Indications and Mode of Action
; ; ;
Background: It is estimated that up to 24% of the population in Germany suffers from allergic rhinoconjunctivitis and 5% from allergic asthma. Allergic rhinoconjunctivitis is closely related to other atopic diseases.
Methods: This review is based on pertinent publications retrieved by a selective search of the Medline database, guidelines from Germany and abroad, and Cochrane meta-analyses.
Results: Specific immunotherapy (SIT) is the only diseases-modifying treatment option for allergies. Meta-analysis reveals standardized mean differences in allergic rhinitis symptom scores of −0.73 for subcutaneous immunotherapy (SCIT) and −0.49 for sublingual immunotherapy (SLIT); the corresponding mean differences in medication scores are −0.57 and −0.32, respectively. The treatment should be carried out for at least three years. It is indicated when the symptoms are severe and allergen avoidance is not a realistic option. The efficacy of treatment depends on the allergen dose; thus, every allergen preparation should be evaluated individually, independent of route of administration. SCIT can cause systemic adverse effects, including anaphylaxis. SLIT is safer but often causes allergic symptoms of the oral mucosa at the beginning of treatment.
Conclusion: Even though the efficacy of SIT is well documented, it is still underused. SIT should be offered as standard treatment to patients suffering from allergic rhinitis.
An increase in allergies to ubiquitous aeroallergens over the last few decades has been well documented (1). Among 13- and 14-year olds around the world, the prevalence of self-reported rhinitis symptoms now ranges from 3.2% to 66% (2). It is estimated that up to 24% of the German population suffers from allergic rhinoconjunctivitis, and 5% from allergic asthma (3). The symptoms are classified as either intermittent (present for less than four weeks per year) or persistent (present for more than four weeks per year). They are called moderate to severe if rinorrhea, nasal obstruction, and eye symptoms interfere with the untreated patient’s daily activities and/or sleep. An inhalation allergy should always be considered as a diagnostic possibility when the symptoms tend to arise at certain times of year or in particular situations. The allergic march often starts in childhood with atopic dermatitis and food allergies, followed by allergic asthma and allergic rhinoconjunctivitis.
Allergies are often trivialized and held to be more of a nuisance than a disease (4). Allergy is often not even considered as a possible cause of the patient’s symptoms. On the other hand, many people know they have allergies but still do not consult a doctor (3). In a recent Forsa survey (5), 58% of the persons with allergies who responded said that they treated their allergy themselves with non-prescription medications or allergen avoidance. 28% received specific immunotherapy (SIT), and 70% of those receiving SIT were satisfied with the outcome.
The purpose of treating allergies is to lessen the burden of symptoms and to prevent disease progression. SIT is currently the only disease-modifying treatment capable of inducing tolerance to individual allergens. When indicated, it can be performed successfully even in childhood (6, 7).
The socioeconomic cost of respiratory allergies in Europe has been estimated to lie between 36.7 and 385.1 billion euros per year, depending on the assumptions on which the calculation is based (8). The more severe the allergy, the more difficult and expensive the treatment. The overall cost per patient is about €1670/year for mild asthma and about €6000/year for severe asthma (9).
This article is intended to inform readers of the current state of knowledge regarding specific immunotherapy:
- its indications, contraindications, and adverse effects,
- its efficacy and the principles of allergen extract selection,
- and the manner in which the treatment is administered.
This article is based on information from the following sources:
- recent analyses from the Cochrane Database (10–12),
- an S2 guideline on specific immunotherapy (SIT) (13),
- the position papers of
– the Global Allergy and Asthma European Network (GA2LEN) (16),
- the recommendations of the British Society for Allergy and Clinical Immunology (19),
- the guidelines of the Committee for Medicinal Products for Human Use (CHMP) (20, 21), and
- pertinent publications retrieved by selective searches in the Medline database (main search term: “allergen-specific immunotherapy”), with special attention to recent large-scale, double-blind placebo-controlled (DBPC) clinical trials.
The treatment of allergic diseases of the respiratory tract
Allergen avoidance is the first recommendation for patients with inhalative allergies. It may be successful, for example, for patients with allergies to pets. For patients with mite allergies, however, adequate allergen avoidance is often impossible, while the attempt to avoid pollen would most probably interfere excessively with a “normal” lifestyle.
Antihistamines can be used for the symptomatic treatment of allergic rhinoconjunctivitis. Topical and systemic corticosteroids and leukotriene receptor antagonists can also be used to treat allergic asthma. These medications relieve symptoms, but they are not curative.
The efficacy of SIT has been documented in a large number of clinical trials. The results of many trials employing diverse allergen preparations in various dosages have been summarized in meta-analyses (10, 11) whose findings are presented in Table 1.
A meta-analysis of the efficacy of subcutaneous immunotherapy (SCIT) for allergic asthma yielded standardized mean differences (SMDs) of −0.59 (−0.83, −0.35) for the symptom score and −0.53 (−0.80, −0.27) for the medication score (12).
Despite differences in the study design of trials analyzing the efficacy of symptomatic treatments and of SIT there is ecidence that the therapeutic effect of SCIT is superior to that of symptomatic medication even during the first year of treatment (Table 2) (22).
The mechanism of action of specific immunotherapy
Until a few years ago, specific immunotherapy was thought to exert its beneficial effect mainly by inducing “blocking” IgG antibodies. This concept, with its functional implications for antigen presentation and effector cell function, has now been supplemented by that of regulation of the allergen-specific immune response. When the immune system is confronted with a high enough dose of allergen, tolerance is induced. The precise mechanism of action of specific immunotherapy has not yet been definitively characterized (23, 24).
Dose-dependence of the immunological effect—the definition of an optimal therapeutic dose
The dose-effect relationship of SIT has been shown in clinical trials (14). The clinical benefit of a mite extract containing 7 µg of Der p 1 per injection in the maintenance phase (Der p 1 is a major allergen of the house-dust mite Dermatophagoides pteronyssinus) cannot be significantly augmented by raising the dose to 21 µg of Der p 1, although this does lead to an increase in adverse effects. The efficacy of 0.7 µg of Der p 1 was in the range of placebo (25). Circa 8 µg of group 5 allergen in a grass-pollen tablet is about as effective as placebo, and three times this dose (25 µg per day) yields the maximum effect, without any further benefit from still higher doses (26). These findings imply that it is possible to determine optimal dosages for SCIT and SLIT.
Allergen quantification for immunotherapy
The standardization and characterization of allergen extracts was once left entirely up to the manufacturers. The characterization of extract strength is based on measurement of protein concentrations, electrochemical techniques such as immunoelectrophoresis, wheal diameter in prick tests, and in vitro inhibition tests (RAST inhibition). The development of obligatory, validated methods for allergen quantification has now become a matter of central importance.
Allergen extracts contain proteins, glycoproteins, lectins, DNA, pigments, and other substances. The immune system interacts with only a few allergens, which are called major allergens if more than 50% of patients sensitized against the allergen extract react to this particular protein. It should be a requirement that the concentration of a major allergen is declared. This is principally unproblematic when an allergen source contains only a single major allergen (e.g., Bet v 1 in birch-pollen extract), but extracts containing multiple major allergen proteins (e.g., grass-pollen extracts) are more difficult to characterize.
The quantification of individual proteins is further complicated by the fact that allergens are found in nature in different isoforms, with potentially varying biological activity. This may affect the results of protein quantification by immunological techniques.
A comparison of major allergen concentrations in different extracts can only be valid if obligatory and validated analytic methods have been used, with comparison to standardized reference allergens. In a continuation of the European CREATE project (27), a round-robin testing program (BSP90) is now being carried out with the support of the European Directorate for Quality Assurance in Medicine (EDQM) for the testing of biological reagents and standardized analytic methods for allergens in extracts. Once these reagents and methods have been published in the European Pharmacopoeia, they will become obligatory.
The allergen concentrations that are currently declared by manufacturers are an inadequate basis for the evaluation of allergen extracts. There is no substitute for clinical trials to demonstrate the efficacy of each and every allergen extract.
Requirements for allergen extracts that are to be used for SIT
A European technical guideline currently delineates the qualitative requirements for allergen extracts and their classification and composition. The most important new feature of this guideline is the definition of homologous groups of allergens, which is based on structural similarity, rather than on botanical relatedness (20). Another guideline of the European Medicines Agency (EMA) contains recommendations for the performance of clinical trials with allergen preparations; from now on, such preparations are to be developed in a standardized, stepwise algorithm with dose-finding studies and double-blind, placebo-controlled trials of efficacy (21). In Germany, more than 6000 different allergen mixtures were commercially available until the Regulation on Therapeutic Allergens (Therapie-Allergene-Verordnung, TAV) went into effect in November 2008. Most of these mixtures were then withdrawn from the market (data from the Paul Ehrlich Institute).
At present, single-substance preparations are preferred, as defined according to the concept of homologous allergen groups. The major allergens of grass and grain pollens are so highly homologous that “mixtures” of pollens from these sources are considered to be monopreparations. The same holds for allergens from birch, hazel, and alder pollen.
The evaluation of clinical effects in SIT trials
The clinical effect of SIT is evaluated by a comparison of the symptom and medication scores (SMS) during the allergy season of patients receiving either the active substance or placebo. The results obtained in different trials cannot be direcly compared for a number of reasons, but mainly because no standardized SMS has yet been defined.
A 30% difference in SMS between the active-substance group and the placebo group used to be required as the criterion for a clinically significant effect. This requirement was based on evaluation of the per-protocol (PP) population, measuring the real effect of SIT itself. At present, however, intention-to-treat (ITT) analysis is considered standard. In this method, the data from all patients enrolled in the study, including those with low compliance, are included in the analysis so that the findings will more closely correspond to the effect that can be expected under real-life conditions. The two methods of analysis can yield very disparate results: In a trial of tree-pollen SIT, for example, the SMS improvement was found to be 38.9% by PP analysis, but only 11.5% by ITT analysis (28).
The selection of allergen products
One allergen preparation cannot be recommended over another, because the findings relating to products tested in different clinical trials cannot be compared. In general, the allergen to be used should be selected by a physician who has undergone further training in allergology within his or her specialty (e.g., internal medicine), or who has specialty certification in allergology itself. The recommendations of the current guideline (13) are as follows:
- The efficacy of allergen preparations should be evaluated individually and independently of route of administration (e.g., subcutaneous or sublingual).
- High-quality allergen extracts with demonstrated efficacy should be used.
Allergen extracts are categorized as either unmodified (native) or modified (allergoids). The latter are proteins that have been treated with formaldehyde or glutaraldehyde to lower their binding affinity for IgE.
In the extracts that are commonly used today, aluminum hydroxide is the most common adsorbent for prolonging release of the allergen. Some preparations additionally contain adjuvants to enhance the immunological effect (Figure).
The best currently available evidence for the efficacy of SCIT and SLIT concerns the treatment of allergic rhinoconjunctivitis with grass-pollen extracts. Grass-pollen tablets (SLIT) have been officially approved for the treatment of adults and children on the basis of results from clinical trials. The German pediatric specialty society, however, currently hesitates to recommend SLIT because of concern about local adverse effects that are common at the start of treatment and that may interfere with long-term compliance. Long-term trials have been published that document the sustained effect of SLIT in adults after the end of treatment (29, 30). The efficacy of SLIT against allergic asthma, its potential preventive effect against asthma, and its potential preventive effect against new sensitization have not yet been adequately studied; large-scale prospective studies of these questions are currently in progress, and their findings should be published in the next few years (31). The state of the evidence for SLIT with other antigens is held to be inadequate by most specialists in Germany (13), although individual extracts from other allergen sources have achieved the status of an approved product. Information about the approval status of allergen preparations in Germany is available on the Internet (32, in German).
It is currently up to the allergist to evaluate the efficacy of allergen preparations. In the future, however, all newly approved allergen extracts will be subject to the requirements of the TAV, and their efficacy will have to be demonstrated in clinical trials whose validity will be assessed by the Paul Ehrlich Institute. Some allergen extracts are still available today whose efficacy cannot be evaluated at all because they have not been clinically tested.
The available evidence for the efficacy of SCIT and SLIT against grass-pollen allergy currently supports a positive recommendation for the preparations that have been shown to be effective in clinical trials. Patients should be informed about both treatment options so that they can make an informed choice between them in collaboration with the treating physician. (Under the new Patients’ Rights Law in Germany [Patientenrechtegesetz], patients have the right to participate in decision-making). For allergens of other sources, the evidence for SCIT is somewhat stronger and for this reason it is preferred by many allergists in Germany (Table 3). It bears pointing out once again that current evidence permits neither a comparison of SCIT against SLIT nor a comparison of different SCIT preparations with one another.
The indications for SIT
It is stated in the German guideline (13) that SIT is indicated when the causative allergen cannot be avoided, or when avoidance is not adequately effective; for further requirements, see Box 1.
As a rule of thumb, immunotherapy can be recommended if the symptoms have been present for more than two years, if allergen avoidance is impossible or insufficiently effective, and if the patient suffers from moderate or severe symptoms that would call for long-term symptomatic treatment. There is no longer any reason to set age limits (in the past, immunotherapy was said to be indicated only for patients between the ages of 5 and 50). The treatment of children requires special consideration of the individual compliance factor; school-age children are generally capable of taking their medication as instructed. In elderly patients, the contraindications to SIT play an increasingly important role. These contraindications are derived from the potential dangers of treatment (Box 2).
The benefits and risks of the treatment should be weighed against each other for each patient. For medicolegal reasons, special attention should also be paid to all information contained in the package insert.
Predictors of the success of SIT
SIT is especially likely to succeed in patients who are sensitized against a single allergen and are in an early stage of disease. Thus, early treatment with SIT is recommended, particularly for children. The treatment is also effective, however, for patients sensitized against multiple allergens (33). For them, too, SIT is the only treatment than can have a lasting effect on the disease.
According to the guideline, patients may be treated with up to three allergen extracts at once (13). The selection is based on the severity and duration of symptoms, the degree to which they impair the patient’s quality of life, and the avoidability of the individual allergens.
Individual prediction of the response to SIT is currently not possible. A potential approach that is currently under discussion is to analyze IgE antibodies against allergen components and then treat patients who are found to be sensitized to major allergens (34, 35).
The duration of the therapeutic benefit of SIT is also hard to predict in individual cases. The longest published follow-up to date is for SCIT with a grass-pollen allergoid: The effect was still demonstrable 12 years after the end of treatment (36).
The recommendation to repeat the treatment if allergic rhinoconjunctivitis recurs after initially successful SIT is based on clinical experience, rather than on data from clinical trials, as adequate evidence of this type is not yet available.
The performance of SIT
The treatment begins at a low dose, which is gradually increased until the maintenance dose is reached. This process may take up to 20 weeks with native allergens; with allergoids, a single day may suffice. Clinical trials have been conducted to test the efficacy of treatment with allergoid extracts of grass pollen (37–39), tree pollen (40), and mites (e1, e2).
Depending on the preparation, the treatment with with pollen extract can be given either before the allergy season or year-round; some allergoids have been approved for both treatment schedules. No adequate comparison of these two treatment schedules has yet been published.
The adverse effects of SCIT include allergic reactions that can range all the way to severe anaphylaxis. No official statistics on severe reactions have been published, but cases of fatal anaphylaxis are known to have occurred in recent years. The physician must inform the patient thoroughly of all possible adverse effects (including generalized skin reactions, systemic reactions, and anaphylaxis) and document in writing that this information has been provided. The injection must be performed by the physician, who must have experience in the treatment of systemic allergic reactions. The physician’s office should be properly equipped for the treatment of anaphylaxis, with the appropriate medications and equipment close at hand. As a minimum, the following must be available:
- a defibrillator
- an IV infusion set
- an antihistamine
- an inhalable beta-2-sympathomimetic drug
- a corticosteroid for intravenous administration.
The patient should be asked about current contraindications before every injection (Box 3). 30 minutes of observation after each injection are obligatory. Intense physical activity shortly before or after the injection may induce an anaphylactic reaction and should therefore be strictly avoided.
SLIT is administered either year-round (pre-saisonal) or before and during the allergy season (pre/co-saisonal). In patients who are to receive high-dose preparations, the initial administration must be performed under medical supervision. The patient must have an intact oral mucosa, as mucosal injuries may promote adverse effects. After dental extractions or gingival treatments, SLIT should be temporarily interrupted. SLIT should not be administered immediately after tooth-brushing.
Pretreatment with an antihistamine is a useful means of diminishing the local reactions that often arise at the beginning of treatment. SLIT causes mild adverse effects more commonly, but severe ones less commonly, than SCIT. To our knowledge, fatal adverse reactions have never been reported for SLIT.
Whatever the mode of administration, SIT should be continued for at least three years. It has been shown for SCIT that longer treatment confers no statistically significant additional benefit (e3).
It is recommended that the treatment be continued until no further therapeutic benefit is observable, or for one further year after complete relief of symptoms has been achieved.
If allergic symptoms recur after initially successful SIT, repetition of the treatment is recommended.
The ideal time to start SIT
There was an earlier recommendation to start SIT before the allergy season. Updosing during the pollen season should be avoided, however, due to a potentially increased risk of adverse effects.
No studies have yet been published addressing the question of when the effect of SCIT sets in. For SLIT with a grass-pollen tablet, statistically significant efficacy has been documented 30 days after the start of treatment (e4).
The effect of concurrent medication on the efficacy of SIT
An effect of concurrent treatment on the efficacy of SIT has not been systematically studied in clinical trials. Immune suppressants would presumably diminish the treatment effect, and, as a rule, immune-suppressed or immunocompromised patients should not undergo SIT. In a small-scale trial in which children with asthma and house-dust mite allergy were treated with SIT with a house-dust mite extract, simultaneous treatment with montelukast apparently lowered the efficacy of SIT (e5).
There is insufficient evidence for further recommendations to avoid or specifically add any particular medication.
The purpose of adding adjuvants is to enhance the immunological effect of SIT by modulating the allergen-specific T-cell response in the direction of tolerance. For this purpose an allergen extract containing monophosphoryl lipid A is available in Germany. The postulated enhancement of the immunological effect by the bacterial molecule contained in this preparation cannot be judged at present, as there has been no comparative clinical study of the efficacy of allergen treatment with and without added adjuvants.
In animals, aluminum hydroxide has been found to to have strong adjuvant effects (e6). No tests have yet been performed to determine whether it might act as one in man as well.
Other molecules that might be useful as adjuvants are now being clinically tested.
The major allergens of the main inhaled allergen sources have been characterized and can be produced with recombinant techniques. The problem of standardization can thus be solved for SIT, as large amounts of these proteins can be produced with consistent quality. Clinical trials of the use of recombinant grass pollen, birch pollen, and cat allergens have been published.
In a proof-of-concept study, SCIT with a mixture of five recombinant grass-pollen proteins led to a 38.5% reduction in SMS compared to placebo (e7).
15 µg of natural or recombinant Bet v 1 were as effective as treatment with a native birch-pollen extract containing 15 µg of Bet v 1 (e8).
By analogy with the production of allergoids, the three-dimensional structure of recombinant proteins can be modified. Testing of a modified Bet v 1 molecule (folding variant) has shown it to be clinically effective and well tolerated at a high dose (80 µg) (e9).
Peptides containing the necessary T-cell epitopes are promising substances for treatment with relatively few adverse effects once the IgE-binding epitopes that cause adverse effects have been eliminated. This approach is used in the treatment of cat allergy (e10).
Modes of administration
Both the subcutaneous and the sublingual administration of allergen extracts are now well established. Recently, intralymphatic immunotherapy (ILIT) and epicutaneous allergen application have been described as potential alternatives. In a proof-of-concept study, three injections of very small allergen amounts in an inguinal lymph node sufficed for effective treatment (e11). Epicutaneous allergen application has also been found to have an effect (e12). It is not yet clear whether allergen preparations for intralymphatic or epicutaneous application will become commercially available.
SCIT and SLIT are now the only treatments for allergic diseases that induce long-lasting disease modification with sustained improvement of symptoms. The therapeutic potential of SIT is not reflected by its current use in Germany. Patients with allergies are undertreated here. All allergic patients should undergo an appropriate diagnostic evaluation followed by appropriate allergy treatment, and SIT should be offered as the standard treatment for suitable patients.
Allergen preparations with documented safety and efficacy are to be preferred. The new German Regulation on Therapeutic Allergens (TAV) ought to simplify the choice of suitable preparations.
To be successful, SIT should be given for an adequate period of time (at least three years). Recent surveys indicate, however, that less than half of all patients who start SIT continue to receive it for the full three years (e25). The main reasons for premature termination of treatment are apparently adverse effects, insufficient efficacy, and the expenditure of time. Means of improving patient compliance need to be developed.
Conflict of interest statement
Prof. Brehler has received consultant’s fees and reimbursement of participation fees for scientific meetings from Allergopharma, Novartis, and Stallergenes. He has received reimbursement of travel and accommodation expenses from Allergopharma, Novartis, Stallergenes, and ALK. He has also received honoraria for the preparation of continuing medical education presentations from Allergopharma, Novartis, Stallergenes, Bencard, and HAL. He has received payment for the performance of clinical trials on behalf of Allergopharma, Novartis, Leti, HAL, Stallergenes and ALK (funds deposited in an account of his hospital department for external research support).
Prof. Klimek has received consultant’s fees from ALK, Allergopharma, Bencard, Boehringer, Lofarma, and Novartis. He has also received reimbursement of participation fees in scientific meetings and continuing medical education events, and of travel expenses, from ALK, Allergopharma, Bencard, HAL, Novartis, Lofarma, Roxall, and Stallergenes. He has received payment for the preparation of continuing medical education presentations from ALK, Allergopharma, Bencard, GSK, HAL, Lofarma, Novartis, Roxall, and Stallergenes. He has received honoraria for carrying out clinical trials on behalf of ALK, Allergopharma, ArtuBiologicals, Bencard, Biomay, Bionorica, BMBF, Cytos, EAACI, HAL, GSK, Leti, Lofarma, Novartis, PierreFabre, Roxall, Ursapharm, Teva, Stallergenes, and Zambon. He has received payment for a research project from Bencard, ALK, Allergopharma, and HAL.
Prof. Kopp has received consultant’s fees from Bencard, ALK, Abelló, and Novartis. He has received honoraria for preparing continuing medical education events from Bencard and Novartis and for performing clinical trials on behalf of Novartis.
Prof. Virchow has received consultant’s fees from Allergopharma, ALK, and Stallergenes.
Manuscript submitted on 18 June 2012, revised version accepted on
17 January 2013.
Translated from the original German by Ethan Taub, M.D.
Prof. Dr. med. Randolf Brehler
Klinik für Hautkrankheiten
Ambulanz für Allergologie, Berufsdermatologie und Umweltmedizin
48149 Münster, Germany
@For eReferences please refer to:
Center for Rhinology and Allergology, Wiesbaden: Prof. Dr. med. Klimek
Pediatric Pneumology & Allergology, Department of Pediatric Medicine, University Medical Center Schleswig-Holstein, Campus Centrum Lübeck: Prof. Dr. med. Kopp
University of Rostock, Medical Clinics, Division of Pulmonology: Prof. Dr. med. Virchow
|1.||Asher MI, Montefort S, Björkstén B, et al.: Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC phases one and three repeat multicountry cross-sectional surveys. Lancet 2006; 368: 733–43. CrossRef MEDLINE|
|2.||Björkstén B, Clayton T, Ellwood P, Stewart A, Strachan D: ISAAC Phase III Study Group Worldwide time trends for symptoms of rhinitis and conjunctivitis: Phase III of the International Study of Asthma and Allergies in Childhood. Pediatr Allergy Immunol 2008; 19: 110–24. CrossRef MEDLINE|
|3.||Ring J, Bachert C, Bauer C P, Czech W (eds.): Weißbuch Allergie in Deutschland. München: Urban & Vogel 2009.|
|4.||Maurer M, Zuberbier T: Undertreatment of rhinitis symptoms in Europe: findings from a cross-sectional questionnaire survey. Allergy 2007; 62: 1057–63. CrossRef MEDLINE|
|5.||FORSA Umfrage 2012: www.derma.de/fileadmin/eingang/FORSA_Allergien.de|
|6.||Jacobsen L, Niggemann B, Dreborg S, et al.: (The PAT investigator group). Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007; 62: 943–8. CrossRef MEDLINE|
|7.||Calderon MA, Gerth van Wijk R, Eichler I, et al.: Perspectives on allergen-specific immunotherapy in childhood: an EAACI position statement. Pediatr Allergy Immunol 2012; 23: 300–6. CrossRef MEDLINE|
|8.||Zuberbier T, Lötvall J: Allergies have a socioeconomic impact: a model calculation. Allergy 2008; 63 (Suppl. 88): 612–21.|
|9.||Graf von der Schulenburg JM, Greiner W, Molitor S, Kielhorn A: Medizinische Ökonomie – Kosten der Asthmatherapie nach Schweregrad, Eine empirische Untersuchung. Medizinische Klinik 1996; 91: 670–6. MEDLINE|
|10.||Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S: Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD001936. DOI: 10.1002/14651858.CD001936 MEDLINE|
|11.||Radulovic S, Calderon MA, Wilson D, Durham S: Sublingual immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2010; (12): CD002893 MEDLINE|
|12.||Abramson MJ, Puy RM,Weiner JM: Injection allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD001186. DOI: 10.1002/14651858.CD001186.pub2. CrossRef MEDLINE|
|13.||Kleine-Tebbe J, Bufe A, Ebner C, et al.: Leitlinien der Deutschen Gesellschaft Allergologie und klinische Immunologie (DGAKI), des Ärzteverbandes Deutscher Allergologen (ÄDA), der Gesellschaft für pädiatrische Allergologie und Umweltmedizin (GPA), der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI) und der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI). Die spezifische Immuntherapie (Hyposensibilisierung) bei IgE vermittelten allergischen Erkrankungen. Allergo J 2009; 18: 508–37.|
|14.||Calderon MA, Larenas D, Kleine-Tebbe J, et al.: European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'. Allergy 2011; 66: 1345–59 CrossRef MEDLINE|
|15.||Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, et al.: Local immunotherapy. Allergy 1998; 53: 933–44. CrossRef MEDLINE|
|16.||Zuberbier T, Bachert C, Bousquet PJ, et al.: GA² LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma. Allergy 2010; 65: 1525–30. CrossRef MEDLINE|
|17.||Bousquet J, Lockey R, Malling HJ: WHO position paper. Allergen immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998; 53(Suppl 54): 1–42. CrossRef|
|18.||Canonica GW, Bousquet J, Casale T, et al.: Sublingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy 2009; 64 (Suppl 91): 1–59. CrossRef MEDLINE|
|19.||Walker SM, Durham SR, Till SJ, et al.: British Society for Allergy and Clinical Immunology; Immunotherapy for allergic rhinitis. Clin Exp Allergy 2011; 41: 1177–200. CrossRef MEDLINE|
|20.||Guidline on allergen products: Production and quality issues des comittee for medical products for human use (CHMP): www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003333.pdf|
|21.||Guidline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases des comittee for medical products for human use (CHMP): www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003605.pdf|
|22.||Matricardi PM, Kuna P, Panetta V, Wahn U, Narkus A: Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: a comparison based on meta-analyses. J Allergy Clin Immunol. 2011; 128: 791–9. CrossRef MEDLINE|
|23.||Fujita H, Soyka MB, Akdis M, Akdis CA: Mechanisms of allergen-specific immunotherapy. Clin Transl Allergy 2012; 2: 2. CrossRef MEDLINE PubMed Central|
|24.||James LK, Shamji MH, Walker SM, et al.: Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol 2011; 127: 509–16. CrossRef MEDLINE|
|25.||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: 709–22. CrossRef MEDLINE|
|26.||Didier A, Malling HJ, Worm M, Horak F, et al.: Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007; 120: 1338–45. CrossRef MEDLINE|
|27.||Chapman MD, Ferreira F, Villalba M, et al; CREATE consortium. The European Union CREATE project: a model for international standardization of allergy diagnostics and vaccines. J Allergy Clin Immunol 2008; 122: 882–9. CrossRef MEDLINE|
|28.||Pfaar O, Robinson DS, Sager A, Emuzyte R. Immunotherapy with depigmented-polymerized mixed tree pollen extract: a clinical trial and responder analysis. Allergy 2010; 65: 1614–21. CrossRef MEDLINE|
|29.||Durham SR, Emminger W, Kapp A, et al.: SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012; 129: 717–25. CrossRef MEDLINE|
|30.||Ott H, Sieber J, Brehler R, Fölster-Holst R, Kapp A, Klimek L, Pfaar O, Merk H.: Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study. Allergy 2009; 64: 1394–401. CrossRef MEDLINE|
|31.||Valovirta E, Berstad AK, de Blic J, et al.: GAP investigators. Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis. Clin Ther 2011; 33: 1537–46. CrossRef MEDLINE|
|32.||Paul-Ehrlich Institut: Therapieallergene www.pei.de/DE/arzneimittel/allergene/therapieallergene/therapieallergene-inhalt.html. Last accessed on 12 February 2013|
|33.||Calderón MA, Cox L, Casale TB, Moingeon P, Demoly P: Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: Looking at the published evidence. J Allergy Clin Immunol 2012; 129: 924–34. CrossRef MEDLINE|
|34.||Valenta R, Laffer S, Vrtala S, et al.: Recombinant allergens. Steps on the way to diagnosis and therapy of type I allergy. Adv Exp Med Biol 1996; 409: 185–96. CrossRef MEDLINE|
|35.||Schmid-Grendelmeier P: Recombinant allergens. For routine use or still only science? Hautarzt 2010; 61: 946–53. CrossRef MEDLINE|
|36.||Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP: Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 2006; 61: 198–201. CrossRef MEDLINE|
|37.||Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A, Study Group: Efficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid. Allergy 2005; 60: 801–7. CrossRef MEDLINE|
|38.||DuBuske LM, Frew AJ, Horak F, et al.: Ultrashort-specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc 2011; 32: 239–47. CrossRef MEDLINE|
|39.||Pfaar O, Urry Z, Robinson DS, et al.: A randomized placebo-controlled trial of rush preseasonal depigmented polymerized grass pollen immunotherapy. Allergy 2012; 67: 272–9. CrossRef MEDLINE|
|40.||Pfaar O, Robinson DS, Sager A, Emuzyte R: Immunotherapy with depigmented-polymerized mixed tree pollen extract: a clinical trial and responder analysis. Allergy 2010; 65: 1614–21. CrossRef MEDLINE|
|e1.||Zielen S, Kardos P, Madonini E: Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. J Allergy Clin Immunol 2010; 126: 942–9. CrossRef MEDLINE|
|e2.||Riechelmann H, Schmutzhard J, van der Werf JF, Distler A, Kleinjans HA: Efficacy and safety of a glutaraldehyde-modified house dust mite extract in allergic rhinitis. Am J Rhinol Allergy 2010; 24: 104–9. CrossRef MEDLINE|
|e3.||Durham SR, Walker SM, Varga EM, et al.: Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341: 468–75. MEDLINE|
|e4.||Horak F, Zieglmayer P, Zieglmayer R, et al.: Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. J Allergy Clin Immunol 2009; 124: 471–7. MEDLINE|
|e5.||Majak P, Rychlik B, Pułaski L, et al.: Montelukast treatment may alter the early efficacy of immunotherapy in children with asthma. J Allergy Clin Immunol 2010; 125: 1220–7. MEDLINE|
|e6.||Rask C, Lund L, Lund G: An alternative allergen: adjuvant formulation potentiates the immunogenicity and reduces allergenicity of a novel subcutaneous immunotherapy product for treatment of grass-pollen allergy. Clin Exp Allergy 2012; 42: 1356–6. CrossRef MEDLINE|
|e7.||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: 608–13. CrossRef MEDLINE|
|e8.||Pauli G, Larsen TH, Rak S, et al.: Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol 2008; 122: 951–60. MEDLINE|
|e9.||Kettner J, Meyer H, Cromwell O, Narkus A, Jost K: Specific immunotherapy with recombinant birch pollen allergen rBet v 1-FV results of 2 years treatment (Phase II trial). Allergy 2007; 62: 262.|
|e10.||Worm M, Lee HH, Kleine-Tebbe J, et al.: Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy. J Allergy Clin Immunol 2011; 127: 89–97. MEDLINE|
|e11.||Senti G, Prinz Vavricka BM, Erdmann I, et al.: Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008; 105: 17908–12. CrossRef MEDLINE PubMed Central|
|e12.||Senti G, von Moos S, Tay F, et al.: Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced rhinoconjunctivitis: A double-blind, placebo-controlled dose escalation study. J Allergy Clin Immunol 2012; 129: 128–35. MEDLINE|
|e13.||Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein DI: Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. J Allergy Clin Immunol 2011; 127: 72–80. CrossRef MEDLINE|
|e14.||Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP: Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. J Allergy Clin Immunol 2011; 127: 64–71. CrossRef MEDLINE|
|e15.||Pfaar O, Klimek L: Efficacy and safety of specific immunotherapy with a high-dose sublingual grass pollen preparation: a double-blind, placebo-controlled trial. Ann Allergy Asthma Immunol 2008; 100: 256–63. CrossRef MEDLINE|
|e16.||Mösges R, Brüning H, Hessler HJ, Götz G, Knaussmann HG: Sublingual immunotherapy in pollen-induced seasonal rhinitis and conjunctivitis: a randomized controlled trial. Acta Dermatovenerol Alp Panonica Adriat 2007; 16: 143–8. MEDLINE|
|e17.||Wahn U, Tabar A, Kuna P, et al.: Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis. J Allergy Clin Immunol 2009; 123: 160–6. MEDLINE|
|e18.||Wahn U, Klimek L, Ploszczuk A, et al.: High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: A double-blind, placebo-controlled study. J Allergy Clin Immunol 2012; 130: 886–93. MEDLINE|
|e19.||Worm M: Efficacy and tolerability of high dose sublingual immunotherapy in patients with rhinoconjunctivitis. Eur Ann Allergy Clin Immunol. 2006; 38: 55–60. MEDLINE|
|e20.||Tabar AI, Arroabarren E, Echechipía S, García BE, Martin S, Alvarez-Puebla MJ: Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy. J Allergy Clin Immunol 2011; 127: 57–63. CrossRef MEDLINE|
|e21.||Calamita Z, Saconato H, Pelá AB, Atallah AN: Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006; 61: 1162–72. CrossRef MEDLINE|
|e22.||Jacobsen L, Wahn U, Bilo MB: Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit—the centenary of allergen specific subcutaneous immunotherapy. Clinical and Translational Allergy 2012; 2: 8. CrossRef MEDLINE PubMed Central|
|e23.||Novembre E, Galli E, Landi F, et al.: Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004; 114: 851–7. MEDLINE|
|e24.||Des Roches A, Paradis L, Knani J, et al.: Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol 1997; 99: 450–3. MEDLINE|
|e25.||Sieber J, De Geest S, Shah-Hosseini K, Mösges R: Medication persistence with long-term, specific grass pollen immunotherapy measured by prescription renewal rates. Curr Med Res Opin 2011; 27: 855–61. CrossRef MEDLINE|