International consensus on allergy immunotherapy Jutel, Marek, MD; Agache, Ioana, MD; Bonini, Sergio, MD ...
Journal of allergy and clinical immunology,
09/2015, Volume:
136, Issue:
3
Journal Article
Peer reviewed
Open access
Allergen immunotherapy (AIT) has been used to treat allergic disease since the early 1900s. Despite numerous clinical trials and meta-analyses proving AIT efficacious, it remains underused and is ...estimated to be used in less than 10% of patients with allergic rhinitis or asthma worldwide. In addition, there are large differences between regions, which are not only due to socioeconomic status. There is practically no controversy about the use of AIT in the treatment of allergic rhinitis and allergic asthma, but for atopic dermatitis or food allergy, the indications for AIT are not well defined. The elaboration of a wider consensus is of utmost importance because AIT is the only treatment that can change the course of allergic disease by preventing the development of asthma and new allergen sensitizations and by inducing allergen-specific immune tolerance. Safer and more effective AIT strategies are being continuously developed both through elaboration of new allergen preparations and adjuvants and alternate routes of administration. A number of guidelines, consensus documents, or both are available on both the international and national levels. The international community of allergy specialists recognizes the need to develop a comprehensive consensus report to harmonize, disseminate, and implement the best AIT practice. Consequently, the International Collaboration in Asthma, Allergy and Immunology, formed by the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the World Allergy Organization, has decided to issue an international consensus on AIT.
This article continues the comprehensive international consensus (ICON) statement on allergen immunotherapy (AIT). The initial article also recently appeared in the Journal . The conclusions below ...focus on key mechanisms of AIT-triggered tolerance, requirements in allergen standardization, AIT cost-effectiveness, and regulatory guidance. Potential barriers to and facilitators of the use of AIT are described in addition to future directions. International allergy specialists representing the European Academy of Allergy and Clinical Immunology; the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma and Immunology; and the World Allergy Organization critically reviewed the existing literature and prepared this summary of recommendations for best AIT practice. The authors contributed equally and reached consensus on the statements presented herein.
Allergy immunotherapy (AIT) is an effective treatment for allergic asthma and rhinitis, as well as venom-induced anaphylaxis. In addition to reducing symptoms, AIT can change the course of allergic ...disease and induce allergen-specific immune tolerance. In current clinical practice immunotherapy is delivered either subcutaneously or sublingually; some allergens, such as grass pollen, can be delivered through either route, whereas others, such as venoms, are only delivered subcutaneously. Both subcutaneous and sublingual immunotherapy appear to have a duration of efficacy of up to 12 years, and both can prevent the development of asthma and new allergen sensitivities. In spite of the advances with AIT, safer and more effective AIT strategies are needed, especially for patients with asthma, atopic dermatitis, or food allergy. Novel approaches to improve AIT include use of adjuvants or recombinant allergens and alternate routes of administration. As part of the PRACTALL initiatives, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology nominated an expert team to develop a comprehensive consensus report on the mechanisms of AIT and its use in clinical practice, as well as unmet needs and ongoing developments in AIT. This resulting report is endorsed by both academies.
Background According to meta-analyses and reviews, subcutaneous allergen immunotherapy (SCIT) and sublingual allergen immunotherapy (SLIT) are beneficial in patients with allergic rhinitis (AR) and ...allergic asthma (AA) induced by house dust mites (HDMs). However, the reported effect sizes have varied greatly from one study to another. Objective We sought to perform an evidence-based medicine assessment of commercially available SCIT and SLIT formulations in patients with HDM-induced AA and HDM-induced AR. Methods We searched for double-blind, placebo-controlled randomized clinical trials and analyzed study designs, doses, regimens, patient-reported outcomes, safety reporting, and compliance. Results Forty-four studies met our inclusion criteria. Some studies tested both SLIT and SCIT or scored both AA and AR outcomes; therefore we reviewed 35 treatment arms in patients with AA (20 for SCIT and 15 for SLIT) and 23 treatment arms in patients with AR (7 for SCIT and 16 for SLIT). The treatment duration ranged from 6 weeks to 3 years. For SCIT, the dose of Der p 1 major allergen (when reported) ranged from 7 to 30 μg for maintenance doses and 60 to 420 μg for cumulative doses. For SLIT, the doses of Der p 1 (when reported) were 0.8 to 70 μg for maintenance doses and 60 to 23,695 μg for cumulative doses. Safety data were often absent or poorly reported. A statistically significant active versus placebo symptom score was observed more frequently for SCIT than for SLIT. Conclusion There is no consensus on basic treatment parameters (eg, dose and duration) in HDM SCIT and SLIT. There is an urgent need for rigorous, long-term, double-blind, placebo-controlled randomized clinical trials with an efficacy criterion that reflects the particular features of HDM-induced allergic disease.
Background Immunotherapy inhibits basophil histamine release, but the assay is cumbersome, and no one has studied the effects of immunotherapy withdrawal. Objective Intracellular fluorochrome-labeled ...diamine oxidase (DAO) was used as a novel functional readout of basophil histamine release after immunotherapy. Results were compared with conventional basophil surface expression of activation markers. Methods Subcutaneous immunotherapy (SCIT)–treated patients (n = 14), sublingual immunotherapy (SLIT)–treated patients (n = 12), participants who completed 3 years of treatment with grass pollen sublingual immunotherapy (the SLIT-TOL group; n = 6), patients with untreated seasonal allergic rhinitis (SAR; n = 24), and nonatopic control subjects (n = 12) were studied. Intracellularly labeled DAO+ and surface expression of CD203cbright , CD63+ , and CD107a+ on chemoattractant receptor-homologous molecule expressed on TH 2 lymphocytes (CRTh2)–positive basophils were measured by means of flow cytometry. Serum IgG4 levels and serum inhibitory activity for IgE-allergen complex binding to B cells (IgE-FAB) and basophil histamine release were also determined. Results Proportions of allergen-stimulated DAO+ CRTh2+ basophils were higher in participants in the SCIT, SLIT, and SLIT-TOL groups (all P < .0001) compared with those in patients in the SAR group. Similarly, there were lower proportions of CRTh2+ basophils expressing surface CD203cbright (all P < .001), CD63 (all P < .001), and CD107a (all P < .01). Rhinitis symptoms were lower in the SCIT, SLIT, and SLIT-TOL groups ( P < .001) compared with those in the SAR group. Serum inhibitory activity for IgE-FAB and basophil histamine release were also significantly greater in all immunotherapy groups ( P < .05) compared with the SAR group. Conclusion These results support long-term clinical and immunologic tolerance during and after grass pollen immunotherapy. Intracellularly labeled DAO expression by basophils merits further investigation as a surrogate biomarker for monitoring efficacy and tolerance after immunotherapy.
Background Grass pollen immunotherapy is an effective treatment for seasonal allergic rhinitis that provides the opportunity to study the induction and maintenance of allergen-specific immune ...tolerance. Objectives We investigated the relationship between clinical responsiveness, regulatory cytokine production, and antibody responses to allergen during 1 year of immunotherapy. Methods Eighteen subjects with severe seasonal allergic rhinitis were randomized double-blind to receive active or placebo injections of an alum-adsorbed grass pollen vaccine (Alutard SQ). Subjects underwent repeated testing of early- and late-phase skin responses to intradermal allergen, and cellular responses to grass pollen allergen were tested. Sera were tested for allergen-specific IgG4, IgA, and inhibitory activity in biologic assays of IgE responses. Results Grass pollen immunotherapy was effective in reducing overall symptom scores ( P < .05) and conjunctival reactivity ( P < .05). In the active group significant IL-10 production occurred early at low allergen doses and at a similar time as inhibition of late skin responses at 2 to 4 weeks. Serum allergen-specific IgG4, IgA, and inhibitory antibody activity for basophil histamine release and IgE-facilitated allergen binding to B cells occurred later, at 6 to 12 weeks, at higher allergen doses and preceded inhibition of early skin responses. Conclusion IL-10 responses occur early but at immunotherapy doses that are not clinically effective. Later induction of inhibitory antibodies, including IgG4 and IgA, might be required for efficacy through modulation of IgE-mediated events.
Background Allergen immunotherapy is currently the only disease-modifying treatment available for allergic rhinitis and allergic asthma. Objectives We sought to evaluate the induction of sustained ...tolerance to allergen when anti–IL-4 was combined with a suboptimal course of grass pollen subcutaneous immunotherapy (SCIT) using the allergen-induced skin late-phase response (LPR) and exploratory immune monitoring as surrogate markers of therapeutic response. Methods In this randomized, double-blind, 3-group parallel design trial, 37 participants with seasonal allergic rhinitis received suboptimal SCIT (30,000 standardized quality units) in combination with anti–IL-4 (VAK694) and suboptimal SCIT (30,000 standardized quality units) plus placebo antibody or double placebo (placebo SCIT and placebo antibody) restricted to 13 weeks before the grass pollen season. The primary end point was the size of the LPR at 12 months. Exploratory end points included measures of the immunomodulatory activity of treatment by using IL-4 and IL-10 FluoroSpot assays, flow cytometry of T cells, and measurement of IgE, IgG4 , and facilitated antigen binding. Results Both active treatment arms led to a substantial and sustained reduction of the LPR with no additional suppression with addition of anti–IL-4. Treatment with anti–IL-4 and SCIT compared with SCIT alone led to a sustained reduction in allergen-specific IL-4–producing cell counts ( P < .01). Both active treatment arms led to induction of dual IL-4/IL-10–producing cells during the pollen season. Conclusion The combination of anti–IL-4 with SCIT provided no additional benefit over SCIT alone in suppressing the allergen-induced skin LPR. A larger trial is needed to assess whether the observed ex vivo downregulation of TH 2 responses might translate into clinical benefit.
Sublingual allergen immunotherapy provides a new option for patients with allergic rhinitis in the United States. The efficacy of these sublingual immunotherapy tablets in the treatment of allergic ...rhinitis has been firmly established in large multicenter clinical trials. In addition, the clinical benefits of sublingual immunotherapy might persist after treatment is discontinued. Local reactions, such as gastrointestinal or oropharyngeal symptoms, are common. However, severe anaphylaxis is rare, and therefore the immunotherapy tablets can be administered at home. Sublingual immunotherapy for allergic rhinitis has been used successfully for years in Europe, and these products might be appropriate for patients who do not do well with standard drug therapy or for those who prefer a disease-modifying approach.
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