GUIDELINES FOR THE USE OF ALLERGEN IMMUNOTHERAPY
Working Group Consensus
Gordon L. Sussman, MD, FRCPC, FACP (President) Head Section of Allergy, Division of Immunology, Wellesley Hospital, Toronto, Assistant Professor, University of Toronto.
David William Moote, MD, FRCPC (Past President) Director Allergy Clinic, Victoria Hospital, Medical School Faculty, Professor of Medicine, University of Western Ontario, London, Ontario.
Committee Members
Deborah Danoff, MD, FRCPC, Montreal General Hospital, Associate Professor of Medicine, McGill University.
Michel A.Drouin, MD, FRCPC, Head, Allergy Service, Ottawa Civic Hospital, Ottawa General Hospital, Clinical Assistant Professor of Medicine, University of Ottawa.
Eric Stephen Leith, MD, FRCPC, Women's College Hospital, Oakville-Trafalgar Memorial Hospital, Lecturer, University of Toronto.
Keith B.Payton, MD, FRCPC, Chief, Allergy & Clinical Immunology, St. Joseph's Health Centre, Professor of Medicine, University of Western Ontario, London, Ontario.
F.Estelle R.Simons, MD, FRCPC, Prof. & Head Section Allergy & Clinical Immunology, Department of Pediatrics & Child Health, University of Manitoba.
Peter Small, MD, FRCPC, Chief, Division of Allergy & Clinical Immunology, Jewish General Hospital, Associate Professor, McGill University.
Kam S.Tse, MD, FRCPC, Vancouver General Hospital, Clinical Professor of Medicine, University of British Columbia.
William H.Yang, MD, FRCPC, Head, Section of Allergy and Clinical Immunology, Department of Medicine, Ottawa Civic Hospital, Clinical Assistant Professor, Ottawa Medical School.
Donald Stark, MD, FRCPC, Medical School Faculty, University of British Columbia.
Reprint Requests
OBJECTIVES: To recommend guidelines on the use of allergen immunotherapy to treat allergic disorders in patients in which allergen avoidance and pharmacotherapy have not been sufficiently effective.
OPTIONS: Allergen immunotherapy have been used to treat IgE- mediated insect allergy, rhinoconjunctivitis and asthma. High dose and low dose allergen immunotherapy are treatment options.
OUTCOMES: Clinical evaluation of symptoms, and objective measurement by nasal or bronchial allergen challenge were assessed using high dose, low dose and placebo allergen immunotherapy. Immunologic changes occurring with allergen immunology were reviewed. Clinical outcome in patients with anaphylactic reactions to stinging insects were assessed by intentional re-sting challenge.
EVIDENCE: A MEDLINE literature search was done to identify articles that presented data on allergen immunotherapy. Symposia by international subcommittees and consensus meetings and references obtained therein were also reviewed. The articles were grouped into those concerned with immunologic effects, specific allergic diseases, randomized placebo controlled clinical trials, type of allergen extract and protocol for allergen immunotherapy, adverse effects and deficiencies of allergen immunotherapy.
VALUES: Each member of the committee individually assessed the importance of issues including basic immunology, clinical efficacy, adverse effects and inappropriate allergen immunotherapy. A consensus is presented.
BENEFITS, RISKS & COSTS: Guideline implementation is expected to lead to the appropriate use of allergen immunotherapy and help control inappropriate treatment which may increase the cost of services to patients with allergic disorders and has potential adverse effects.
RECOMMENDATIONS: In patients with allergy to insect stings or allergic rhinoconjunctivitis and in some with asthma, in which a correct diagnosis has been made through a meticulous history corroborated by positive skin tests, allergen immunotherapy with specific standardized allergenic materials in high dose schedules can be effective in those in which avoidance of the allergen and pharamacotherapy are not sufficiently effective.
VALIDATION: These guidelines are similar to recommendations from the United States and have undergone extensive clinical testing.
SPONSORS: These guidelines were prepared by the committee members without financial support.
The treatment of allergic diseases can involve allergen avoidance, pharmacotherapy and allergen immunotherapy. Desensitization, hyposensitization or immunotherapy are terms used for injections of incremental doses of allergenic substances to treat atopic diseases such as allergic rhinitis and asthma (1,2,3).
Allergen immunotherapy is commonly used clinically, but is the subject of considerable controversy, some of which reflects opinion rather than objective evaluation of the results and validity of scientific study. However, allergen immunotherapy has withstood the scrutiny of controlled clinical investigations over the past 20 years.
In order to review the issue in an unbiased fashion the Canadian Society of Allergy and Clinical Immunology (CSACI) formed a working group to evaluate the literature and recommend specific guidelines on the clinical use of allergen immunotherapy. Members of the committee were chosen by the executive of the CSACI with representation from both academic and practicing clinical allergy specialists. The chairman was responsible for a complete literature search and review. A list of about one hundred publications were chosen and members reviewed, discussed and selected articles cited in the final review manuscript. This included reviews of other published recommendations (1-3,55,56).
The final guidelines addressed all areas of concern to the committee. Issues felt to be important considerations of allergen immunotherapy are shown in Table 1.
Immunology
Immunotherapy is immunologically specific for the allergen injected (4,5,6). The immunologic changes occurring during immunotherapy include the generation of specific suppressor T cells (7), decreased allergen-specific IgE, increased allergen-specific IgG (8), decreased inflammatory cells (9), decreased mediators of inflammation (10,11) and decreased histamine releasing factors (12) resulting in decreased target organ reactivity to allergen (13). Immunotherapy has proven to be safe in numerous long-term studies (1-3,6).
The Decision to Use Immunotherapy
Careful identification of factors provoking symptoms in order to make the correct diagnosis is the most important consideration in evaluating patients with allergic disease. Symptoms must be shown to be temporally related to allergen exposure. The disease must be IgE mediated and be caused by an antigen proven to be amenable to allergen immunotherapy.
The diagnosis is supported by measurement of specific sensitivity (IgE antibody) to an antigen which correlates with clinical symptoms. At present the simplest, least expensive and most sensitive means of determining allergen-specific IgE is by (epicutaneous) prick skin testing. Intradermal skin testing and radioallergosorbent tests (RASTS) may also be helpful (14).
Immunotherapy should be considered for patients with a history of systemic reactions to Hymenoptera venom (15) and patients with allergic rhinitis (4-7) or asthma (16,17) who have significant allergic provoking factors and who are not obtaining adequate relief with avoidance of environmental allergens and the use of optimal medication (Table 2) (1,2,3). Before recommending immunotherapy every attempt should be made by the physician to educate the patient on the importance of preventative measures and the proper use of prescribed medications. Therefore allergen immunotherapy should be only after symptoms have been occurring for 2 or more successive allergy seasons.
Treatment Schedule
The effectiveness of allergen immunotherapy is antigen-specific and dose-dependent (4). High doses of allergens deemed relevant on the basis of the history as well as positive skin tests are necessary for a beneficial response (4, 18, 19, 20, 21). Low dose treatment has not proven effective (22, 23, 24, 25). Maintenance schedules and doses vary with the specific allergen and the severity of the patient's allergic disorder(s) (6,21,26,27). In controlled scientific studies incremental doses of aqueous allergenic extracts have been administered over several years (28-30). Standardized allergens should be used where available (31). Short term preseasonal or modified allergenic extracts, have been reported to be effective in some studies. However, because these are few and the allergenic potency of these modified extracts needs to be assessed individually we presently cannot recommend their general use (32). The duration of allergen injection treatments is usually 4-5 years (1-3). The criteria for discontinuing immunotherapy are not well established.
Allergic Rhinitis
Well designed, double-blind, placebo-controlled studies have demonstrated the efficacy of immunotherapy in allergic rhinitis, even in patients who are unresponsive to optimal pharmacologic treatment (33,34,35). Tree, grass and ragweed pollens are the main allergens studied. Because avoidance and pharmacologic treatment are usually effective, allergen immunotherapy is required in fewer than ten percent of patients.
Asthma
In asthma, a disorder with many potential non-immunologic triggers, it has been more difficult to obtain convincing proof of efficacy of allergen immunotherapy than in allergic rhinitis (36). Some studies of allergen immunotherapy in asthma have not been performed under optimal, properly controlled conditions; nevertheless efficacy has been demonstrated in other well-designed, double-blind, placebo-controlled studies in which asthma has been
clearly defined (37,38,39). Reduction of asthmatic symptoms has been reported after allergen immunotherapy with house dust mite, cat, grass pollen, and alternaria (40-43). In most studies decreased sensitivity of the airway to allergen induced bronchoconstriction has been demonstrated (40-44). Allergen immunotherapy has been reported to reduce the late phase inflammatory reaction in the lungs (40,45,46). Avoidance of allergens and pollutants, and the use of optimal medication, for example inhaled glucocorticoid treatment are still the first line
of treatment. This is usually effective in allergic asthmatic patients. However, in some patients with poorly controlled allergic asthma, immunotherapy with standardized allergen may be considered.
Insect Venom
Insect venom immunization treatment (yellow jacket, yellow hornet, white faced hornet, wasp and honeybee venom) is reported to be 95% or more protective in patients with previous anaphylactic reactions to venoms (47). It is not indicated in children with urticaria and no other systemic symptoms after insect stings (48,49). Current recommendations are for maintenance venom immunotherapy (100 microgram insect venom) to be administered every 4-6 weeks (48,49). Venom immunotherapy should be continued for five years (15,50).
Adverse Effects and Contra-Indications
The only serious risk of allergen immunotherapy is anaphylaxis. Fatal anaphylactic reactions have been reported rarely (51). Care must be taken to avoid errors in allergen dosage. All health care personnel involved in allergen immunotherapy treatment should be trained to recognize and treat anaphylactic reactions promptly. Other shortcomings of allergen immunotherapy are summarized on Table 3.
Future Research
Immunotherapy has proven to be effective if used properly. In addition, recent advances in immunologic intervention have been developed and it is hoped will achieve practical clinical significance. Modification of allergens allows reduced allergenicity with decreased likelihood of side effects while maintaining immunogenicity (52,53). Current forms of allergen immunotherapy being studied have the potential to shut down specific IgE antibody production and potentially cure symptomatic allergic diseases (54). In contrast to pharmacologic therapy, immunotherapy has the potential for long-term favourable alteration of the patient's immunologic status.
Conclusions and Recommendations
Allergen immunotherapy is a treatment used in the management of patients with atopic disease. It is most important that an appropriate history, physical examination and laboratory investigation be done to define the specific allergic etiology. Immunotherapy should be used when other modalities of therapy are not effective. Specific standardized antigen should be used in a treatment schedule which ensures an adequate amount of antigen is injected in a controlled manner.
Appropriate Indications for Allergen Immunotherapy (55,56)
1.Severe seasonal IgE dependent allergic rhinoconjunctivitis for 2 or more years (55) not managed by optimal allergen avoidance and medication.
2.Some cases of IgE mediated allergic asthma. There must be a clear temporal association between allergen exposure and signs and symptoms of asthma. Symptoms should be occurring during 2 or more allergen seasons during successive years (55). Regular use of anti-inflammatory medications such as inhaled corticosteroids will suppress symptoms in most patients. Allergen avoidance measures must be properly instituted. IgE mediated asthma from house dust mite or ragweed pollen may occasionally be treated with allergen immunotherapy.
3.IgE mediated insect sting anaphylactic reactions. Venom immunotherapy with yellow jacket, yellow hornet, white faced hornet, wasp, honeybee and fireant is effective.
Inappropriate Allergen Immunotherapy - Contra-Indications
1.History, physical exam, laboratory and radiologic studies do not support IgE mediated disease despite positive skin tests or in vitro tests.
2.Non-IgE mediated symptoms of rhinitis, asthma or insect allergy.
3.IgE dependent allergy to foods.
4.Urticaria or atopic dermatitis.
5.Use of extracts of bacteria, histamine or urine.
6.Co-existent autoimmune disease.
7.Severe uncontrolled asthma
8.Children less than 5 years of age (57).
9.Previous properly administered allergen immunotherapy was not successful.
10. No reduction of symptoms after 2 years of allergen injections.
11. Allergen injections have been given longer than 5 years.
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A.ADEQUATE VS. LOW DOSE ALLERGEN IMMUNOTHERAPY
B.IMMUNOLOGIC SPECIFICITY VS. NON-SPECIFICITY (IMMUNOLOGIC CHANGES/NASAL CHALLENGE STUDIES IN RHINITIS, BRONCHIAL CHALLENGE STUDIES IN ASTHMA)
C.EFFECT OF IMMUNOTHERAPY ON LATE PHASE ALLERGEN INFLAMMATORY RESPONSE
D.STANDARDIZED ALLERGENIC EXTRACTS
RAGWEED POLLEN, CAT DANDER, DUST MITE, INSECT VENOM
E.RECURRENCE OF SYMPTOMS AFTER DISCONTINUING ALLERGEN IMMUNOTHERAPY
F.DISEASE SPECIFIC USE
ALLERGIC RHINITIS, INSECT ANAPHYLAXIS, ASTHMA
G.COST AND EFFICACY OF IMMUNOTHERAPY VERSUS PHARMACOTHERAPY
H.RESEARCH STUDIES COMPARED TO CLINICAL USE IN PRACTICE
I.MODIFIED ALLERGEN COMPARED TO PERENNIAL ALLERGEN INJECTION TREATMENT
J.SYMPTOMATIC VERSUS CURATIVE TREATMENT
1. ALLERGENIC AVOIDANCE:
ANIMAL DANDER, DUST MITE, POLLEN, MOULD.
11. PHARMACOTHERAPY FOR ALLERGIC RHINOCONJUNCTIVITIS:
H1 RECEPTOR ANTAGONISTSORAL, NASAL SPRAY, EYEDROPS
DECONGESTANTS
NASAL SPRAY (SHORT TERM USE ONLY) ORAL
CORTICOSTEROIDS
NASAL SPRAY, METERED DOSE INHALER, ORAL
DISODIUM CROMOGLYCATE/NEDOCROMIL
NOSE SPRAY, EYE DROPS, METERED DOSE INHALER
IPRATROPIUM BROMIDE
NOSE SPRAY, METERED DOSE INHALER
111. IMMUNOTHERAPY
A.PITFALLS
1. COST2. INCONVENIENCE (FREQUENCY AND DURATION OF TREATMENT)
3. FEW STANDARDIZED ALLERGENIC EXTRACTS AVAILABLE
4. INABILITY TO PREDICT FAVOURABLE RESPONDERS
5. DIFFICULT TO OBJECTIVELY DETERMINE CLINICAL RESPONSE
6. NO LABORATORY PARAMETERS AVAILABLE TO GUIDE DISCONTINUATION OF ALLERGEN IMMUNOTHERAPY
7. PRESENTLY NOT CURATIVE
B.POTENTIAL ADVERSE EFFECTS OF ALLERGEN IMMUNOTHERAPY
1. A) ANAPHYLAXIS (URTICARIA, ASTHMA, HYPOTENSION, DEATH)B) SEVERE AND FATAL ANAPHYLAXIS IF TAKING BETA- BLOCKING AGENTS
2. AGGRAVATION OF ALLERGIC SYMPTOMS (ASTHMA AND RHINITIS)
3. LOCAL SWELLING AT INJECTION SITE
4. CONCERN ABOUT THE POTENTIAL TO PRECIPITATE AND/OR ADVERSELY AFFECT EXISTING IMMUNOLOGIC DISEASES (SERUM SICKNESS, SLE, RHEUMATOID ARTHRITIS).
5. SENSITIZATION (IF INAPPROPRIATELY USED)