Advertisement
Mayo Clinic Proceedings Home

Allergen Immunotherapy

      Allergen immunotherapy involves exposing a patient to a gradually escalating dose of a specific allergen with the intention of decreasing allergic and inflammatory responses, ultimately leading to a sustained decrease in allergic symptoms. A build-up phase (once weekly injections) is followed by a maintenance phase (once monthly injections) that generally continues for 3 to 5 years. Allergen immunotherapy is indicated for select patients with allergic rhinoconjunctivitis, allergic asthma, and stinging insect hypersensitivity. The safety and efficacy of allergen immunotherapy have been confirmed by numerous well-designed studies. Recent research has helped uncover the mechanisms by which allergen immunotherapy exerts its therapeutic effect, paving the way for the development of safer, more effective therapy for a wider range of allergic diseases.
      AIT (allergen immunotherapy), ARC (allergic rhinoconjunctivitis), CI (confidence interval), EPR-3 (Expert Panel Report-3 Asthma Full Report), GINA (Global Initiative for Asthma), IgE (immunoglobulin E), JCAAI (Joint Council of Allergy, Asthma, and Immunology), OR (odds ratio), SLIT (sublingual immunotherapy), VIT (venom immunotherapy)
      Allergic rhinoconjunctivitis (ARC), allergic asthma, and stinging insect hypersensitivity are commonly encountered medical conditions that cause substantial morbidity and mortality worldwide. Affecting between 5% and 22% of the population and decreasing quality of life, ARC was estimated in one study to have the 5th highest direct and indirect economic burden, with only hypertension, heart disease, mental illness, and arthritis ranked higher.
      • Bellanti JA
      • Wallerstedt DB
      Allergic rhinitis update: epidemiology and natural history.
      • Law AW
      • Reed SD
      • Sundy JS
      • Schulman KA
      Direct costs of allergic rhinitis in the United States: estimates from the 1996 Medical Expenditure Panel Survey.
      • Goetzel RZ
      • Long SR
      • Ozminkowski RJ
      • Hawkins K
      • Wang S
      • Lynch W.
      Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers.
      Asthma, too, is a chronic disease leading to substantial morbidity and mortality, causing thousands of deaths and nearly 500,000 hospitalizations annually.
      • Mannino DM
      • Homa DM
      • Akinbami LJ
      • Moorman JE
      • Gwynn C
      • Redd SC
      Surveillance for asthma—United States, 1980-1999.
      Although the prevalence of asthma may have plateaued in some areas, it remains a concerning and costly epidemic that is largely unexplained.
      • Eder W
      • Ege MJ
      • von Mutius E.
      The asthma epidemic.
      Hypersensitivity reactions to honeybee, wasp, yellow jacket, hornet, or fire ant stings lead to potentially life-threatening reactions in 0.4% to 0.8% of children and 3.0% of adults, causing an estimated 40 deaths per year.
      • Barnard JH
      Studies of 400 hymenoptera sting deaths in the United States.
      • Moffitt JE
      • Golden DBK
      • Reisman RE
      • et al.
      Stinging insect hypersensitivity: a practice parameter update.
      Avoidance of the suspected allergen(s) is the first-line treatment for these conditions. However, in many cases, exposure to a particular allergen cannot be completely avoided. Medical therapies directed at reversing allergic inflammation (corticosteroids) and controlling the effects of released mediators (antihistamines and leukotriene modifiers) are not always fully effective or well tolerated.
      Allergen immunotherapy (AIT) offers a unique approach, one that reduces allergic symptoms on a long-term basis by altering the immune response. First reported in 1911 with grass pollen extracts, AIT administration has remained an important treatment option for ARC, allergic asthma, and venom hypersensitivity.
      • Noon L.
      Prophylactic inoculation against hay fever.
      • Freeman J.
      Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.
      Research has clarified the immunological mechanisms underlying AIT
      • Till SJ
      • Francis JN
      • Nouri-Aria K
      • Durham SR
      Mechanisms of immunotherapy.
      ; the immune system is steered from a type 2 (allergic) to a type 1 (nonallergic) T helper cell response through a variety of immunological pathways. Allergen immunotherapy leads to increased production of specific IgG4 antibodies that block immunoglobulin E (IgE)-mediated histamine release from basophils and disrupts IgE-mediated antigen presentation to T cells.
      • Till SJ
      • Francis JN
      • Nouri-Aria K
      • Durham SR
      Mechanisms of immunotherapy.
      Interleukin 10, elevated levels of which are observed after AIT, has been shown to suppress mast cells, eosinophils, and T cells.
      • Till SJ
      • Francis JN
      • Nouri-Aria K
      • Durham SR
      Mechanisms of immunotherapy.
      Our understanding of the immunological mechanisms of AIT has improved, and controlled prospective studies have provided insight into AIT administration. However, the allergist must artfully apply the currently available evidence to patients because each requires an individual assessment of benefit and risk.

      IMMUNOTHERAPY FOR ALLERGIC RHINOCONJUNCTIVITIS

      Poorly controlled ARC causes poor performance at work and school and a diminished quality of life. Medications and avoidance provide suboptimal control in up to 40% of some patient populations.
      • White P
      • Smith H
      • Webley F
      • Frew A.
      A survey of the quality of information leaflets on hayfever available from general practices and community pharmacies.
      A meta-analysis of AIT for ARC showed that patients receiving AIT had significant improvements in symptom and medication scores (odds ratio [OR], 1.81; 95% confidence interval [CI], 1.48-2.23).
      • Ross RN
      • Nelson HS
      • Finegold I.
      Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-controlled studies.
      A double-blind, randomized, placebo-controlled study
      • Frew AJ
      • Powell RJ
      • Corrigan CJ
      • Durham SR
      • for the UK Immunotherapy Study Group
      Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.
      showed that patients with grass allergy that was inadequately controlled with standard drug therapy experienced significant reductions in their symptom and medication scores (a reduction of 29% and 32%, respectively) after just one season of grass AIT, suggesting that AIT may be of some benefit to patients whose allergy is inadequately controlled by conventional medical therapies. Clinical and immunological evidence supports the long-term efficacy of AIT, an attractive aspect for patients wishing to reduce or avoid allergy medications in the future.
      • Durham SR
      • Walker SM
      • Varga EM
      • et al.
      Long-term clinical efficacy of grass-pollen immunotherapy.
      Additionally, AIT may play an important preventive role in the pediatric population. Preliminary data from Italy and France suggest that AIT, when initiated early, may decrease the development of new allergic sensitivities.
      • Pajno GB
      • Barberio G
      • De Luca F
      • Moribito L
      • Parmiani S.
      Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy: a six-year follow-up study.
      • Des Roches A
      • Paradis L
      • Menardo JL
      • Bouges S
      • Daures JP
      • Bousquet J
      Immunotherapy with a standardized Dermatophagoides pteronyssinus extract, IV: specific immunotherapy prevents the onset of new sensitizations in children.
      • Purello-D'Ambrosio F
      • Gangemi S
      • Merendino R
      • et al.
      Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not: a retrospective study.
      It may prevent the onset of asthma; 5- and 10-year follow-up of the preventive allergy treatment study showed that 3 years of AIT with grass or birch pollen decreased the likelihood of asthma development in the long term.
      • Niggemann B
      • Jacobsen L
      • Dreborg S
      • et al.
      PAT Investigator Group. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.
      • Valovirta E
      • Jacobsen L
      • Niggemann B
      • et al.
      A 3-year course of subcutaneous specific immunotherapy results in long-term prevention of asthma in children: ten year follow-up on the PAT-study.

      IMMUNOTHERAPY FOR ASTHMA

      A meta-analysis reviewed placebo-controlled trials for AIT and asthma; compared to placebo, patients treated with AIT were more likely to have statistically significant improvement in asthma symptoms (OR, 2.76; 95% CI, 2.22-3.42) and pulmonary function (OR, 2.87; 95% CI, 1.82-4.52), increases in protection against bronchial challenge (OR, 1.81; 95% CI, 1.32-2.49), and decreases in medication requirements (OR, 2.00; 95% CI, 1.46-2.72).
      • Ross RN
      • Nelson HS
      • Finegold I.
      Effectiveness of immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies.
      A Cochrane review of AIT and asthma found that the number needed to treat to avoid a deterioration of asthma symptoms is 4, and the number needed to treat to avoid an increase in asthma medication is 5.
      • Abramson MJ
      • Puy RM
      • Weiner JM
      Allergen immunotherapy for asthma.
      The review found that AIT significantly reduced bronchial hyperreactivity but had no consistent effect on pulmonary function.
      • Abramson MJ
      • Puy RM
      • Weiner JM
      Allergen immunotherapy for asthma.
      An interesting study that compared inhaled budesonide and AIT for 1 year found them to be equal at 12 months for symptom scores and forced expiratory volume in the first second of expiration, but also noted that the budesonide group improved more rapidly.
      • Shaikh WA
      Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial.
      However, the AIT group maintained efficacy after treatment was stopped, whereas the budesonide group did not.
      • Shaikh WA
      Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial.
      Patients with allergic asthma benefit from AIT, but safety concerns arise when AIT is used for patients with severe uncontrolled asthma. Caution is advised for patients with asthma who have a forced expiratory volume in the first second of expiration that is less than 70% of predicted.

      IMMUNOTHERAPY FOR STINGING INSECT HYPERSENSITIVITY

      Venom immunotherapy (VIT) is an effective treatment option to reduce the risk of an anaphylactic reaction in an allergic patient after a sting. A comprehensive management program for stinging insect hypersensitivity also includes instruction in sting avoidance and prescription of epinephrine and directions for its appropriate use.
      • Freeman TM
      Hypersensitivity to hymenoptera stings.
      Only patients with systemic symptoms after the sting should be tested for allergy; those with large local reactions have not been shown to benefit from VIT (although research is ongoing in this area). Falsely negative venom skin tests are possible, especially immediately after the anaphylactic reaction.
      • Golden DB
      • Tracy JM
      • Freeman TM
      • Hoffman DR
      Insect Committee of the American Academy of Allergy, Asthma and Immunology. Negative venom skin test results in patients with histories of systemic reaction to a sting.
      Patients with negative venom skin tests should undergo further assessment with venom-specific IgE antibody tests.
      • Golden DB
      • Tracy JM
      • Freeman TM
      • Hoffman DR
      Insect Committee of the American Academy of Allergy, Asthma and Immunology. Negative venom skin test results in patients with histories of systemic reaction to a sting.
      Patients with negative skin or in vitro tests are not good candidates for VIT. Controlled trials have found the efficacy of VIT to be 95% to 98%.
      • Hunt KJ
      • Valentine MD
      • Sobotka AK
      • Benton AW
      • Amodio FJ
      • Lichtenstein LM
      A controlled trial of immunotherapy in insect hypersensitivity.
      • Muller U
      • Thurnheer U
      • Patrizzi R
      • Spiess J
      • Hoigne R.
      Immunotherapy in bee sting hypersensitivity: bee venom versus wholebody extract.
      In fact, only 5% of children treated with VIT experience a subsequent systemic reaction if stung again within 10 to 20 years after VIT, compared to 32% of untreated children.
      • Golden DBK
      • Kagey-Sobotka A
      • Norman PS
      • Hamilton RG
      • Lichtenstein LM
      Outcomes of allergy to insect stings in children, with and without venom immunotherapy.
      Local reactions are common in VIT, but they should not substantially alter the planned treatment course. Rush VIT programs have been used successfully and safely.
      • Moffitt JE
      • Golden DBK
      • Reisman RE
      • et al.
      Stinging insect hypersensitivity: a practice parameter update.
      Duration of therapy is typically 3 to 5 years but may be longer for those with a history of a near-fatal reaction, a systemic reaction while receiving VIT, or honeybee allergy.
      • Golden DBK
      Insect sting allergy and venom immunotherapy.

      PATIENT SELECTION

      Carefully identifying appropriate candidates is the first step in designing an effective and safe AIT program (Table 1). Strong candidates for AIT are the following: those who have positive immediate hypersensitivity skin test results (or serum-specific IgE test results) that correlate with clinical symptoms and are not controlled by avoidance measures and medications; those who wish to avoid the adverse effects of medications; those who wish to reduce the long-term costs of allergy medication; or, in the case of venom hypersensitivity, those who have had a systemic reaction after an insect sting. It is important to identify any patient characteristics (such as uncontrolled asthma) that may increase the risk of a serious reaction.
      • Bernstein DI
      • Wanner M
      • Borish L
      • Liss GM
      Immunotherapy Committee of the American Academy of Allergy, Asthma and immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
      In a study that reviewed fatal anaphylaxis, late epinephrine administration was associated with an increased risk for fatal anaphylaxis after AIT administration.
      • Bernstein DI
      • Wanner M
      • Borish L
      • Liss GM
      Immunotherapy Committee of the American Academy of Allergy, Asthma and immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
      Patients taking β-blocker medications and those with serious heart disease may respond poorly to resuscitative efforts should anaphylaxis occur. Caution should be exercised in administering AIT to children younger than 5 years because they may not be able to report symptoms of impending anaphylaxis. Allergen immunotherapy can be continued in pregnant patients as a maintenance prescription, but a new build-up prescription should be delayed until after delivery.
      TABLE 1Allergen Immunotherapy Indications
      • Allergic rhinoconjunctivitis
        • Positive allergy test results correlate with symptoms
        • Symptom control is inadequate despite avoidance measures and medications
        • Patient wishes to avoid cost or adverse effects of medications
      • Allergic asthma
        • Positive allergy test results correlate with symptoms
        • Asthma control is inadequate while patient is taking daily preventive medications
        • Symptoms occur nearly year round
        • Allergic rhinitis coexists with allergic asthma
      • Stinging insect hypersensitivity
        • Skin or in vitro testing reveals evidence of venom-specific IgE
        • There is evidence of systemic (not local) reaction
        • There is evidence of urticarial reaction (in those older than 16 years)
        • Patient has a high risk of exposure

      IMMUNOTHERAPY SAFETY

      After careful selection of the AIT candidate, the allergist must discuss the risks and benefits of AIT with the patient so that he or she can make an informed decision. On the basis of data from a large survey, the risk of a fatal anaphylactic reaction from AIT has been calculated to be 1 in 2.5 million injections (about 3 deaths per year in the United States); near-fatal reactions occur once in every 200,000 injections.
      • Bernstein DI
      • Wanner M
      • Borish L
      • Liss GM
      Immunotherapy Committee of the American Academy of Allergy, Asthma and immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
      • Amin HS
      • Liss GM
      • Bernstein DI
      Evaluation of near-fatal reactions to allergen immunotherapy injections.
      The dosing schedule also plays a role in the reaction rate. It involves a build-up phase, during which the allergen dose is gradually increased, and a maintenance phase, during which the target dose of allergen that is immunologically necessary to decrease allergic symptoms is administered. A rush immunotherapy schedule, in which the maintenance dose is very rapidly achieved, can result in a higher reaction rate. Recent data suggest that cluster immunotherapy, which involves 2 to 4 injections per week, is as safe as a standard schedule of 1 injection per week.
      • Tabar AI
      • Echechipia S
      • Garcia BE
      • et al.
      Double-blind comparative study of cluster and conventional immunotherapy schedules with Dermatophagoides pteronyssinus.
      • Cox L.
      Accelerated immunotherapy schedules: review of efficacy and safety.
      Because many patients find the frequent visits to a medical office and the requisite 30-minute monitoring period after injection to be inconvenient, patient nonadherence can compromise the safety of an AIT program.

      IMMUNOTHERAPY ADMINISTRATION

      To ensure proper administration, an AIT program should be monitored by an allergist at 6- to 12-month intervals. However, patients may prefer to receive their injections in the office of their primary care physician. Thus, primary care physicians must understand how to administer immunotherapy and how to identify and treat adverse reactions. Recently published guidelines emphasize the need to standardize injection administration and prescription forms, mixing protocols (using color-coded bottles), and, when possible, extracts (Table 2).
      • Joint Task Force on Practice Parameters
      Allergen immunotherapy: a practice parameter.
      TABLE 2Standardized Allergy Extracts
      • Cat hair and pelt
      • Dust mites (Dermatophagoides pteronyssinus and D farinae)
      • Short ragweed
      • Grasses (Bermuda, perennial rye, orchard, Timothy, sweet vernal, Kentucky bluegrass, meadow fescue, red top)
      • Hymenoptera venoms (yellow jacket, honeybee, wasp, yellow hornet, and white-faced hornet)
      After receiving a subcutaneous injection in the upper arm, the patient must be monitored for an adverse reaction for at least 30 minutes. Local reactions can be treated with cool compresses, topical corticosteroids, or antihistamines, whereas systemic reactions must be treated with administration of epinephrine (preferably intramuscular), placement of a tourniquet above the injection site, and other supportive measures (oxygen, intravenous fluids, and inhaled β-agonists).
      • Joint Task Force on Practice Parameters
      The diagnosis and management of anaphylaxis: an updated practice parameter.
      Delayed adverse reactions should be reported to the allergist. It is important to decrease the dose by approximately 50% after receiving a new lot of allergen, as even standardized vials differ from bottle to bottle in their actual concentrations.

      THE FUTURE OF AIT

      Clinical evidence strongly supports the efficacy and safety of AIT for pollens, dust mites, cat allergy, and venom; however, fewer studies have examined the use of AIT for mold and dog allergy. Small, well-controlled trials suggest that 3 to 5 years of successful AIT may result in long-lasting benefit, but confirmatory studies are needed. Further studies in the pediatric population are needed to confirm any preventive effects of AIT.
      Perhaps the best studied investigational approach is high-dose sublingual immunotherapy (SLIT). A meta-analysis of available SLIT data from randomized controlled trials found a significant reduction in symptoms and medication use in the SLIT group.
      • Wilson DR
      • Lima MT
      • Durham SR
      Sublingual immunotherapy for allergic rhinitis: systemic review and meta-analysis.
      More studies are needed to clarify the efficacy of SLIT vs standard subcutaneous immunotherapy. Currently, SLIT is not licensed in the United States and is much more commonly prescribed in Europe.
      In a second investigational approach, anti-IgE therapy is administered before and during AIT. Reductions in the rates of anaphylactic reactions to immunotherapy (up to a 5-fold decrease) and in symptom scores have been observed in prospective studies.
      • Rolinck-Werninghaus C
      • Hamlemann E
      • Keil T
      • et al.
      Omalizumab Rhinitis Study Group. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children.
      • Casale TB
      • Busse WW
      • Kline JN
      • Immune Tolerance Network Group
      • et al.
      Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis.
      • Kuehr J
      • Brauburger J
      • Zielen S
      • et al.
      Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis.
      The Federal Drug Administration, which recently added a black box warning for omalizumab that describes the risk of anaphylaxis, recommends that patients be observed for at least 2 hours after administration and that they be educated in the recognition and treatment of anaphylaxis.
      • US Food and Drug Administration
      FDA proposes to strengthen label warning for Xolair.
      Third, novel vaccine delivery systems have been developed to improve the efficacy and safety of AIT. Recombinant vaccines, smaller peptides, or costimulatory adjuvants have been used to improve immune recognition. Creticos et al
      • Creticos PS
      • Schroeder JT
      • Hamilton PG
      • Immune Tolerance Network Group
      • et al.
      Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.
      showed that long-term clinical efficacy could be achieved with a ragweed pollen antigen that had been conjugated to an immunostimulatory DNA sequence capable of binding dendritic cell toll-like receptors.
      Finally, promising studies using immunotherapy for food allergies and atopic dermatitis have been published.
      • 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.
      • 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.
      Future research in these areas may expand the therapeutic repertoire for these challenging diseases.

      GUIDELINES FOR AIT

      The 2003 guidelines for AIT will soon be updated 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 (JCAAI). Other guidelines related to immunotherapy include the Expert Panel Report-3 Asthma Full Report (EPR-3) (in preparation), the Global Initiative for Asthma (GINA),
      • Global strategy for asthma management and prevention, Global Initiative for Asthma (GINA)
      the JCAAI practice parameters for stinging insect hypersensitivity,
      • Moffitt JE
      • Golden DBK
      • Reisman RE
      • et al.
      Stinging insect hypersensitivity: a practice parameter update.
      and the JCAAI practice parameters for the diagnosis and management of anaphylaxis.
      • Joint Task Force on Practice Parameters
      The diagnosis and management of anaphylaxis: an updated practice parameter.
      Both the GINA and draft EPR-3 guidelines recognize the importance of allergic triggers in asthma. The draft EPR-3 guidelines recommend careful history taking combined with testing for specific IgE sensitivities. Persistent asthma should be treated with daily preventive medications, such as inhaled corticosteroids or leukotriene modifiers. According to the draft EPR-3 guidelines, AIT for asthma may be considered if there is clear evidence of symptoms and exposure (with a confirmed IgE sensitivity), if symptoms occur nearly year round, and if the asthma is not controlled by medications.

      CONCLUSIONS

      Allergen immunotherapy is a safe and effective therapy for ARC, allergic asthma, and stinging insect hypersensitivity. It should be considered for all patients with ARC as well as for those with persistent asthma, confirmed allergic sensitivities, and poor asthma control despite treatment with inhaled corticosteroids or leukotriene modifiers. Allergen immunotherapy should be strongly considered for patients with poor symptom control or adverse reactions to medications and for those with systemic reactions to insect stings and confirmatory skin or in vitro testing. Exciting new research in AIT may very well expand the allergic patient population that could benefit from this therapy.

      REFERENCES

        • Bellanti JA
        • Wallerstedt DB
        Allergic rhinitis update: epidemiology and natural history.
        Allergy Asthma Proc. 2000; 21: 367-370
        • Law AW
        • Reed SD
        • Sundy JS
        • Schulman KA
        Direct costs of allergic rhinitis in the United States: estimates from the 1996 Medical Expenditure Panel Survey.
        J Allergy Clin Immunol. 2003; 111: 296-300
        • Goetzel RZ
        • Long SR
        • Ozminkowski RJ
        • Hawkins K
        • Wang S
        • Lynch W.
        Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers.
        J Occup Environ Med. 2004; 46: 398-412
        • Mannino DM
        • Homa DM
        • Akinbami LJ
        • Moorman JE
        • Gwynn C
        • Redd SC
        Surveillance for asthma—United States, 1980-1999.
        MMWR Surveill Summ. 2002; 51: 1-13
        • Eder W
        • Ege MJ
        • von Mutius E.
        The asthma epidemic.
        N Engl J Med. 2006; 355: 2226-2235
        • Barnard JH
        Studies of 400 hymenoptera sting deaths in the United States.
        J Allergy Clin Immunol. 1973; 52: 259-264
        • Moffitt JE
        • Golden DBK
        • Reisman RE
        • et al.
        Stinging insect hypersensitivity: a practice parameter update.
        J Allergy Clin Immunol. 2004; 114: 869-886
        • Noon L.
        Prophylactic inoculation against hay fever.
        Lancet. 1911; 177: 1572-1573
        • Freeman J.
        Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.
        Lancet. 1911; 178: 814-817
        • Till SJ
        • Francis JN
        • Nouri-Aria K
        • Durham SR
        Mechanisms of immunotherapy.
        J Allergy Clin Immunol. 2004; 113: 1025-1034
        • White P
        • Smith H
        • Webley F
        • Frew A.
        A survey of the quality of information leaflets on hayfever available from general practices and community pharmacies.
        Clin Exp Allergy. 2004; 34: 1438-1443
        • Ross RN
        • Nelson HS
        • Finegold I.
        Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-controlled studies.
        Clin Ther. 2000; 22: 342-350
        • Frew AJ
        • Powell RJ
        • Corrigan CJ
        • Durham SR
        • for the UK Immunotherapy Study Group
        Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis.
        J Allergy Clin Immunol. 2006; 117: 319-325
        • Durham SR
        • Walker SM
        • Varga EM
        • et al.
        Long-term clinical efficacy of grass-pollen immunotherapy.
        N Engl J Med. 1999; 341: 468-475
        • Pajno GB
        • Barberio G
        • De Luca F
        • Moribito L
        • Parmiani S.
        Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy: a six-year follow-up study.
        Clin Exp Allergy. 2001; 31: 1392-1397
        • Des Roches A
        • Paradis L
        • Menardo JL
        • Bouges S
        • Daures JP
        • Bousquet J
        Immunotherapy with a standardized Dermatophagoides pteronyssinus extract, IV: specific immunotherapy prevents the onset of new sensitizations in children.
        J Allergy Clin Immunol. 1997; 99: 450-453
        • Purello-D'Ambrosio F
        • Gangemi S
        • Merendino R
        • 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
        • Niggemann B
        • Jacobsen L
        • Dreborg S
        • et al.
        PAT Investigator Group. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children.
        Allergy. 2006; 61: 855-859
        • Valovirta E
        • Jacobsen L
        • Niggemann B
        • et al.
        A 3-year course of subcutaneous specific immunotherapy results in long-term prevention of asthma in children: ten year follow-up on the PAT-study.
        J Allergy Clin Immunol. 2006; 117: 721
        • Ross RN
        • Nelson HS
        • Finegold I.
        Effectiveness of immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies.
        Clin Ther. 2000; 22: 329-341
        • Abramson MJ
        • Puy RM
        • Weiner JM
        Allergen immunotherapy for asthma.
        Cochrane Database Syst Rev. 2003; (CD001186)
        • Shaikh WA
        Immunotherapy vs inhaled budesonide in bronchial asthma: an open, parallel, comparative trial.
        Clin Exp Allergy. 1997; 27: 1279-1284
        • Freeman TM
        Hypersensitivity to hymenoptera stings.
        N Engl J Med. 2004; 351: 1978-1984
        • Golden DB
        • Tracy JM
        • Freeman TM
        • Hoffman DR
        Insect Committee of the American Academy of Allergy, Asthma and Immunology. Negative venom skin test results in patients with histories of systemic reaction to a sting.
        J Allergy Clin Immunol. 2003; 112: 495-498
        • 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: 157-161
        • Muller U
        • Thurnheer U
        • Patrizzi R
        • Spiess J
        • Hoigne R.
        Immunotherapy in bee sting hypersensitivity: bee venom versus wholebody extract.
        Allergy. 1979; 34: 369-378
        • Golden DBK
        • 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: 668-674
        • Golden DBK
        Insect sting allergy and venom immunotherapy.
        Ann Allergy Asthma Immunol. 2006; 96: S16-S21
        • Bernstein DI
        • Wanner M
        • Borish L
        • Liss GM
        Immunotherapy Committee of the American Academy of Allergy, Asthma and immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001.
        J Allergy Clin Immunol. 2004; 113: 1129-1136
        • Amin HS
        • Liss GM
        • Bernstein DI
        Evaluation of near-fatal reactions to allergen immunotherapy injections.
        J Allergy Clin Immunol. 2006; 117: 169-175
        • 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: 109-118
        • Cox L.
        Accelerated immunotherapy schedules: review of efficacy and safety.
        Ann Allergy Asthma Immunol. 2006; 97: 126-137
        • Joint Task Force on Practice Parameters
        Allergen immunotherapy: a practice parameter.
        Ann Allergy Asthma Immunol. 2003; 90: 1-40
        • Joint Task Force on Practice Parameters
        The diagnosis and management of anaphylaxis: an updated practice parameter.
        J Allergy Clin Immunol. 2005; 115: S483-S523
        • Wilson DR
        • Lima MT
        • Durham SR
        Sublingual immunotherapy for allergic rhinitis: systemic review and meta-analysis.
        Allergy. 2005; 60: 4-12
        • Rolinck-Werninghaus C
        • Hamlemann E
        • Keil T
        • et al.
        Omalizumab Rhinitis Study Group. The co-seasonal application of anti-IgE after preseasonal specific immunotherapy decreases ocular and nasal symptom scores and rescue medication use in grass pollen allergic children.
        Allergy. 2004; 59: 973-979
        • Casale TB
        • Busse WW
        • Kline JN
        • Immune Tolerance Network Group
        • et al.
        Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis.
        J Allergy Clin Immunol. 2006 Jan; 117 (Epub 2005 Dec 2.): 134-140
        • Kuehr J
        • Brauburger J
        • Zielen S
        • et al.
        Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis.
        J Allergy Clin Immunol. 2002; 109: 274-280
        • US Food and Drug Administration
        FDA proposes to strengthen label warning for Xolair.
        (Accessed May 23, 2007.)
        • Creticos PS
        • Schroeder JT
        • Hamilton PG
        • Immune Tolerance Network Group
        • et al.
        Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.
        N Engl J Med. 2006; 355: 1445-1455
        • 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 Nov; 116 (Epub 2005 Oct 3.): 1073-1079
        • 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: 202-205
        • Global strategy for asthma management and prevention, Global Initiative for Asthma (GINA)
        (Accessed May 23, 2007.)