will predict who will remain in clinical remission after discontinuing effective allergen immunotherapy. Some patients might sustain lasting remission of their allergic symptoms after discontinuing allergen immunotherapy,13 but others might experience a recurrence of their symptoms after discontinuation of allergen immunotherapy.14 As with the decision to initiate allergen immunotherapy, the decision to discontinue treatment should be individualized, taking into account factors such as the severity of the patient's illness before treatment, the treatment benefit sustained, and the inconvenience immunotherapy represents to a specific patient and the potential effect a clinical relapse might have on the patient. Ultimately, the duration of immunotherapy should be individualized on the basis of the patient's clinical response, disease severity, immunotherapy reaction history, and patient preference.

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Immunotherapy glossary 

For more information on immunotherapy definitions, see the article by Kao.15

The allergen immunotherapy extract is defined as the mixture of the manufacturer's allergen extract or extracts that is used for allergen immunotherapy. Allergen extracts used to prepare the allergen immunotherapy extract can be complex mixtures containing multiple allergenic and nonallergenic macromolecules (proteins, glycoproteins, and polysaccharides) and low-molecular-weight compounds (pigments and salts; see the Allergen selection and handling section). Other terms used to describe the allergen immunotherapy extract include allergen product,16 allergy serum, allergen vaccine,17 and allergen solution.

Allergen immunotherapy is defined as the repeated administration of specific allergens to patients with IgE-mediated conditions for the purpose of providing protection against the allergic symptoms and inflammatory reactions associated with natural exposure to these allergens.18 Other terms that have been used for allergen immunotherapy include hyposensitization, allergen-specific desensitization, and the lay terms allergy shots or allergy injections.15

Anaphylaxis is an immediate systemic reaction often occurring within minutes and occasionally as long as an hour or longer after exposure to an allergen. It can be IgE mediated, as can occur with allergen immunotherapy, or non–IgE mediated, as occurs with radiocontrast media. It is caused by the rapid release of vasoactive mediators from tissue mast cells and peripheral blood basophils.

The build-up phase involves receiving injections with increasing amounts of the allergen. The frequency of injections during this phase generally ranges from 1 to 3 times a week, although more rapid build-up schedules are sometimes used. The duration of this phase depends on the frequency of the injections but generally ranges from 3 to 6 months (at a frequency of 2 times and 1 time per week, respectively).

Cluster immunotherapy is an accelerated build-up schedule that entails administering several injections at increasing doses (generally 2-3 per visit) sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is generally achieved more rapidly than with a conventional (single injection per visit) build-up schedule (generally within 4 to 8 weeks).

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

The dose is the actual amount of allergen administered in the injection. The volume and concentration can vary such that the same delivered dose can be given by changing the volume and concentration (ie, 0.05 mL of a 1:1 vol/vol allergen would equal 0.5 mL of a 1:10 vol/vol allergen). The dose can be calculated by using the following formula: concentration of allergen multiplied by volume of administered dose (see Table II for a dose-calculation table).

Table II. Allergen immunotherapy dose-calculation table
•Express weight per volume as a fraction: or 1:N.
•Calculate concentration of individual allergens in mixtures. If a mixture is made of equal amounts of N individual allergens to make a total concentration (C), the final concentration of an individual allergen (Ca) can be calculated by using the following equation:
or C:N.
For example, if a mixture of equal amounts of 5 (N) allergens has a total concentration (C) of 100,000 BAU/mL, then the final concentration of each individual allergen (Ca) is:
Likewise, if C = 1:10 (wt/vol), then: or or 1:50.
•Dilution of individual allergen: If an initial volume, Vi (in milliliters), of an individual antigen with concentration, Ci, is added to an allergen extract to make a final volume of Vf (in milliliters), the final allergen concentration (Ca) in the allergen extract mixture will be: .
•Final concentration of an allergen in a mixture of mixtures is determined by multiplying the initial concentration by the dilution factors from each mixing step.
For example, consider a mixture containing equal amounts of 5 (N) allergens with a total concentration (C) of 100,000 BAU/mL (first dilution). If an initial volume (Vi) of 0.5 mL of this mixture is further mixed with other components and diluent to make a final allergen extract mixture volume (Vf) of 5.0 mL (second dilution), the final concentration of an individual allergen (Ca) will be:
Likewise, if C = 1:10 (wt/vol), then: or 1:500.

The effective therapeutic dose or maintenance dose is the dose that provides therapeutic efficacy without significant adverse local or systemic reactions. The effective therapeutic dose might not be the initially calculated projected effective dose (eg, cat, 1000 BAU, [highest tolerated dose] vs 2000 BAU [projected effective dose]).

Hyposensitization is a term formerly used interchangeably with allergen immunotherapy. It was introduced to distinguish allergen immunotherapy from classical desensitization. Hyposensitization denotes a state of incomplete desensitization because complete desensitization is rarely accomplished with allergen immunotherapy.

Immunomodulation is a term that denotes a wide variety of drug or immunologic interventions that alter normal or abnormal immune responses by deletion of specific T cells, B cells, or both; immune deviation; induction of peripheral/central tolerance; or modification of various inflammatory pathways (eg, chemotaxis, adhesions, or intracytoplasmic signaling).

Immunotherapy is a treatment modality that appeared soon after adaptive immune responses were discovered and has gradually evolved to encompass any intervention that might benefit immune-induced aberrant conditions by a variety of immunologic transformations. Early definitions of the term immunotherapy included active and passive immunization for the purpose of improving a host's defenses against microorganisms. Allergen immunotherapy was originally conceived as a form of active immunization, the purpose of which was to alter the host's abnormal immune responses and not augment the host's defenses against microorganisms. The modern rubric of immunotherapy includes all methods used to overcome abnormal immune responses by means of induction of clonal deletion, anergy, immune tolerance, or immune deviation.

The maintenance concentrate is a preparation that contains individual or mixtures of manufacturer's allergen extracts intended for allergen immunotherapy treatment. A maintenance 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 extract mixture. Subsequent dilutions can be prepared from the maintenance concentrate for the build-up phase or if the patient cannot tolerate the maintenance concentrate.

The maintenance dose (or effective therapeutic dose) is the dose that provides therapeutic efficacy without significant adverse local or systemic reactions. The effective therapeutic dose may not be the initially calculated projected effective dose.

The maintenance goal (or projected effective dose) is the allergen dose projected to provide therapeutic efficacy. The maintenance goal is based on published studies, but a projected effective dose has not been established for allergens. Not all patients will tolerate the projected effective dose, and some patients experience therapeutic efficacy at lower doses.

The maintenance phase begins when the effective therapeutic dose is reached. Once the maintenance dose is reached, the intervals between the allergy injections are increased. The dose generally is the same with each injection, although modifications can be made based on several variables (ie, new vials or a persistent large local reaction causing discomfort). The intervals between maintenance immunotherapy injections generally ranges from 4 to 8 weeks for venom and every 2 to 4 weeks for inhalant allergens but can be advanced as tolerated if clinical efficacy is maintained.

A major allergen is an antigen that binds to the IgE sera from 50% or more of a clinically allergic group of patients. Such allergens are defined either by means of immunoblotting or crossed allergoimmunoelectrophoresis.

For a definition of projected effective dose, see maintenance goal.

Rush immunotherapy is an accelerated immunotherapy build-up schedule that entails administering incremental doses of allergen at intervals varying between 15 and 60 minutes over 1 to 3 days until the target therapeutic dose is achieved. Rush immunotherapy schedules for inhalant allergens can be associated with a greater risk of systemic reactions, particularly in high-risk patients (eg, those with markedly positive prick/puncture test responses), and premedication with antihistamines and corticosteroids appears to reduce the risk associated with rush immunotherapy. However, rush protocols for administration of Hymenoptera VIT have not been associated with a similar high incidence of systemic reactions.

Off the board into one syringe is a phrase that describes a method of allergen immunotherapy preparation and administration that involves specifically mixing the patient's allergen immunotherapy injection in a single syringe, which is not recommended. This syringe might be inserted into more than one allergen extract vial, and this poses a risk of cross-contamination of the allergen extracts and might dull the needle with repeated penetration of the rubber stopper.

Shared specific patient vials is a method of allergen immunotherapy preparation and administration in which the allergy immunotherapy extract is withdrawn from a shared vial (eg, mixed vespids or dust mite mix). This is sometimes referred to as off the board, but it is distinct from the method of off the board into one syringe in that the syringe enters only one allergen extract vial.

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Introduction 

Immunity has been defined as protection against certain diseases. The initial immunotherapeutic interventions, which included the use of preventive vaccines and xenogenic antisera by Jenner, Pasteur, Koch, and von Behring, were effective for disease prevention. These initial efforts in immune modulation served as a model for later developments in the field of allergen immunotherapy. From its humble empiric emergence in 1900, when ragweed injections were proposed as therapy for autumnal hay fever, allergen immunotherapy has progressed in both theory and practice from the passive immunologic approach to the active immunologic procedures pioneered by Noon19 and Freeman.20, 21 Advances in allergen immunotherapy have depended on the improved understanding of IgE-mediated immunologic mechanisms, the characterization of specific antigens and allergens, and the standardization of allergen extracts. Proof of the efficacy of allergen immunotherapy has accumulated rapidly during the past 10 years. Numerous well-designed controlled studies have demonstrated that allergen immunotherapy is efficacious in the treatment of allergic rhinitis, allergic asthma, and stinging insect hypersensitivity. Some studies have suggested that allergen immunotherapy might prevent the development of asthma in individuals with allergic rhinitis.6, 7, 8, 9

Effective subcutaneous allergen immunotherapy appears to correlate with administration of an optimal maintenance dose in the range of 5 to 20 μg of major allergen for inhalant allergens,22, 23, 24, 25, 26 and it should be differentiated from unproved methods, such as neutralization-provocation therapy and low-dose subcutaneous regimens based on the Rinkel technique, which have been found to ineffective in a double-blind placebo-controlled study.27, 28

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Summary statements 

Mechanisms of immunotherapy 

Summary Statement 1: Immunologic changes during immunotherapy are complex. D

Summary Statement 2: Successful immunotherapy is associated with a change toward a TH1 CD4+ cytokine profile. A

Summary Statement 3: Allergen immunotherapy is also associated with immunologic tolerance, defined as a relative decrease in allergen-specific responsiveness and by the generation of CD4+CD25+ regulatory T lymphocytes. A

Summary Statement 4: Efficacy from immunotherapy is not dependent on reduction in specific IgE levels. A

Summary Statement 5: Increases in allergen-specific IgG antibody titers are not predictive of the duration and degree of efficacy of immunotherapy. However, alterations in the allergen-specific IgG specificity with immunotherapy might play a role in determining clinical efficacy. A

Allergen extracts 

Summary Statement 6: When possible, standardized extracts should be used to prepare the allergen immunotherapy extract treatment sets. A

Summary Statement 7: Nonstandardized extracts might vary widely in biologic activity and, regardless of a particular wt/vol or PNU potency, should not be considered equipotent. B

Summary Statement 8: In choosing the components for a clinically relevant allergen immunotherapy extract, the physician should be familiar with local and regional aerobiology and indoor and outdoor allergens, paying special attention to potential allergens in the patient's own environment. D

Cross-reactivity of allergen extract 

Summary Statement 9: Knowledge of allergen cross-reactivity is important in the selection of allergens for immunotherapy because limiting the number of allergens in a treatment vial is necessary to attain optimal therapeutic doses for the individual patient. B

Efficacy of immunotherapy 

Allergic rhinitis, allergic asthma, and stinging insect hypersensitivity 

Summary Statement 10: Immunotherapy is effective for treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma, and stinging insect hypersensitivity. Therefore immunotherapy merits consideration in patients with these disorders as a possible treatment option. A

Food allergy, urticaria, and atopic dermatitis 

Summary Statement 11: Clinical studies do not support the use of allergen immunotherapy for food hypersensitivity or chronic urticaria, angioedema, or both at this time. Therefore allergen immunotherapy for patients with food hypersensitivity or chronic urticaria, angioedema, or both is not recommended. D

Summary Statement 11b: There are limited data indicating that immunotherapy might be effective for atopic dermatitis when this condition is associated with aeroallergen sensitivity. C

Summary Statement 11c: The potential for benefit in symptoms related to oral allergy syndrome with inhalant immunotherapy directed at the cross-reacting pollens has been observed in some studies but not in others. For this reason, more investigation is required to substantiate that a benefit in oral allergy symptoms will occur with allergen immunotherapy. C

Measures of efficacy 

Summary Statement 12: Clinical parameters, such as symptoms and medication use, might be useful measures of the efficacy of immunotherapy in a clinical setting; however, repetitive skin testing of patients receiving immunotherapy is not recommended. A

Safety of immunotherapy 

Reaction rates 

Summary Statement 13: Published studies indicate that individual local reactions do not appear to be predictive of subsequent systemic reactions. However, some patients with greater frequency of large local reactions might be at an increased risk for future systemic reactions. C

Summary Statement 14: Although there is a low risk of severe systemic reactions with appropriately administered allergen immunotherapy, life-threatening and fatal reactions do occur. C

Summary Statement 15: An assessment of the patient's current health status should be made before administration of the allergy immunotherapy injection to determine whether there were any recent health changes that might require modifying or withholding that patient's immunotherapy treatment. Risk factors for severe immunotherapy reactions include symptomatic asthma and injections administered during periods of symptom exacerbation. Before the administration of the allergy injection, the patient should be evaluated for the presence of asthma or allergy symptom exacerbation. One might also consider an objective measure of airway function (eg, peak flow) for the asthmatic patient before allergy injections. B

Timing of anaphylactic reactions to immunotherapy injections 

Summary Statement 16: Because most systemic reactions that result from allergen immunotherapy occur within 30 minutes after an injection, patients should remain in the physician's office at least 30 minutes after an injection. C

β-Adrenergic blocking agents 

Summary Statement 17: β-Adrenergic blocking agents might make allergen immunotherapy–related systemic reactions more difficult to treat and delay the recovery. Therefore a cautious attitude should be adopted toward the concomitant use of β-blocker agents and inhalant allergen immunotherapy. However, immunotherapy is indicated in patients with life-threatening stinging insect hypersensitivity who also require β-blocker medications because the risk of the stinging insect hypersensitivity is greater than the risk of an immunotherapy-related systemic reaction. C

Contraindications 

Summary Statement 18: Medical conditions that reduce the patient's ability to survive the systemic allergic reaction or the resultant treatment are relative contraindications for allergen immunotherapy. Examples include severe asthma uncontrolled by pharmacotherapy and significant cardiovascular disease. C

Reducing the risk of anaphylaxis to immunotherapy injections 

Summary Statement 19: Allergen immunotherapy should be administered in a setting where procedures that can reduce the risk of anaphylaxis are in place and where the prompt recognition and treatment of anaphylaxis is ensured. C

Patient selection 

Clinical indications 

Summary Statement 20: 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 depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, and the adverse effects of medications. A

Special precautions in patients with asthma 

Summary Statement 21: Allergen immunotherapy in asthmatic patients should not be initiated unless the patient's asthma is stable with pharmacotherapy. C

Clinical indications for VIT 

Summary Statement 22: VIT should be strongly considered if the patient has had a systemic reaction to a Hymenoptera sting, especially if such a reaction was associated with respiratory symptoms, cardiovascular symptoms, or both and if the patient has demonstrable evidence of specific IgE antibodies. A

Summary Statement 23: Patients selected for immunotherapy should be cooperative and compliant. D

Allergen selection and handling 

Clinical evaluation 

Summary Statement 24: The selection of the components of an allergen immunotherapy extract that are most likely to be effective should be based on a careful history of relevant symptoms with knowledge of possible environmental exposures and correlation with positive test results for specific IgE antibodies. A

Clinical correlation 

Summary Statement 25: The allergen immunotherapy extract should contain only clinically relevant allergens. A

Skin tests and in vitro IgE antibody tests 

Summary Statement 26: Skin testing has been the primary diagnostic tool in clinical studies of allergen immunotherapy. Therefore in most patients, skin testing should be used to determine whether the patient has specific IgE antibodies. Appropriately interpreted in vitro tests for specific IgE antibodies can also be used. A

Specific allergens 

Summary Statement 27: Immunotherapy is effective for pollen, mold, animal allergens, cockroach, dust mite, and Hymenoptera hypersensitivity. Therefore immunotherapy should be considered as part of the management program in patients who have symptoms related to exposure to these allergens, supported by the presence of specific IgE antibodies. A

Principles of mixing 

Summary Statement 28: Consideration of the following principles is necessary when mixing allergen extract: (1) cross-reactivity of allergens, (2) optimization of the dose of each constituent, and (3) enzymatic degradation of allergens. B

Mixing cross-reactive extracts 

Summary Statement 29: The selection of allergens for immunotherapy should be based (in part) on the cross-reactivity of clinically relevant allergens. Many botanically related pollens contain allergens that are cross-reactive. When pollens are substantially cross-reactive, selection of a single pollen within the cross-reactive genus or subfamily might suffice. When pollen allergens are not substantially cross-reactive, testing for and treatment with multiple locally prevalent pollens might be necessary. B

Dose selection 

Summary Statement 30: The efficacy of immunotherapy depends on achieving an optimal therapeutic dose of each of the constituents in the allergen immunotherapy extract. A

Proteolytic enzymes and mixing 

Summary Statement 31: Separation of extracts with high proteolytic enzyme activities, such as mold/fungi and cockroach, from other extracts, such as pollens, is recommended. B

Summary Statement 32: Allergen immunotherapy extract preparation should be performed by individuals experienced and trained in handling allergenic products. D

Allergen immunotherapy extract handling 
Storage 

Summary Statement 33a: Allergen immunotherapy extracts should be stored at 4°C to reduce the rate of potency loss. B

Summary statement 33b: Extract manufacturers conduct stability studies with standardized extracts that expose them to various shipping conditions. It is the responsibility of each supplier or manufacturer to ship extracts under validated conditions that are shown not to adversely affect the product's potency or safety. C

Storing dilute extracts 

Summary Statement 34a: More dilute concentrations of allergen immunotherapy extracts (diluted greater than 1:10 vol/vol) are more sensitive to the effects of temperature and lose potency more rapidly than more concentrated allergen immunotherapy extracts. The expiration date for more dilute concentrations should reflect this shorter shelf life. B

Summary Statement 34b: In determining the allergen immunotherapy extract expiration date, consideration must be given to the fact that the rate of potency loss over time is influenced by a number of factors separately and collectively, including (1) storage temperature, (2) presence of stabilizers and bactericidal agents, (3) concentration, (4) presence of proteolytic enzymes, and (5) volume of the storage vial. B

Immunotherapy schedules and doses 

Summary Statement 35: A customized individual allergen immunotherapy extract should be prepared from a manufacturer's extract or extracts in accordance to the patient's clinical history and allergy test results and might be based on single or multiple allergens. D

Maintenance concentrate 

Summary Statement 36: The highest-concentration allergy immunotherapy vial (eg, 1:1 vol/vol vial) that is used for the projected effective dose is called the maintenance concentrate vial. The maintenance dose is the dose that provides therapeutic efficacy without significant adverse local or systemic reactions and might not always reach the initially calculated projected effective dose. This reinforces that allergy immunotherapy must be individualized. D

Recommended doses 

Summary Statement 37: The maintenance concentrate should be formulated to deliver a dose considered to be therapeutically effective for each of its constituent components. The projected effective dose is referred to as the maintenance goal. Some individuals unable to tolerate the projected effective dose will experience clinical benefits at a lower dose. The effective therapeutic dose is referred to as the maintenance dose. A

Effect of dilution on dose 

Summary Statement 38: Dilution limits the number of antigens that can be added to a maintenance concentrate if a therapeutic dose is to be delivered. A

Dilutions of the maintenance concentrate 

Summary Statement 39: Serial dilutions of the maintenance concentrate should be made in preparation for the build-up phase of immunotherapy. D

Labeling dilutions 

Summary Statement 40: A consistent uniform labeling system for dilutions from the maintenance concentrate might reduce errors in administration and therefore is recommended. D

Individualized treatment vials 

Summary Statement 41: Administration of an incorrect injection is a potential risk of allergen immunotherapy. An incorrect injection is an injection given to the wrong patient or a correct patient receiving an injection of an incorrect dose.

A customized individual maintenance concentrate of the allergen immunotherapy extract and serial dilutions, whether a single extract or a mixture of extracts, prepared and labeled with the patient's name and birth date might reduce the risk of incorrect (ie, wrong patient) injection. The mixing of antigens in a syringe is not recommended because of the potential for cross-contamination of extracts. C

Starting doses 

Summary Statement 42: The starting dose for build-up is usually a 1000- or 10,000-fold dilution of the maintenance concentrate, although a lower starting dose might be advisable for highly sensitive patients. D

Summary Statement 43: The frequency of allergen immunotherapy administration during the build-up phase is usually 1 to 2 injections per week. D

Dose adjustments for systemic reactions 

Summary Statement 44: The dose of allergen immunotherapy extract should be appropriately reduced after a systemic reaction if immunotherapy is continued. D

Reductions during periods of exacerbation of symptoms 

Summary Statement 45: Immunotherapy given during periods when the patient is exposed to increased levels of allergen to which they are sensitive might be associated with an increased risk of a systemic reaction. Consider not increasing or even reducing the immunotherapy dose in highly sensitive patients during the time period when they are exposed to increased levels of allergen, especially if they are experiencing an exacerbation of their symptoms. C

Dose adjustments for late injections 

Summary Statement 46: It is customary to reduce the dose of allergen immunotherapy extract when the interval between injections is prolonged. D

Cluster schedules 

Summary Statement 47: With cluster immunotherapy, 2 or more injections are administered per visit to achieve a maintenance dose more rapidly than with conventional schedules. C

Rush schedules 

Summary Statement 48: Rush schedules can achieve a maintenance dose more quickly than weekly schedules. A

Systemic reactions and rush schedules 

Summary Statement 49: Rush schedules are associated with an increased risk of systemic reactions. However, rush protocols for administration of Hymenoptera VIT have not been associated with a similarly high incidence of systemic reactions. A

Premedication and weekly immunotherapy 

Summary Statement 50: Premedication might reduce the frequency of systemic reactions caused by conventional immunotherapy. A

Premedication with cluster and rush immunotherapy 

Summary Statement 51: Premedication should be given before cluster and rush immunotherapy with aeroallergens to reduce the rate of systemic reactions. A

Maintenance schedules 

Summary Statement 52: Once a patient reaches a maintenance dose, the interval between injections often can be progressively increased as tolerated up to an interval of up to 4 weeks for inhalant allergens and up to 8 weeks for venom. Some individuals might tolerate longer intervals between maintenance dose injections. A

Continuing care 
Time course of improvement 

Summary Statement 53: Clinical improvement can be demonstrated very shortly after the patient reaches a maintenance dose. A

Follow-up visits 

Summary Statement 54: Patients should be evaluated at least every 6 to 12 months while they receive immunotherapy. D

Duration of treatment 

Summary Statement 55a: At present, there are no specific tests or clinical markers that will distinguish between patients who will relapse and those who will remain in long-term clinical remission after discontinuing effective inhalant allergen immunotherapy, and the duration of treatment should be determined by the physician and patient after considering the benefits and risks associated with discontinuing or continuing immunotherapy. D

Summary Statement 55b: Although there are no specific tests to distinguish which patients will relapse after discontinuing VIT, there are clinical features that are associated with a higher chance of relapse, notably a history of very severe reaction to a sting, a systemic reaction during VIT (to a sting or a venom injection), honeybee venom allergy, and treatment duration of less than 5 years. C

Summary Statement 55c: The patient's response to immunotherapy should be evaluated on a regular basis. A decision about continuation of effective immunotherapy should generally be made after the initial period of up to 5 years of treatment. D

Summary Statement 55d: The severity of disease, benefits sustained from treatment, and convenience of treatment are all factors that should be considered in determining whether to continue or stop immunotherapy for any individual patient. D

Summary Statement 55e: Some patients might experience sustained clinical remission of their allergic disease after discontinuing immunotherapy, but others might relapse. B

Documentation and record keeping 

Summary Statement 56: The allergen immunotherapy extract contents, informed consent for immunotherapy, and administration of extracts should be carefully documented. D

Injection techniques 

Summary Statement 57: Allergen immunotherapy extract injections should be administered with a 1-mL syringe with a 26- to 27-gauge half-inch nonremovable needle. D

Summary Statement 58: The injection should be administered subcutaneously in the posterior portion of the middle third of the upper arm. D

Location of allergen immunotherapy administration 

Physician's office 

Summary Statement 59: The preferred location for administration of allergen immunotherapy is in the office of the physician who prepared the patient's allergen immunotherapy extract. D

Summary Statement 60: Patients at high risk of systemic reactions, where possible, should receive immunotherapy in the office of the physician who prepared the patient's allergen immunotherapy extract. D

Other locations 

Summary Statement 61: Regardless of the location, allergen immunotherapy should be administered under the supervision of an appropriately trained physician and personnel. D

Home administration 

Summary Statement 62: In rare and exceptional cases, when allergen immunotherapy cannot be administered in a medical facility and withholding this therapy would result in a serious detriment to the patients' health (eg, VIT for a patient living in a remote area), very careful consideration of potential benefits and risks of at-home administration of allergen immunotherapy should be made on an individual patient basis. If this approach is used, informed consent should be obtained from the patient, and the person administering the injection to the patient must be educated about how to administer immunotherapy and recognize and treat anaphylaxis. D

Summary Statement 63: If a patient receiving immunotherapy transfers from one physician to another, a decision must be made by the physician to whom the patient has transferred as to whether to continue immunotherapy. If immunotherapy is continued, a decision must then be made about whether to continue an unchanged immunotherapy program initiated by the previous physician or to prepare a new immunotherapy program. D

Summary Statement 64: If a patient transfers from one physician to another and continues on an immunotherapy program without changes to either the schedule or allergen immunotherapy extract, the risk of a systemic reaction is not substantially increased. D

Summary Statement 65: A full, clear, and detailed documentation of the patient's schedule must accompany a patient when he or she transfers responsibility for his or her immunotherapy program from one physician to another. In addition, a record of previous response to and compliance with this program should be communicated to the patient's new physician. D

Summary Statement 66: An allergen immunotherapy extract must be considered different from a clinical standpoint if there is any change in the constituents of the extract. These include changes in the lot, manufacturer, allergen extract type (eg, aqueous, glycerinated, standardized, and nonstandardized), and/or components or relative amounts in the mixture. D

Summary Statement 67: There is an increased risk of a systemic reaction in a patient who transfers from one physician to another if the immunotherapy extract is changed because of the significant variability in content and potency of allergen extracts. The risk of a systemic reaction with a different extract might be greater with nonstandardized extracts and with extracts that contain mixtures of allergens. D

Summary Statement 68: Immunotherapy with a different extract should be conducted cautiously. If there is inadequate information to support continuing with the previous immunotherapy program, re-evaluation might be necessary, and a new schedule and allergen immunotherapy extract might need to be prepared. D

Special considerations in immunotherapy 

Allergen immunotherapy in children 

Summary Statement 69: Immunotherapy for children is effective and often well tolerated. Therefore immunotherapy should be considered (along with pharmacotherapy and allergen avoidance) in the management of children with allergic rhinitis, allergic asthma, and stinging insect hypersensitivity. It might prevent the new onset of allergen sensitivities or progression to asthma. A

Summary Statement 70: Children under 5 years of age can have difficulty cooperating with an immunotherapy program. Therefore the physician who evaluates the patient must consider the benefits and risks of immunotherapy and individualize treatment in patients under the age of 5 years. A

Pregnancy 

Summary Statement 71: Allergen immunotherapy can be continued but is usually not initiated in the pregnant patient. C

Immunotherapy in the elderly patient 

Summary Statement 72: Comorbid medical conditions and certain medication use might increase the risk from immunotherapy in elderly patients. Therefore special consideration must be given to the benefits and risks of immunotherapy in this patient population. D

Immunotherapy in patients with immunodeficiency and autoimmune disorders 

Summary Statement 73: Immunotherapy can be considered in patients with immunodeficiency and autoimmune disorders. D

Alternative routes of immunotherapy 

Sublingual and oral immunotherapy 

Summary Statement 74: Optimal high-dose sublingual swallow and oral immunotherapies are under clinical investigation in the United States. Studies of oral immunotherapy have demonstrated conflicting results. High-dose sublingual immunotherapy has been found to be effective in many studies of adults and children with allergic rhinitis and asthma, but a consistent relationship among allergen dose, treatment duration, and clinical efficacy has not been established. However, there is no US Food and Drug Administration (FDA)–approved formulation for sublingual or oral immunotherapy in the United States. Therefore sublingual and oral immunotherapy should be considered investigational at this time. A

Summary Statement 75: Intranasal immunotherapy is undergoing evaluation in children and adults with allergic rhinitis, but there is no FDA-approved formulation for this modality in the United States. B

Immunotherapy techniques that are not recommended 

Summary Statement 76: Low-dose immunotherapy, enzyme-potentiated immunotherapy, and immunotherapy (parenteral or sublingual) based on provocation-neutralization testing are not recommended. D

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Mechanisms of immunotherapy 

Summary Statement 1: Immunologic changes during immunotherapy are complex. D

Summary Statement 2: Successful immunotherapy is associated with a change toward a TH1 CD4+ cytokine profile. A

Summary Statement 3: Allergen immunotherapy is also associated with immunologic tolerance, which is defined as a relative decrease in allergen-specific responsiveness, and by the generation of CD4+CD25+ regulatory T lymphocytes. A

Summary Statement 4: Efficacy from immunotherapy is not dependent on reduction in specific IgE levels. A

Summary Statement 5: Increases in allergen-specific IgG antibody titers are not predictive of the duration and degree of efficacy of immunotherapy. However, alterations in the allergen-specific IgG specificity with immunotherapy might play a role in determining clinical efficacy. A

The immunologic changes associated with immunotherapy are complex, and the exact mechanism or mechanisms responsible for its' clinical efficacy are continually being elucidated. Data support the concept that successful immunotherapy is associated with a change to a TH1 CD4+ cytokine profile.29, 30, 31, 32, 33, 34 Data indicate that increased production of IL-12, a strong inducer of TH1 responses, contributes to this shift.33 Clinically successful immunotherapy has been reported to be associated with immunologic tolerance, which is defined as a relative decrease in antigen-specific responsiveness, immune deviation, or anergy. For example, lymphoproliferative responses to allergen are reduced with immunotherapy.32 Successful immunotherapy results in generation of a population of T regulatory cells, which are CD4+CD25+ T lymphocytes producing IL-10, TGF-β, or both.35, 36, 37, 38, 39 Regulatory T-cell release has been described in allergen immunotherapy with Hymenoptera venom,35 grass pollen extract,37 and house dust mites.38 IL-10 reduces B-cell antigen-specific IgE and increases IgG4 levels; reduces proinflammatory cytokine release from mast cells, eosinophils, and T cells; and elicits tolerance in T cells by means of selective inhibition of the CD28 costimulatory pathway.36, 37

Allergen immunotherapy has been shown to block both the immediate and late-phase allergic response.40 Allergen immunotherapy has been shown to decrease the recruitment of mast cells, basophils, and eosinophils in the skin, nose, eye, and bronchial mucosa after provocation or natural exposure to allergens.41

In patients receiving immunotherapy, initially there is an increase in specific IgE antibody levels, followed by a gradual decrease to a level that is still higher than that present before treatment. Clinical improvement in many patients develops before decreases in their IgE antibody levels occur or in other patients whose IgE antibody levels never decrease, thereby demonstrating that efficacy is not dependent on reductions in specific IgE levels.42, 43 Immunotherapy does diminish the seasonal increase in specific IgE levels.44 Despite the persistence of significant levels of specific IgE antibody levels, immunotherapy usually causes a reduction in release of mediators, such as histamine, from basophils and mast cells, a phenomenon most relevant to the immediate phase of allergic reactions. Suppression of late-phase inflammatory responses in the skin and respiratory tract generally also occur with allergen immunotherapy.45, 46, 47, 48

An increase in serum allergen-specific IgA and IgG levels, particularly of the IgG4 isotype, has also been associated with immunotherapy. The properties of allergen-specific IgA have yet to be determined, and there is a weak correlation between the increase in allergen-specific IgG levels and immunotherapy's clinical efficacy.30, 49, 50

Immunotherapy might alter the affinity and specificity of allergen-specific IgG.51, 52 During the initial phase of ultrarush VIT, a change in IgG specificity (ie, a change in the set of epitopes dominantly recognized by IgG on wasp venom antigens) occurred concomitantly with early clinical tolerance and was seen within 12 hours of ultrarush VIT (P < .001).51 VIT resulted in a change in IgG specificity to the major bee venom allergen, phospholipase A2, to a specificity similar to that seen in healthy nonallergic individuals.52 This change in IgG specificity preceded the increase in IgG titers and was sustained for up to 6 months.52

Allergen-specific IgG induced from immunotherapy can block IgE-dependent histamine release and subsequent IgE-mediated antigen presentation to T cells.53 This effect might be dependent on IgE, allergen concentration, and CD23, the low-affinity receptor for IgE.

Whereas serum immunoreactive specific IgG levels are not predictive, it is possible that functional assays of IgG, such as detection of IgG-associated serum inhibitory activity for IgE-facilitated allergen presentation, basophil histamine release, or both, might be more closely associated with the clinical response to immunotherapy, although this remains to be tested in larger clinical trials.37, 53

The relationship between these immunologic changes and immunotherapy efficacy is not completely understood.

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Allergen extracts 

Summary Statement 6: When possible, standardized extracts should be used to prepare the allergen immunotherapy extract treatment sets. A

Allergen extracts are commercially available for most of the commonly recognized allergens. Allergen extract potency variability and product composition inconsistency has several potential consequences. Diagnostic allergy skin testing and allergen immunotherapy efficacy and safety are dependent on the quality of the allergen extracts. When possible, standardized extracts should be used to prepare allergen immunotherapy treatment sets.2, 18, 54, 55, 56 The advantage of standardized extracts is that the biologic activity is more consistent, and therefore the risk of an adverse reaction caused by extract potency variability should be diminished.

United States–licensed extracts can be obtained in aqueous, glycerinated, lyophilized, and acetone-precipitated and alum-precipitated formulations. Some commonly used allergens are standardized. These include extracts for cat hair, cat pelt, Dermatophagoides pteronyssinus, Dermatophagoides farinae, short ragweed, Bermuda grass, Kentucky bluegrass, perennial rye grass, orchard grass, timothy grass, meadow fescue, red top, sweet vernal grass, and Hymenoptera venoms (yellow jacket, honeybee, wasp, yellow hornet, and white-faced hornet). However, most allergen extracts are not yet standardized. Allergen standardization comprises 2 components: (1) selection of a reference extract and (2) selection of an assay or procedure to compare the manufactured extract with the reference extract. Allergen standardization in the United States is based on assessment of the potency of allergen extracts by using quantitative skin tests and reported as BAU values. The quantitative test method is called the intradermal dilution for 50 mL sum of erythema (ID50EAL) system for determining BAU values.57 The ID50EAL method entails preparing a series of 3-fold dilutions of a candidate reference extract and injecting 0.05 mL intradermally to 15 to 20 “highly 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 (D50). The mean D50 is calculated, and the potency of the extract is assigned.

Most standardized extracts are labeled in BAU. Short ragweed potency units were originally based on the content of the major allergen Amb a 1. Ragweed potency is reported in FDA units and BAU. One FDA unit of Amb a 1 equals 1 μg of Amb a 1, and 350 units of Amb a 1/mL is equivalent to 100,000 BAU/mL. Cat extracts were also originally standardized based on the content of major allergen (Fel d 1), with 100,000 arbitrary units (AU) per milliliter containing between 10 to 19.9 FDA units of Fel d 1 per milliliter (1 FDA unit of Fel d 1 equals 2 to 4 μg of Fel d 1).55, 58, 59 Subsequently, ID50EAL testing suggested that 100,000 AU/mL was equal to 10,000 BAU/mL.60 Approximately 22% of individuals with cat allergy have specific IgE antibodies to cat albumin.61 Cat pelt extracts have a greater amount of albumin than cat hair extracts.60

Dust mites were originally standardized in AU by means of inhibition radioimmunoassay (RIA), and subsequent ID50EAL testing indicated that the AU was bioequivalent to the BAU, and the original AU nomenclature was kept. Dust mite extracts are still labeled in AU.

Summary Statement 7: Nonstandardized extracts can vary widely in biologic activity and, regardless of a particular wt/vol or PNU potency, should not be considered equipotent. B

Nonstandardized extracts are labeled as wt/vol, which expresses weight in grams per volume in milliliters; that is, a potency of 1:100 indicates that 1 g of dry allergen (eg, ragweed) was added to 100 ml of a buffer for extraction. Nonstandardized extracts can also be labeled in PNU, where 1 PNU equals 0.01 g of protein nitrogen. Neither method confers any direct or comparative information about an extract's biologic potency. Nonstandardized extracts can have a wide range of potencies. Extracts with a particular wt/vol or PNU potency can have widely varying biologic activities.62, 63, 64 Therefore they should not be considered equipotent.

Summary Statement 8: In choosing the components for a clinically relevant allergen immunotherapy extract, the physician should be familiar with local and regional aerobiology and indoor and outdoor allergens, paying special attention to potential allergens in the patient's own environment. D

Because North America is botanically and ecologically diverse, it is not possible to devise a common list of appropriate allergen extracts for each practice location. The major clinically relevant aeroallergens of North America are listed in Table III. Furthermore, nonrelevant allergens in such mixtures could act as sensitizers rather than as tolerogens.65, 66 The physician must therefore select only those aeroallergens for testing and treatment that are clinically relevant in a particular geographic area.

Table III. The major clinically relevant aeroallergens of North America∗
Tree pollen
Chinese elm (Ulmus parvifolia)†‡; Siberian elm (Ulmus pumila)†‡; American elm (Ulmus Americana)†‡
Red oak (Quercus rubra)†; White oak (Quercus alba)†
Paper birch (Betula papyrifera)
Alder (Alnus rubra)
Box elder (Acer negundo)†; Red maple (Acer rubra)†
Eastern cottonwood (Populus deltoides)
Sycamore (Platanus occidentalis)
White ash (Fraxinus americana)†; Olive (Olea europaea)†‡
Black walnut (Juglans nigra)
Mulberry (Morus rubra)
Mountain cedar (Juniperus ashei)
Pecan (Carya illinoensis)
Grass pollen
Rye (Lolium perenne)§‖
Timothy (Phleum pratense)§‖
Meadow fescue (Festuca elatior)§‖
Bermuda (Cynodon dactylon)‖
Johnson (Holcus halepensis)
Bahia (Paspalum notatum)
Weed pollen
Short ragweed (Ambrosia artemisiifolia)‖
English (narrow leaf) plantain (Plantago lanceolata)
Mugwort (Artemisia vulgaris)
Russian thistle (Salsola kali)
Burning bush (Kochia scoparia)
Sheet (red) sorrel (Rumex asetosella)
Red root pigweed (Amaranthus retroflexus)
Indoor aeroallergens
Cat epithelium (Felis domesticus)‖
Dog epithelium (Canis familiaris)
Arthropods (domestic mites: Dermatophagoides farinae, Dermatophagoides pteronyssinus)‖
Insects (German cockroach: Blattella germanica)
Fungi
Alternaria alternata
Cladosporium (C cladosporioides, C herbarum)
Penicillium (P chrysogenum, P expansum)
Aspergillus fumigatus
Epicoccum nigrum, Drechslera or Bipolaris type (eg, Helminthosporium solani)

∗Compiled and selected in collaboration with the AAAAI Immunotherapy Committee Allergen Subcommittee for the identification of 35 key allergens of North America.

†Extensive cross-reaction of species within the genus.

‡Apart from regional prevalence, they are limited to local sites with substantial stands of these trees.

§Extensively cross-react with one another and bluegrass, orchard, red top, and sweet vernal.

‖Allergens for which standardized extracts are commercially available.

Species that are widely distributed and clinically important.

The clinical relevance of an aeroallergen depends on certain key properties: (1) its intrinsic allergenicity, (2) its aerodynamic properties, (3) whether it is produced in large enough quantities to be sampled, (4) whether it is sufficiently buoyant to be carried long distances, and (5) whether the plant releasing the pollen is widely and abundantly prevalent in the region. The primary allergens used for immunotherapy are derived from plant (grasses, trees, and weeds), arthropod (house dust mites), fungus, animal (cat, dog), insect (cockroach), and Hymenoptera venom source materials.

Cross-reactivity of allergen extract 

Summary Statement 9: Knowledge of allergen cross-reactivity is important in the selection of allergens for immunotherapy because limiting the number of allergens in a treatment vial is necessary to attain optimal therapeutic doses for the individual patient. B

Cumulative data, both in vitro and in vivo, concerning cross-reactivity offer a practical advantage in the selection of several categories of pollen allergens for immunotherapy. However, because cross-reactivity is variable for many grass and weed pollens, their intrinsic allergenicity, prevalence, and aerobiologic characteristics within a specific region should be considered. A summary of cross-reactivity patterns of the clinically relevant North American aeroallergens can be found in Fig 2. Because many temperate pasture grasses (subfamily Pooideae; eg, fescue, rye, timothy, blue, and orchard), which are widely distributed throughout the United States, share major allergens,67 inclusion of a representative member (eg, perennial rye, meadow fescue, or timothy) generally provides efficacy against the entire group.68, 69, 70, 71, 72, 73, 74, 75 Grasses in other subfamilies (eg, Bermuda, Bahia, and Johnson) show greater diversity and should be evaluated separately.76, 77, 78 Bermuda and Johnson grasses are increasingly important in the South, and Bahia has become an important allergenic grass in the lower southern states. Because it is uncertain whether palms, sedges, and cattails have the ability to trigger allergy symptoms, immunotherapy with these allergens is generally not recommended.

Although cross-reactivity among tree pollens is not as pronounced as that among grass or ragweed pollens, it does occur. Pollen from members of the cypress family (Cupressaceous; eg, juniper, cedar, and cypress) strongly cross-react.79, 80, 81, 82 Therefore pollen from one member of this family should be adequate for skin testing and immunotherapy. The closely related birch family (Betulaceae; eg, birch, alder, hazel, hornbeam, and hop hornbeam) and oak (Fagaceae; eg, beech, oak, and chestnut) have strong cross-allergenicity.83, 84, 85 Significant cross-reactivity between Betulaceae pollens and oak of the Fagaceae family has been demonstrated with percutaneous skin testing.75 RAST inhibition studies have shown cross-inhibition between oaks and other Fagales species.86 IgE immunoblot inhibition experiments have demonstrated that the Fagales species might be strongly inhibited by birch species.87 The use of one of the locally prevalent members (eg, birch and alder) should be adequate.88

Ash and European olive trees are strongly cross-reactive; the extract that is the most prevalent in the region and best correlates with symptoms could be used.89, 90 Maple and box elder trees are found throughout the United States, except for the arid southwest. Although in the same genus as maple, Acer, box elders appear different and should be considered separately. Oaks and elms (eg, Chinese, Siberian, some American) are prevalent in eastern and central states but have a more limited distribution west of the continental divide. The distribution of other trees is variable enough to require botanical observation in a given locale.

There is strong cross-reactivity between major allergens of common ragweed species (eg, short, giant, false, and western). However, southern and slender ragweed do not cross-react as well,91, 92 and there are allergenic differences between major and minor allergens of short and giant ragweed that might be clinically significant.93

Weeds other than ragweed, such as marsh elders, sages, and mugwort, have an abundant distribution, predominantly in the western states. These weeds and sages (Artemisia species) must be treated separately from the ragweeds. Sages are strongly cross-reactive, and a single member can provide adequate coverage of the group.94 Similarly, Chenopod-Amaranth families have wide ranges in the western regions but are present throughout North America.95 Current information on cross-reactivity of these families is limited.96, 97, 98 Skin testing suggests strong cross-reactivity across Chenopod and Amaranth family boundaries. The Amaranth family also seems to have strong cross-reactivity by means of RAST inhibition and immunodiffusion.99 The use of a single Amaranth extract should be sufficient to cover this family.100, 101 Similarly, Atriplex species (eg, saltbushes and scales) show near identity, and use of a single member is adequate. Among other subfamily Chenopod members, Russian thistle appears to have the most cross-allergenicity.

The most prevalent house dust mites, D pteronyssinus and D farinae, are ubiquitous except in arid or semiarid climates and regions of higher altitudes. D pteronyssinus and D farinae are members of the same family and genus. They have allergens with extensive cross-reacting epitopes, as well as unique allergenic epitopes. Generally, D pteronyssinus and D farinae are considered individually. Establishing the practical importance of various allergenic fungi involves many of the same problems encountered in treating pollen allergy. In general, the genera of deuteromycetes occur in all but the coldest regions. For clinical purposes, molds often are characterized as outdoor (eg, Alternaria, Cladosporium, and Drechslera [Helminthosporium] species) or indoor (eg, Aspergillus and Penicillium).

Immunotherapy with standardized extracts of cat hair (Fel d 1 only) or pelt (Fel d 1 plus cat albumin) is available for cat allergy. Although German cockroaches are most likely to occur in American homes, an extract representing an equal mixture of German and American cockroaches might be appropriate for immunotherapy.102, 103 Stinging Hymenoptera insects occur throughout the United States; the fire ant is found only in Gulf Coast states, Texas, and some other southern and western states. Commercial venom extracts are available for some Hymenoptera species, except the fire ant, for which only whole-body extract is available.

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Efficacy of immunotherapy 

Allergic rhinitis, allergic asthma, and stinging insect hypersensitivity 

Summary Statement 10: Immunotherapy is effective for treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma, and stinging insect hypersensitivity. Therefore immunotherapy merits consideration in patients with these disorders as a possible treatment option. A

Many double-blind, placebo-controlled, randomized clinical trials demonstrate a beneficial effect of immunotherapy under a variety of conditions.104, 105, 106, 107, 108, 109, 110, 111 Immunotherapy is effective for the treatment of allergic rhinitis107 (including ocular symptoms112, 113), allergic asthma,104, 109, 111, 114, 115 and stinging insect hypersensitivity108, 116 and is effective in both adults and children.117, 118, 119, 120, 121, 122, 123, 124 Its efficacy is confirmed for the treatment of inhalant allergy caused by pollens,13, 125, 126, 127, 128, 129, 130, 131, 132 fungi,133, 134, 135, 136, 137, 138 animal allergens,22, 25, 26, 139, 140, 141, 142, 143 dust mite,114, 115, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153 and cockroach.154 There have been no controlled trials of fire ant whole-body extract, but it does appear to be effective in uncontrolled trials.155, 156, 157 A variety of different types of extracts have been evaluated in these clinical trials, including aqueous and modified extracts. Outcome measures used to measure the efficacy of immunotherapy include symptom and medication scores, organ challenge, and immunologic changes in cell markers and cytokine profiles. A number of studies have also demonstrated a significant improvement in quality of life, as measured by using standardized questionnaires.24, 158, 159, 160, 161 The magnitude of the effect depends on the outcome that is used (Table IV). For dust mite, the effect size ranges from a 2.7-fold improvement in symptoms to a 13.7-fold reduction in bronchial hyperresponsiveness. Although many studies demonstrate the efficacy of immunotherapy, some do not. A review of the studies that do not demonstrate efficacy failed to identify a systematic deficiency.110 Instead, this review notes that many studies evaluating immunotherapy are only marginally powered to show efficacy, making it likely that some would fail to demonstrate efficacy by chance alone, even when it is present (a type II error). Meta-analyses of the efficacy of immunotherapy both for rhinitis107 and asthma104, 109, 111 have been performed to deal with the issue of power. One review of 75 trials involving 3188 asthmatic patients found that, overall, there was a significant reduction in asthma symptoms and medication and improvement in bronchial hyperreactivity after immunotherapy, and it would have been necessary to treat 4 patients (95% CI, 3-5) with immunotherapy to avoid 1 deterioration in asthma symptoms and 5 (95% CI, 4-6) patients to avoid 1 requiring increased medication.111 These meta-analyses strongly support the efficacy of allergen immunotherapy. Allergen immunotherapy for allergic rhinitis might have persistent benefits after immunotherapy is discontinued13, 162, 163 and might reduce the risk for the future development of asthma in patients with allergic rhinitis.6, 9, 122, 162, 163, 164, 165 Allergen immunotherapy might also prevent the development of new allergen sensitivities in monosensitized patients.120, 166, 167

Table IV. Improvement of symptoms and reduction in medication and bronchial hyperresponsiveness after immunotherapy
Outcome measureHouse dust miteOther allergens∗†
Symptomatic improvement2.7 (1.7-4.4)4.8 (2.3-10.1)
Reduction in medication4.2 (2.2-7.9)ND
Reduction in bronchial hyperresponsiveness13.7 (3.8-50)5.5 (2.8-10.7)

Data are used with permission from Abramson et al.104

ND, Not done.

∗Odds ratio (95% CI).

†Pollen, mold, or animal dander.

Food allergy, urticaria, and atopic dermatitis 

Summary Statement 11: Clinical studies do not support the use of allergen immunotherapy for food hypersensitivity or chronic urticaria, angioedema, or both at this time. Therefore allergen immunotherapy for patients with food hypersensitivity or chronic urticaria, angioedema, or both is not recommended. D

Summary Statement 11b: There are limited data indicating that immunotherapy can be effective for atopic dermatitis when this condition is associated with aeroallergen sensitivity. C

Summary Statement 11c: The potential for benefit in symptoms related to oral allergy syndrome with inhalant immunotherapy directed at the cross-reacting pollens has been observed in some studies but not in others. For this reason, more investigation is required to substantiate that a benefit in oral allergy symptoms will occur with allergen immunotherapy. C

The use of allergen immunotherapy for individuals with the potential for IgE-mediated (anaphylaxis) reactions to foods should be regarded as investigational at this time.168, 169, 170, 171 There have been 2 investigational studies demonstrating efficacy in food hypersensitivity, the first using aqueous subcutaneous injections to peanut and the second using sublingual immunotherapy to hazelnut.171, 172, 173

In the subcutaneous peanut immunotherapy study there was 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 concluded a modified peanut extract is needed for clinical application of this method of treatment.171 There is currently no FDA-approved formulation for sublingual immunotherapy, and this route of allergen immunotherapy is currently considered investigational at this time (see Summary Statement 73).

At the present time, there is not enough evidence to support food immunotherapy.

There is no evidence supporting the efficacy of immunotherapy for individuals with chronic urticaria, angioedema, or both.

There are limited data indicating that immunotherapy might be effective for atopic dermatitis when this condition is associated with aeroallergen sensitivity.174, 175, 176 One randomized, double-blind study of adults with atopic dermatitis demonstrated a dose-response effect of dust mite immunotherapy on atopic dermatitis severity, as measured by using the SCORAD score (P = .0379) and topical corticosteroid use (P = .0007).174

The potential for benefit in symptoms related to oral allergy syndrome with the cross-reacting inhalant immunotherapy, which includes cross-reacting pollens, has been observed in some studies but not in others. One controlled prospective study demonstrated the potential to decrease oral allergy syndrome symptoms with subcutaneous immunotherapy directed against birch tree,177 whereas another double-blind, double-dummy, placebo-controlled study comparing the effect of subcutaneous immunotherapy with sublingual immunotherapy demonstrated no significant effect on the severity of apple allergy symptoms with either method compared with the placebo group, despite a significant effect on seasonal hay fever symptoms, medication use, and decrease in IgE reactivity.178 More investigation is required to substantiate the contention that benefits in oral symptoms will occur with immunotherapy.

Measures of efficacy 

Summary Statement 12: Clinical parameters, such as symptoms and medication use, might be useful measures of the efficacy of immunotherapy in a clinical setting; however, repetitive skin testing of patients receiving immunotherapy is not recommended. A

Whether immunotherapy is effective can be determined by measuring objective and subjective parameters. Objective measures, such as increase in allergen-specific IgG levels and decreased skin test reactivity, as measured by skin test titration, are changes generally associated with effective immunotherapy but, at present, are not practical for routine clinical use.147 Nonquantitative skin testing or in vitro IgE antibody testing of patients during immunotherapy is not recommended because it has not been demonstrated that skin test reactivity (to a single dilution) or specific IgE antibody levels correlate closely with a patient's clinical response. For that reason, most allergists rely on subjective assessments, such as a patient'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 of immunotherapy, they are not very reliable given the strong placebo-like effect (Hawthorne effect) associated with any treatment. A more objective means for determining efficacy as validated in controlled clinical studies is the use of clinical symptom scores and the amount of medication required to control symptoms and maintain peak flow rates or pulmonary function tests within acceptable limits. Successful immunotherapy often results in a reduction in medication. Sequential measurement of disease-specific quality of life also might be helpful.

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Safety of immunotherapy 

Reaction rates 

Summary Statement 13: Published studies indicate that individual local reactions do not appear to be predictive of subsequent systemic reactions. However, some patients with greater frequency of large local reactions might be at an increased risk for future systemic reactions. C

Large local reactions associated with allergen immunotherapy are fairly common, with a frequency ranging from 26% to 86% of injections.179 Two retrospective studies compared the effect of not adjusting immunotherapy dose based on large local reactions on the immunotherapy systemic reaction rate with dose-adjustment protocols.179, 180 There was a total of 12,464 injections administered with a dose-adjustment protocol in the 2 studies compared with 9542 injections administered with a no-dose-adjustment protocol. Both studies found no statistical difference between the dose-adjustment and no-dose-adjustment protocols in terms of immunotherapy-induced systemic reactions. Both authors concluded that local reactions were poor predictors for subsequent systemic reactions, and dose reductions for most local reactions are unnecessary.

However, a retrospective review of a large, multicenter, allergy practice group's database comparing the frequency of large local reactions, defined as 25 mm or larger, in patients who had experienced systemic reactions with age-, sex-, and allergen sensitivity–matched control subjects who had not had allergen immunotherapy systemic reactions found the rate of large local reactions was 4 times higher among the 258 patients who had subsequently experienced a systemic reaction compared with those who had never experienced a systemic reaction.181 Patients who had experienced systemic reactions had 1573 large local reactions in 4460 visits (ie, 35.2% of visits) and 8081 injections (ie, 19.5% of injections) compared with the matched control group without systemic reactions who had 1388 large local reactions in 15,540 visits (8.9% per visit) and 26,259 injections (5.3% per injection; difference between groups, P < .001). Individual large local reactions were not predictive of future systemic reactions, but large local reactions preceded systemic reactions in approximately one third of the systemic reactions. These findings suggest that individuals with a greater frequency of large local reactions might be at greater risk for systemic reaction. Prospective studies investigating the sensitivity and specificity of large local reactions and the effect of immunotherapy protocol modifications based on them are needed.

Summary Statement 14: Although there is a low risk of severe systemic reactions with appropriately administered allergen immunotherapy, life-threatening and fatal reactions do occur. C

The prevalence of severe systemic reactions after allergen immunotherapy ranges from less than 1% of patients receiving conventional immunotherapy to greater than 36% of patients in some studies of patients receiving rush immunotherapy.182, 183

In a recent survey of fatal and near-fatal reactions (NFRs) sent to physician members of the AAAAI, 273 of 646 respondents reported NFRs during the period of 1990-2001.184

The incidence of unconfirmed NFRs was 23 per year (5.4 events per million injections). Administration during the height of pollen season (46% of respondents) and immunotherapy dosing errors (25% of respondents) were cited as the 2 most important contributing factors in the NFRs. The most severe NFR was respiratory failure (10% of NFRs). One patient with an NFR was receiving a β-blocker, and none were taking concomitant angiotensin-converting enzyme inhibitors. Ninety-three percent of the NFRs occurred in clinics staffed by allergists, and none occurred in medically unsupervised settings.

In a retrospective analysis of the incidence and characteristics of nonfatal systemic reactions to subcutaneous immunotherapy over a 20-year period (1981-2000) during which 435,854 injections were administered to 4000 patients, there were 115 systemic reactions (5.2% of patients and 0.06% of injections) in the first 10 years and 26 systemic reactions (1.08% of patients and 0.01% of injections) in the second 10 years.185, 186 In a prospective multicenter study there were 53 systemic reactions (0.3% of the doses) out of 17,526 administered doses in 18 (3.7%) of 423 patients.187 All systemic reactions were mild to moderate and responded well to treatment. Five patients experienced more than 3 systemic reactions (total of 36 reactions), and the authors noted that 40% of the systemic reactions (21 reactions) would have been avoided if patients experiencing the third systemic reaction had been withdrawn.

In the previously mentioned AAAAI physician members' survey of fatal reactions and NFRs, there were 41 fatalities identified in the initial brief survey (20 directly reported and 17 with completed detailed questionnaire) from immunotherapy injections.188 The estimated fatality rate was 1 per 2.5 million injections, (average of 3.4 deaths per year), which is similar to 2 previous surveys of AAAAI physician members.189, 190 Therefore although severe systemic reactions to allergen immunotherapy are not common, serious systemic reactions (some fatal) can occur.

Summary Statement 15: An assessment of the patient's current health status should be made before administration of the allergy immunotherapy injection to determine whether there were any recent health changes that might require modifying or withholding that patient's immunotherapy treatment. Risk factors for severe immunotherapy reactions include symptomatic asthma and injections administered during periods of symptom exacerbation. Before the administration of the allergy injection, the patient should be evaluated for the presence of asthma or allergy symptom exacerbation. One might also consider an objective measure of airway function (eg, peak flow) for the asthmatic patient before allergy injections. B

In the AAAAI survey of physician members on immunotherapy and skin testing, fatal reactions, and NFRs during the period of 1990-2001, 15 of the 17 fatalities had asthma, and in 9 patients asthma was considered the susceptibility factor that contributed to the fatal outcome.188

The most severe NFR, respiratory failure, occurred exclusively in asthmatic patients, and 4 (57%) of 7 asthmatic patients had a baseline FEV1 of less than 70% of predicted value.184

Administration during the peak pollen season (3 patients) and previous systemic reactions (4 patients) were cited as other contributing factors. Five fatalities occurred in outside medical facilities, and 2 fatalities occurred at home. No patients were receiving β-blockers; 1 patient was taking an angiotensin-converting enzyme inhibitor. In the most comprehensive evaluation of fatalities associated with allergen immunotherapy, from 1945-1987, there were 40 fatalities during allergen immunotherapy and 6 fatalities during skin testing.189 Ten fatalities occurred during seasonal exacerbation of the patient's disease, 4 in patients who had been symptomatic at the time of the injection, 2 of whom had been receiving β-adrenergic blockers. Of the 24 fatalities associated with immunotherapy, 4 had experienced previous reactions, 11 manifested a high degree of sensitivity, and 4 had been injected with newly prepared extracts. In a prospective study of 125 asthmatic patients with mite allergy that used a 3-day rush immunotherapy protocol, FEV1 was identified as a predictor for systemic reactions, with 73.3% of patients with an FEV1 of less than 80% of predicted value experiencing an asthma reaction during rush immunotherapy, whereas only 12.6% of patients with an FEV1 of greater than 80% of predicted value had asthmatic reactions (P < .0001).191 The authors noted that if the patients with an FEV1 of less than 80% of predicted value had been excluded from the study, the systemic reaction rate would have been 19.7% of patients. These studies suggest that symptomatic asthma, severe asthma, or both might be a risk factor for immunotherapy.

In addition to symptomatic asthma and injections giving during periods of exacerbation of symptoms, other risk factors for immunotherapy that have been identified include the presence of a high degree of hypersensitivity, use of β-blockers, injections from new vials, and dosing errors.17 With the exception of dosing errors and high degree of hypersensitivity, these risk factors can be minimized by performing a preinjection health screen before the administration of the allergy immunotherapy injection. This preinjection evaluation might include a health inquiry administered verbally or as a written questionnaire directed to determine whether there were any recent health changes that might require modifying or withholding that patient's immunotherapy treatment. The preinjection health inquiry might include questions regarding the presence of asthma or allergy symptom exacerbation, β-blocker use, change in health status (including pregnancy), or adverse reaction to previous allergen immunotherapy injection. The preinjection evaluation might also include a peak flow measurement to assess the airway function of asthmatic patients.

A patient's asthma must be stable before the allergen immunotherapy injection is administered, and patients with significant systemic illness generally should not receive an allergy immunotherapy injection.

Timing of anaphylactic reactions to immunotherapy injections 

Summary Statement 16: Because most systemic reactions that result from allergen immunotherapy occur within 30 minutes after an injection, patients should remain in the physician's office at least 30 minutes after an injection. C

In a retrospective study the time to onset of a systemic reaction after an immunotherapy injection was less than 30 minutes in most cases.189 A review of the literature indicates that 70% of systemic reactions occur within 30 minutes after an injection.183 In the AAAAI fatal reaction and NFR surveys previously discussed, 10 (77%) patients with fatal reactions and 65 (96%) patients with NFRs, for whom information on the timing of the onset of symptoms was available, had symptoms within 30 minutes of the injection.184, 188 The onset of symptoms before the fatal immunotherapy reaction was greater than 30 minutes in 3 patients. In 1 patient the reaction began within 35 minutes after the injection, but treatment was not administered until 45 minutes after the injection. A second late reaction occurred after the patient had left the clinic early, and it was estimated that treatment was initiated at least 50 minutes after the injection. A third late reaction occurred in the office of a primary care physician and began 30 to 40 minutes after the injection, but treatment was initiated 20 minutes after the onset of symptoms. The timing of the reaction was unknown in 4 of the fatal reactions.

In an earlier AAAAI survey, 17 fatalities associated with allergen immunotherapy were reported for the years 1985-1989.190 Onset of anaphylaxis occurred within 20 minutes in 11 patients, within 20 to 30 minutes in 1 patient, and after more than 30 minutes in 1 patient. Four patients did not wait after the injection, and the onset of their systemic reaction symptoms is not known.

In a prospective study a total of 20,588 extract injections were administered to 628 patients, resulting in 52 systemic reactions in 42 patients, with 38% of the systemic reactions occurring from 30 minutes to 6 hours after the allergy vaccine administration.192 In another prospective study 8% of systemic reactions occurred more than 2 hours after injection.193

Most of the extract manufacturers' package inserts recommend a wait period of either 20 to 30 minutes or 30 minutes after administration of the immunotherapy injection. The European Academy of Allergy and Clinical Immunology's recommended observation period after an allergen immunotherapy injection is 30 minutes.194

Because most reactions that resulted from allergen immunotherapy occurred within 30 minutes after an injection, patients should remain in the physician's office for at least 30 minutes after receiving an injection, but longer waits are reasonable, as directed by the physician. In addition, patients who are at increased risk of a systemic reaction might need to carry injectable epinephrine. Such patients might also need to remain in the physician's office more than 30 minutes after an injection. These patients should be instructed in the use of epinephrine to treat a systemic reaction that occurs after they have left the physician's office or other location where the injection was given. The risks and benefits of continuing allergen immunotherapy in patients who have had a severe systemic reaction should be carefully considered.

β-Adrenergic blocking agents 

Summary Statement 17: β-Adrenergic blocking agents might make allergen immunotherapy–related systemic reactions more difficult to treat and delay the recovery. Therefore a cautious attitude should be adopted toward the concomitant use of β-blocker agents and inhalant allergen immunotherapy. However, immunotherapy is indicated in patients with life-threatening stinging insect hypersensitivity who also require β-blocker medications because the risk of the stinging insect hypersensitivity is greater than the risk of an immunotherapy-related systemic reaction. C

β-Blockade enhances pulmonary, cardiovascular, and dermatologic end-organ effects of mediators and increases mortality associated with experimental anaphylaxis induced by either immunologic or nonimmunologic mechanisms. Patients who are receiving β-adrenergic blocking medications might be at increased risk if they experience a systemic reaction to an allergen immunotherapy injection because the β-receptor blockade might attenuate the response to epinephrine.195, 196, 197, 198, 199, 200, 201, 202 Patients who are receiving β-blocking drugs were almost 9 times more likely to be hospitalized after an anaphylactoid reaction from radiocontrast media.198 Although topical β-blockers have markedly less systemic β-antagonist effects than oral β-blockers, they still might exhibit some systemic β-antagonist effects. Whether topical β-blockers pose the same or a smaller risk than oral β-blockers in regard to the treatment of allergen immunotherapy–related systemic reactions is not known.

There have been very few studies that have examined the effect of β-blocker medications on allergen immunotherapy. A prospective 1-year study designed to determine whether patients taking β-blocker drugs were at increased risk of immunotherapy-induced systemic reactions found that there were 166 systemic reactions out of 56,105 injection visits in 3178 patients (68 were receiving a β-blocker).203 The systemic reactions occurred in 144 (4.5%) patients, and only 1 of these patients was receiving a β-blocker medication. The authors calculated that by chance, 3.08 patients receiving the β-blocker medications drugs were expected to have had an systemic reaction and concluded that β-blocker medications did not increase the frequency of allergen immunotherapy systemic reactions (P > .95).

In another study of 1389 patients prescribed immunotherapy for Hymenoptera venom hypersensitivity who were followed for 34 months, there were 25 patients who received concomitant β-blocker medications.204 Three (12%) of the 25 patients receiving β-blocker medications experienced systemic reactions during immunotherapy compared with 23 (16.7%) of 117 patients with cardiovascular disease not receiving β-blockers. Systemic reactions after a field sting or challenge occurred in 1 (14.3%) of 7 cardiovascular patients receiving β-blocker medications compared with 4 (13.8%) of 29 cardiovascular patients not receiving β-blocker medications. No severe reactions to immunotherapy or sting re-exposure were observed in patients receiving β-blockers medications.

Immunotherapy is indicated in patients with life-threatening stinging insect hypersensitivity who also require β-blocker medications because the risk of the stinging insect hypersensitivity is greater than the risk of an immunotherapy-related systemic reaction. In such cases, intravenous glucagon, which might reverse the refractory bronchospasm and hypotension by activating the adenyl cyclase directing and bypassing the β-adrenergic receptor, might be used if epinephrine has not been effective.205, 206 Prospective studies are necessary to clarify the magnitude of the risk of systemic reactions to allergens in patients who are receiving concomitant therapy with β-blockers, and a cautious attitude should be adopted toward the concomitant use of β-blocker agents and inhalant allergen immunotherapy.

Contraindications 

Summary Statement 18: Medical conditions that reduce the patient's ability to survive the systemic allergic reaction or the resultant treatment are relative contraindications for allergen immunotherapy. Examples include severe asthma uncontrolled by pharmacotherapy and significant cardiovascular disease. C

Alternatives to allergen immunotherapy should be considered in patients with any medical condition that reduces the patient's ability to survive a systemic allergic reaction. Examples include patients with markedly compromised lung function (either chronic or acute), poorly controlled asthma, unstable angina, recent myocardial infarction, significant arrhythmia, and uncontrolled hypertension. Under some circumstances, immunotherapy might be indicated for high-risk patients, such as those with Hymenoptera venom hypersensitivity and cardiac disease being treated with β-blocker medications.

Reducing the risk of anaphylaxis to immunotherapy injections 

Summary Statement 19: Allergen immunotherapy should be administered in a setting where procedures that can reduce the risk of anaphylaxis are in place and where the prompt recognition and treatment of anaphylaxis is ensured. C

The major risk of allergen immunotherapy is anaphylaxis, which in extremely rare cases can be fatal, despite optimal management. Therefore allergen immunotherapy should be administered in a setting where anaphylaxis will be promptly recognized and treated by a physician or other health care professional appropriately trained in emergency treatment.

The health care professional who administers immunotherapy injections should be able to recognize and treat the early symptoms and signs of anaphylaxis and administer emergency treatment, if necessary. Epinephrine is the first-line treatment for anaphylaxis. Health care professionals should know the potential pharmacologic benefits, risks, and routes of administration of epinephrine, as well as the potential reasons for lack of response.12, 207, 208, 209, 210, 211, 212, 213 It is important to administer epinephrine early in the management of anaphylaxis. Appropriate personnel, equipment, and medications should be immediately available to treat anaphylaxis, should it occur. Suggested actions to reduce the risk of anaphylaxis and recommended equipment and medications to treat anaphylaxis are listed in Table V, Table VI, respectively. Before allergen immunotherapy is chosen as a treatment, the physician should educate the patient about the benefits and risks of immunotherapy, as well as methods for minimizing risks. The patient also should be told that despite appropriate precautions, reactions might occur without warning signs or symptoms. Informed consent should include a discussion of the potential immunotherapy adverse reactions, and this discussion should be documented in the patient's medical record.

Table V. Actions to reduce the risk of anaphylaxis
•Assess the patient's general medical condition at the time of injection (eg, asthma exacerbation).
•Consider obtaining a PEFR before administration of the injection. If the PEFR is significantly less than the patient's baseline value, the clinical condition of the patient should be evaluated before administration of the injection.
•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 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 from allergen immunotherapy (eg, patients with increased allergen sensitivity or those who have previously had a systemic reaction) might need to wait longer.
•Carefully evaluate any patient with a late reaction (eg, persistent large local reaction lasting >24 hours, systemic reaction occurring more than 30 minutes after the immunotherapy injection).
•Ensure procedures to avoid clerical or nursing errors (eg, careful checking of patient identification).
•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.

PEFR, Peak expiratory flow rate measurement.

Table VI. Recommended equipment and medications to treat anaphylaxis
Adequate equipment and medications should be immediately available to treat anaphylaxis, should it occur. This should include at least the following equipment and medications:
•stethoscope and sphygmomanometer;
•tourniquet, syringes, hypodermic needles, and large-bore needles (14-gauge);
•aqueous epinephrine HCL 1:1000 wt/vol;
•equipment to administer oxygen by mask.
•intravenous fluid set-up;
•antihistamine for injection (second-line agents for anaphylaxis, but H1 and H2 antihistamines work better together than either one alone);
•corticosteroids for intravenous injection;
•vasopressor;
•equipment to maintain an airway appropriate for the supervising physician's expertise and skill.

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Patient selection 

Clinical indications 

Summary Statement 20: 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 depends on the degree to which symptoms can be reduced by avoidance and medication, the amount and type of medication required to control symptoms, and the adverse effects of medications. A

Randomized, prospective, single- or double-blind, placebo-controlled studies demonstrate the effectiveness of specific immunotherapy in the treatment of allergic rhinitis.107 Prospective, randomized, double-blind, placebo-controlled studies demonstrate the effectiveness of specific immunotherapy in the treatment of allergic asthma.104, 109, 111

Allergen immunotherapy is an effective form of treatment for many allergic patients, provided they have undergone an appropriate allergy evaluation. The expected response to allergen immunotherapy is antigen specific and depends on proper identification and selection of component allergens on the basis of the patient's history, exposure, and diagnostic test results.

Aeroallergen immunotherapy should be considered for patients who have symptoms of allergic rhinitis, rhinoconjunctivitis, and/or asthma after natural exposure to allergens and who demonstrate specific IgE antibodies to relevant allergens (Table VII). The severity and duration of symptoms should also be considered in assessing the need for specific allergen immunotherapy. Severity of symptoms can be defined by subjective, as well as objective, parameters. In addition, specific allergen immunotherapy should be considered if the patient wishes to avoid long-term pharmacotherapy. Time lost from work, emergency department or physician's office visits, and responses to pharmacotherapy are important objective indicators of allergic disease severity.

Table VII. Clinical indications for allergen immunotherapy
Indications for allergen immunotherapy in patients with allergic rhinitis, allergic conjunctivitis, or both:
•symptoms of allergic rhinitis after natural exposure to aeroallergens and demonstrable evidence of clinically relevant specific IgE
AND (one of the following)
•poor response to pharmacotherapy, allergen avoidance, or both;
•unacceptable adverse effects of medications;
•wish to reduce or avoid long-term pharmacotherapy and the cost of medication;
•coexisting allergic rhinitis and asthma;
•possible prevention of asthma in patients with allergic rhinitis
Symptoms of asthma after natural exposure to aeroallergens and demonstrable evidence of clinically relevant specific IgE
AND (one of the following)
•poor response to pharmacotherapy, allergen avoidance, or both;
•unacceptable adverse effects of medication;
•wish to reduce or avoid long-term pharmacotherapy and the cost of medications;
•coexisting allergic rhinitis and allergic asthma.
Indications for allergen immunotherapy in patients with reactions to Hymenoptera stings:
•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;
•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);
•adults and children with a history of a systemic reaction to imported fire ant and demonstrable evidence of clinically relevant specific IgE antibodies.

Patients with allergic rhinitis who are unable to sleep because of symptoms or whose symptoms interfere with their work or school performance should be considered strong candidates for specific allergen immunotherapy. The effect of the patient's symptoms on quality of life and responsiveness to other forms of therapy, such as allergen avoidance or medication, should also be considered. Unacceptable adverse effects of medications should also favor one's decision to initiate allergen immunotherapy. Immunotherapy is usually not more costly than pharmacotherapy over the projected course of treatment.214

Allergen immunotherapy for allergic rhinitis might have persistent benefits after immunotherapy is discontinued, and it might reduce the risk for the future development of asthma in patients with allergic rhinitis.6, 7, 8, 9, 122, 162, 163, 164, 165 These benefits of immunotherapy should be discussed with patients and might provide a clinical indication for immunotherapy for individual patients with allergic rhinitis.

Coexisting medical conditions should also be considered in the evaluation of a patient who might be a candidate for allergen immunotherapy. Patients with moderate or severe allergic asthma and allergic rhinitis should be managed with a combined aggressive regimen of allergen avoidance and pharmacotherapy and might also benefit from allergen immunotherapy.215, 216

However, the patient's asthma must be stable before allergen immunotherapy is administered.188, 191

Special precautions in patients with asthma 

Summary Statement 21: Allergen immunotherapy in asthmatic patients should not be initiated unless the patient's asthma is stable with pharmacotherapy. C

Patients with severe or uncontrolled asthma might be at increased risk for systemic reactions to immunotherapy injections.182, 188, 191 Two surveys found that deaths from immunotherapy were more common in symptomatic subjects with asthma.188, 189 Thus allergen immunotherapy should not be initiated in patients with poorly controlled asthma symptoms.2, 217

Clinical indications for VIT 

Summary Statement 22: VIT should be strongly considered if the patient has had a systemic reaction to a Hymenoptera sting, especially if such a reaction was associated with respiratory symptoms, cardiovascular symptoms, or both and if the patient has demonstrable evidence of specific IgE antibodies. A

Systemic reactions to Hymenoptera stings, especially when associated with respiratory symptoms, cardiovascular symptoms, or both and positive skin test or in vitro test results for specific IgE antibodies, are a strong indication for allergen immunotherapy.218 In the United States patients older than 16 years with a systemic reaction limited to the skin are also candidates for allergen immunotherapy. Several studies of patients with imported fire ant allergy have demonstrated the effectiveness of immunotherapy with whole-body extracts of fire ants.155, 156, 219 Adults and children with a history of systemic reactions to the imported fire ant (Solenopsis species) who have positive skin test results or venom-specific IgE antibodies should be treated with allergen immunotherapy. Patients younger than 16 years of age who present only with a cutaneous reaction to imported fire ant or Hymenoptera stings might not require immunotherapy.218, 220, 221, 222 In addition to allergen immunotherapy, patients with imported fire ant and Hymenoptera venom sensitivity should be instructed in how to best avoid insect stings, be prescribed epinephrine, and be taught how to inject it.

Venom skin test results are positive in more than 65% of patients with a history of a systemic reaction to a Hymenoptera sting compared with 15% of the population that has not had a systemic reaction.223 In patients with negative venom skin test results who have a severe systemic reaction, further evaluation for the presence of venom-specific IgE is recommended.218 If the venom-specific IgE test result is also negative, it is recommended that the skin tests, venom-specific IgE tests, or both be repeated 3 to 6 months later. Approximately 5% to 10% of patients with negative venom skin test results with a history of a systemic reaction have a positive venom-specific IgE test result.224 There are no published results of the effectiveness of allergen immunotherapy in patients with negative skin test results and positive venom-specific IgE test results who have experienced systemic reactions resulting from a Hymenoptera sting. There are data to indicate that these patients might have another episode of anaphylaxis if they are re-stung. The chance of another systemic reaction to a sting is relatively small (5% to 10%) in adults with negative venom skin test results with a history of systemic reactions compared with the risk associated with positive venom skin test results (25% to 70%).225 However, even though the risk is small, the reaction can be severe, and VIT is recommended for patients with negative venom skin test results and positive venom-specific IgE test results who have had severe anaphylaxis to an insect sting.

Some patients who have negative venom skin test results and negative venom-specific IgE test results are reported to have had subsequent systemic reactions to stinging insects.225, 226, 227 Controlled studies designed to evaluate the efficacy of immunotherapy in these patients have not been performed. There are very few anecdotal reports of patients with negative venom skin test results and negative venom-specific IgE test results being successfully treated with VIT if the selected venom is based on the results of a sting challenge. Generally, there are not sufficient data on the efficacy of immunotherapy in these patients to form conclusive recommendations.

The AAAAI Insect Committee's modified working guidelines state that a negative venom skin test result or in vitro assay result is not a guarantee of safety, and patients with suspected higher risk should be counseled about avoidance strategies, use of epinephrine injectors, and the emergency and follow-up care of the acute allergic reaction.226 The AAAAI Insect Committee also acknowledged that the management of patients with a positive history and negative venom skin test results requires clinical judgment and ongoing research.

Summary Statement 23: Patients selected for immunotherapy should be cooperative and compliant. D

Patients who are mentally or physically unable to communicate clearly with the physician and patients who have a history of noncompliance might be poor candidates for immunotherapy. If a patient cannot communicate clearly with the physician, it will be difficult for the patient to report signs and symptoms, especially early symptoms, suggestive of systemic reactions.

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Allergen selection and handling 

Allergen selection 

Clinical evaluation 

Summary Statement 24: The selection of the components of an allergen immunotherapy extract that are most likely to be effective should be based on a careful history of relevant symptoms with knowledge of possible environmental exposures and correlation with positive test results for specific IgE antibodies. A

A careful history, noting environmental exposures and an understanding of the local and regional aerobiology of suspected allergens, such as pollen, fungi (mold), animal dander, dust mite, and cockroach, is required in the selection of the components for a clinically relevant allergen immunotherapy extract. Although the relationship between day-to-day outdoor pollen and fungi exposure and the development of clinical symptoms is not always clear, symptoms that occur during periods of increased exposure to allergens, in association with positive skin or in vitro test results for specific IgE antibodies, provide good evidence that such exposures are relevant. Information concerning regional and local aerobiology is available on various Web sites or through the National Allergy Bureau at http://www.aaaai.org/nab. There are no data to support allergen immunotherapy as a treatment for non–IgE-mediated symptoms of rhinitis or asthma. As is the case in interpreting positive immediate hypersensitivity skin test results, there must be a clinical correlation with the demonstration of in vitro allergen-specific IgE levels and clinical history of an allergic disease.

There is no evidence to support the administration of immunotherapy based solely on results of specific in vitro testing, as is being done by both commercial laboratories and some physician's offices. This is promoting the remote practice of allergy, which is not recommended.

Clinical correlation 

Summary Statement 25: The allergen immunotherapy extract should contain only clinically relevant allergens. A

The omission of clinically relevant allergens from an allergic patient's allergen immunotherapy extract contributes to decreased effectiveness of allergen immunotherapy. The inclusion of all allergens to which IgE antibodies are present, without establishing the possible clinical relevance of these allergens, might dilute the content of other allergens in the allergen immunotherapy extract and can make allergen immunotherapy less effective.

Knowledge of the total allergenic burden facing a patient and the realistic possibility of avoidance is important in determining whether allergen immunotherapy should be initiated. A patient's lifestyle can produce exposure to a wide variety of aeroallergens from different regions, necessitating inclusion in the extract of multiple allergens from different geographic areas. Many individuals travel extensively for business or pleasure into different regions, and symptoms might worsen at these times. However, inclusion of allergens to which IgE antibodies are present but that are not clinically relevant might dilute the essential allergen components of the allergen immunotherapy extract so that immunotherapy might be less effective. Determination of the significance of indoor allergens for a particular patient is harder because it is difficult to determine exposure in the home, school, and/or workplace. Historical factors, such as the presence of a furry animal in the home, a history of water damage and subsequent fungal exposure, or a history of insect infestation, might be helpful. However, such information is subjective and is often of uncertain reliability. In addition, some studies have demonstrated significant indoor levels of cat and dog allergen in households without pets228 and significant levels of mouse allergen in suburban229 and inner-city230 homes of asthmatic children. In the National Cooperative Inner-City Asthma Study, 33% of the homes had detectable rat allergen (Rat n 1), and a correlation between rat allergen sensitization with increased asthma morbidity in inner-city children was found.231 Fur-bearing pets and the soles of shoes are also conduits by which molds and other “outdoor” allergens can enter the home.

Several commercial immunoassays to measure the presence of indoor allergens (eg, dust mite, cat, cockroach, and dog) in settled house dust samples are available and might provide useful estimates of indoor allergen exposure. Nevertheless, for most patients, determination of the clinical relevance of an allergen requires a strong correlation between the patient's history and evidence of allergen-specific IgE antibodies.

Skin tests and in vitro IgE antibody tests 

Summary Statement 26: Skin testing has been the primary diagnostic tool in clinical studies of allergen immunotherapy. Therefore in most patients, skin testing should be used to determine whether the patient has specific IgE antibodies. Appropriately interpreted in vitro tests for specific IgE antibodies can also be used. A

The use of standardized allergens has greatly increased the consistency of skin test results for these antigens. Controlled studies in which the clinical history has correlated with the skin test results have demonstrated the efficacy of immunotherapy for relevant allergens.25, 26, 112, 130, 134, 135, 140, 141, 149, 154 Skin testing can also provide the physician with useful information about the appropriate starting dose of selected allergens. On rare occasions, systemic reactions can occur from skin testing in a highly sensitive individual.232, 233 In addition, skin tests might be difficult to perform in patients with dermatographism or atopic dermatitis. In vitro tests are particularly useful in such patients.

Studies indicate that skin testing is generally more sensitive than in vitro tests in detecting allergen-specific IgE.234, 235 Based on inhalation challenge test results, skin tests have shown specificity and sensitivity generally superior to those of in vitro tests. The comparability of skin tests and in vitro tests for specific IgE antibodies depends on the allergen being tested. For all of these reasons, skin testing is preferable as a method for selection of allergens for inclusion in immunotherapy and determining the starting dose for an immunotherapy program. Among the skin testing techniques available, a properly applied percutaneous (prick/puncture) test consistently produces reproducible results. Generally, prick testing is sensitive enough to detect clinically relevant IgE antibodies when potent extracts, such as grass236 and cat,237 are used. Intradermal/intracutaneous skin testing might be required for some allergen extracts. It is appropriate in some patients to use in vitro tests for specific IgE antibody as an alternative to skin tests in the diagnosis of allergic rhinitis, allergic rhinoconjunctivitis, allergic asthma, and stinging insect hypersensitivity. In vitro tests can also be used to define the allergens that should be used in allergen immunotherapy. If the allergy skin test result is negative and the in vitro test result is positive, a controlled challenge can be performed, and if the latter is positive, immunotherapy can be considered. In the case of Hymenoptera venom, immunotherapy can be started even without a live sting challenge in patients with negative skin test results and positive in vitro test results. However, there are no published results of the effectiveness of Hymenoptera VIT in patients with negative skin test results and positive in vitro test results.

Specific allergens 

Summary Statement 27: Immunotherapy is effective for pollen, mold, animal allergens, cockroach, dust mite, and Hymenoptera hypersensitivity. Therefore immunotherapy should be considered as part of the management program in patients who have symptoms related to exposure to these allergens, as supported by the presence of specific IgE antibodies. A

Pollen 

Pollen extracts have been shown to be safe and effective in many controlled clinical trials.17, 104, 106, 107, 109 It seems reasonable to extrapolate information about pollen extracts that have been studied to those that have not been subjected to rigorous investigation and to assume that the latter are also safe and effective. Less information is available with respect to mixtures of pollen extracts. However, those studies that have been conducted with mixtures have demonstrated clinical effectiveness.112, 122 Because a particular pollen extract is a mixture of multiple glycoproteins, this suggests that mixing pollen allergens does not alter biologic activity.

Fungi (molds) 

Several studies with Alternaria and Cladosporium species suggest that allergen immunotherapy with fungi might be effective.133, 134, 135, 136, 137, 138 The allergen content of most mold extracts is highly variable.238, 239 However, there is evidence that proteolytic enzymes present in some mold extracts could digest other antigens, such as pollens, when combined in a mixture.240 For this reason, it might be desirable to separate all pollen extracts from mold extracts when using mixtures.

Unfortunately, extracts for some potentially clinically important fungi are not available.241 For example, there are no commercially available extracts for many fungal ascospores, even though they frequently are the dominant type of airborne bioparticulate during certain seasons. Another example is the lack of basidiospore (mushroom) extracts, especially given the evidence that such exposures can be associated with epidemics of asthma in the late fall. It is important that the practicing physician distinguish between molds that are predominantly found indoors (eg, Penicillium and Aspergillus genera) and many other molds that are found either exclusively outdoors or both indoors and outdoors and be able to assess the potential clinical effect of each.

Animal dander 

Although the best treatment for animal allergy is avoidance, this is not always possible. Exposure to both dog and cat allergen has been shown to be ubiquitous and can occur even without an animal in the home, making avoidance even more difficult.

Because immunotherapy has been shown to be effective for cat22, 26, 139, 140, 141, 142, 143, 242 and dog,25, 141 the decision to include dog or cat allergen in an allergen immunotherapy extract should be considered in those circumstances in which there is exposure.

Dust mites and cockroach allergens 

Crude house dust extract is generally an inappropriate substitute for house dust mite extract because the protein content measured is not restricted to dust mite allergens, nor does it necessarily guarantee inclusion of dust mite protein. Immunotherapy with standardized dust mite is generally more effective than that with crude house dust allergens. The house dust mites D farinae and D 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 dust mite groups. Allergens from other species of mites, such as Blomia tropicalis and Euroglyphus maynei, partially cross-react with allergens from Dermatophagoides species. Only 50% of the projected amounts of each of the 2 house dust mites (D pteronyssinus and D farinae) need to be included when preparing an allergen immunotherapy extract based on the high degree of cross-allergenicity between the major allergens in these 2 species. Immunotherapy for dust mites is effective144, 147, 148, 149, 151 and should be considered in conjunction with avoidance measures in patients who have symptoms consistent with dust mite allergy and specific IgE antibodies for dust mite allergens. Dust mite hypersensitivity should particularly be considered in patients who have perennial symptoms exacerbated by a dusty environment at home, work, or both and periods of high humidity.

The most common species of cockroach identified in dwellings are the German cockroach, Blatella germanica, and the American cockroach, Periplaneta americana. Allergens derived from B germanica include Bla g 2, Bla g 4, and Bla g 5. The major allergen of P americana is Per a 1. Partial cross-reactivity between cockroach allergens exists, but each regionally relevant species should be represented in the immunotherapy extract.243 Immunotherapy with cockroach allergens is effective154 and should be considered in conjunction with aggressive avoidance measures, particularly in patients living in the inner city who have perennial allergic symptoms and specific IgE antibodies to cockroach allergens.

Hymenoptera venom 

Randomized, double-blind, placebo-controlled studies show that immunotherapy with Hymenoptera venom is effective in dramatically reducing the risk of anaphylaxis to honeybee, yellow jacket, hornet, and wasp stings.108, 116, 244 Efficacy has also been demonstrated with immunotherapy by using whole-body extracts of imported fire ants.155, 156

Foods 

Only a single clinical study accessing the efficacy and safety of subcutaneous immunotherapy with foods has been performed.171, 173 This study, which evaluated immunotherapy with peanut, found the incidence of systemic reactions, even during maintenance, was unacceptable. Thus there is no evidence to support the use of immunotherapy with food extracts. Currently, strict avoidance of the offending food is advisable, and subcutaneous immunotherapy for food allergy is not recommended.

Mixing of extracts 

Principles of mixing 

Summary Statement 28: Consideration of the following principles is necessary when mixing allergen extract: (1) cross-reactivity of allergens, (2) optimization of the dose of each constituent, and (3) enzymatic degradation of allergens. B

Once the relevant allergens for each patient are identified, it is necessary to prepare a mixture that contains each of these allergens. Standardized extracts should be used, when available, and can be mixed with nonstandardized extracts. A number of factors need to be considered when combining extracts, including (1) cross-reactivity of allergens, (2) the need to include the optimal dose for each constituent, and (3) potential interactions between different types of allergens, when mixed, that could lead to degradation or unmasking of epitopes on exposure to proteolytic enzymes.

Mixing cross-reactive extracts 

Summary Statement 29: The selection of allergens for immunotherapy should be based (in part) on the cross-reactivity of clinically relevant allergens. Many botanically related pollens contain allergens that are cross-reactive. When pollens are substantially cross-reactive, selection of a single pollen within the cross-reactive genus or subfamily might suffice. When pollen allergens are not substantially cross-reactive, testing for and treatment with multiple locally prevalent pollens might be necessary. B

Immunologic and allergenic cross-reactivity is the recognition by the patient's immune system of different extracts' constituents as the same or similar. When one allergen elicits the same immunologic responses as another cross-reacting allergen, it is not necessary or even desirable to include both in the same mixture.71 Such a practice might result in the addition of too much of a given allergen, which could lead to an adverse reaction, as well as the unnecessary dilution of other allergens, with a resultant reduction in efficacy. A knowledge of each allergen's classification according to species and the fact that there is immunologic cross-reactivity within allergens of the same genera or subfamily allows one to select components of the allergen immunotherapy extract that are maximally effective. In general, the patterns of allergenic cross-reactivities among pollens follow their taxonomic relationships (see the Allergen extract section, Fig 2, and the allergens and allergy diagnostic tests practice parameters).

Dose selection 

Summary Statement 30: The efficacy of immunotherapy depends on achieving an optimal therapeutic dose of each of the constituents in the allergen immunotherapy extract. A

The maintenance dose of allergen immunotherapy must be adequate.22, 23, 24, 25, 26, 128, 149, 245 Low maintenance doses are generally not effective (eg, dilutions of 1:1,000,000 vol/vol).28 A consideration when mixing extract is the need to deliver an optimal therapeutically effective dose of each of the constituents in the allergen immunotherapy vaccine. Failure to do so might reduce the efficacy of immunotherapy. This occurs because of a dilution effect; that is, as one mixes multiple extracts, the concentration of each in the final mixture will be decreased (see the Immunotherapy schedules and doses section for further discussion and for recommended maintenance doses).

Proteolytic enzymes and mixing 

Summary Statement 31: Separation of extracts with high proteolytic enzyme activities, such as fungi (mold) and cockroach, from other extracts, such as pollens, is recommended. B

Many allergen extracts contain mixtures of proteins and glycoproteins. Proteolytic enzymes can degrade other allergenic proteins. There have been reports of interactions between extracts when mixed together.240, 246, 247 Extracts such as Alternaria species have been shown to reduce the IgE-binding activity of timothy grass extract when mixed together. Studies designed to investigate the effect of combining mold/fungi extracts with pollen extracts have demonstrated a significant loss of potency of grass pollen, cat, birch, white oak, box elder, and some weeds.240, 246, 247 Cockroach had a similar deleterious effect on pollen extract potency.246, 248 Short ragweed appeared resistant to the effects of the proteolytic enzymes in one study,240 but another study found short ragweed Amb a 1 was susceptible to proteases present in Penicillium and Alternaria species extracts at relatively low (10%) glycerin levels.247

Dust mite extracts do not appear to have a deleterious effect on pollen extracts.240, 246, 248 These studies suggest that pollen, dust mite, and cat extracts can be mixed together. The effect of the combination of high proteolytic-containing extracts on each other or the extent of self-degradation of allergenic proteins has not been extensively studied. The evidence on mixing cockroach extract with other extracts is conflicting, and the clinical relevance of the changes is also unclear; therefore the clinician has the option of separating cockroach or not.

Because such interactions between extracts have not been fully delineated, consideration should be given to keeping extracts that tend to have high proteolytic enzyme activities, such as fungi and cockroach extracts, separate from those with lesser activities, such as pollen extracts.

It is not recommended to mix venoms together (eg, wasps or honeybee with yellow jacket), even though yellow jacket and hornet venom are available premixed as a mixed-vespid extract.

In this regard the number of separate injections that need to be given at each patient visit depends on whether all of the relevant extracts mixed into a single vial still deliver an optimal dose of each allergen. If mixing causes excessive dilution or if there are advantages to separating allergens into separate vials, then more than one vial might be necessary for successful immunotherapy.

Summary Statement 32: Allergen immunotherapy extract preparation should be performed by individuals experienced and trained in handling allergenic products. D

Allergen immunotherapy extracts are high-alert products that carry the risk for anaphylaxis. Policies, procedures, and processes intended for conventional drugs and medications might be highly inappropriate for allergenic products. For example, substitution with differing lots, manufacturers, or dose formulations might be routine for conventional drugs and medications but could lead to fatal anaphylactic reactions with allergenic products. Prepared allergenic products usually have expiration dates of 3 to 12 months from the date of preparation but should not extend beyond the shortest expiration date of the individual components. There are no reports of infection associated with allergen immunotherapy injections. Allergen vaccines are prepared by using sterile manufacturer's extracts and sterile diluents containing antibacterial constituents (usually phenol). A summary of the AAAAI/ACAAI/JCAAI proposed USP allergen immunotherapy extract preparation guidelines can be found in Table VIII.

Table VIII. AAAAI/ACAAI/JCAAI-proposed USP Allergen Immunotherapy Extract Preparation Guidelines
1. Qualifications of extract preparation personnel:
•Compounding personnel must pass a written test on aseptic technique and extract preparation.
•Compounding personnel must be trained in preparation of allergenic products.
•Compounding personnel must annually pass a media-fill test, as described below.∗
•Compounding personnel who fail written or media-fill tests would be reinstructed and re-evaluated.
•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.
2. Physician responsibility: A physician with training and expertise in allergen immunotherapy is responsible for ensuring that compounding personnel are instructed and trained in the preparation of immunotherapy using an aseptic technique as defined below and that they meet the requirements of these guidelines. Evidence of such compliance shall be documented and maintained in personnel files.
3. Bacteriostasis: Allergen extract dilutions must be bacteriostatic, meaning that they must contain phenol concentrations of at least 0.25%, or if phenol 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.
6. Mixing of extracts with high and low proteolytic enzymes—cross-reactivity of antigens: Separation of aqueous extracts with high proteolytic enzyme activities from other extracts is recommended.
7. Storage: Extracts should be stored at 4°C to reduce the rate of potency loss or according to the manufacturer's directions. Extracts beyond the expiration 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 the FDA-approved package insert or accepted standards of clinical practice permit another route of administration.
9. Aseptic technique: Preparation of allergy immunotherapy shall follow aseptic manipulations defined as follows:
•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.
•The extract preparation area must be sanitized with 70% isopropanol that does not contain added ingredients, such as dyes and glycerin.
•Extract preparation personnel must thoroughly wash hands to wrists with detergent or soap and potable water. Substitution of hand washing by treatment with sanitizing agents containing alcohol and/or 70% isopropanol is acceptable.
•Necks of ampules to be opened and stoppers of vials to be needle punctured must be sanitized with isopropanol.
•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 the physical integrity of the vial.
10. Labeling: Immunotherapy vials are to be clearly labeled with the patient's name and beyond-use date of the vial.
11. 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.
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.

∗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 media, such as from Valiteq (http://www.valiteq.com), is transferred in ten 0.5-mL increments with a sterile syringe to a sterile 10-mL vial. Five milliliters of sterile water (preservative free) is added. This is the concentrate. The vial is incubated within a range of 20°C to 35°C for 14 days. Failure is indicated by visible turbidity in the medium on or before 14 days.

Allergen immunotherapy extract handling 

Storage 

Summary Statement 33a: Allergen immunotherapy extracts should be stored at 4°C to reduce the rate of potency loss. B

Summary statement 33b: Extract manufacturers conduct stability studies with standardized extracts that expose them to various shipping conditions. It is the responsibility of each supplier or manufacturer to ship extracts under validated conditions that are shown not to adversely affect the product's potency or safety. C

Because the efficacy and safety of immunotherapy depend on the use of allergen immunotherapy extracts with reasonably predictable biologic activity, it is important that they be stored under conditions that preserve such activity. The potency of allergen immunotherapy extracts is affected by a number of factors, including the passage of time, temperature, concentration, number of allergens in a vial, volume of the storage vial, and presence of stabilizers and preservatives. Allergen immunotherapy extract, including reconstituted lyophilized extracts, should be stored at 4°C to minimize the rate of potency loss because storage at higher temperatures (eg, room temperature) can result in rapid deterioration.249

Extract manufacturers conduct stability studies with standardized extracts that expose them to various shipping conditions (personal communication). These studies include actual shipments made by their carriers to places like Phoenix in the summer and Alaska in the winter. The results of these studies are on file under each manufacturer's product licenses. Each study is specific to each manufacturer because the packaging (eg, use of insulation) varies from company to company. It is the responsibility of each supplier or manufacturer to ship allergen extracts under validated conditions that have been shown not to adversely affect the product's potency or safety.

Storing dilute extracts 

Summary Statement 34a: More dilute concentrations of allergy immunotherapy extracts (diluted greater than 1:10 vol/vol) are more sensitive to the effects of temperature and lose potency more rapidly than do more concentrated allergen immunotherapy extracts. The expiration date for more dilute concentrations should reflect this shorter shelf life. B

Summary Statement 34b: In determining the allergy vaccine expiration date, consideration must be given to the fact that the rate of potency loss over time is influenced by a number of factors separately and collectively, including (1) storage temperature, (2) presence of stabilizers and bactericidal agents, (3) concentration, (4) presence of proteolytic enzymes, and (5) volume of the storage vial. D

The potency of concentrated allergen immunotherapy extracts (1:1 vol/vol up to 1:10 vol/vol) when kept at 4°C is relatively constant and allows the allergen immunotherapy extract to be used until the expiration date that is present on the label. Less concentrated allergen immunotherapy extracts are more sensitive to the effects of temperature and might not maintain their potency until the listed expiration date.249, 250

The mixing of other allergens might decrease the loss of potency with time because the additional allergens might prevent adherence of proteins to the vial's glass wall. Thus highly concentrated extracts are more stable than diluted ones. Extracts are prepared as aqueous, glycerinated, freeze-dried, and alum formulations. Aqueous and glycerin diluents are compatible for mixing standardized with nonstandardized products. Lyophilization is used to maintain the strength of the dry powder, but once the allergen immunotherapy extract is reconstituted, stabilizing agents, such as human serum albumin (0.03%) or 50% glycerin, are needed to maintain potency.250 Phenol is a preservative added to extracts to prevent growth of microorganisms.

Phenol can denature proteins in allergen extracts.251, 252 Human serum albumin might protect against the deleterious effect of phenol on allergen extracts.251 Human serum albumin might also prevent the loss of potency within storage vials by preventing absorption of allergen on the inner surface of the glass vial. Glycerin is also a preservative. At a concentration of 50%, glycerin appears to prevent loss of allergenic potency,250, 253 possibly through inhibition of the activity of proteolytic and glycosidic enzymes that are present in certain extracts. However, it is irritating when injected and should be diluted before beginning immunotherapy. Recommendations for extract stability are found in the manufacturers' product insert sheets. The extract manufacturers' package insert advises care when administering a volume greater than 0.2 mL of an extract in 50% glycerin because of the potential discomfort and pain it might cause. The pain associated with glycerin increases in proportion to the glycerin concentration and injection volume, and the pain is proportional to the total injected dose of glycerin.254 However, individual pain perception can vary substantially. Total glycerin doses of less than 0.05 mL rarely produce clinically important pain.

There have been few studies that have investigated the potency of dilutions of allergen extract mixture over time. Expiration dates for allergen extract dilutions are somewhat empiric and not strongly evidence based. A study undertaken by the AAAAI Immunotherapy and Allergy Diagnostic committee designed to study the stability of a mixture of standardized extracts in 4 conditions of storage (with and without intermittent room temperature exposure and diluted in normal saline or human serum albumin) found that short ragweed at 1:10 vol/vol dilution, as measured by means of radial immunodiffusion, was stable in all conditions of storage over 12 months. Dust mite and cat at 1:10 and 1:100 vol/vol dilution were also stable in all conditions of storage over 12 months, as measured by an ELISA assay using an mAb for Der p 1, Der f 1, and Fel d 1.

The expiration date of any dilution should not exceed the expiration date of the earliest expiring constituent that is added to the mixture.

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Immunotherapy schedules and doses 

Summary Statement 35: A customized individual allergen immunotherapy extract should be prepared from a manufacturer's extract or extracts in accordance to the patient's clinical history and allergy test results and can be based on single or multiple allergens. D

An allergen extract is a solution of elutable materials derived from allergen source materials, such as pollens or molds. They consist of complex mixtures of proteins and glycoproteins to which antibodies can bind. Animal dander contains between 10 and 20 antigens,255 house dust mites between 20 and 40 antigens,256 and pollens between 30 and 50 antigens,257, 258 and fungal extract can contain as many as 80 antigens.259

Extracts obtained from extract manufacturing companies should be called the manufacturer's extract. Vials of manufacturer's extract contain individual or limited mixtures of allergens that can be used alone as a concentrated dose of single allergen or combined with other concentrated allergens to prepare an individual patient's customized allergen mixture. This is designated as the patient's maintenance concentrate.

Nonstandardized manufacturer's extracts usually are available at concentrations of between 1:10 and 1:50 wt/vol or 20,000 and 100,000 PNU. Standardized extracts are available with biologic potencies of 10,000 and 100,000 BAU for grasses; 5000 and 10,000 BAU for cat allergen; 5000, 10,000, or 30,000 AU for dust mite; and 100,000 AU or 1:10 and 1:20 wt/vol for short ragweed, with the Amb a 1 concentration listed in FDA units on the label of the wt/vol extracts (Table IX). The main factor that limits how concentrated an allergen immunotherapy extract can be is the tendency of highly concentrated antigen solutions to develop precipitates. This is an unpredictable and poorly understood phenomenon. Although there is no evidence that such precipitates adversely affect the extract, the FDA does not permit a manufacturer to ship an extract that has a precipitate.

Table IX. Potency of selected manufacturer's extracts currently available
ExtractPotency
Cat hair and pelt5000 and 10,000 BAU/mL
Dust mite3000, 5000, 10,000, and 30,000 AU/mL
Bermuda grass10,000 AU/mL
Short ragweed1:10-1:20 wt/vol or 100,000 AU/mL
Other grasses∗10,000 and 100,000 BAU/mL
Other pollen1:10 to 1:40 (wt/vol) or 10,000 PNU/mL
Molds1:10 to 1:40 (wt/vol) or 20,000 to 100,000 PNU/mL

AU, Allergy unit; BAU, bioequivalent allergy unit; PNU, protein nitrogen unit.

∗Perennial rye, Kentucky blue/June, timothy, sweet vernal, redtop, orchard, and meadow.

Summary Statement 36: The highest-concentration allergy immunotherapy vial (eg, 1:1 vol/vol vial) that is used for the projected effective dose is called the maintenance concentrate vial. The maintenance dose is the dose that provides therapeutic efficacy without significant adverse local or systemic reactions and might not always reach the initially calculated projected effective dose. This reinforces that allergy immunotherapy must be individualized. D

The highest concentration of an allergen extract mixture that is projected to be used as the therapeutically effective dose is called the maintenance concentrate. This should be prescribed individually for each patient by an allergist/immunologist. The maintenance concentrate (if a mixture of extracts) should either be obtained from the manufacturer as a customized mixture or should be prepared by the physician under sterile conditions by adding an appropriate volume of individual manufacturer's extracts. Some patients might be unable to attain the projected therapeutically effective dose of the maintenance concentrate because of local reactions, systemic reactions, or both (eg, cat, 1000 BAU [highest tolerated dose] vs 2000 BAU [projected effective dose]; see Table X for probable effective therapeutic dose range). Such patients might need weaker dilutions of their maintenance concentrate. Even so, the original projected maintenance concentration of the allergen immunotherapy extract is still referred to as the maintenance concentrate, and the specific patient's therapeutic dose is referred to as the maintenance dose. The consistent use of this nomenclature system is essential because errors in choosing the correct vial are a common cause of systemic reactions, especially when the patient transfers from one physician to another. Therefore it is important that standard terminology be adopted by all physicians who prescribe allergen immunotherapy.

Table X. Probable effective dose range for allergen extracts US standardized unitsa
AntigenLabeled potency or concentrationabProbable effective dose range
Dust mites: D farinae and D pteronyssinusc3000, 5000, 10,000, and 30,000 AU/mL500-2000 AU
Catd5000-10,000 BAU/mL1000-4000 BAU
Grass, standardizede10,000-100,000 BAU/mL1000-4000 BAU
Short ragweedf1:10 to 1:20 wt/vol 100,000 AU/mL6-12 μg of Amb a 1 1000-4000 AU Concentration of Amb a 1 is on the label of wt/vol extracts in FDA units358
Nonstandardized extract, dogg1:10 to 1:100 wt/vol15 μg of Can f 1
Nonstandardized extracts1:10 to 1:40 wt/vol or 10,000-40,000 PNU/mLHighest tolerated dose

aMultiple studies have demonstrated that the efficacious dose for allergen immunotherapy is between 5 and 20 μg of the major allergen per injection. Only 2 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).

bThe 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).

cThere have been no dose-response studies with United States–licensed dust mite extracts, and dosing recommendations in AU value are extrapolated from published European studies that used aqueous349 and alum-precipitated149, 151 extracts. One study designed to investigate the effect of 3 doses of an alum-precipitated D pteronyssinus extract (0.7, 7, and 21 μg of Der p 1) found a dose-response effect on efficacy and side effects.149 The authors suggested the optimal maintenance dose was 7 μg of Der p 1. Corresponding doses were based on specific allergen measurements of US commercially available standardized extracts provided by manufacturers. Extrapolating effective and safe doses in this manner might not be scientifically valid. D farinae and D pteronyssinus are similar in group 1 allergen content according to the FDA's current reference standards. Appropriate dose reductions would need to be made when combining antigens that have a strong degree of cross-reactivity, such as D pteronyssinus and D farinae.

dThe major cat allergen Fed d 1 is reported in FDA units, with 1 Fel d 1 unit equaling approximately 2 to 4 μg of Fel d 1.55, 58, 59 The amount of Fel d 1 in 10,000 BAU/mL ranges from 10 to 19.9 U/mL. One study demonstrated clinical efficacy of a maintenance dose of 4.56 FDA units of Fel d 1 dose in terms of decreased cat extract PD20, titrated skin test results, and allergen-specific IgE and IgG levels.350, 351 In a recent study that investigated the efficacy in terms of immunologic changes of 3 doses of a United States–licensed cat extract (0.6, 3, and 15 μg) demonstrated that a significant effect on titrated skin prick test results, allergen-specific IgG4 levels, and CD4+/IL-4 levels was only seen in the group treated with 15 μg of Fel d 1, although the 3-μg dose group did demonstrate a significant change in titrated skin test response and increase in cat-specific IgG4 levels.22

eThere have been no dose-response studies with United States–licensed standardized grass extracts. Recommended doses are extrapolated from published European studies that have used aqueous,130 alum-precipitated,24, 161 and calcium phosphate–precipitated grass pollen extracts.352 One of these studies compared a dose of 2 μg with 20 μg of major timothy allergen (Phl p 5) and found clinical efficacy at both doses.24 The efficacy was greater in the 20 μg of Phl p 5 dose, but the systemic reaction rate was also higher in the high-dose group. The package inserts for United States–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 BAU. Extrapolating effective and safe doses in this manner might not be scientifically valid. 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).

fRagweed is reported in FDA units, with 1 U of Amb a 1 equaling 1 μg of Amb a 1. The potency units for short ragweed extracts were originally assigned based on their Amb a 1 content. Subsequent data suggested that 1 unit of Amb a 1 is equivalent to 1 μg of Amb a 1, and 350 Amb a 1 units/mL is equivalent to 100,000 BAU/mL.60 The package insert of the short ragweed 100,000 AU/mL extract states the optimal immunotherapy dose is 2000 AU, with a range of 1000-4000 AU. One open study of patients with ragweed-induced allergic rhinitis demonstrated a significant improvement in ragweed nasal challenge in patients treated with a mean dose of 6 μg of Amb a 1 for 3 to 5 years compared with an untreated matched control group.45 A ragweed dose-response study (0.6, 12.4, and 24.8 μg of Amb a 1) demonstrated efficacy, as measured by nasal challenge, at 12 and 24 μg of Amb a 1.128 The efficacy of the 24-μg dose was not significantly better than the 12-μg dose, and the authors concluded that the optimal dose for ragweed extract was greater than 0.6 μg but not more than 12.4 μg of Amb a 1.

gDog extracts are not standardized. However, one dose-response study with a United States–licensed acetone-precipitated dog extract investigated the efficacy of 3 doses (AP dog; Hollister-Stier, Spokane, Wash; 0.6, 3, and 15 μg) in terms of immunologic changes and found the dose of 15 μg of Can f 1 to be most efficacious.25 The 3-μg dose also demonstrated significant efficacy, although not as great as the 15-μg dose. The extract used in the dosing study was assayed at 160 μg/mL. Subsequent lots have assayed between 128 and 208 μg/mL (average Can f 1, 162 μg/mL [SD ± 26 μg/mL]; information provided by the extract manufacturer, Hollister-Stier).

Recommended doses 

Summary Statement 37: The maintenance concentrate should be formulated to deliver a dose considered to be therapeutically effective for each of its constituent components. The projected effective dose is referred to as the maintenance goal. Some individuals unable to tolerate the projected effective dose will experience clinical benefits at a lower dose. The effective therapeutic dose is referred to as the maintenance dose. A

The effective maintenance dose of immunotherapy for a particular patient must be individualized. To do this, the allergist/immunologist who prepares the allergen immunotherapy extract must balance the dose necessary to produce efficacy and the risk of reactions if such a dose is reached. The allergist/immunologist might need to prepare more than one maintenance concentrate to provide a therapeutic dose of each of the allergens for the polysensitized patient. Therapeutically effective doses for immunotherapy have been reported for some allergen extracts.22, 24, 25, 128, 134, 135, 149, 246, 260, 261 Effective doses have been determined for Hymenoptera venom, dust mite, cat allergen, dog, grass, and short ragweed (Table X).

Controlled studies demonstrate that the content of particular allergens in allergen immunotherapy extracts can be used to predict a therapeutic dose for those allergens, particularly when the extracts are standardized. For antigens that have not been standardized, the effective dose must be estimated and individualized. It is important to keep a separate record of the contents of each extract, including final dilutions of each of the constituents. The therapeutically effective doses used in the most recent controlled clinical studies are the basis of the recommended dosage range of standardized extracts presented in Table X. Although early improvement in symptoms has been documented with these doses, long-term benefit appears to be related not only to the individual maintenance dose but also the duration of time that it is administered.14

Because a full dose-response curve has not been determined for most allergens, it is possible (and supported by expert opinion) that therapeutic response can occur with doses lower than those that have been shown to be effective in controlled studies. In general, however, low doses are less likely to be effective, and very low doses usually are ineffective.27 Although administration of a higher maintenance dose of immunotherapy increases the likelihood of clinical effectiveness, it also increases the risk of systemic reactions. In particular, highly sensitive patients might be at risk of systemic reactions to immunotherapy injections with higher maintenance doses. The maintenance concentrate should be formulated to deliver a full therapeutic dose of each of its constituent components. However, some sensitive patients might not tolerate the targeted therapeutic dose, and their maintenance dose would be lower. Individuals who have systemic reactions with doses that are less than the projected effective dose should be maintained on the highest tolerated dose, providing this dose is effective. The highest tolerated effective therapeutic dose is referred to as the maintenance dose.

Regardless of dose schedule, some patients are unable to progress to the predetermined maintenance dose because of large local or systemic reactions to the allergen immunotherapy extract. The evidence is not clear whether large local reactions are a potential risk for subsequent allergen immunotherapy systemic reactions.

Published studies do not indicate that an individual large local reaction is predictive of a subsequent systemic reaction.179, 180 However, one retrospective study found that individuals who have a history of repeated large local reactions (defined as >25 mm) might be at greater risk for a subsequent systemic reaction.181

The concept of highest tolerated dose does not apply for VIT, and all patients are expected to achieve the full recommended dose to achieve the necessary degree of protection. There are conflicting data over whether lower doses (50 μg) are less effective, but there are also data showing that 200 μg is more reliably effective.245 In the case of VIT, patients are asked to tolerate more large local reactions to achieve the full dose, even though with inhalant immunotherapy the dose can be reduced for such large local reactions to minimize patient discomfort.

Effect of dilution on dose 

Summary Statement 38: Dilution limits the number of antigens that can be added to a maintenance concentrate if a therapeutic dose is to be delivered. A

The more antigens that are added to the maintenance concentrate, the more there is the potential to dilute other antigens in the vaccine, thereby limiting the ability to deliver a therapeutic effective dose for any given allergen. If the appropriate concentration of each allergen extract is added, then adding additional allergens to the maintenance concentration will have no effect on the concentration of the other allergens, as long as the additional allergens are replacing diluent. For example, if the desired maintenance concentration for cat is 2000 BAU/mL, 2 mL of the manufacturer's extract (cat, 10,000 BAU/mL) can be added to 8 mL of diluent or 8 mL of other allergens, and the final concentration of cat will be 2000 BAU/mL in both mixtures. Once the diluent is all replaced, addition of further allergens will result in undesirable dilution of all allergens in the maintenance mixture.

Dilutions of the maintenance concentrate 

Summary Statement 39: Serial dilutions of the maintenance concentrate should be made in preparation for the build-up phase of immunotherapy. D

In preparation for the build-up phase of immunotherapy, serial dilutions should be produced from each maintenance concentrate. Typically, these are 10-fold dilutions, although other dilutions occasionally are used. These dilutions should be labeled in terms of vol/vol to indicate that they are dilutions derived from the maintenance concentrate. For example, serial 10-fold dilutions from the maintenance concentrate would be labeled as 1:10 (vol/vol) or 1:100 (vol/vol). Alternatively, the vial dilutions can be labeled in actual units (eg, 1000 BAU or 100 BAU), but this system can be complicated if allergens with different potency units are used (eg, wt/vol, BAU, AU, or PNU) and make it difficult to easily interpret the vial label.

Instructions on how to prepare various allergen extracts dilutions are shown in Table XI. If the final volume of the diluted allergen immunotherapy extract to be produced is 10 mL, then one tenth of that final volume, or 1.0 mL, should be removed from the more concentrated allergen immunotherapy extract and added to a new bottle containing 9.0 mL of diluent.

Table XI. Procedure for dilutions from the maintenance concentrate (which is termed 1:1 vol/vol)
Dilution from maintenance concentrate vaccineVolumeVolume (mL)Diluent volume (mL)Final volume
1:1 (vol/vol)1.00.01.01:1 (vol/vol)
1:1 (vol/vol)2.08.010.01:5 (vol/vol)
1:1 (vol/vol)1.09.010.01:10 (vol/vol)
1:10 (vol/vol)1.09.010.01:100 (vol/vol)
1:100 (vol/vol)1.09.010.01:1000 (vol/vol)

All dilutions are expressed as vol/vol from the maintenance concentrate.

Labeling dilutions 

Summary Statement 40: A consistent uniform labeling system for dilutions from the maintenance concentrate might reduce errors in administration and therefore is recommended. D

During the build-up phase of immunotherapy, a number of dilutions of the patient's maintenance concentrate are needed. Use of one labeling system to indicate dilutions might help to avoid administration errors (Table XII). In addition to the labeled dilution from the maintenance concentrate (vol/vol), a numbering system, a color-coding system, or an alphabetical system should be used. If this uniform labels system is used, it is essential that it be used in the same way by all physicians to reduce potential administration errors by staff unfamiliar with the labeling system. 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 administration of allergen immunotherapy should be involved with the planning of this transition.

Table XII. Suggested nomenclature for labeling dilutions from the maintenance concentrate
Dilution from maintenance concentrateVol/vol labelNo.Color
Maintenance concentrate1:11Red
10-fold1:102Yellow
100-fold1:1003Blue
1000-fold1:10004Green
10,000-fold1:10,0005Silver

If a numbering system is used, the highest concentration should be numbered 1. This is necessary to provide consistency in labeling because if larger numbers are used to indicate more concentrated extracts, the number of the maintenance concentrate would vary from patient to patient depending on the number of dilutions made. If a color-coding system is used, it should be consistent (eg, the highest concentration should be red, the next highest yellow, followed by blue, green, and silver in that order) (Fig 3, Fig 4).

Regardless of the labeling system used for indicating dilutions from the maintenance concentrate, the specific contents of each allergen immunotherapy extract should be listed separately. The volume and concentration of each of its constituents should be listed on the immunotherapy prescription form.

Consistency is essential as a basis for adoption of a standardized system. Some allergists/immunologists, however, have found it helpful to use letters for designating different component mixtures of extracts (eg, trees [T], grasses [G], and molds [M] [see Appendix 2]).

Individualized treatment vials 

Summary Statement 41: Administration of an incorrect injection is a potential risk of allergen immunotherapy. An incorrect injection is an injection given to the wrong patient or a correct patient receiving an injection of an incorrect dose.

A customized individual maintenance concentrate of the allergen immunotherapy extract and serial dilutions, whether a single extract or a mixture of extracts, prepared and labeled with the patient's name and birth date might reduce the risk of incorrect (wrong patient) injection. The mixing of antigens in a syringe is not recommended because of the potential for cross-contamination of extracts. C

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). Labels on patient-specific vials can provide at least 2 patient identifiers (birth date and patient name), which would be consistent with the recommendations of the Joint Commission on Accreditation of Health Care Organizations National Patient Safety Goals: “Goal 1: Improve the accuracy of patient identification by using at least two patient identifiers when providing care, treatment or services.”5 The risk of errors of administration might be reduced because the individually prepared allergen immunotherapy vials labeled with the patient's name and birth date will allow the person administering the extract and the patient an opportunity to verify the name/birth date on the label before administration of the injection.4, 5

In a survey of 1717 allergists endorsed by the AAAAI and JCAAI, 57% of the 476 respondents reported at least one wrong-patient injection, and 74% of the 473 respondents reported at least one wrong-dose injection.4 The incorrect injections resulted in 1 death, 29 hospital admissions, and 59 emergency department visits. In addition to patient identifiers on vial labels, the authors cited several reasons why this might reduce incorrect injection errors. One reason was that patient-specific vials can be prepared in a quiet laboratory setting, which might provide substantially less distraction than the nurse in a room with a patient who is trying to concentrate only on drawing up the injection correctly. In addition, the specific components are mixed once with the preparation of individually prepared patient-labeled vials, whereas the mixing would be repeated on every injection visit if the allergen extract is withdrawn from different stock solutions, as it is in the off-the-board method. For safety reasons and to avoid cross-mixing of allergens removed from the manufacturer's extract, the mixing of antigens in the syringe (off the board) is not recommended.

Some allergists/immunologists prefer to administer immunotherapy doses drawn directly from a single stock dilution of individual allergens or common mixes (shared specific patient vials). In this way the immunotherapy dose is transferred to the patient without cross-contamination. If shared-patient (eg, mixed vespids and dust mite mix) vials are used, it is essential that policies and procedures are developed to verify that the correct dose from the correct vial is administered to the correct patient.

Starting doses 

Summary Statement 42: The starting dose for build-up is usually a 1000- or 10,000-fold dilution of the maintenance concentrate, although a lower starting dose might be advisable for highly sensitive patients. D

There are 2 phases of allergen immunotherapy administration: the initial build-up phase, when the dose and concentration of allergen immunotherapy extract are slowly increased, and the maintenance phase, when the patient receives an effective therapeutic dose over a period of time. If the starting dose is too dilute, an unnecessarily large number of injections will be needed, resulting in a delay in achieving a therapeutically effective dose. On the other hand, if the starting dose is too concentrated, the patient might be at increased risk of having a systemic reaction.

When choosing the starting dose, most allergists/immunologists start at a dilution of the maintenance concentrate that is appropriate based on the sensitivity of the patient to the allergens in the extract, which in turn is based on the history and skin test reactivity.

Common starting dilutions from the maintenance concentrate are 1:10,000 (vol/vol) or 1:1000 (vol/vol), although more diluted concentrations frequently are used for patients who are highly sensitive, as indicated by history or skin test reaction (see Appendix 3 for an example of a conventional immunotherapy schedule).

Frequency of build-up injections 

Summary Statement 43: The frequency of allergen immunotherapy administration during the build-up phase is usually 1 to 2 injections per week. D

A number of schedules are used for the build-up phase of immunotherapy. The most commonly used schedule is for increasing doses of allergen immunotherapy extract to be administered 1 to 2 times per week. This weekly schedule is recommended in most of the allergen extract package inserts. With this schedule, a typical patient can expect to reach a maintenance dose in 4 to 6 months, depending on the starting dilution and the occurrence of reactions. It is acceptable for patients to receive injections more frequently, provided there is adequate spacing between injections. The interval between injections is empiric but might be as short as 1 day without any increase in the occurrence of systemic reactions262 if there is some urgency to achieve a maintenance dose (eg, allergy season is approaching) or for practical reasons (eg, patient's schedule). Alternatively, treatment schedules can be used that more rapidly achieve maintenance dosing. These cluster and rush dosing schedules are discussed in Summary Statements 47 through 49.

Allergen immunotherapy extracts used during the build-up phase usually consist of three or four 10-fold dilutions of the maintenance concentrate. The volume generally is increased at a rate that depends on a number of 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 increments being given at higher concentrations).

Dose adjustments for systemic reactions 

Summary Statement 44: The dose of allergen immunotherapy extract should be appropriately reduced after a systemic reaction if immunotherapy is continued. D

It is customary to either reduce the dose if a systemic reaction has occurred or consider discontinuation of immunotherapy, especially if the reaction has been severe. Although there are no evidence-based guidelines on dose adjustment after a systemic reaction, many allergists/immunologists reduce the dose to one that was previously tolerated or an even lower dose if the reaction was severe. Once the patient tolerates a reduced dose, a cautious increase in subsequent doses can be attempted. It is important for the physician who prescribed the allergen immunotherapy extract to review the course of immunotherapy to determine whether the benefit/risk ratio justifies continuation of immunotherapy.

Reductions during periods of exacerbation of symptoms 

Summary Statement 45: Immunotherapy given during periods when the patient is exposed to increased levels of allergen to which they are sensitive might be associated with an increased risk of a systemic reaction. Consider not increasing or even reducing the immunotherapy dose in highly sensitive patients during the time period when they are exposed to increased levels of allergen, especially if they are experiencing an exacerbation of their symptoms. C

Immunotherapy administered during periods of exacerbation of symptoms is considered a risk factor for immunotherapy.17, 184 Injections administered during periods when a patient is exposed to increased levels of allergen to which they are sensitive might be associated with an increased risk of a systemic reaction, especially if the patient is experiencing a significant exacerbation of symptoms and, in particular, asthma symptoms.184 Therefore it is reasonable to consider not increasing or even reducing the dose of the allergen immunotherapy extract during seasons when the patient is exposed to increased levels of allergen to which they are sensitive, especially if their symptoms are poorly controlled.

Dose adjustments for late injections 

Summary Statement 46: It is customary to reduce the dose of allergen immunotherapy extract when the interval between injections is prolonged. D

During the build-up phase, it is customary to repeat or even reduce the dose of allergen immunotherapy extract if there has been a substantial time interval between injections. This depends on (1) the concentration of allergen immunotherapy extract that is to be administered, (2) whether there is a previous history of systemic reactions, and (3) the degree of variation from the prescribed interval of time, with longer intervals since the last injection leading to greater reductions in the dose to be administered (see Appendix 4 for an example of a dose-modification regimen for gaps in treatment).

Cluster schedules 

Summary Statement 47: With cluster immunotherapy, 2 or more injections are administered per visit to achieve a maintenance dose more rapidly than with conventional schedules. C

Cluster schedules are designed to accelerate the build-up phase of immunotherapy. Cluster immunotherapy usually is characterized by visits for administration of allergen immunotherapy extract 1 or 2 times per week with a schedule that contains fewer total injections than are used with conventional immunotherapy. With cluster immunotherapy, 2 or more injections are given per visit on nonconsecutive days (see Appendix 5).22, 26 The injections are typically given at 30-minute intervals, but longer intervals have also been used in some protocols. This schedule can permit a patient to reach a maintenance dose in as brief a period of time as 4 weeks. The cluster schedule is associated with the same or a slightly increased frequency of systemic reactions compared with immunotherapy administered with more conventional schedules.145, 263, 264, 265, 266 The occurrence of both local and systemic reactions to cluster immunotherapy can be reduced with administration of an antihistamine 2 hours before dosing.267

Rush schedules 

Summary Statement 48: Rush schedules can achieve a maintenance dose more quickly than weekly schedules. A

Rush schedules are more rapid than cluster immunotherapy. An early study used a schedule that permitted patients to achieve a maintenance dose in 6 days; however, patients were required to remain in the hospital.268 As experience with accelerated forms of immunotherapy was acquired, schedules were developed to reach a maintenance dose more rapidly.191, 269, 270, 271, 272

The most accelerated schedule that has been described for inhalant allergens involves administering 7 injections over the course of 4 hours.273 Ultrarush immunotherapy schedules have been described for stinging insect hypersensitivity to achieve a maintenance dose in as little as 3.5 to 4 hours.274, 275, 276 The advantage of a cluster or rush schedule is that it permits patients to attain a therapeutically effective maintenance dose more rapidly than with a conventional schedule. Controlled studies have shown symptomatic improvement shortly after reaching maintenance doses by using cluster145, 266 and rush134, 277 schedules.

Systemic reactions and rush schedules 

Summary Statement 49: Rush schedules are associated with an increased risk of systemic reactions. However, rush protocols for administration of Hymenoptera VIT have not been associated with a similarly high incidence of systemic reactions. A

The advantages of rush immunotherapy come at a cost because there is an increased risk of local and systemic reactions. Systemic reaction rates have been reported to be as high as 73% of patients, with the risk of such reactions reduced to 27% by premedication in one study.272 Most reactions to rush immunotherapy are not severe, and the most common systemic reaction is usually flushing.273

Systemic reactions with rush schedules have been reported to occur up to 2 hours after the final injection. For that reason, individuals receiving rush immunotherapy should remain under physician supervision for a longer waiting period than the usual 30 minutes recommended for conventional schedules (eg, 1.5-3 hours on the day of allergen immunotherapy extract administration).

Rush protocols for administration of Hymenoptera venom have not been associated with a similarly high incidence of systemic reactions.274, 275, 276, 278, 279

Premedication and weekly immunotherapy 

Summary Statement 50: Premedication can reduce the frequency of systemic reactions caused by conventional immunotherapy. A

There is concern that antihistamines taken before each injection with conventional immunotherapy might mask a minor reaction that would otherwise alert a physician to an impending systemic reaction. However, one randomized controlled study demonstrated that premedication reduced the frequency of severe systemic reactions caused by conventional immunotherapy and increased the proportion of patients who achieved the target maintenance dose.280 One study that compared terfenadine premedication with placebo premedication during rush VIT demonstrated greater clinical efficacy in the terfenadine-premedicated group in terms of subsequent responses to field stings or sting challenge.281 There was also a significant difference in the systemic reaction rate between the 2 groups: 6 patients in the placebo-premedicated group had systemic reactions, whereas none of the patients in the terfenadine-premedicated group had systemic reactions (P = .012).

Unfortunately, patients might still have life-threatening anaphylaxis despite premedication treatment. Because many patients might take an antihistamine as part of their overall allergy management, it is important to determine whether they have taken it on the day that they receive an allergen immunotherapy extract injection. For consistency in interpretation of reactions, it also might be desirable that they consistently either take their antihistamine or avoid it on days when they receive immunotherapy. Other attempts to reduce the occurrence of systemic reactions, such as the addition of epinephrine to the allergen immunotherapy extract or use of concomitant corticosteroids, are not justified and might delay the onset of a systemic reaction beyond the waiting time when the patient is in the physician's office, thus increasing the risk.

Premedication with cluster and rush immunotherapy 

Summary Statement 51: Premedication should be given before cluster and rush immunotherapy with aeroallergens to reduce the rate of systemic reactions. A

Premedication with a nonsedating antihistamine (loratadine) 2 hours before the first injection of each visit reduced both the number and severity of systemic reactions during cluster immunotherapy.267 Premedication with a 3-day course of prednisone, an H1 histamine receptor antagonist, and an H2 histamine receptor antagonist before rush immunotherapy with inhalant allergens reduced the risk of a systemic reaction from approximately 73% to 27% of patients.272 In one study designed to investigate the effect of 12 weeks of premedication with a humanized monoclonal anti-IgE antibody (omalizumab) on the safety and efficacy of rush immunotherapy, there was a 5-fold decrease in the risk of anaphylaxis in the group premedicated with omalizumab compared with the placebo premedication group.282

There are anecdotal reports of reductions in systemic reaction rates with the addition of a leukotriene receptor antagonist, but there have been no published studies. Because the risk of a systemic reaction from rush VIT is relatively low, routine premedication before rush VIT is usually unnecessary.274, 276, 278, 279 In a study evaluating premedication with antihistamines and steroids for rush immunotherapy with imported fire ant venom, there was no statistically significant differences in the systemic reaction rates between the premedication and placebo premedication group (3.6% of the premedication group vs 6.7% of the placebo group, P = .87).157

Maintenance schedules 

Summary Statement 52: Once a patient reaches a maintenance dose, the interval between injections often can be progressively increased as tolerated up to an interval of up to 4 weeks for inhalant allergens and up to 8 weeks for venom. Some individuals might tolerate longer intervals between maintenance dose injections. A

Once a patient who is receiving inhalant allergen immunotherapy reaches a maintenance dose, an interval of 2 to 4 weeks between injections is recommended, provided clinical improvement is maintained. Some individuals might tolerate longer intervals between maintenance dose injections.

The interval between venom injections can be safely increased up to 8 weeks in some patients without loss of efficacy. In other patients, greater efficacy, fewer reactions, or both might occur with shorter intervals between injections. Therefore the interval between allergen immunotherapy injections should be individualized to provide the greatest efficacy and safety for each patient.

Continuing care 

Time course of improvement 

Summary Statement 53: Clinical improvement can be demonstrated very shortly after the patient reaches a maintenance dose. A

Clinical improvement can be demonstrated very shortly after the patient reaches a maintenance dose.24, 134, 143, 277 Improvement might not be observed for a number of reasons, including (1) failure to remove significant allergenic exposures (eg, a cat), (2) exposure to high levels of allergen (eg, pollen or molds), (3) continued exposure to nonallergen triggers (eg, tobacco smoke), or (4) incomplete identification and treatment of clinically relevant allergens. If clinical improvement is not apparent after 1 year of maintenance therapy, possible reasons for lack of efficacy should be evaluated. If none are found, discontinuation of immunotherapy should be considered, and other treatment options should be pursued.

Follow-up visits 

Summary Statement 54: Patients should be evaluated at least every 6 to 12 months while they receive immunotherapy. D

Patients should be evaluated at least every 6 to 12 months while receiving immunotherapy:

•to assess efficacy;

•to implement and reinforce its safe administration and to monitor adverse reactions;

•to assess the patient's compliance with treatment

•to determine whether immunotherapy can be discontinued; and

•to determine whether adjustments in immunotherapy dosing schedule or allergen content are necessary.

Patients might need more frequent office visits for evaluation and management of immunotherapy (eg, treatment of local reactions, systemic reactions, or both or changes in their immunotherapy vials or lots) or changes in the management of underlying allergic disease or comorbid conditions.

Duration of treatment 

Summary Statement 55a: At present, there are no specific tests or clinical markers that will distinguish between patients who will relapse and those who will remain in long-term clinical remission after discontinuing effective inhalant allergen immunotherapy, and the duration of treatment should be determined by the physician and patient after considering the benefits and risks associated with discontinuing or continuing immunotherapy. D

Summary Statement 55b: Although there are no specific tests to distinguish which patients will relapse after discontinuing VIT, there are clinical features that are associated with a higher chance of relapse, notably a history of very severe reaction to a sting, a systemic reaction during VIT (to a sting or a venom injection), honeybee venom allergy, and treatment duration of less than 5 years. C

Summary Statement 55c: The patient's response to immunotherapy should be evaluated on a regular basis. A decision about continuation of effective immunotherapy should generally be made after the initial period of up to 5 years of treatment. D

Summary Statement 55d: The severity of disease, benefits sustained from treatment, and convenience of treatment are all factors that should be considered in determining whether to continue or stop immunotherapy for any individual patient. D

Summary Statement 55e: Some patients might experience sustained clinical remission of their allergic disease after discontinuing immunotherapy, but others might relapse. B

The patient's response to immunotherapy should be evaluated on a regular basis. The severity of disease, benefits sustained from treatment, and convenience of treatment are all factors that should be considered in determining whether to continue or stop immunotherapy for any individual patient. If allergen immunotherapy is effective, treatment might be continued for longer than 3 years, depending on the patient's ongoing response to treatment. Some patients experience a prolonged remission after discontinuation, but others might relapse after discontinuation of immunotherapy. Therefore the decision to continue or stop immunotherapy must be individualized.

There have been very few studies designed specifically to look at the question of when to discontinue effective allergen immunotherapy or the duration of immunotherapy efficacy after termination of treatment. The duration of allergen immunotherapy efficacy has probably been most extensively studied in Hymenoptera hypersensitivity. Long-term follow-up studies suggest that a 5-year immunotherapy treatment course for Hymenoptera hypersensitivity might be sufficient for most allergic individuals.283, 284, 285 However, relapse rates as high as 15% of patients in the 10-year period after discontinuing VIT have been reported.283, 285 Nevertheless, systemic reactions to stings after discontinuing VIT were generally much milder than the pretreatment reactions and were rarely severe. Two studies did not find a difference in relapse rates between the patients treated for 3 years compared with those treated for 5 years,283, 286 but one of the studies noted that the small number of patients in the 3-year treatment group prevented them from making any conclusions about the risk of discontinuing treatment after 3 years.283 However, one study found that patients who had experienced re-sting reactions after discontinuing VIT had received VIT for a significantly shorter duration (mean, 43.35 months) than those with continued protection (mean, 54.65 months; P < .01).285 Another study reported that 5 years of VIT provided better immunologic and clinical outcomes than 2 to 4 years of treatment.287

Change in skin test reactivity did not appear to predict persistent efficacy after discontinuation because the skin test response was negative in some of the patients who experienced a systemic sting reaction. However, no relapses were observed among patients without detectable venom-specific IgE.286, 288 Some of the patients who experienced systemic sting reactions after discontinuing VIT had experienced systemic reactions during the VIT treatment.288 The relapse rate and the frequency of severe reactions were greater in patients who had a history of very severe reactions to stings before treatment, in patients who had systemic reactions during VIT (to a sting or a venom injection), in patients with honeybee allergy, and in those who had less than 5 years of treatment.

The duration of inhalant allergen immunotherapy efficacy has not been as extensively studied. Some studies have suggested that a 3- to 5-year treatment duration is sufficient for inhalant allergen immunotherapy, but others have reported a significant relapse rate within 3 years of discontinuing allergen immunotherapy.

One prospective controlled study was designed to study the immunotherapy relapse rate during the 3-year period after discontinuation of immunotherapy in 40 asthmatic patients who had been treated with immunotherapy with a standardized dust mite (D pteronyssinus) extract for 12 to 96 months.14 Fifty-five percent of the patients relapsed. The duration of efficacy was related to the reduction of skin test reactivity at the end of immunotherapy treatment (P = .003) and the duration of immunotherapy treatment. The relapse rate was 62% in the group treated for less than 35 months compared with 48% in the group treated for greater than 36 months (P = .04). Prolonged clinical efficacy was demonstrated in a double-blind, placebo-controlled study of patients with severe grass pollen–induced allergic rhinitis who had been treated for 3 to 4 years with immunotherapy.13 There was a switch to placebo in half of the group (16 patients) after 3 to 4 years of immunotherapy, and efficacy parameters were monitored over the next 3 years. Seasonal symptom scores and the use of rescue medication remained low for 3 to 4 years after the discontinuation of immunotherapy, and there was no significant difference between patients who continued and those who discontinued immunotherapy. These studies demonstrate the uncertainty of the long-term benefit of inhalant immunotherapy after discontinuation.

Currently, there are inadequate diagnostic tools available to identify which patients will experience a sustained clinical remission after discontinuing inhalant immunotherapy, and the duration of treatment should be determined by the physician and patient after considering the benefits and risks associated with discontinuing or continuing inhalant immunotherapy.

A form to document indication for continuation of immunotherapy can be found at http://www.aaaai.org or http://www.jcaai.org.

Documentation and record keeping 

Summary Statement 56: The allergen immunotherapy extract contents, informed consent for immunotherapy, and administration of extracts should be carefully documented. D

An immunotherapy injection should not be given unless adequate documentation is available in the patient's medical record. This also means that patients who receive injections in a health care facility other than the office of the prescribing physician must have appropriate documentation. The recommended documentation for informed consent allergy immunotherapy and prescription forms can be found in the Appendix (Appendix 6, Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, Appendix 12, Appendix 13, Appendix 14, Appendix 15), and these include examples of immunotherapy prescription and administration forms. These forms, along with examples of immunotherapy consent and instruction forms, can also be found at http://www.aaaai.org.

Injection techniques 

Summary Statement 57: Allergen immunotherapy extract injections should be given using a 1-mL syringe with a 26- to 27-gauge half-inch nonremovable needle. C

Immunotherapy should be given with a 26- to 27-gauge syringe with a half-inch nonremovable needle. Syringes specifically designed for immunotherapy are available from medical supply companies. Although recent Occupational Safety and Health Administration guidelines mandate the use of safety needles with allergy injections, recent publications indicate a potential increase in accidental needle sticks with the use of safety needles compared with standard syringes.289, 290, 291

If using shared specific patient vials (stock vials, such as mixed vespid or dust mite mix), a single dose should be drawn from each vial. Antigens from different vials should not be combined in a single syringe. Furthermore, extra care is needed to prevent using the wrong stock antigen.

Summary Statement 58: The injection should be given subcutaneously in the posterior portion of the middle third of the upper arm. D

Each immunotherapy injection should be given in the posterior portion of the middle third of the upper arm at the junction of the deltoid and triceps muscles. This location tends to have a greater amount of subcutaneous tissue than adjacent areas. The skin should be wiped with an alcohol swab before giving the immunotherapy injection. This does not sterilize the area, but it does remove gross contamination from the skin surface.

Immunotherapy should be given subcutaneously. Subcutaneous injections result in formation of a reservoir of allergen immunotherapy extract that is slowly absorbed. Absorption that is too rapid, such as after an intramuscular injection, could lead to a systemic reaction. The skin should be pinched and lifted off of the muscles to avoid intramuscular or intravenous injection and to increase access to the subcutaneous tissues.

The syringe should be aspirated to check for blood return in the syringe before injecting. If blood is present, the syringe should be removed and discarded in an appropriate container (“sharps” box). Another dose of the allergen extract should be drawn into a new syringe and a different site 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 syringe should be appropriately discarded. A fresh syringe and needle are necessary to determine whether a blood vessel has been entered.

The plunger should be depressed at a rate that does not result in wheal formation or excessive pain. Mild pressure should then be applied to the injection site for about 1 minute immediately after removal of the needle. This reduces the chance of leakage of the allergen extract, which could result in a local reaction.

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Location of allergen immunotherapy administration 

Physician's office 

Summary Statement 59: The preferred location for administration of allergen immunotherapy is in the office of the physician who prepared the patient's allergen immunotherapy extract. D

The preferred location of allergen immunotherapy administration is in the office of the physician who prepared the patient's allergen immunotherapy extract. The physician's office should have the expertise, personnel, and procedures in place for the safe and effective administration of immunotherapy. However, in many cases it might be necessary to administer the allergen immunotherapy extract in another physician's office. Allergen immunotherapy should be administered with the same care wherever it is administered. A physician or qualified physician extender to treat anaphylaxis should be in the immediate vicinity when immunotherapy injections are administered.

Summary Statement 60: Patients at high risk of systemic reactions, where possible, should receive immunotherapy in the office of the physician who prepared the patient's allergen immunotherapy extract. D

Patients at high risk of systemic reactions (highly sensitive, severe symptoms, comorbid conditions, and history of recurrent systemic reactions), where possible, should receive immunotherapy in the allergist/immunologist's office.292 The allergist/immunologist who prepared the patient's allergen immunotherapy extract and his or her support staff should have the experience and procedures in place for the administration of allergen immunotherapy to such patients.184 The early signs of an allergic reaction are more likely to be recognized and early treatment initiated, which will decrease the possibility of a serious outcome. Modifications might be frequently necessary in the patient's immunotherapy schedule, as well as the patients total treatment program.

Other locations 

Summary Statement 61: Regardless of the location, allergen immunotherapy should be administered under the supervision of an appropriately trained physician and personnel. D

The physician and personnel administering immunotherapy should be aware of the technical aspects of this procedure and have available appropriately trained personnel, resuscitative equipment/medicines, and storage facilities for allergen immunotherapy extract.292 The health care professional and staff should be able to recognize early signs and symptoms of anaphylaxis and administer emergency medications as necessary.

The physician and staff should be aware of situations that might place the patient at greater risk for systemic reactions (eg, concomitant medications that can interfere with emergency treatment, such as β-blockers, acute illness, or allergy/asthma exacerbations at the time of allergen immunotherapy extract injection or poorly controlled asthma).

Appropriate adjustment of dose should be made as clinically indicated. The physician who prepared the patient's allergen immunotherapy extract should provide adequately labeled allergen immunotherapy extract vials, detailed directions regarding dosage schedule for build-up and maintenance, and instructions on adjustments that might be necessary under the following circumstances:

1.when providing patients with new vials;

2.during seasonal exposure to allergens that are in the patient's allergen vaccine, to which the patient is very sensitive, or both;

3.if the patient has missed injections; and

4.when reactions occur to the allergen immunotherapy extract.

Any systemic reaction to allergen immunotherapy should be treated immediately, and the physician who prepared the allergen immunotherapy extract should be informed. This might require a return to the allergist/immunologist's office for treatment and re-evaluation.

Home administration 

Summary Statement 62: In rare and exceptional cases, when allergen immunotherapy cannot be administered in a medical facility and withholding this therapy would result in a serious detriment to the patients' health (eg, VIT for a patient living in a remote area), very careful consideration of potential benefits and risks of at-home administration of allergen immunotherapy should be made on an individual patient basis. If this approach is used, informed consent should be obtained from the patient, and the person administering the injection to the patient must be educated about how to administer immunotherapy and recognize and treat anaphylaxis. D

Allergen immunotherapy should be administered in a medical facility with trained staff and medical equipment capable of recognizing and treating anaphylaxis. Under rare circumstances, when the benefit of allergen immunotherapy clearly outweighs the risk of withholding immunotherapy (eg, patients with a history of venom anaphylaxis living in a remote region), at-home administration of allergen immunotherapy can be considered on an individual basis. In this instance there should be a discussion with the patient with very careful consideration of the potential benefits and risks involved in home administration and alternatives. Informed consent should be obtained from the patient and appropriate family members after this discussion. Under these circumstances, another adult person should be fully trained to administer the injection and to treat anaphylaxis if this should occur. It should be noted, however, that the package insert approved by the FDA that accompanies all allergen extracts, including venom, implies that allergy injections should be administered in a clinical setting under the supervision of a physician. Intuitively, the risk from administering allergenic extracts outside a clinical setting would appear to be greater. Recognition and treatment of anaphylaxis might be delayed or less effective than in a clinical setting in which supports (personnel, medications, supplies, and equipment) are more optimal for encouraging prompt recognition and treatment of anaphylaxis (Table V). Home administration should only be considered in the rare circumstance when the benefit of immunotherapy clearly outweighs the risks. Frequent or routine prescription of home immunotherapy is not appropriate under any circumstances.

Summary Statement 63: If a patient on immunotherapy transfers from one physician to another, a decision must be made by the physician to whom the patient has transferred as to whether to continue immunotherapy. If immunotherapy is continued, a decision must then be made about whether to continue an unchanged immunotherapy program initiated by the previous physician or to prepare a new immunotherapy program. D

Summary Statement 64: If a patient transfers from one physician to another and continues on an immunotherapy program without changes to either the schedule or allergen immunotherapy extract, the risk of a systemic reaction is not substantially increased. D

Summary Statement 65: A full, clear, and detailed documentation of the patient's schedule must accompany a patient when he or she transfers responsibility for their immunotherapy program from one physician to another. In addition, a record of previous response to and compliance with this program should be communicated to the patient's new physician. D

Summary Statement 66: An allergen immunotherapy extract must be considered different from a clinical standpoint if there is any change in the constituents of the extract. These include changes in the lot, manufacturer, allergen extract type (eg, aqueous, glycerinated, standardized, and nonstandardized), and/or components or relative amounts in the mixture. D

Summary Statement 67: There is an increased risk of a systemic reaction in a patient who transfers from one physician to another if the immunotherapy extract is changed because of the significant variability in content and potency of allergen extracts. The risk of a systemic reaction with a different extracts might be greater with nonstandardized extracts and with extracts that contain mixtures of allergens. D

Summary Statement 68: Immunotherapy with a different extract should be conducted cautiously. If there is inadequate information to support continuing with the previous immunotherapy program, re-evaluation might be necessary, and a new schedule and allergen immunotherapy extract might need to be prepared. D

Patients often transfer from one physician (previous physician) to another (current physician) while receiving allergen immunotherapy. When this occurs, a decision must be made by the current physician about whether to continue immunotherapy and, if so, what allergen immunotherapy extract and schedule should be used: the one that the patient brought from the previous physician (ie, an unchanged immunotherapy program) or one to be prepared by the current physician (ie, a new immunotherapy program).

If the patient transfers from one physician to another and continues on the previous immunotherapy program without changing either the schedule or allergen immunotherapy extract, he or she is not at substantially increased risk of having systemic reactions as long as there is a full, clear, and detailed documentation of the patient's previous schedule and the contents of the allergen immunotherapy extract (see Appendix 7, Appendix 8, Appendix 11, Appendix 12, Appendix 14 for examples of allergen immunotherapy prescription and administration forms and documentation guidelines for allergen immunotherapy forms). In addition, the patient's previous response to and compliance with this program must accompany the patient who transfers responsibility for the immunotherapy program from one physician to another. This should include a record of any reactions to immunotherapy and how they were managed, as well as the patient's response to immunotherapy. Under these circumstances, immunotherapy can be continued with the allergen immunotherapy extract that the patient was previously receiving if (1) the previous physician is willing and able to continue to provide the patient with a schedule and the allergen immunotherapy extract, (2) the patient has shown significant improvement on this immunotherapy program, and (3) the contents of the allergen immunotherapy extract are appropriate for the area in which the patient is now living.

An allergen immunotherapy extract must be considered different from a clinical standpoint if there is any change in the constituents of the allergen immunotherapy extract. These include changes in the lot, manufacturer, vaccine type (eg, aqueous, glycerinated, standardized, and nonstandardized), and component allergens and their respective concentrations in the allergen immunotherapy extract. There is increased risk of a systemic reaction if the allergen immunotherapy extract is changed and the patient's dose is not modified. This increased risk is due to the significant variability in content and potency of extracts and the variability in methods used by physicians to prepare the patient's maintenance concentrate and its dilutions. For example, the strength of a given concentration of nonstandardized extracts might vary significantly from vial to vial. The risk of systemic reactions in such a situation might be greater with nonstandardized extracts and allergen immunotherapy extracts that contain mixtures of allergens.

Therefore if the allergen immunotherapy extract is to be changed, the patient might need to be retested for specific IgE to the appropriate allergens and started on an immunotherapy schedule and immunotherapy extract formulation that is appropriate. In this situation the starting dose should be comparable with the initial dose that would be used if the patient had not previously been receiving immunotherapy. If the information that accompanies the patient is thorough, the current physician can prepare an allergen immunotherapy extract identical or almost identical to that provided by the previous physician. In such a case, all that might be required is a decrease in the dose from the patient's previous injection provided the interval of time since the last injection has not been too long. For lot changes from the same manufacturer, the physician can consider decreasing the dose by 50% to 90%. For changes in manufacturer and nonstandardized extracts, a greater decrease in dose might be necessary.

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Special considerations in immunotherapy 

Allergen immunotherapy in children 

Summary Statement 69: Immunotherapy for children is effective and often well tolerated. Therefore immunotherapy should be considered (along with pharmacotherapy and allergen avoidance) in the management of children with allergic rhinitis, allergic rhinoconjunctivitis, allergic asthma, and stinging insect hypersensitivity. It might prevent the new onset of allergen sensitivities or progression to asthma. A

Immunotherapy for children has been shown to be effective and often well tolerated,137, 242 although at least one study did not show efficacy.293 However, this study did not include an important allergen, cockroach, which has been shown to correlate with asthma severity in other studies of inner-city asthmatic children.294 In general, the clinical indications for immunotherapy for allergic rhinitis and asthma are similar for adults and children (see the Patient selection section and Table VII). In recent studies children receiving allergen immunotherapy have demonstrated:

1.improvement in symptom control for asthma117, 119, 121, 122 and allergic rhinitis118;

2.increased PC20 to histamine121;

3.increased PC20 to cat and house dust mite allergens121, 149;

4.decreased risk of development of asthma6, 9, 163, 164, 165;

5.decreased development of new sensitivities120, 166; and

6.modification in release of mediators in children receiving immunotherapy that correlates with decreased clinical symptoms.123

Summary Statement 70: Children under 5 years of age can have difficulty cooperating with an immunotherapy program. Therefore the physician who evaluates the patient must consider the benefits and risks of immunotherapy and individualize treatment in patients under the age of 5 years. A

Although there is some disagreement about the role of allergen immunotherapy in children under the age of 5 years, there have been reports of effectiveness of allergen immunotherapy in this age group.117, 122 In children with allergic rhinitis, allergen immunotherapy might prevent the development of asthma.6, 9, 163, 164, 165 However, allergen immunotherapy for inhalant allergens is usually not considered necessary in infants and toddlers because (1) there is difficulty in communicating with the child regarding systemic reactions, and (2) injections can be traumatic to very young children. Therefore each case should be considered individually by weighing the benefits and risks. For children who have had a history of anaphylaxis to stinging insects or have severe allergic disease, the benefits of allergen immunotherapy might outweigh the risks.

Immunotherapy in pregnancy 

Summary Statement 71: Allergen immunotherapy might be continued but is usually not initiated in the pregnant patient. C

The physician must be aware of the benefits and risks of immunotherapy in pregnant patients. The recommended precautions for prevention of adverse reactions are especially important in the pregnant patient. Allergen immunotherapy is effective in the pregnant patient. Thus allergen immunotherapy maintenance doses can be continued during pregnancy. Allergen immunotherapy is usually not initiated during pregnancy because of risks associated with systemic reactions and their treatment (ie, spontaneous abortion, premature labor, or fetal hypoxia). The initiation of immunotherapy might be considered during pregnancy when the clinical indication for immunotherapy is a high-risk medical condition, such as anaphylaxis caused by Hymenoptera hypersensitivity. When a patient receiving immunotherapy reports that she is pregnant, the dose of immunotherapy is usually not increased, and the patient is maintained on the dose that she is receiving at that time.

Immunotherapy in the elderly patient 

Summary Statement 72: Comorbid medical conditions and certain medication use might increase the risk from immunotherapy in elderly patients. Therefore special consideration must be given to the benefits and risks of immunotherapy in this patient population. D

Immunotherapy might be considered in the treatment of the elderly patient, but the benefit/risk assessment must be evaluated carefully in this population. Older patients might be taking medications that could make treatment of anaphylaxis with epinephrine more difficult, such as β-blockers, or might have significant comorbid medical conditions, such as hypertension, coronary artery disease, cerebrovascular disease, and/or cardiac arrhythmias. However, elderly patients may also benefit from allergen immunotherapy and age alone should not preclude the consideration of allergen immunotherapy.295

Immunotherapy in patients with immunodeficiency and autoimmune disorders 

Summary Statement 73: Immunotherapy can be considered in patients with immunodeficiency and autoimmune disorders. D

There are no controlled studies about the effectiveness or risks associated with immunotherapy in patients with immunodeficiency or autoimmune disorders. Therefore the decision to begin immunotherapy in patients with major humoral or cellular immune defects must be individualized. Concern about the increased risk of immunotherapy in such patients is largely hypothetical.

Although concern about the safety of allergen immunotherapy in patients with autoimmune disease or connective tissue disease has been raised in the past, there is no substantive evidence that such treatment is harmful in these diseases. Therefore the benefits and risks of allergen immunotherapy in patients with autoimmune or connective tissue must be assessed on an individual basis.

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Alternative routes of immunotherapy 

Sublingual and oral immunotherapy 

Summary Statement 74: Optimal high-dose sublingual swallow and oral immunotherapies are under clinical investigation in the United States. Studies of oral immunotherapy have demonstrated conflicting results. High-dose sublingual immunotherapy has been found to be effective in many studies of adults and children with allergic rhinitis and asthma, but a consistent relationship among allergen dose, treatment duration, and clinical efficacy has not been established. However, there is no FDA-approved formulation for sublingual or oral immunotherapy in the United States. Therefore sublingual and oral immunotherapy should be considered investigational at this time. B

Alternative routes of administration of allergen immunotherapy are “a viable alternative to parenteral injection therapy” in some cases.106, 296 Studies of oral immunotherapy have provided conflicting results for ragweed,297 birch,298 and cat299 immunotherapy. The present dosage of oral immunotherapy extract is 20 to 200 times the parenteral injected dosage, which requires a cost assessment for this type of therapy. Furthermore, adverse effects have included gastrointestinal and oral reactions (50% in 1 study) that might preclude home therapy. Oral immunotherapy should be considered investigational at this time.

Optimal-dose (high-dose) sublingual swallow immunotherapy is effective in adults and children.300, 301, 302, 303, 304 In a study of 855 patients with grass pollen allergy and allergic rhinitis randomized to placebo or one of 3 grass tablet doses, there was a significant reduction in symptom and medication scores in the highest-dose subgroup, who were treated for at least 8 weeks before the grass pollen season, compared with the placebo group (symptoms, 21%, P = .0020; medication use, 29%, P = .0120).303

Sublingual allergen studies have evaluated house dust, olive pollen, grass pollen, ragweed, birch, cat, latex, Alternaria species, and Parietaria judaica.305, 306, 307, 308, 309, 310, 311, 312, 313 Sublingual immunotherapy has been shown to be effective in patients sensitized to 2 non–cross-reacting allergens, grass and birch.314 It has been noted that the allergen is not degraded by saliva and that there is no direct sublingual absorption of allergen. Radiolabeled allergen has been detected after 48 hours in the sublingual region.315, 316 Alternative protocols, such as rush and ultrarush (20 minutes) sublingual swallow307, 316, 318 and no induction (build-up) phase,301, 303, 317, 319, 320 have been studied. Several studies have suggested a relationship between dose and efficacy with sublingual immunotherapy,303, 310, 321 but a consistent relationship among allergen dose, treatment duration, and clinical efficacy has not been established. The majority of sublingual studies have demonstrated some evidence of clinical efficacy in the form of either improved symptom scores, medication scores, or both, but approximately 35% of the randomized, double-blind, placebo-controlled studies did not demonstrate efficacy in either parameter during the first year of treatment.322 Further studies are needed to confirm the optimal dose for sublingual immunotherapy.

One of the potential advantages of sublingual immunotherapy is that it appears to be safe, even at very high doses (up to 500 times the usual monthly subcutaneous dose), and to be associated with a lower incidence of serious side effects.310, 320, 323 This appears to apply to young children (<5 years), for whom there are prospective safety data324, 325 and a postmarketing survey.326

There have been no SLIT-related fatalities, but there have been 3 case reports of anaphylaxis caused by sublingual immunotherapy. One patient with latex hypersensitivity had anaphylactic shock 20 minutes after reaching the maximal dose on the fourth day of latex rush sublingual rush immunotherapy.327

The other 2 reported cases of SLIT anaphylaxis involved patients treated with multiple inhalant allergens. In one case a patient with allergic rhinitis and asthma who was prescribed a sublingual immunotherapy extract composed of multiple non–cross-reacting allergens (Alternaria species, dog, cat, ragweed mix, weed mix, and grass mix)328 had generalized pruritis, followed by angioedema, shortness of breath, and dizziness, within a few minutes of administering 6 drops of the 1:100 vol/vol dilution on the third day of treatment. This episode was preceded by a milder systemic reaction the previous day (generalized pruritis). In the other case, a 13-year-old girl with allergic rhinitis and asthma had swelling of her lower lip 3 minutes after pollen drops, high fever, chest pain, nausea, and abdominal pain.329 She was treated in the emergency department for anaphylaxis and hospitalized for observation. The reaction occurred 1 month after she had reached the maintenance dose during the peak of the spring season.

There is currently no FDA-approved formulation for sublingual immunotherapy in the United States at this time, and this modality should be considered investigational. Current investigation of sublingual immunotherapy should not be confused with low-dose sublingual immunotherapy based on provocation neutralization testing or Rinkel-type skin testing.

Intranasal immunotherapy 

Summary Statement 75: Intranasal immunotherapy is undergoing evaluation in children and adults with allergic rhinitis, but there is no FDA-approved formulation for this modality in the United States. B

Based on controlled, well-designed studies, intranasal immunotherapy has been shown to improve the nasal symptoms of rhinitis.330 Intranasal dry powder extract immunotherapy has been studied in grass,330 birch,331 P judaica,332, 333, 334 and house dust mite335 allergy. Clinical efficacy was noted in all of these studies. Nasal reactivity to allergen challenge was reduced, and only minor side effects were noted in 2 of the above studies. A 3-year study with P judaica reported to provide persistent benefits for up to 12 months after conclusion of allergen immunotherapy.333 Local administration of nasal allergen in an aqueous solution for immunotherapy might be limited by the local side effects. Further studies in both pediatric and adult groups are needed. In human studies the antigen has been noted to appear in the serum within 15 to 30 minutes of administration, with a peak level occurring within 2 to 3 hours.315 Some allergens have been reported to be retained in the nasal mucosa for up to 48 hours after administration. Intranasal immunotherapy is not currently available in the United States but has gained some acceptance in other parts of the world.

Immunotherapy techniques that are not recommended 

Summary Statement 76: Low-dose immunotherapy, enzyme-potentiated immunotherapy, and immunotherapy (parenteral or sublingual) based on provocation-neutralization testing are not recommended. D

Low-dose regimens, including coseasonal low-dose immunotherapy for aeroallergens and the Rinkel low-dose titration techniques, are not effective.27, 28 Immunotherapy based on provocation–neutralization testing with food and aeroallergens and enzyme-potentiated desensitization is not effective.336

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Future trends in immunotherapy 

Therapy with aeroallergen extracts will become more uniform (as is the current practice for insect venoms) as greater numbers of biologically standardized allergen extracts become available. The actual number of commercially available allergen extracts will be reduced based on consensus agreements about the regional prevalence of aeroallergens, their cross-allergenicity, and the relevance of their effect on human health in specific locales. Novel routes for more effective, convenient, and safer allergen immunotherapy are being investigated throughout the world.

For example, the sublingual route of administering allergen immunotherapy has been studied extensively in Europe. A meta-analysis confirmed its clinical effectiveness in allergic rhinitis,302 and it has been reported to be effective in asthma as well.337 Sublingual immunotherapy appears to have a very low risk of serious life-threatening systemic side effects, which might allow for home administration.324, 338 In some studies the clinical benefits of sublingual immunotherapy were not significant until the second year of treatment,306, 339 and comparisons suggest that the magnitude of the clinical benefit of sublingual immunotherapy might not be as great as that of subcutaneous immunotherapy.311

Trials with non–IgE-binding peptides containing T-cell stimulating peptides have been reported.340 Site-directed mutagenesis has produced allergens with decreased IgE-binding capacity without decreased T-cell responses.341, 342

Immunostimulatory sequences mimicking bacterial and viral DNA have been prepared that stimulate the innate immune system to direct T-cell responses toward TH1 rather than TH2 phenotypes.343 The results of clinical trials with a conjugate of the immunostimulatory sequence to the major allergen of ragweed, Amb a 1 (AIC), have been reported.34, 343 In a double-blind, placebo-controlled study of 25 adults who received 6 weekly injections of the AIC or placebo vaccine before ragweed season, the AIC group had better peak-season rhinitis scores on the visual analog scale (P = .006), peak-season daily nasal symptom diary scores (P = .02), and midseason overall quality-of-life scores (P = .05) than the placebo group during the first ragweed season, and this effect was observed in the subsequent ragweed season.344

Humanized anti-IgE mAb has been shown to have clinical effects in both allergic rhinitis and asthma.345, 346, 347, 348 Theoretically, this new therapeutic modality could be used as protective cover for clinical applications of rapid forms of immunotherapy. It is possible that preadministration of anti-IgE could provide a more effective protective effect than premedication with antihistamines and therefore permit a rush allergen immunotherapeutic regimen with reduced risk of serious systemic reactions.282

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Author's note 

Examples of allergen immunotherapy prescription and administration forms, immunotherapy labels, conventional and cluster build-up schedules, immunotherapy dose adjustments for unscheduled gaps in allergen immunotherapy injection intervals, summaries of documentation guidelines, systemic reaction reporting sheets, and 2 systemic reaction grading systems (the European Academy of Allergy and Clinical Immunology's grading of severity for systemic side effects and the Portnoy method for numeric grading of reactions to allergen immunotherapy) can be found in the Appendix section. These forms can also be found along with examples of immunotherapy instruction and consent forms, preinjection health questionnaires, and indications for beginning and continuing immunotherapy forms at www.aaaai.org.

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Appendix 1. American College of Medical Quality's policy on the development and use of practice parameters for medical quality decision-making1 

Practice parameters are strategies for patient management developed to assist health care professionals in clinical decision making. Practice parameters include standards, guidelines, and other patient management strategies. Standards are accepted principles for patient management. Guidelines are recommendations for patient management that identify a particular management strategy or a range of management strategies. Other strategies for patient management include practice policies and practice options. Practice parameters are to be used as screening tools to identify possible deviations from the applicable standards of care. Such parameters are not to be used as absolute standards or to profile or report on health care personnel. Parameters are designed to trigger a process in which possible deviations from the standard of care are identified as outlier practice patterns. Once a deviation from the parameter is identified, such a deviation should be referred to the appropriate qualified physician advisor or reviewer for a determination of medical necessity that conforms to the applicable standard of care. Parameters used in the day-to-day practice of clinical medicine should be clinically relevant. They should not be considered as substitutes for the standard of care but might contribute to its formulation.
Practice parameters must be developed, designed, and implemented only by board-certified, clinically practicing, specialty-matched physician advisors/reviewers with unrestricted medical licenses. Qualified nonphysicians might participate in the development of these parameters only in the areas in which their clinical expertise based on the standard of care is applicable. The health care personnel who develop these parameters should sign their names and date the final version as evidence of their participation and support. Practice parameters must be based on sound scientific research findings, professional literature, clinical experience and appropriate well-recognized methodologies and reflect professionally recognized national standards of care practiced in the clinical community of medicine. The development procedures followed, the participants involved, the evidence used, the assumptions and rationales accepted, and the analytic methods used should be meticulously documented, described, and made publicly available for national peer review. Parameters should be updated as needed.
Practice parameters are used as tools to enhance medical decision making but not as replacements for physicians' clinical judgment. They can be considered as means to enhance the performance of clinical and review personnel but not to replace them. It is below the standard of care of the medical review process to substitute qualified physician reviewer experts with unqualified reviewers who are using parameters.

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Appendix 2. Examples of possible abbreviations for allergen immunotherapy extract components 

TreeT
GrassG
BermudaB
WeedsW
RagweedR
MoldM
AlternariaAlt
CladosporiumCla
PenicilliumPcn
CatC
DogD
CockroachCr
Dust miteDM
D farinaeDf
D pteronyssinusDp
MixtureMx

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Appendix 3. Example of a build-up schedule for weekly immunotherapy 

Dilution (vol/vol)Volume (mL)
1:10000.05
0.10
0.20
0.40
1:1000.05
0.10
0.20
0.30
0.40
0.50
1:100.05
0.07
0.10
0.15
0.25
0.35
0.40
0.45
0.50
Maintenance concentrate0.05
0.07
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50

Dilutions are expressed as vol/vol from the maintenance concentrate.

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Appendix 4. Example of immunotherapy dose adjustments for unscheduled gaps in allergen immunotherapy injection intervals (modification of the AAAAI skin testing and immunotherapy consent and instruction forms: immunotherapy administration instruction form, which can be found at http://www.aaaai.org) 

Build-up phase for weekly or biweekly injections (time intervals from missed injection)
• Up to 7 days, continue as scheduled (ie, if on weekly build-up, then it would be up to 14 days after administered injection or 7 days after the missed scheduled injection).
• Eight to 13 days after missed scheduled injection; repeat previous dose.
• Fourteen to 21 days after missed scheduled injection; reduce dose 25%.
• Twenty-one to 28 days after missed scheduled injection; reduce previous dose 50%.
Then increase dose each injection visit as directed on the immunotherapy schedule until therapeutic maintenance dose is reached.
This suggested approach to modification of doses of allergen immunotherapy because of gaps between treatment during the build-up phase is not based on retrospective or prospective published evidence, but it is presented as a sample for your consideration. The individual physician should use this or a similar protocol as a standard operating procedure for the specific clinical setting. A similar dose-reduction protocol should be developed for gaps in maintenance immunotherapy.

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Appendix 5. Example of a cluster immunotherapy schedule22, 26 

VisitDose (mL)Concentration as dilution of maintenance vial
10.101:1000 vol/vol
0.401:1000 vol/vol
0.101:100 vol/vol
20.201:100 vol/vol
0.401:100 vol/vol
0.071:10 vol/vol
30.101:10 vol/vol
0.151:10 vol/vol
0.251:10 vol/vol
40.351:10 vol/vol
0.501:10 vol/vol
50.071:1 vol/vol
0.101:1 vol/vol
60.151:1 vol/vol
0.201:1 vol/vol
70.301:1 vol/vol
0.401:1 vol/vol
80.501:1 vol/vol

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Appendix 6. Recommended documentation for allergen immunotherapy prescription forms 

The purpose of the allergen immunotherapy prescription form is to define the contents of the allergen immunotherapy extract in enough detail that it could be precisely duplicated. The following information should be on an immunotherapy prescription form:
Patient information:
• Patient name, patient number (if applicable), birth date, telephone number, and picture (if available) should be included.
Preparation information:
• Name of person and signature preparing the allergen immunotherapy extract should be included.
• Date of preparation should be recorded.
• Bottle name should be included (eg, trees and grass). If abbreviations are used, a legend should be included to describe the meaning of the abbreviations.
Allergen immunotherapy extract content information:
• The following information for each allergen should be included on the form in a separate column:
Content of the allergen immunotherapy extract, including common name or genus and species of individual antigens and detail of all mixes, should be included.
• Concentration of available manufacturer's extract should be included.
• Volume of manufacturer's extract to add to achieve the projected effective concentration should be included. This can be calculated by dividing the projected effective concentration by the concentration of available manufacturer's extract times the total volume.
• The type of diluent (if used) should be included.
• Extract manufacturer should be included.
• Lot number should be included.
• Expiration date should be recorded and should not exceed the expiration date of any of the individual components.

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Appendix 7. Allergen immunotherapy extract prescription form 

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Appendix 8. Maintenance concentrate prescription form 

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Appendix 9. Labels for allergen immunotherapy extracts 

Each vial of allergen immunotherapy extract should be labeled in a way that permits easy identification. Each label should include the following information (example in Fig 3, Fig 4):
• Appropriate patient identifiers might include the patient's name, patient's number, patient's picture, and birth date.
• The contents of the allergen immunotherapy extract in a general way should be included. The detail with which this can be identified depends on the size of the label and the number of allergens in the vial. Ideally, allergens should be identified as trees, grasses, weeds, mold, dust mite, cockroach, cat, and dog. Because of space limitations, it might be necessary to abbreviate the antigens (eg, T, G, W, M, DM, Cr, C, and D respectively [see Appendix 2]). A full and detailed description of vial contents should be recorded on the prescription/content form.
• The dilution from the maintenance concentrate (vol/vol) should be recorded. If colors, numbers, or letters are used to identify the dilution, they also should be included.
• The expiration date should be included.

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Appendix 10. Allergen immunotherapy administration form recommended documentation 

The purpose of the allergen immunotherapy administration form is to document the administration of the allergen immunotherapy extract to a patient. Its design should be clear enough so that the person administering an injection is unlikely to make an error in administration. It also should provide documentation in enough detail to determine what was done on each visit. The following recommendations on allergen immunotherapy are taken from The Joint Task Force on Practice Parameters.
Patient information:
• Patient's name, date of birth, telephone number, and patient's picture (optional but helpful).
Allergen immunotherapy extract information:
• Allergen immunotherapy extract name and dilution from maintenance in vol/vol bottle letter (eg, A and B), bottle color, or number, if used.
• Expiration date of all dilutions.
Administration information in separate columns:
• Date of injection.
• Arm administered injection, which might facilitate determination of exact cause of local reaction.
• Projected build-up schedule.
• Delivered volume reported in milliliters.
• Description of any reactions. The details of any treatment given in response to a reaction would be documented elsewhere in the medical record and referenced on the administration form.
• Patient's health before injection. This can be performed through a verbal or written interview of the patient before administering the immunotherapy injection. The patient should be questioned about increased asthma or allergy symptoms, β-blocker use, change in health status (including pregnancy and recent infections), or an adverse reaction to a previous injection (including delayed large local reactions persisting through the next day). Patients with significant systemic illness generally should not receive an injection.
• Antihistamine use. Antihistamines are frequently a component of an allergy medication regimen, and it would be important to note whether a patient is taking an antihistamine on the day he or she receives his or her immunotherapy injection. For consistency in interpretation of reactions, it might be desirable for a patient to either take or avoid antihistamines on a regular basis on the days he or she receives immunotherapy. The physician should note on the form whether he or she recommends the patient consistently take an antihistamine on immunotherapy treatment days.
• Peak flow reading. Consider obtaining a peak expiratory flow rate measurement before administering an immunotherapy injection to asthmatic patients. Poorly controlled asthma is considered a risk factor for immunotherapy. Obtaining a peak expiratory flow rate measurement before the immunotherapy injection might help identify patients with symptomatic asthma. The patient's baseline peak expiratory flow rate should be provided on the form as a reference. Health care professionals administering immunotherapy injections should be provided with specific guidelines about the peak expiratory flow rate measurement for when an immunotherapy injection should be withheld and the patient referred for clinical evaluation.
• Baseline blood pressure. It might be useful to record the patient's blood pressure as a baseline for future reference.

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Appendix 11. Allergen immunotherapy administration form 

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Appendix 12. Health screen record 

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Appendix 13. Allergen immunotherapy informed consent 

•Documentation that informed consent has been obtained.•Informed consent is a process by which a patient and physician discuss various aspects of a proposed treatment. Although many allergists use a written consent form before starting immunotherapy, a reasonable alternative is simply to document the consent process in the medical record. The consent process usually consists of the following:
•what the treatment is and alternatives to the treatment;
•potential benefits to be expected from the treatment;
•potential risks, including a fair description of how frequently they are likely to occur, if known, including the possibility of death;
•costs associated with immunotherapy and who pays for them;
•the anticipated duration of treatment; and
•any specific office policies that affect treatment.
•Since the informed consent process is complex and details might vary from state to state, each allergist/immunologist should decide how they should document informed consent. Legal advice might be useful.

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Appendix 14. Allergen immunotherapy systemic reaction/anaphylaxis treatment record 

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Appendix 15. Grading severity of allergen immunotherapy reactions: Two methods 

1. The European Academy of Allergy and Clinical Immunology grading of severity for systemic side effects∗
Classification of systemic reactions
0 = No symptoms or nonspecific symptoms
I = Mild systemic reactions: symptoms—localized urticaria, rhinitis, or mild asthma (PF <20% decrease from baseline).
II = Moderate systemic reaction: symptoms—slow onset (>15 minutes) of generalized urticaria, moderate asthma, or both (PF < 40% decrease from baseline).
III = Severe (non–life-threatening) systemic reactions: symptoms—rapid onset (<15 minutes) of generalized urticaria, angioedema, or severe asthma (PF > 40% decrease from baseline).
IV = Anaphylactic shock: symptoms—immediate evoked reaction of itching, flushing, erythema, generalized urticaria, stridor (angioedema), immediate asthma, and hypotension, for example.
2. Portnoy method for numeric grading of reactions to allergen immunotherapy†
Local
0+ = No significant reaction or small area of erythema less than the size of a half dollar without swelling or wheal formation
1+ = Erythema greater than the size of a half dollar, swelling or wheal formation, or both
Systemic
2+ = Systemic reactions: cutaneous only—might consist of a cutaneous eruption, such as urticaria
3+ = Systemic reaction: generalized pruritus, sneezing, or both—might consist of increased allergy symptoms, such as nasal congestion, sneezing, or pruritus, especially in the mouth or throat
4+ = Systemic reaction: pulmonary—consists of wheezing, shortness of breath, and tightness. Might be associated with decreased pulmonary function tests
5+ = Systemic reaction: anaphylaxis—a sensation of not feeling right is a frequent prelude; might consist of hypotension, laryngeal edema, severe wheezing, and cramping
6+ = Cardiopulmonary arrest

PF, Peak expiratory flow.

∗Subcutaneous immunotherapy. Allergy 2006;61(suppl 82):5-13.

†Sharkey P, Portnoy J. Rush immunotherapy: experience with a one-day schedule. Ann Allergy Asthma Immunol 1996;76:175-80.

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References 

  1. American College of Medical Quality's policy on development and use of practice parameters for medical quality decision-making. Available at: http://www.acmq.orq/profess/PDFs/policy5.pdf. Accessed September 26, 2006.
  2. American Academy of Allergy, Asthma and Immunology , American College of Allergy, Asthma and Immunology . Allergen immunotherapy: a practice parameter. Ann Allergy Asthma Immunol. 2003;90(suppl 1):1–40
  3. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinical guidelines: developing guidelines. BMJ. 1999;318:593–596
  4. Aaronson DW, Gandhi TK. Incorrect allergy injections: allergists' experiences and recommendations for prevention. J Allergy Clin Immunol. 2004;113:1117–1121III
  5. Joint Commission National Patient Safety Goals. Available at: http://www.jointcommission.org/PatientSafety/NationalPatientSafetyGoals/. Accessed December 26, 2006.
  6. Niggemann B, Jacobsen L, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. 2006:855-9. III
  7. Polosa R, Li Gotti F, Mangano G, et al. Effect of immunotherapy on asthma progression, BHR and sputum eosinophils in allergic rhinitis. Allergy. 2004;59:1224–1228III
  8. Polosa R, Al-Delaimy WK, Russo C, Piccillo G, Sarva M. Greater risk of incident asthma cases in adults with allergic rhinitis and effect of allergen immunotherapy: a retrospective cohort study. Respir Res. 2005;6:153;III
  9. Moller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109:251–256Ib
  10. Williams PB, Ahlstedt S, Barnes JH, Soderstrom L, Portnoy J. Are our impressions of allergy test performances correct?. Ann Allergy Asthma Immunol. 2003;91:26–33
  11. Sampson HA, Munoz-Furlong A, Bock SA, et al. Symposium on the definition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005;115:584–591
  12. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115(suppl 2):S483–S523
  13. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341:468–475Ib
  14. Des Roches A, Paradis L, Knani J, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy. 1996;51:430–433III
  15. Kao N. Terminology used for allergen immunotherapy. Ann Allergy Asthma Immunol. 2000;84:273–274
  16. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR, Malling HJ, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy. 2006;61(suppl 82):1–20
  17. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Geneva: January 27-29 1997. Allergy. 1998;53(suppl):1–42
  18. Nicklas RA, Bernstein IL, Blessing-Moore J, et al. Practice parameters for allergen immunotherapy. J Allergy Clin Immunol. 1996;98:1001–1011
  19. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;1:1572–1573
  20. Freeman J. Further observations of the treatment of hay fever by hypodermic inoculations of pollen vaccine. Lancet. 1911;2:814–817
  21. Freeman J. “Rush Inoculation,” with special reference to hay fever treatment. Lancet. 1930;1:744–747
  22. Ewbank PA, Murray J, Sanders K, Curran-Everett D, Dreskin S, Nelson HS. A double-blind, placebo-controlled immunotherapy dose-response study with standardized cat extract. J Allergy Clin Immunol. 2003;111:155–161Ib
  23. Creticos PS, Van Metre TE, Mardiney MR, Rosenberg GL, Norman PS, Adkinson NF. Dose response of IgE and IgG antibodies during ragweed immunotherapy. J Allergy Clin Immunol. 1984;73:94–104Ib
  24. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117:319–325Ib
  25. Lent AM, Harbeck R, Strand M, et al. Immunologic response to administration of standardized dog allergen extract at differing doses. J Allergy Clin Immunol. 2006;118:1249–1256
  26. Nanda A, O'Connor M, Anand M, et al. Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J Allergy Clin Immunol. 2004;114:1339–1344Ib
  27. Van Metre TE, Adkinson NF, Amodio FJ, et al. A comparative study of the effectiveness of the Rinkel method and the current standard method of immunotherapy for ragweed pollen hay fever. J Allergy Clin Immunol. 1980;66:500–513III
  28. Van Metre TE, Adkinson NF, Lichtenstein LM, et al. A controlled study of the effectiveness of the Rinkel method of immunotherapy for ragweed pollen hay fever. J Allergy Clin Immunol. 1980;65:288–297III
  29. Till SJ, Durham SR. Immunological responses to allergen immunotherapy. Clin Allergy Immunol. 2004;18:85–104
  30. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J Allergy Clin Immunol. 2004;113:1025–1035
  31. Durham SR, Ying S, Varney VA, et al. Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. J Allergy Clin Immunol. 1996;97:1356–1365Ib
  32. Evans R, Pence H, Kaplan H, Rocklin RE. The effect of immunotherapy on humoral and cellular responses in ragweed hayfever. J Clin Invest. 1976;57:1378–1385IIa
  33. Hamid QA, Schotman E, Jacobson MR, Walker SM, Durham SR. Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol. 1997;99:254–260IIb
  34. Tulic MK, Fiset PO, Christodoulopoulos P, et al. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response. J Allergy Clin Immunol. 2004;113:235–241Ib
  35. Bellinghausen I, Metz G, Enk AH, Christmann S, Knop J, Saloga J. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol. 1997;27:1131–1139LB
  36. Blaser K, Akdis CA. Interleukin-10, T regulatory cells and specific allergy treatment. Clin Exp Allergy. 2004;34:328–331
  37. Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol. 2003;111:1255–1261LB
  38. Jutel M, Akdis M, Budak F, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003;33:1205–1214IIb
  39. Savolainen J, Laaksonen K, Rantio-Lehtimaki A, Terho EO. Increased expression of allergen-induced in vitro interleukin-10 and interleukin-18 mRNA in peripheral blood mononuclear cells of allergic rhinitis patients after specific immunotherapy. Clin Exp Allergy. 2004;34:413–419IIa
  40. Durham SR, Varney VA, Gaga M, et al. Grass pollen immunotherapy decreases the number of mast cells in the skin. Clin Exp Allergy. 1999;29:1490–1496Ib
  41. Moingeon P, Batard T, Fadel R, Frati F, Sieber J, Overtvelt L. Immune mechanisms of allergen-specific sublingual immunotherapy. Allergy. 2006;61:151–165
  42. Bousquet J, Braquemond P, Feinberg J, Guerin B, Maasch H, Michel FB. Specific IgE response before and after rush immunotherapy with a standardized allergen or allergoid in grass pollen allergy. Ann Allergy. 1986;56:456–459LB
  43. Gleich GJ, Zimmermann EM, Henderson LL, Yunginger JW. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. J Allergy Clin Immunol. 1982;70:261–271IIa
  44. Lichtenstein LM, Ishizaka K, Norman PS, Sobotka AK, Hill BM. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest. 1973;52:472–482IIb
  45. Creticos P, Adkinson NF, Kagey-Sobotka A, et al. Nasal challenge with ragweed pollen in hay fever patients: effect of immunotherapy. J Clin Invest. 1985;76:2247–2253IIb
  46. Rak S, Lowhagen O, Venge P. The effect of immunotherapy on bronchial hyperresponsiveness and eosinophil cationic protein in pollen-allergic patients. J Allergy Clin Immunol. 1988;82:470–480IIb
  47. Sadan N, Rhyne MB, Mellitis ED, Goldstein EO, Levy DA, Lichtenstein LM. Immunotherapy of pollinosis in children. Investigation of the immunologic basis of clinical improvement. N Engl Med. 1969;280:623–627IIa
  48. Varney VA, Hamid QA, Gaga M, et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest. 1993;92:644–651IIb
  49. Ewan PW, Deighton J, Wilson AB, Lachmann PJ. Venom-specific IgG antibodies in bee and wasp allergy: lack of correlation with protection from stings. Clin Exp Allergy. 1993;23:647–660IIb
  50. Djurup R, Malling HJ. High IgG4 antibody level is associated with failure of immunotherapy with inhalant allergens. Clin Allergy. 1987;17:459–468IIb
  51. Michils A, Baldassarre S, Ledent C, Mairesse M, Gossart B, Duchateau J. Early effect of ultrarush venom immunotherapy on the IgG antibody response. Allergy. 2000;55:455–462IIb
  52. Michils A, Mairesse M, Ledent C, Gossart B, Baldassarre S, Duchateau J. Modified antigenic reactivity of anti-phospholipase A2 IgG antibodies in patients allergic to bee venom: conversion with immunotherapy and relation to subclass expression. J Allergy Clin Immunol. 1998;102:118–126IIb
  53. Wachholz PA, Soni NK, Till SJ, Durham SR. Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. J Allergy Clin Immunol. 2003;112:915–922Ib
  54. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998;102:558–562
  55. American Academy of Allergy, Asthma and Immunology (AAAAI) . The use of standardized allergen extracts. J Allergy Clin Immunol. 1997;99:583–586
  56. Nelson HS. The use of standardized extracts in allergen immunotherapy. J Allergy Clin Immunol. 2000;106:41–45
  57. Turkeltaub P. Allergenic extracts. II. In vivo standardization. In:  Middleton E,  Reed CE,  Ellis EF,  Adkinson NF,  Yunginger JW editor. Allergy: principles and practice. 3rd ed.. St Louis: CV Mosby; 1988;p. 388–401
  58. Lombardero M, Carreira J, Duffort O. Monoclonal antibody based radioimmunoassay for the quantitation of the main cat allergen (Fel d I or Cat-1). J Immunol Methods. 1988;108:71–76LB
  59. Ohman JL, Sundin B. Standardized allergenic extracts derived from mammals. Clin Rev Allergy. 1987;5:37–47
  60. Lockey R, Slater J, Esch E. Preparation of standardization of allergen extracts. In:  Adkinson F,  Yunginger J,  Busse W,  Bochner B,  Holgate S,  Simons E editor. Middleton's allergy: principles and practice. 6th ed.. St Louis: Mosby; 2003;p. 573–584
  61. Cabanas R, Lopez-Serrano MC, Carreira J, et al. Importance of albumin in cross-reactivity among cat, dog and horse allergens. J Investig Allergol Clin Immunol. 2000;10:71–77LB
  62. Baer H, Godfrey H, Maloney CJ, Norman PS, Lichtenstein LM. The potency and antigen E content of commercially prepared ragweed extracts. J Allergy. 1970;45:347–354IIb
  63. Baer H, Maloney CJ, Norman PS, Marsh DG. The potency and group I antigen content of six commercially prepared grass pollen extracts. J Allergy Clin Immunol. 1974;54:157–164IIb
  64. Greenert S, Bernstein IL, Michael JG. Immune responses of non-atopic individuals to prolonged immunisation with ragweed extract. Lancet. 1971;2:1121–1123IIb
  65. Modrzynski M, Zawisza E, Moverare R, et al. Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System. Przegl Lek. 2003;60:130–132IIa
  66. Moverare R, Elfman L, Vesterinen E, Metso T, Haahtela T. Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System. Allergy. 2002;57:423–430IIa
  67. Leiferman KM, Gleich GJ. The cross-reactivity of IgE antibodies with pollen allergens. I. Analyses of various species of grass pollens. J Allergy Clin Immunol. 1976;58(suppl):129–139LB
  68. Fahlbusch B, Muller WD, Rudeschko O, Jager L, Cromwell O, Fiebig H. Detection and quantification of group 4 allergens in grass pollen extracts using monoclonal antibodies. Clin Exp Allergy. 1998;28:799–807LB
  69. Gonzalez RM, Cortes C, Conde J, et al. Cross-reactivity among five major pollen allergens. Ann Allergy. 1987;59:149–154LB
  70. Karl S, Rakoski J. Hyposensitization with cross-reacting pollen allergens. Z Hautkr. 1988;63(suppl 4):55–57LB
  71. Leavengood DC, Renard RL, Martin BG, Nelson HS. Cross allergenicity among grasses determined by tissue threshold changes. J Allergy Clin Immunol. 1985;76:789–794III
  72. Lowenstein H. Timothy pollen allergens. Allergy. 1980;35:188–191LB
  73. Martin BG, Mansfield LE, Nelson HS. Cross-allergenicity among the grasses. Ann Allergy. 1985;54:99–104LB
  74. van Ree R, van Leeuwen WA, Aalberse RC. How far can we simplify in vitro diagnostics for grass pollen allergy?: a study with 17 whole pollen extracts and purified natural and recombinant major allergens. J Allergy Clin Immunol. 1998;102:184–190LB
  75. Bernstein IL, Perera M, Gallagher J, Michael JG, Johansson SG. In vitro cross-allergenicity of major aeroallergenic pollens by the radioallergosorbent technique. J Allergy Clin Immunol. 1976;57:141–152LB
  76. Phillips JW, Bucholtz GA, Fernandez-Caldas E, Bukantz SC, Lockey RF. Bahia grass pollen, a significant aeroallergen: evidence for the lack of clinical cross-reactivity with timothy grass pollen. Ann Allergy. 1989;63:503–507IIa
  77. Eusebius NP, Papalia L, Suphioglu C, et al. Oligoclonal analysis of the atopic T cell response to the group 1 allergen of Cynodon dactylon (Bermuda grass) pollen: pre- and post-allergen-specific immunotherapy. Int Arch Allergy Immunol. 2002;127:234–244LB
  78. Blaher B, Suphioglu C, Knox RB, Singh MB, McCluskey J, Rolland JM. Identification of T-cell epitopes of Lol p 9, a major allergen of ryegrass (Lolium perenne) pollen. J Allergy Clin Immunol. 1996;98:124–132LB
  79. Barletta B, Afferni C, Tinghino R, Mari A, Di Felice G, Pini C. Cross-reactivity between Cupressus arizonica and Cupressus sempervirens pollen extracts. J Allergy Clin Immunol. 1996;98:797–804LB
  80. Black J. Cedar hay fever. J Allergy. 1929;1:71–73III
  81. Pham NH, Baldo BA, Bass DJ. Cypress pollen allergy. Identification of allergens and crossreactivity between divergent species. Clin Exp Allergy. 1994;24:558–565LB
  82. Yoo TJ, Spitz E, McGerity JL. Conifer pollen allergy: studies of immunogenicity and cross antigenicity of conifer pollens in rabbit and man. Ann Allergy. 1975;34:87–93III
  83. Lowenstein H. Cross reactions among pollen antigens. Allergy. 1980;35:198–200LB
  84. Weber RW. Cross-reactivity of pollen allergens. Curr Allergy Asthma Rep. 2004;4:401–408III
  85. Zetterstrom O, Fagerberg E, Wide L. An investigation of pollen extracts from different deciduous trees in patients with springtime allergy in Sweden. Acta Allergol. 1972;27:15–21III
  86. Eriksson NE, Wihl JA, Arrendal H, Strandhede SO. Tree pollen allergy. III. Cross reactions based on results from skin prick tests and the RAST in hay fever patients. A multi-centre study. Allergy. 1987;42:205–214LB
  87. Niederberger V, Pauli G, Gronlund H, et al. Recombinant birch pollen allergens (rBet v 1 and rBet v 2) contain most of the IgE epitopes present in birch, alder, hornbeam, hazel, and oak pollen: a quantitative IgE inhibition study with sera from different populations. J Allergy Clin Immunol. 1998;102:579–591LB
  88. White JF, Bernstein DI. Key pollen allergens in North America. Ann Allergy Asthma Immunol. 2003;91:425–43692
  89. Bousquet J, Guerin B, Hewitt B, Lim S, Michel FB. Allergy in the Mediterranean area. III: cross reactivity among Oleaceae pollens. Clin Allergy. 1985;15:439–448LB
  90. Kernerman SM, McCullough J, Green J, Ownby DR. Evidence of cross-reactivity between olive, ash, privet, and Russian olive tree pollen allergens. Ann Allergy. 1992;69:493–496III
  91. Leiferman KM, Gleich GJ, Jones RT. The cross-reactivity of IgE antibodies with pollen allergens. II. Analyses of various species of ragweed and other fall weed pollens. J Allergy Clin Immunol. 1976;58(suppl):140–148LB
  92. Yunginger JW, Gleich GJ. Measurement of ragweed antigen E by double antibody radioimmunoassay. J Allergy Clin Immunol. 1972;50:326–337LB
  93. Asero R, Weber B, Mistrello G, Amato S, Madonini E, Cromwell O. Giant ragweed specific immunotherapy is not effective in a proportion of patients sensitized to short ragweed: analysis of the allergenic differences between short and giant ragweed. J Allergy Clin Immunol. 2005;116:1036–1041IIa
  94. Katial RK, Lin FL, Stafford WW, Ledoux RA, Westley CR, Weber RW. Mugwort and sage (Artemisia) pollen cross-reactivity: ELISA inhibition and immunoblot evaluation. Ann Allergy Asthma Immunol. 1997;79:340–346LB
  95. Lewis W, Vinay P, Zenger VE. Airborne and allergenic pollen of North America. Baltimore (MD): The John Hopkins University Press; 1983;
  96. Barderas R, Villalba M, Lombardero M, Rodriguez R. Identification and characterization of Che a 1 allergen from Chenopodium album pollen. Int Arch Allergy Immunol. 2002;127:47–54LB
  97. Gomez J, Mansfield LE, Frederick RW, Rael ED. Analysis of the individual allergens of Russian thistle pollen by an enzyme-linked immunoblotting technique. J Asthma. 1989;26:243–250LB
  98. Shafiee A, Yunginger JW, Gleich GJ. Isolation and characterization of Russian thistle (Salsola pestifer) pollen allergens. J Allergy Clin Immunol. 1981;67:472–481LB
  99. Weber RW, Nelson HS. Pollen allergens and their interrelationships. Clin Rev Allergy. 1985;3:291–318III
  100. Weber RW NH. Chenopod-Amaranth cross-allergenicity: evaluated by RAST inhibition. Ann Allergy 1984;52:226. LB
  101. Weber R. Cross-reactivity among Chenopod-Amaranth weeds: skin test correlation. Ann Allergy. 1987;58:287;LB
  102. Helm RM, Squillace DL, Jones RT, Brenner RJ. Shared allergenic activity in Asian (Blattella asahinai), German (Blattella germanica), American (Periplaneta americana), and Oriental (Blatta orientalis) cockroach species. Int Arch Allergy Appl Immunol. 1990;92:154–161LB
  103. Jeong KY, Lee J, Lee IY, Ree HI, Hong CS, Yong TS. Allergenicity of recombinant Bla g 7, German cockroach tropomyosin. Allergy. 2003;58:1059–1063LB
  104. Abramson MJ, Puy MR, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med. 1995;151:969–974Ia
  105. Bousquet J, Lockey R, Malling HJ, et al. Allergen immunotherapy: therapeutic vaccines for allergic diseases. World Health Organization. American Academy of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998;81:401–405
  106. Lockey RF. “ARIA”: global guidelines and new forms of allergen immunotherapy. J Allergy Clin Immunol. 2001;108:497–499
  107. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis. Clin Ther. 2000;22:342–350Ia
  108. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of Hymenoptera venom hypersensitivity: a meta-analysis. Clin Ther. 2000;22:351–358Ia
  109. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther. 2000;22:329–341Ia
  110. Portnoy JM. Immunotherapy for asthma: unfavorable studies. Ann Allergy Asthma Immunol. 2001;87(suppl 1):28–32
  111. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev. 2003;CD001186. Ia
  112. Lowell FC, Franklin W. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl J Med. 1965;273:675–679Ib
  113. Pichler CE, Helbling A, Pichler WJ. Three years of specific immunotherapy with house-dust-mite extracts in patients with rhinitis and asthma: significant improvement of allergen-specific parameters and of nonspecific bronchial hyperreactivity. Allergy. 2001;56:301–306IIb
  114. Aas K. Hyposensitization in house dust allergy asthma. A double-blind controlled study with evaluation of the effect on bronchial sensitivity to house dust. Acta Paediatr Scand. 1971;60:264–268Ib
  115. Bonno M, Fujisawa T, Iguchi K, et al. Mite-specific induction of interleukin-2 receptor on T lymphocytes from children with mite-sensitive asthma: modified immune response with immunotherapy. J Allergy Clin Immunol. 1996;97:680–688IIa
  116. Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM. A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med. 1978;299:157–161IIa
  117. Cantani A, Arcese G, Lucenti P, Gagliesi D, Bartolucci M. A three-year prospective study of specific immunotherapy to inhalant allergens: evidence of safety and efficacy in 300 children with allergic asthma. J Investig Allergol Clin Immunol. 1997;7:90–97IIa
  118. Cantani A, Micera M. Is specific immunotherapy safe and effective in children?. Eur Rev Med Pharmacol Sci. 2000;4:139–143IV
  119. Cools M, Van Bever HP, Weyler JJ, Stevens WJ. Long-term effects of specific immunotherapy, administered during childhood, in asthmatic patients allergic to either house-dust mite or to both house-dust mite and grass pollen. Allergy. 2000;55:69–73IIa
  120. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures JP, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol. 1997;99:450–453III
  121. Hedlin G, Wille S, Browaldh L, et al. Immunotherapy in children with allergic asthma: Effect on bronchial hyperreactivity and pharmacotherapy. J Allergy Clin Immunol. 1999;103:609–614Ib
  122. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children—a 14-year study. Pediatrics. 1968;42:793–802Ib
  123. Ohashi Y, Nakai Y, Tanaka A, et al. Serologic study of the working mechanisms of immunotherapy for children with perennial allergic rhinitis. Arch Otolaryngol Head Neck Surg. 1998;124:1337–1346III
  124. Portnoy JM. Immunotherapy for allergic diseases. Clin Rev Allergy Immunol. 2001;21:241–259
  125. Ariano R, Kroon AM, Augeri G, Canonica GW, Passalacqua G. Long-term treatment with allergoid immunotherapy with Parietaria. Clinical and immunologic effects in a randomized, controlled trial. Allergy. 1999;54:313–319Ib
  126. Bousquet J, Becker WM, Hejjaoui A, et al. Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species. II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts. J Allergy Clin Immunol. 1991;88:43–53Ib
  127. Bousquet J, Hejjaoui A, Skassa-Brociek W, et al. Double-blind, placebo-controlled immunotherapy with mixed grass-pollen allergoids. I. Rush immunotherapy with allergoids and standardized orchard grass-pollen extract. J Allergy Clin Immunol. 1987;80:591–598Ib
  128. Creticos PS, Marsh DG, Proud D, et al. Responses to ragweed-pollen nasal challenge before and after immunotherapy. J Allergy Clin Immunol. 1989;84:197–205Ib
  129. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med. 1996;334:501–506Ib
  130. Dolz I, Martinez-Cocera C, Bartolome JM, Cimarra M. A double-blind, placebo-controlled study of immunotherapy with grass-pollen extract Alutard SQ during a 3-year period with initial rush immunotherapy. Allergy. 1996;51:489–500Ib
  131. Franklin W, Lowell FC. Comparison of two dosages of ragweed extract in the treatment of pollenosis. JAMA. 1967;201:951–957
  132. Ortolani C, Pastorello EA, Incorvaia C, et al. A double-blind, placebo-controlled study of immunotherapy with an alginate-conjugated extract of Parietaria judaica in patients with Parietaria hay fever. Allergy. 1994;49:13–21Ib
  133. Malling HJ, Djurup R. Diagnosis and immunotherapy of mould allergy. VII. IgG subclass response and relation to the clinical efficacy of immunotherapy with Cladosporium. Allergy. 1988;43:60–70
  134. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol. 1990;85:460–472IIa
  135. Malling HJ, Dreborg S, Weeke B. Diagnosis and immunotherapy of mould allergy. V. Clinical efficacy and side effects of immunotherapy with Cladosporium herbarum. Allergy. 1986;41:507–519Ib
  136. Malling HJ. Diagnosis and immunotherapy of mould allergy. IV. Relation between asthma symptoms, spore counts and diagnostic tests. Allergy. 1986;41:342–350IIa
  137. Karlsson R, Agrell B, Dreborg S, et al. A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. II. In vitro results. Allergy. 1986;41:141–150Ib
  138. Dreborg S, Agrell B, Foucard T, Kjellman NI, Koivikko A, Nilsson S. A double-blind, multicenter immunotherapy trial in children, using a purified and standardized Cladosporium herbarum preparation. I. Clinical results. Allergy. 1986;41:131–140Ib
  139. Alvarez-Cuesta E, Cuesta-Herranz J, Puyana-Ruiz J, Cuesta-Herranz C, Blanco-Quiros A. Monoclonal antibody-standardized cat extract immunotherapy: risk-benefit effects from a double-blind placebo study. J Allergy Clin Immunol. 1994;93:556–566Ib
  140. Haugaard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results. Allergy. 1992;47:249–254IIa
  141. Hedlin G, Graff-Lonnevig V, Heilborn H, et al. Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment. J Allergy Clin Immunol. 1991;87:955–964IIa
  142. Ohman JL, Findlay SR, Leitermann KM. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses. J Allergy Clin Immunol. 1984;74:230–239Ib
  143. Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy. 1997;27:860–867Ib
  144. Maestrelli P, Zanolla L, Pozzan M, Fabbri LM. Effect of specific immunotherapy added to pharmacologic treatment and allergen avoidance in asthmatic patients allergic to house dust mite. J Allergy Clin Immunol. 2004;113:643–649Ib
  145. Tabar AI, Echechipia S, Garcia BE, et al. Double-blind comparative study of cluster and conventional immunotherapy schedules with Dermatophagoides pteronyssinus. J Allergy Clin Immunol. 2005;116:109–118Ib
  146. Pichler CE, Marquardsen A, Sparholt S, et al. Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae results in decreased bronchial hyperreactivity. Allergy. 1997;52:274–283Ib
  147. Bousquet J, Calvayrac P, Guerin B, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J Allergy Clin Immunol. 1985;76:734–744Ib
  148. Bousquet J, Hejjaoui A, Clauzel AM, et al. Specific immunotherapy with a standardized Dermatophagoides pteronyssinus extract. II. Prediction of efficacy of immunotherapy. J Allergy Clin Immunol. 1988;82:971–977IIa
  149. Haugaard L, Dahl R, Jacobsen L. A controlled dose-response study of immunotherapy with standardized, partially purified extract of house dust mite: clinical efficacy and side effects. J Allergy Clin Immunol. 1993;91:709–722Ib
  150. McHugh SM, Lavelle B, Kemeny DM, Patel S, Ewan PW. A placebo-controlled trial of immunotherapy with two extracts of Dermatophagoides pteronyssinus in allergic rhinitis, comparing clinical outcome with changes in antigen-specific IgE, IgG, and IgG subclasses. J Allergy Clin Immunol. 1990;86:521–531Ib
  151. Olsen OT, Larsen KR, Jacobsan L, Svendsen UG. A 1-year, placebo-controlled, double-blind house-dust-mite immunotherapy study in asthmatic adults. Allergy. 1997;52:853–859Ib
  152. Pauli G, Bessot JC, Bigot H, et al. Clinical and immunologic evaluation of tyrosine-adsorbed Dermatophagoides pteronyssinus extract: a double-blind placebo-controlled trial. J Allergy Clin Immunol. 1984;74:524–535Ib
  153. Wang H, Lin X, Hao C, et al. A double-blind, placebo-controlled study of house dust mite immunotherapy in Chinese asthmatic patients. Allergy. 2006;61:191–197Ib
  154. Kang BC, Johnson J, Morgan C, Chang JL. The role of immunotherapy in cockroach asthma. J Asthma. 1988;25:205–218IB
  155. Freeman TM, Hylander R, Ortiz A, Martin ME. Imported fire ant immunotherapy: effectiveness of whole body extracts. J Allergy Clin Immunol. 1992;90:210–215IIa
  156. Triplett RF. Sensitivity to the imported fire ant: successful treatment with immunotherapy. South Med J. 1973;66:477–480III
  157. Tankersley MS, Walker RL, Butler WK, Hagan LL, Napoli DC, Freeman TM. Safety and efficacy of an imported fire ant rush immunotherapy protocol with and without prophylactic treatment. J Allergy Clin Immunol. 2002;109:556–562Ib
  158. Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A. Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy. 2005;60:801–807Ib
  159. Ferrer M, Burches E, Pelaez A, et al. Double-blind, placebo-controlled study of immunotherapy with Parietaria judaica: clinical efficacy and tolerance. J Investig Allergol Clin Immunol. 2005;15:283–292Ib
  160. Jutel M, Jaeger L, Suck R, Meyer H, Fiebig H, Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005;116:608–613Ib
  161. Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol. 2001;107:87–93Ib
  162. Jacobsen L, Nuchel Petersen B, Wihl JA, Lowenstein H, Ipsen H. Immunotherapy with partially purified and standardized tree pollen extracts. IV. Results from long-term (6-year) follow-up. Allergy. 1997;52:914–920III
  163. Eng PA, Borer-Reinhold M, Heijnen IAFM, Gnehm HPE. Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy. 2006;61:198–201IIa
  164. Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of preseasonal grass pollen immunotherapy in children. Allergy. 2002;57:306–312IIa
  165. Jacobsen L. Preventive aspects of immunotherapy: prevention for children at risk of developing asthma. Ann Allergy Asthma Immunol. 2001;87(suppl 1):43–46IV
  166. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy. 2001;31:1392–1397IIa
  167. Purello-D'Ambrosio F, Gangemi S, Merendino RA, et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy. 2001;31:1295–1302
  168. Sampson HA. Food anaphylaxis. Br Med Bull. 2000;56:925–935
  169. Rance F. [Current childhood food allergies]. Allerg Immunol (Paris). 2000;32:366–376IIb
  170. Bannon GA, Cockrell G, Connaughton C, et al. Engineering, characterization and in vitro efficacy of the major peanut allergens for use in immunotherapy. Int Arch Allergy Immunol. 2001;124:70–72LB
  171. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol. 1997;99:744–751IIa
  172. Enrique E, Pineda F, Malek T, et al. Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol. 2005;116:1073–1079Ib
  173. Oppenheimer JJ, Nelson HS, Bock SA, Christensen F, Leung DY. Treatment of peanut allergy with rush immunotherapy. J Allergy Clin Immunol. 1992;90:256–262Ib
  174. Werfel T, Breuer K, Rueff F, et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study. Allergy. 2006;61:202–205Ib
  175. Glover MT, Atherton DJ. A double-blind controlled trial of hyposensitization to Dermatophagoides pteronyssinus in children with atopic eczema. Clin Exp Allergy. 1992;22:440–446Ib
  176. Bussmann C, Böckenhoff A, Henke H, Werfel T, Novak N. Does allergen-specific immunotherapy represent a therapeutic option for patients with atopic dermatitis?. J Allergy Clin Immunol. 2006;118:1292–1298
  177. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy. 2004;59:1272–1276IIa
  178. Hansen KS, Khinchi MS, Skov PS, Bindslev-Jensen C, Poulsen LK, Malling HJ. Food allergy to apple and specific immunotherapy with birch pollen. Mol Nutr Food Res. 2004;48:441–448Ib
  179. Tankersley MS, Butler KK, Butler WK, Goetz DW. Local reactions during allergen immunotherapy do not require dose adjustment. J Allergy Clin Immunol. 2000;106:840–843III
  180. Kelso JM. The rate of systemic reactions to immunotherapy injections is the same whether or not the dose is reduced after a local reaction. Ann Allergy Asthma Immunol. 2004;92:225–227III
  181. Roy SR, Sigmon JR, Olivier J, Moffitt JE, Brown DA, Marshall GD. Increased frequency of large local reactions in patients who experience systemic reactions on allergen immunotherapy. Ann Allergy Asthma Immunol. 2007;99:82–86III
  182. Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities associated with allergen immunotherapy. Ann Allergy Asthma Immunol. 2001;87(suppl 1):47–55III
  183. Malling HJ. Minimising the risks of allergen-specific injection immunotherapy. Drug Saf. 2000;23:323–332
  184. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol. 2006;117:169–175III
  185. Ragusa FV, Passalacqua G, Gambardella R, et al. Nonfatal systemic reactions to subcutaneous immunotherapy: a 10-year experience. J Investig Allergol Clin Immunol. 1997;7:151–154III
  186. Ragusa VF, Massolo A. Non-fatal systemic reactions to subcutaneous immunotherapy: a 20-year experience comparison of two 10-year periods. Allerg Immunol (Paris). 2004;36:52–55III
  187. Moreno C, Cuesta-Herranz J, Fernandez-Tavora L, Alvarez-Cuesta E. Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy. 2004;34:527–531III
  188. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol. 2004;113:1129–1136III
  189. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol. 1987;79:660–677III
  190. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Survey of fatalities from skin testing and immunotherapy 1985-1989. J Allergy Clin Immunol. 1993;92:6–15III
  191. Bousquet J, Hejjaoui A, Dhivert H, Clauzel AM, Michel FB. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. Systemic reactions during the rush protocol in patients suffering from asthma. J Allergy Clin Immunol. 1989;83:797–802IIa
  192. Greenberg MA, Kaufman CR, Gonzalez GE, Rosenblatt CD, Smith LJ, Summers RJ. Late and immediate systemic-allergic reactions to inhalant allergen immunotherapy. J Allergy Clin Immunol. 1986;77:865–870
  193. Matloff SM, Bailit IW, Parks P, Madden N, Greineder DK. Systemic reactions to immunotherapy. Allergy Proc. 1993;14:347–350IV
  194. Subcutaneous immunotherapy. Allergy. 2006;61(suppl 82):5–13
  195. Javeed N, Javeed H, Javeed S, Moussa G, Wong P, Rezai F. Refractory anaphylactoid shock potentiated by beta-blockers. Catheter Cardiovasc Diagn. 1996;39:383–384
  196. Kivity S, Yarchovsky J. Relapsing anaphylaxis to bee sting in a patient treated with beta-blocker and Ca blocker. J Allergy Clin Immunol. 1990;85:669–670IV
  197. Lang DM, Alpern MB, Visintainer PF, Smith ST. Elevated risk of anaphylactoid reaction from radiographic contrast media is associated with both beta-blocker exposure and cardiovascular disorders. Arch Intern Med. 1993;153:2033–2040III
  198. Lang DM, Alpern MB, Visintainer PF, Smith ST. Increased risk for anaphylactoid reaction from contrast media in patients on beta-adrenergic blockers or with asthma. Ann Intern Med. 1991;115:270–276III
  199. Bickell WH, Dice WH. Military antishock trousers in a patient with adrenergic-resistant anaphylaxis. Ann Emerg Med. 1984;13:189–190IV
  200. Jacobs RL, Rake GW, Fournier DC, Chilton RJ, Culver WG, Beckmann CH. Potentiated anaphylaxis in patients with drug-induced beta-adrenergic blockade. J Allergy Clin Immunol. 1981;68:125–127IV
  201. Newman BR, Schultz LK. Epinephrine-resistant anaphylaxis in a patient taking propranolol hydrochloride. Ann Allergy. 1981;47:35–37IV
  202. Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol. 1988;81:1–5IV
  203. Hepner MJ, Ownby DR, Anderson JA, Rowe MS, Sears-Ewald D, Brown EB. Risk of systemic reactions in patients taking beta-blocker drugs receiving allergen immunotherapy injections. J Allergy Clin Immunol. 1990;86:407–411III
  204. Muller UR, Haeberli G. Use of beta-blockers during immunotherapy for Hymenoptera venom allergy. J Allergy Clin Immunol. 2005;115:606–610III
  205. Sherman MS, Lazar EJ, Eichacker P. A bronchodilator action of glucagon. J Allergy Clin Immunol. 1988;81:908–911IV
  206. Thomas M, Crawford I. Best evidence topic report. Glucagon infusion in refractory anaphylactic shock in patients on beta-blockers. Emerg Med J. 2005;22:272–273IV
  207. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000;30:1144–1150III
  208. Simons FE, Chan ES, Gu X, Simons KJ. Epinephrine for the out-of-hospital (first-aid) treatment of anaphylaxis in infants: is the ampule/syringe/needle method practical?. J Allergy Clin Immunol. 2001;108:1040–1044IIa
  209. Simons FE, Gu X, Johnston LM, Simons KJ. Can epinephrine inhalations be substituted for epinephrine injection in children at risk for systemic anaphylaxis?. Pediatrics. 2000;106:1040–1044Ib
  210. Simons FE, Gu X, Silver NA, Simons KJ. EpiPen Jr versus EpiPen in young children weighing 15 to 30 kg at risk for anaphylaxis. J Allergy Clin Immunol. 2002;109:171–175Ib
  211. Simons FE, Gu X, Simons KJ. Outdated EpiPen and EpiPen Jr autoinjectors: past their prime?. J Allergy Clin Immunol. 2000;105:1025–1030Ib
  212. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108:871–873Ib
  213. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998;101:33–37Ib
  214. Bernstein JA. Pharmacoeconomic considerations for allergen immunotherapy. Clin Allergy Immunol. 2004;18:151–164III
  215. Practice parameters for the diagnosis and treatment of asthma. Joint Task Force on Practice Parameters, representing the American Academy of Allergy Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 1995;96(suppl):S707–S870
  216. Li JT, Pearlman DS, Nicklas RA, et al. Algorithm for the diagnosis and management of asthma: a practice parameter update: Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma and Immunology, the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998;81:415–420
  217. Current status of allergen immunotherapy: Shortened Version of a World Health Organisation/International Union of Immunological Societies Working Group Report. Lancet. 1989;333:259–261
  218. Moffitt JE, Golden DB, Reisman RE, et al. Stinging insect hypersensitivity: a practice parameter update. J Allergy Clin Immunol. 2004;114:869–886
  219. Duplantier JE, Freeman TM, Bahna SL, Good RA, Sher MR. Successful rush immunotherapy for anaphylaxis to imported fire ants. J Allergy Clin Immunol. 1998;101:855–856IV
  220. Nguyen SA, Napoli DC. Natural history of large local and generalized cutaneous reactions to imported fire ant stings in children. Ann Allergy Asthma Immunol. 2005;94:387–390III
  221. Valentine MD, Schuberth KC, Kagey-Sobotka A, et al. The value of immunotherapy with venom in children with allergy to insect stings. N Engl J Med. 1990;323:1601–1603III
  222. Golden DB, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Outcomes of allergy to insect stings in children, with and without venom immunotherapy. N Engl J Med. 2004;351:668–674III
  223. Golden DB, Marsh DG, Kagey-Sobotka A, et al. Epidemiology of insect venom sensitivity. JAMA. 1989;262:240–244III
  224. Golden DB. Insect sting allergy and venom immunotherapy: a model and a mystery. J Allergy Clin Immunol. 2005;115:439–448IV
  225. Golden DB, Kagey-Sobotka A, Norman PS, Hamilton RG, Lichtenstein LM. Insect sting allergy with negative venom skin test responses. J Allergy Clin Immunol. 2001;107:897–901IIa
  226. Golden DB, Tracy JM, Freeman TM, Hoffman DR. Negative venom skin test results in patients with histories of systemic reaction to a sting. J Allergy Clin Immunol. 2003;112:495–498IV
  227. Reisman RE. Insect sting allergy: the dilemma of the negative skin test reactor. J Allergy Clin Immunol. 2001;107:781–782IV
  228. Arbes SJ, Cohn RD, Yin M, Muilenberg ML, Friedman W, Zeldin DC. Dog allergen (Can f 1) and cat allergen (Fel d 1) in US homes: results from the National Survey of Lead and Allergens in Housing. J Allergy Clin Immunol. 2004;114:111–117III
  229. Matsui EC, Wood RA, Rand C, Kanchanaraksa S, Swartz L, Eggleston PA. Mouse allergen exposure and mouse skin test sensitivity in suburban, middle-class children with asthma. J Allergy Clin Immunol. 2004;113:910–915III
  230. Matsui EC, Simons E, Rand C, et al. Airborne mouse allergen in the homes of inner-city children with asthma. J Allergy Clin Immunol. 2005;115:358–363III
  231. Perry T, Matsui E, Merriman B, Duong T, Eggleston P. The prevalence of rat allergen in inner-city homes and its relationship to sensitization and asthma morbidity. J Allergy Clin Immunol. 2003;112:346–352III
  232. Lin MS, Tanner E, Lynn J, Friday GA. Nonfatal systemic allergic reactions induced by skin testing and immunotherapy. Ann Allergy. 1993;71:557–562III
  233. Valyasevi MA, Maddox DE, Li JT. Systemic reactions to allergy skin tests. Ann Allergy Asthma Immunol. 1999;83:132–136III
  234. Berg TL, Johansson SG. Allergy diagnosis with the radioallergosorbent test: a comparison with the results of skin and provocation tests in an unselected group of children with asthma and hay fever. J Allergy Clin Immunol. 1974;54:209–221IIb
  235. van der Zee JS, de Groot H, van Swieten P, Jansen HM, Aalberse RC. Discrepancies between the skin test and IgE antibody assays: study of histamine release, complement activation in vitro, and occurrence of allergen-specific IgG. J Allergy Clin Immunol. 1988;82:270–281IIb
  236. Nelson HS, Oppenheimer J, Buchmeier A, Kordash TR, Freshwater LL. An assessment of the role of intradermal skin testing in the diagnosis of clinically relevant allergy to timothy grass. J Allergy Clin Immunol. 1996;97:1193–1201IIa
  237. Wood RA, Phipatanakul W, Hamilton RG, Eggleston PA. A comparison of skin prick tests, intradermal skin tests, and RASTs in the diagnosis of cat allergy. J Allergy Clin Immunol. 1999;103:773–779IIa
  238. Esch RE. Manufacturing and standardizing fungal allergen products. J Allergy Clin Immunol. 2004;113:210–215LB
  239. Vailes L, Sridhara S, Cromwell O, Weber B, Breitenbach M, Chapman M. Quantitation of the major fungal allergens, Alt a 1 and Asp f 1, in commercial allergenic products. J Allergy Clin Immunol. 2001;107:641–646LB
  240. Nelson HS, Ikle D, Buchmeier A. Studies of allergen extract stability: the effects of dilution and mixing. J Allergy Clin Immunol. 1996;98:382–388LB
  241. Salvaggio JE, Burge HA, Chapman JA. Emerging concepts in mold allergy: what is the role of immunotherapy?. J Allergy Clin Immunol. 1993;92:217–222
  242. Bertelsen A, Andersen JB, Christensen J, Ingemann L, Kristensen T, Ostergaard PA. Immunotherapy with dog and cat extracts in children. Allergy. 1989;44:330–335Ib
  243. Schou C, Lind P, Fernandez-Caldas E, Lockey RF, Lowenstein H. Identification and purification of an important cross-reactive allergen from American (Periplaneta americana) and German (Blattella germanica) cockroach. J Allergy Clin Immunol. 1990;86:935–946LB
  244. Bousquet J, Muller UR, Dreborg S, et al. Immunotherapy with Hymenoptera venoms. Position paper of the Working Group on Immunotherapy of the European Academy of Allergy and Clinical Immunology. Allergy. 1987;42:401–413
  245. Rueff F, Wenderoth A, Przybilla B. Patients still reacting to a sting challenge while receiving conventional Hymenoptera venom immunotherapy are protected by increased venom doses. J Allergy Clin Immunol. 2001;108:1027–1032III
  246. Kordash TR, Amend MJ, Williamson SL, Jones JK, Plunkett GA. Effect of mixing allergenic extracts containing helminthosporium, D. farinae, and cockroach with perennial ryegrass. Ann Allergy. 1993;71:240–246LB
  247. Grier TJ, LeFevre DM, Duncan EA, Esch RE. Stability of standardized grass, dust mite, cat and short ragweed allergens after mixing with mold or cockroach extracts. Ann Allergy Asthma Immunol. 2007;99:151–160LB
  248. Esch RE. Role of proteases on the stability of allergenic extracts. Arb Paul Ehrlich Inst Bundesamt Sera Impfstoffe Frankf A M. 1992;85:171–179LB
  249. Anderson MC, Baer H. Antigenic and allergenic changes during storage of a pollen extract. J Allergy Clin Immunol. 1982;69:3–10LB
  250. Sridhara S, Singh BP, Arora N, Verma J, Gangal SV. A study on antigenic and allergenic changes during storage in three different biological extracts. Asian Pac J Allergy Immunol. 1992;10:33–38LB
  251. Niemeijer NR, Kauffman HF, van Hove W, Dubois AE, de Monchy JG. Effect of dilution, temperature, and preservatives on the long-term stability of standardized inhalant allergen extracts. Ann Allergy Asthma Immunol. 1996;76:535–540LB
  252. Vijay HM, Young NM, Bernstein IL. Studies on Alternaria allergens. VI. Stability of the allergen components of Alternaria tenuis extracts under a variety of storage conditions. Int Arch Allergy Appl Immunol. 1987;83:325–328LB
  253. Ayuso R, Rubio M, Herrera T, Gurbindo C, Carreira J. Stability of Lolium perenne extract. Ann Allergy. 1984;53:426–431LB
  254. Van Metre TE, Rosenberg GL, Vaswani SK, Ziegler SR, Adkinson NF. Pain and dermal reaction caused by injected glycerin in immunotherapy solutions. J Allergy Clin Immunol. 1996;97:1033–1039
  255. Lowenstein H. Domestic allergens. In:  Kerr J editors. Procedures of the XI International Congress of Allergology & Clinical Immunology. London: MacMillan; 1983;p. 545–548
  256. Lind P, Weeke B, Lowenstein H. A reference allergen preparation of the house dust mite D. pteronyssinus, produced from whole mite culture—a part of the DAS 76 study. Comparison with allergen preparations from other raw materials. Allergy. 1984;39:259–274LB
  257. Lowenstein H, Marsh DG. Antigens of Ambrosia elatior (short ragweed) pollen. I. Crossed immunoelectrophoretic analyses. J Immunol. 1981;126:943–948LB
  258. Lowenstein H, King TP, Goodfriend L, Hussain R, Roebber M, Marsh DG. Antigens of Ambrosia elatior (short ragweed) pollen. II. Immunochemical identification of known antigens by quantitative immunoelectrophoresis. J Immunol. 1981;127:637–642LB
  259. Aukrust L. Crossed radioimmunoelectrophoretic studies of distinct allergens in two extracts of Cladosporium herbarum. Int Arch Allergy Appl Immunol. 1979;58:375–390LB
  260. Bodtger U, Poulsen LK, Jacobi HH, Malling HJ. The safety and efficacy of subcutaneous birch pollen immunotherapy—a one-year, randomised, double-blind, placebo-controlled study. Allergy. 2002;57:297–305Ib
  261. Pence HL, Mitchell DQ, Greely RL, Updegraff BR, Selfridge HA. Immunotherapy for mountain cedar pollinosis. A double-blind controlled study. J Allergy Clin Immunol. 1976;58:39–50Ib
  262. Tipton WR, Nelson HS. Experience with daily immunotherapy in 59 adult allergic patients. J Allergy Clin Immunol. 1982;69:194–199IIa
  263. Cox L. Accelerated immunotherapy schedules: review of efficacy and safety. Ann Allergy Asthma Immunol. 2006;97:126–140202
  264. Mauro M, Russello M, Alesina R, et al. Safety and pharmacoeconomics of a cluster administration of mite immunotherapy compared to the traditional one. Allerg Immunol (Paris). 2006;38:31–34Ib
  265. Van Metre TE, Adkinson NF, Amodio FJ, et al. A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. J Allergy Clin Immunol. 1982;69:181–193Ib
  266. Tabar AI, Muro MD, Garcia BE, et al. Dermatophagoides pteronyssinus cluster immunotherapy. A controlled trial of safety and clinical efficacy. J Investig Allergol Clin Immunol. 1999;9:155–164Ib
  267. Nielsen L, Johnsen CR, Mosbech H, Poulsen LK, Malling HJ. Antihistamine premedication in specific cluster immunotherapy: a double-blind, placebo-controlled study. J Allergy Clin Immunol. 1996;97:1207–1213Ib
  268. Miller DL, Mansmann HC. Rapid injection therapy in children with intractable asthma: safety and technique. Ann Allergy. 1971;29:178–186III
  269. Portnoy J, King K, Kanarek H, Horner S. Incidence of systemic reactions during rush immunotherapy. Ann Allergy. 1992;68:493–498III
  270. Sharkey P, Portnoy J. Rush immunotherapy: experience with a one-day schedule. Ann Allergy Asthma Immunol. 1996;76:175–180III
  271. Hejjaoui A, Dhivert H, Michel FB, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy schedule. J Allergy Clin Immunol. 1990;85:473–479III
  272. Portnoy J, Bagstad K, Kanarek H, Pacheco F, Hall B, Barnes C. Premedication reduces the incidence of systemic reactions during inhalant rush immunotherapy with mixtures of allergenic extracts. Ann Allergy. 1994;73:409–418Ib
  273. Harvey SM, Laurie S, Hilton K, Khan DA. Safety of rush immunotherapy to multiple aeroallergens in an adult population. Ann Allergy Asthma Immunol. 2004;92:414–419III
  274. Roll A, Hofbauer G, Ballmer-Weber BK, Schmid-Grendelmeier P. Safety of specific immunotherapy using a four-hour ultra-rush induction scheme in bee and wasp allergy. J Investig Allergol Clin Immunol. 2006;16:79–85III
  275. Jutel M, Skrbic D, Pichler WJ, Muller UR. Ultra rush bee venom immunotherapy does not reduce cutaneous weal responses to bee venom and codeine phosphate. Clin Exp Allergy. 1995;25:1205–1210III
  276. Bernstein JA, Kagen SL, Bernstein DI, Bernstein IL. Rapid venom immunotherapy is safe for routine use in the treatment of patients with Hymenoptera anaphylaxis. Ann Allergy. 1994;73:423–428III
  277. Kohno Y, Minoguchi K, Oda N, et al. Effect of rush immunotherapy on airway inflammation and airway hyperresponsiveness after bronchoprovocation with allergen in asthma. J Allergy Clin Immunol. 1998;102:927–934IIa
  278. Schiavino D, Nucera E, Pollastrini E, et al. Specific ultrarush desensitization in Hymenoptera venom-allergic patients. Ann Allergy Asthma Immunol. 2004;92:409–413III
  279. Goldberg A, Confino-Cohen R. Rush venom immunotherapy in patients experiencing recurrent systemic reactions to conventional venom immunotherapy. Ann Allergy Asthma Immunol. 2003;91:405–410III
  280. Ohashi Y, Nakai Y, Murata K. Effect of pretreatment with fexofenadine on the safety of immunotherapy in patients with allergic rhinitis. Ann Allergy Asthma Immunol. 2006;96:600–605Ib
  281. Muller U, Hari Y, Berchtold E. Premedication with antihistamines may enhance efficacy of specific-allergen immunotherapy. J Allergy Clin Immunol. 2001;107:81–86Ib
  282. Casale TB, Busse WW, Kline JN, et al. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2006;117:134–140Ib
  283. Golden DB, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol. 2000;105:385–390III
  284. The discontinuation of Hymenoptera venom immunotherapy. J Allergy Clin Immunol. 1998;101:573–575IV
  285. Lerch E, Müller UR. Long-term protection after stopping venom immunotherapy: results of re-stings in 200 patients. J Allergy Clin Immunol. 1998;101:606–612III
  286. van Halteren HK, van der Linden PW, Burgers JA, Bartelink AK. Discontinuation of yellow jacket venom immunotherapy: follow-up of 75 patients by means of deliberate sting challenge. J Allergy Clin Immunol. 1997;100:767–770III
  287. Keating MU, Kagey-Sobotka A, Hamilton RG, Yunginger JW. Clinical and immunologic follow-up of patients who stop venom immunotherapy. J Allergy Clin Immunol. 1991;88:339–348III
  288. Golden DB, Kwiterovich KA, Kagey-Sobotka A, Lichtenstein LM. Discontinuing venom immunotherapy: extended observations. J Allergy Clin Immunol. 1998;101:298–302III
  289. Wolf BL, Marks A, Fahrenholz JM. Accidental needle sticks, the Occupational Safety and Health Administration, and the fallacy of public policy. Ann Allergy Asthma Immunol. 2006;97:52–54III
  290. Kanter L. Accidental needle stick prevention: an important, costly, unsafe policy revisited. Ann Allergy Asthma Immunol. 2006;97:7–9IV
  291. Kanter LJ, Siegel C. Needle sticks and adverse outcomes in office-based allergy practices. Ann Allergy Asthma Immunol. 2003;90:389–392III
  292. Position statement on the administration of immunotherapy outside of the prescribing allergist facility. Drugs and Anaphylaxis Committee of the American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 1998;81:101–102
  293. Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med. 1997;336:324–331Ib
  294. Rosenstreich DL, Eggleston P, Kattan M, et al. The role of cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children with asthma. N Engl J Med. 1997;336:1356–1363III
  295. Asero R. Efficacy of injection immunotherapy with ragweed and birch pollen in elderly patients. Int Arch Allergy Immunol. 2004;135:332–335
  296. Theodoropoulos DS, Lockey RF. Allergen immunotherapy: guidelines, update, and recommendations of the World Health Organization. Allergy Asthma Proc. 2000;21:159–166
  297. Litwin A, Flanagan M, Entis G, et al. Oral immunotherapy with short ragweed extract in a novel encapsulated preparation: a double-blind study. J Allergy Clin Immunol. 1997;100:30–38Ib
  298. Bjorksten B, Moller C, Broberger U, et al. Clinical and immunological effects of oral immunotherapy with a standardized birch pollen extract. Allergy. 1986;41:290–295IIa
  299. Oppenheimer J, Areson JG, Nelson HS. Safety and efficacy of oral immunotherapy with standardized cat extract. J Allergy Clin Immunol. 1994;93:61–67Ib
  300. Penagos M, Compalati E, Tarantini F, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol. 2006;97:141–148Ia
  301. Dahl R, Kapp A, Colombo G, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;118:434–440Ib
  302. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005;60:4–12Ia
  303. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2006;117:802–809
  304. Olaguibel JM, Alvarez Puebla MJ. Efficacy of sublingual allergen vaccination for respiratory allergy in children. Conclusions from one meta-analysis. J Investig Allergol Clin Immunol. 2005;15:9–16Ia
  305. Nelson HS, Oppenheimer J, Vatsia GA, Buchmeier A. A double-blind, placebo-controlled evaluation of sublingual immunotherapy with standardized cat extract. J Allergy Clin Immunol. 1993;92:229–236Ib
  306. La Rosa M, Ranno C, Andre C, Carat F, Tosca MA, Canonica GW. Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol. 1999;104:425–432Ib
  307. Passalacqua G, Albano M, Riccio A, et al. Clinical and immunologic effects of a rush sublingual immunotherapy to Parietaria species: a double-blind, placebo-controlled trial. J Allergy Clin Immunol. 1999;104:964–968Ib
  308. Purello-D'Ambrosio F, Gangemi S, Isola S, et al. Sublingual immunotherapy: a double-blind, placebo-controlled trial with Parietaria judaica extract standardized in mass units in patients with rhinoconjunctivitis, asthma, or both. Allergy. 1999;54:968–973
  309. Sanchez Palacios A, Schamann F, Garcia JA. [Sublingual immunotherapy with cat epithelial extract. Personal experience]. Allergol Immunopathol (Madr). 2001;29:60–65Ib
  310. Andre C, Perrin-Fayolle M, Grosclaude M, et al. A double-blind placebo-controlled evaluation of sublingual immunotherapy with a standardized ragweed extract in patients with seasonal rhinitis. Evidence for a dose-response relationship. Int Arch Allergy Immunol. 2003;131:111–118Ib
  311. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, Malling HJ. Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: a randomized, placebo-controlled, double-blind, double-dummy study. Allergy. 2004;59:45–53Ib
  312. Bernardini R, Campodonico P, Burastero S, et al. Sublingual immunotherapy with a latex extract in paediatric patients: a double-blind, placebo-controlled study. Curr Med Res Opin. 2006;22:1515–1522Ib
  313. Cistero Bahima A, Sastre J, Enrique E, et al. Tolerance and effects on skin reactivity to latex of sublingual rush immunotherapy with a latex extract. J Investig Allergol Clin Immunol. 2004;14:17–25Ib
  314. Marogna M, Spadolini I, Massolo A, et al. Effects of sublingual immunotherapy for multiple or single allergens in polysensitized patients. Ann Allergy Asthma Immunol. 2007;98:274–280
  315. Bagnasco M, Mariani G, Passalacqua G, et al. Absorption and distribution kinetics of the major Parietaria judaica allergen (Par j 1) administered by noninjectable routes in healthy human beings. J Allergy Clin Immunol. 1997;100:122–129IIb
  316. Passalacqua G, Altrinetti V, Mariani G, et al. Pharmacokinetics of radiolabelled Par j 1 administered intranasally to allergic and healthy subjects. Clin Exp Allergy. 2005;35:880–883IIb
  317. Tripodi S, Di Rienzo Businco A, Benincori N, Scala G, Pingitore G. Safety and tolerability of ultra-rush induction, less than one hour, of sublingual immunotherapy in children. Int Arch Allergy Immunol. 2006;139:149–152III
  318. Rossi RE, Monasterolo G. A pilot study of feasibility of ultra-rush (20-25 minutes) sublingual-swallow immunotherapy in 679 patients (699 sessions) with allergic rhinitis and/or asthma. Int J Immunopathol Pharmacol. 2005;18:277–285III
  319. Dahl R, Stender A, Rak S. Specific immunotherapy with SQ standardized grass allergen tablets in asthmatics with rhinoconjunctivitis. Allergy. 2006;61:185–190Ib
  320. Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy. 2006;61:181–184Ib
  321. Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F. Dose dependence of immunological response to sublingual immunotherapy. Allergy. 2005;60:952–956Ib
  322. Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006;117:1021–1035Ia
  323. Bowen T, Greenbaum J, Charbonneau Y, et al. Canadian trial of sublingual swallow immunotherapy for ragweed rhinoconjunctivitis. Ann Allergy Asthma Immunol. 2004;93:425–430Ib
  324. Agostinis F, Tellarini L, Canonica GW, Falagiani P, Passalacqua G. Safety of sublingual immunotherapy with a monomeric allergoid in very young children. Allergy. 2005;60:133;III
  325. Fiocchi A, Pajno G, La Grutta S, et al. Safety of sublingual-swallow immunotherapy in children aged 3 to 7 years. Ann Allergy Asthma Immunol. 2005;95:254–258III
  326. Di Rienzo V, Pagani A, Parmiani S, Passalacqua G, Canonica GW. Post-marketing surveillance study on the safety of sublingual immunotherapy in pediatric patients. Allergy. 1999;54:1110–1113III
  327. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingual immunotherapy. Allergy. 2006;1236–1237
  328. Dunsky EH, Goldstein MF, Dvorin DJ, Belecanech GA. Anaphylaxis to sublingual immunotherapy. Allergy. 2006;61:1235
  329. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis to multiple pollen allergen sublingual immunotherapy. Allergy. 2007;62:567–568
  330. Georgitis JW, Clayton WF, Wypych JI, Barde SH, Reisman RE. Further evaluation of local intranasal immunotherapy with aqueous and allergoid grass extracts. J Allergy Clin Immunol. 1984;74:694–700IIa
  331. Andri L, Senna G, Andri G, et al. Local nasal immunotherapy for birch allergic rhinitis with extract in powder form. Clin Exp Allergy. 1995;25:1092–1099Ib
  332. Andri L, Senna GE, Betteli C, et al. Local nasal immunotherapy in allergic rhinitis to Parietaria. A double-blind controlled study. Allergy. 1992;47:318–323Ib
  333. Passalacqua G, Albano M, Pronzato C, et al. Long-term follow-up of nasal immunotherapy to Parietaria: clinical and local immunological effects. Clin Exp Allergy. 1997;27:904–908Ib
  334. Passalacqua G, Albano M, Ruffoni S, et al. Nasal immunotherapy to Parietaria: evidence of reduction of local allergic inflammation. Am J Respir Crit Care Med. 1995;152:461–466IIa
  335. Andri L, Senna G, Betteli C, Givanni S, Andri G, Falagiani P. Local nasal immunotherapy for Dermatophagoides-induced rhinitis: efficacy of a powder extract. J Allergy Clin Immunol. 1993;91:987–996Ib
  336. Radcliffe MJ, Lewith GT, Turner RG, Prescott P, Church MK, Holgate ST. Enzyme potentiated desensitisation in treatment of seasonal allergic rhinitis: double blind randomised controlled study. BMJ. 2003;327:251–254Ib
  337. Ippoliti F, De Santis W, Volterrani A, et al. Immunomodulation during sublingual therapy in allergic children. Pediatr Allergy Immunol. 2003;14:216–221Ib
  338. Gidaro GB, Marcucci F, Sensi L, Incorvaia C, Frati F, Ciprandi G. The safety of sublingual-swallow immunotherapy: an analysis of published studies. Clin Exp Allergy. 2005;35:565–571III
  339. Smith H, White P, Annila I, Poole J, Andre C, Frew A. Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. J Allergy Clin Immunol. 2004;114:831–837Ib
  340. Norman PS, Ohman JL, Long AA, et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med. 1996;154:1623–1628Ib
  341. Schramm G, Kahlert H, Suck R, et al. “Allergen engineering”: variants of the timothy grass pollen allergen Phl p 5b with reduced IgE-binding capacity but conserved T cell reactivity. J Immunol. 1999;162:2406–2414LB
  342. Smith AM, Chapman MD, Taketomi EA, Platts-Mills TA, Sung SS. Recombinant allergens for immunotherapy: a Der p 2 variant with reduced IgE reactivity retains T-cell epitopes. J Allergy Clin Immunol. 1998;101:423–425LB
  343. Jain VV, Kitagaki K, Kline JN. CpG DNA and immunotherapy of allergic airway diseases. Clin Exp Allergy. 2003;33:1330–1335LB
  344. Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006;355:1445–1455Ib
  345. Adelroth E, Rak S, Haahtela T, et al. Recombinant humanized mAb-E25, an anti-IgE mAb, in birch pollen-induced seasonal allergic rhinitis. J Allergy Clin Immunol. 2000;106:253–259Ib
  346. Milgrom H, Berger W, Nayak A, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108:E36;Ib
  347. Milgrom H, Fick RB, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group. N Engl J Med. 1999;341:1966–1973Ib
  348. Walker S, Monteil M, Phelan K, Lasserson T, Walters E. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev. 2006;CD003559. Ia
  349. Ewan PW, Alexander MM, Snape C, Ind PW, Agrell B, Dreborg S. Effective hyposensitization in allergic rhinitis using a potent partially purified extract of house dust mite. Clin Allergy. 1988;18:501–508
  350. Van Metre TE, Marsh DG, Adkinson NF, Kagey-Sobotka A, Khattignavong A, Norman PS, et al. Immunotherapy for cat asthma. J Allergy Clin Immunol. 1988;82:1055–1068
  351. Van Metre TE, Marsh DG, Adkinson NF, Kagey-Sobotka A, Khattignavong A, Norman PS, et al. Immunotherapy decreases skin sensitivity to cat extract. J Allergy Clin Immunol. 1989;83:888–899
  352. Leynadier F, Banoun L, Dollois B, Terrier P, Epstein M, Guinnepain MT, et al. Immunotherapy with a calcium phosphate-adsorbed five-grass-pollen extract in seasonal rhinoconjunctivitis: a double-blind, placebo-controlled study. Clin Exp Allergy. 2001;31:988–996

 Disclosure of potential conflict of interest: L. Cox has consulting arrangements with Allergy Therapeutics, Genentech/Novartis, and Greer Laboratories and is on the speakers' bureau for Genentech/Novartis, GlaxoSmithKline, and AstraZeneca. R. Lockey has received grant support from Greer Laboratories; served as chairman of an advisory committee for ALK-Abelló for over 7 years; and has served as an expert witness for allergen immunotherapy death for both plaintiff and defendant. H. Nelson has consulting arrangements with Genentech/Novartis, Curalogic, GlaxoSmithKline, Inflazyme Pharmaceuticals, Dey Laboratories, Dynavax Technologies, Altana, and Schering-Plough; has received grant support from Dey Laboratories, IVAX, MediciNova, Wyeth, Sepracor, Genentech, Schering-Plough, Novartis, AstraZeneca, SkyPharma, Altana, and Roche; and is on the speakers' bureau for GlaxoSmithKline and AstraZeneca. D. Bernstein has consulting arrangements with ALK-Abelló and has received grant support from Dynavax and ALK-Abelló. J. Blessing-Moore has received grant support from Novartis-Genentech and AstraZeneca and is on the speakers' bureau for Schering-Plough, Merck, Aventis, Novartis/Genentech, AstraZeneca. D. M. Lang has consulting arrangements with, has received grant support from, and is on the speakers' bureau for GlaxoSmithKline, Merck, AstraZeneca, Centocor, Sanofi-Aventis, Schering-Plough, Verus, and Dey. J. Oppenheimer has consulting arrangements with GlaxoSmithKline, AstraZeneca, Sepracor, and Merck; has received grant support from AstraZeneca, Sepracor, and Merck, Boehringer Ingelheim, Novartis/Genentech, and Schering-Plough; and is on the speakers' bureau for GlaxoSmithKline, AstraZeneca, Sepracor, and Merck. J. M. Portnoy has consulting arrangements with Greer and GlaxoSmithKline; has received grant support from Clorox; and is on the speakers' bureau for Schering-Plough, Merck, Aventis, Secpracor, and AstraZeneca. S. A. Tilles has consulting arrangements with Genentech, Schering-Plough, and GlaxoSmithKline; has received grant support from AstraZeneca, Novartis, Medpoint, Apieron, and ALK-Abelló; and is on the speakers' bureau for GlaxoSmithKline, Pfizer, Genentech, and Alcon. The rest of the authors have declared that they have no conflict of interest.

 Reprint requests: Joint Council of Allergy, Asthma and Immunology, 50 N Brockway St, #3-3, Palatine, IL 60067.

PII: S0091-6749(07)01202-X

doi:10.1016/j.jaci.2007.06.019

Refers to erratum:

  • Correction

    The Journal of Allergy and Clinical Immunology October 2008 (Vol. 122, Issue 4, Page 842)

  • Correction

    The Journal of Allergy and Clinical Immunology June 2009 (Vol. 123, Issue 6, Page 1421)

The Journal of Allergy and Clinical Immunology
Volume 120, Issue 3, Supplement , Pages S25-S85, September 2007

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