Guideline on Allergen-Specific Immunotherapy in Ige

Guideline AIT-Guideline

Guideline on allergen-speci c immunotherapy in IgE-mediated allergic diseases

Key words S2k Guideline of the German Society for Allergology and Clinical Immunology allergen- speci c immunotherapy; (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the AIT; Hypo- Medical Association of German Allergologists (AeDA), the Austrian Society for sensitiza tion; guide line; aller- Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology gen; allergen extract; allergic (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- disease; allergic Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of rhinitis; allergic asthma Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD)

O LIVER PFAAR1, 2, CLAUS BACHERT3, ALBRECHT BUFE 4, ROLAND BUHL 5, CHRISTOF EBNER 6, PETER ENG7, FRANK FRIEDRICHS 8, THOMAS FUCHS9, ECKARD HAMELMANN10, DORIS HARTWIG-BADE11, THOMAS HERING12, ISIDOR HUTTEGGER13, K IRSTEN JUNG14, LUDGER K LIMEK1, MATTHIAS VOLKMAR KOPP15, HANS MERK16, UTA R ABE17, JOACHIM SALOGA18, PETER SCHMID -GRENDELMEIER19, ANTJE SCHUSTER 20, NICOLAUS SCHWERK 21, HELMUT SITTER 22, ULRICH UMPFENBACH23, BETTINA WEDI24, STEFAN WÖHRL 25, MARGITTA WORM26, JÖRG K LEINE-TEBBE 27 COMMENTING PARTICIPANTS AND FACILITATORS: SUSANNE K AUL 28, ANJA SCHWALFENBERG29

Center for Rhinology and Allergology, Wiesbaden, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Mannheim, Germany; Department of Otorhinolaryngology, Ghent University Hospital, Guideline registry Ghent, Belgium; Department of Experimental Pneumology, Ruhr-University Bochum, Germany; Pulmonary Depart- number ment, University Medical Center, Johannes Gutenberg-University, Mainz, Germany; Outpatient Clinic for Allergy and 061 – 004 Clinical Immunology, Vienna, Austria; Department of Children and Adolescent Medicine, Aarau and Children‘s Hospital Lucerne, Switzerland; Pediatric and Adolescent Medicine Practice, Laurensberg, Germany; Department of Dermatology, Completion Venereology and Allergology, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany; 10.10.2014 Department of Pediatric and Adolescent Medicine, Pediatric Center Bethel, Evangelical Hospital, Bielefeld, Germany; Valid until ENT Practice, Lübeck, Germany; Pulmonary Outpatient Practice, Tegel, Berlin, Germany; Department of Pediatric and Adolescent Medicine, Paracelsus Private Medical University, Salzburg Regional Hospitals, Salzburg, Austria; Dermatolo- 31.12.2019 gy Practice, Erfurt, Germany; Clinic of Pediatric and Adolescent Medicine, Lübeck University, Airway Research Center Revision scheduled for North (ARCN), Member of the German Lung Center (DZL), Germany; Department of Dermatology and Allergology, Uni- 01.01.2017 versity Hospital, RWTH Aachen University, Aachen, Germany; Department of Allergology, Johanniter-Krankenhaus im Fläming Treuenbrietzen GmbH, Treuenbrietzen Germany; Department of Dermatology, University Medical Center, Jo- ICD-10 numbers: hannes-Gutenberg University, Mainz, Germany; Allergy Unit, Department of Dermatology, University Hospital of Zu- J30.4; J30.1; J30.3; H10.1; rich, Switzerland; Center for Pediatric and Adolescent Medicine, University Medical Center, Düsseldorf, Germany; Uni- H10.8; J45.0; R94.2; T63.4; versity Children’s hospital, Department of Pediatric Pneumology, Allergology and Neonatology, Hanover Medical Uni- T 88.6; L50.0; Z51.6; Z91.0 versity, Hannover, Germany; Institute for Theoretical Surgery, Marburg University, Marburg, Germany; Pediatric and Adolescent Medicine Practice, Viersen, Germany; Department of Dermatology, Allergology and Venereology, German version Hannover Medical University, Hannover, Germany; Floridsdorf Allergy Center, Vienna, Austria; Allergy-Centre-Charité, www.springer- Department of Dermatology, Venereology, and Allergology, Charité University Hospital, Berlin, Germany; Allergy and medizin.de/ Asthma Center Westend, Berlin, Germany; Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines allergo-journal and Biomedicines, Langen, Germany; German Allergy and Asthma Association, Mönchengladbach, Germany

282 Allergo J Int 2014; 23: 282–319 Summary ambrosia, mold Alternaria, animal allergens) for e present guideline (S2k) on allergen-speci c im- speci c immunotherapy. Mixing these allergens munotherapy (AIT) was established by the German, with TAV allergens is not permitted. Austrian and Swiss professional associations for all- Allergic rhinitis and its associated co-morbidities ergy in consensus with the scienti c specialist soci- (e. g., bronchial asthma) generate substantial direct and eties and professional associations in the elds of oto- indirect costs. Treatment options, in particular AIT, are laryngology, dermatology and venereology, pediatric therefore evaluated using cost-bene t and cost-e ec- and adolescent medicine, pneumology as well as a tiveness analyses. From a long-term perspective, AIT is German patient organization (German All ergy and considered to be signi cantly more cost e ective in al- Asthma Association; Deutscher Allergie- und lergic rhinitis and allergic asthma than pharmaco- Asthmabund, DAAB) according to the criteria of the therapy, but is heavily dependent on patient compliance. Association of the Scienti c Medical Societies in Ger- Meta-analyses provide unequivocal evidence of many (Arbeitsgemeinscha der Wissenscha lichen the e cacy of SCIT and SLIT for certain allergen Medizinischen Fachgesellscha en, AWMF). sources and age groups. Data from controlled AIT is a therapy with disease-modifying e ects. studies di er in terms of scope, quality and dosing By administering allergen extracts, speci c block- regimens and require product-speci c evaluation. ing antibodies, tolerance-inducing cells and media- erefore, evaluating individual preparations ac- tors are activated. ese prevent further exacerba- cording to clearly de ned criteria is recommended. tion of the allergen-triggered immune response, A broad transfer of the e cacy of certain prepara- block the speci c immune response and attenuate tions to all preparations administered in the same the in ammatory response in tissue. way is not endorsed. e website of the German So- Products for SCIT or SLIT cannot be compared at ciety for Allergology and Clinical Immunology present due to their heterogeneous composition, nor (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: can allergen concentrations given by di erent man- Deutsche Gesellscha für Allergologie und ufacturers be compared meaningfully due to the klinische Immunologie) provides tables with spe- varying methods used to measure their active ingre- ci c information on available products for AIT in dients. Non-modi ed allergens are used for SCIT in Germany, Switzerland and Austria. e tables con- the form of aqueous or physically adsorbed (depot) tain the number of clinical studies per product in extracts, as well as chemically modi ed all ergens (al- adults and children, the year of market authoriza- lergoids) as depot extracts. Allergen extracts for SLIT tion, underlying scoring systems, number of ran- are used in the form of aqueous solutions or tablets. domized and analyzed subjects and the method of e clinical e cacy of AIT is measured using vari- evaluation (ITT, FAS, PP), separately given for grass ous scores as primary and secondary study endpoints. pollen, birch pollen and house dust mite allergens, e EMA stipulates combined symptom and medica- and the status of approval for the conduct of clini- tion scores as primary endpoint. A harmonization of cal studies with these products. clinical endpoints, e. g., by using the combined symp- Strong evidence of the e cacy of SCIT in pollen tom and medication scores (CSMS) recommended by allergy-induced allergic rhinoconjunctivitis in adult- the EAACI, is desirable in the future in order to per- hood is well-documented in numerous trials and, in mit the comparison of results from di erent studies. childhood and adolescence, in a few trials. E cacy e current CONSORT recommendations from the in house dust mite allergy is documented by a num- ARIA/GALEN group specify standards for the evalu- ber of controlled trials in adults and few controlled ation, presentation and publication of study results. trials in children. Only a few controlled trials, inde- According to the erapy allergen ordinance pendent of age, are available for mold allergy (in par- (TAV), preparations containing common allergen ticular Alternaria). With regard to animal dander al- sources (pollen from grasses, birch, alder, hazel, lergies (primarily to cat allergens), only small studies, house dust mites, as well as bee and wasp venom) some with methodological de ciencies are available. need a marketing authorization in Germany. Du- Only a moderate and inconsistent therapeutic e ect ring the marketing authorization process, these pre- in atopic dermatitis has been observed in the quite parations are examined regarding quality, safety heterogeneous studies conducted to date. SCIT has and e cacy. In the opinion of the authors, autho- been well investigated for individual preparations in rized allergen preparations with documented e - controlled bronchial asthma as de ned by the Glob- cacy and safety, or preparations tradeable under the al Initiative for Asthma (GINA) 2007 and intermit- TAV for which e cacy and safety have already been tent and mild persistent asthma (GINA 2005) and it documented in clinical trials meeting WAO or EMA is recommended as a treatment option, in addition standards, should be preferentially used. Individual to allergen avoidance and pharmacotherapy, provid- formulations (NPP) enable the prescription of rare ed there is a clear causal link between respiratory allergen sources (e.g., pollen from ash, mugwort or symptoms and the relevant allergen.

Allergo J Int 2014; 23: 282–319 283 Guideline AIT-Guideline

e e cacy of SLIT in grass pollen-induced aller- Treatment adherence among AIT patients is lower gic rhinoconjunctivitis is extensively documented than assumed by physicians, irrespective of the form in adults and children, whilst its e cacy in tree pol- of administration. Clearly, adherence is of vital im- len allergy has only been shown in adults. New con- portance for treatment success. Improving AIT ad- trolled trials (some with high patient numbers) on herence is one of the most important future goals, in house dust mite allergy provide evidence of e cacy order to ensure e cacy of the therapy. of SLIT in adults. Severe, potentially life-threatening systemic reac- Compared with allergic rhinoconjunctivitis, tions during SCIT are possible, but – providing all there are only few studies on the e cacy of SLIT in safety measures are adhered to – these events are allergic asthma. In this context, newer studies show very rare. Most adverse events are mild to moderate an e cacy for SLIT on asthma symptoms in the and can be treated well. subgroup of grass pollen allergic children, adoles- Dose-dependent adverse local reactions occur cents and adults with asthma and e cacy in pri- frequently in the mouth and throat in SLIT. Syste- mary house dust mite allergy-induced asthma in mic reactions have been described in SLIT, but are adolescents aged from 14 years and in adults. seen far less o en than with SCIT. In terms of ana- Aspects of secondary prevention, in particular the phylaxis and other severe systemic reactions, SLIT reduction of new sensitizations and reduced asthma has a better safety pro le than SCIT. risk, are important rationales for choosing to initiate e risk and e ects of adverse systemic reactions in treatment early in childhood and adolescence. In this the setting of AIT can be e ectively reduced by trai- context, those products for which the appropriate ef- ning of personnel, adhering to safety standards and fects have been demonstrated should be considered. prompt use of emergency measures, including early ad- SCIT or SLIT with pollen or mite allergens can be ministration of i. m. epinephrine. Details on the acute performed in patients with allergic rhinoconjunctivi- management of anaphylactic reactions can be found in tis using allergen extracts that have been proven to be the current S2 guideline on anaphylaxis issued by the e ective in at least one double-blind placebo-cont- AWMF (S2-AWMF-LL Registry Number 061-025). rolled (DBPC) study. At present, clinical trials are un- AIT is undergoing some innovative developments derway for the indication in asthma due to house dust in many areas (e. g., allergen characterization, new mite allergy, some of the results of which have alrea- administration routes, adjuvants, faster and safer dy been published, whilst others are still awaited (see dose escalation protocols), some of which are alrea- the DGAKI table “Approved/ potentially completed dy being investigated in clinical trials. studies” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner establishing the indication for AIT, factors that favo- C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, ur clinical e cacy should be taken into consideration. Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek Di erences between SCIT and SLIT are to be consi- L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Gren- dered primarily in terms of contraindications. In in- delmeier P, Schuster A, Schwerk N, Sitter H, Umpfen- dividual cases, AIT may be justi ably indicated des- bach U, Wedi B, Wöhrl S, Worm M, Kleine-Tebbe J. pite the presence of contraindications. Guideline on allergen-speci c immunotherapy in IgE- SCIT injections and the initiation of SLIT are per- mediated allergic diseases – S2k Guideline of the Ger- formed by a physician experienced in this type of man Society for Aller gology and Clinical Immunology treatment and who is able to administer emergency (DGAKI), the Society for Pediatric Allergy and Envi- treatment in the case of an allergic reaction. Patients ronmental Medicine (GPA), the Medical Association must be fully informed about the procedure and of German Allergologists (AeDA), the Austrian Society risks of possible adverse events, and the details of for Allergy and Immunology (ÖGAI), the Swiss Soci- this process must be documented (see “Treatment ety for Allergy and Immunology (SGAI), the German information sheet”; available as a handout via Society of Dermatology (DDG), the German Society of www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treat- Oto-Rhino-Laryngology, Head and Neck Surgery ment should be performed according to the manu- (DGHNO-KHC), the German Society of Pediatrics facturer‘s product information lea et. In cases whe- and Adolescent Medicine (DGKJ), the Society for Pe- re AIT is to be performed or continued by a di erent diatric Pneumology (GPP), the German Respiratory physician to the one who established the indication, Society (DGP), the German Association of ENT Sur- close cooperation is required in order to ensure that geons (BV-HNO), the Professional Federation of Pae- treatment is implemented consistently and at low diatricians and Youth Doctors (BVKJ), the Federal As- risk. In general, it is recommended that SCIT and sociation of Pulmonologists (BDP) and the German SLIT should only be performed using preparations Dermatologists Association (BVDD). Allergo J Int for which adequate proof of e cacy is available from 2014;23:282–319 clinical trials. DOI: 10.1007/s40629-014-0032-2

284 Allergo J Int 2014; 23: 282–319 Abbreviations

AAAAI American Academy of Allergy, Asthma & Immunology HIV Human immunode ciency virus ACE Angiotensin converting enzyme HMG Medicinal Products Act (Switzerland), Heilmittelgesetz AD Atopic dermatitis (Schweiz) ADR Adverse drug reactions HR Hazard ratio AGES Austrian Agency for Health and Nutrition, HRQL Health-related quality of life Österreichische Agentur für Gesundheit und ICER Incremental cost-e ectiveness ratio Ernährungssicherheit GmbH IFN Interferon AIT Allergen-speci c immunotherapy IgA Immunglobulin A Al(OH)3 Aluminum hydroxide IgE Immunglobulin E AMG Arzneimittelgesetz, Medicinal Products Act IgG Immunglobulin G APC Antigen-presenting cells IL Interleukin BASG Austrian Medicines and Medical Devices Agency, ILIT Intralymphatic immunotherapy Bundesamt für Sicherheit im Gesundheitswesen ITT Intention to treat (Österreich) MPL Monophosphoryl lipid A Baso Basophile granulocyte NaCl Sodium chloride BGB Bundesgesetzbuch, german civil code NPP Named patient product BGR professional association regulations, Berufsgenossenschaftsregeln NVL National disease management guideline, Nationale Versorgungsleitlinie Ca3(PO4)2 Calcium phosphate O Oxygen CI Con dence interval 2 OAS Oral allergy syndrome CONSORT Consolidated standards of reporting trials PAT Preventive allergy treatment CSMS Combined symptom and medication score PDCO Paediatric Committee DAAB German Allergy and Asthma Association, Deutscher Allergie- und Asthmabund PEF Peak expiratory ow DBPC Double-blind placebo-controlled PP Per protocol DC Dendritic cells QALY Quality-adjusted life year DELBI German instrument for methodological guideline SCIT Subcutaneous immunotherapy appraisal, Deutsches Leitlinien-Bewertungsinstrument SCORAD Scoring Atopic Dermatitis EAACI European Academy of Allergy and Clinical Immunology SLIT Sublingual immunotherapy EMA European Medicines Agency SMD Standardised mean di erence Eos Eosinophile granulocyte TAV Therapy allergen ordinance, EPIT Epidermal immunotherapy Therapieallergene-Verordnung FAS Full analysis set TGF Transforming growth factor FEV1 Forced expiratory volume in 1 second Th T helper cell GCP Good clinical practice TRBA Technical regulations for biological agents

GINA Global Initiative for Asthma Treg Regulatory T cell GKV Statutory health insurance, TSS Total symptom score Gesetzliche Krankenversicherung VAS Visual analogue scale GMP Good manufacturing practice WAO World Allergy Organization HAART Highly active antiretroviral therapy WHO World Health Organization

Allergo J Int 2014; 23: 282–319 285 Guideline AIT-Guideline

1. Objectives and development of the Pulmonologists (Bundesverband der Pneumolo- guideline gen, BdP: omas Hering) and the German e present guideline was developed on behalf of Dermatologists Association (Berufsverband der and nanced by the German Society for Allergology Deutschen Dermatologen, BVDD: Kirsten Jung). and Clinical Immunology (Deutsche Gesellscha e Paul-Ehrlich Institute (PEI: Susanne Kaul) für Allergologie und klinische Immunologie, and the German Allergy and Asthma Association/ DGAKI) and replaces the S2 guideline published Patient Organization (Deutscher Allergie- und in 2009 [1]. It has been conceived as a S2k guide- Asthmabund, DAAB: Anja Schwalfenberg) were line according to the methodological requirements involved in the consensus process in an advisory set out by the German Working Group of Scientif- capacity. ic Medical Societies (Arbeitsgemeinscha der Wis- e guideline was updated at a consensus con- senscha lichen Medizinischen Fachgesellscha en, ference in Wiesbaden, Gemany, in April 2013, as AWMF). A detailed guideline report in line with well as by written consent and using a web-based AWMF policy (DELBI criteria 1–7) can be found guidelines portal especially set-up and authorized on the AWMF website (www.awmf.org/leitlinien/ by the AWMF (www.leitlinienentwicklung.de). detail/ll/061-004.html) e nal consensus process took place on July 18 In summary, it was decided by the board of the 2014. e guideline was then presented to all re- DGAKI in 2012 that the corresponding author sponsible board members to be authorized and should take over the task of coordinating the re- recommended for adoption. is nal authoriza- vision of the guideline. In addition to members of tion process was formally completed by October the DGAKI (Oliver Pfaar, Jörg Kleine-Tebbe, Eck- 1 2014. ard Hamelmann, Bettina Wedi, Claus Bachert and e guideline is addressed to all physicians with Margitta Worm), representatives of the following a board certi cation or subspeciality in allergy as bodies were involved in drawing up the guideline: well as all physicians that treat and/or monitor al- the Medical Association of German Allergologists lergic patients in the context of AIT, and can be used (Ärzteverband Deutscher Allergologen, AeDA: for all patient groups with allergic rhinoconjuncti- omas Fuchs, Hans Merk, Uta Rabe), the Society vitis with/without allergic asthma and allergic sen- for Pediatric Allergy and Environmental Medi- sitization to inhaled allergens. cine (Gesellscha für Pädiatrische Allergologie e validity of the guideline shall be reviewed by und Umweltmedizin, GPA: Albrecht Bufe, Matth- the authors 5 years following its publication. e ias Volkmar Kopp, Antje Schuster), the Austrian guideline coordinator shall be responsible for this Society for Allergy and Immunology (Öster- task. Further details can be found in the separate reichische Gesellscha für Allergologie und Im- guideline report. munologie, ÖGAI: Christof Ebner, Isidor Hutteg- e guideline will be published and distributed ger, Stefan Wöhrl), the Swiss Society for Allergy by the allergy societies in their o cial associated and Immunology ( Schweizerische Gesellscha für journals; it will also be published (in German Allergologie und Immunologie, SGAI: Peter Eng, language) in the AWMF guideline register, recom- Peter Schmid-Grendelmeier), the German Society mended for adoption by other involved societies of Dermatology (Deutsche Gesellscha für Der- and made available for reprint to interested journals matologie, DDG: Joachim Saloga), the German with allergy-related content. Society of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsche Gesellscha für Hals- 2. Immunological mechanisms of action Nasen-Ohren-Heilkunde, Kopf- und Hals- With AIT, allergen extracts in the form of molecule Chirurgie, DGHNO-KHC: Ludger Klimek), the mixtures are presented to the immune system either German Society of Pediatrics and Adolescent subcutaneously (SCIT) or sublingually (SLIT). e Medicine (Deutsche Gesellscha für Kinder-und patient is already sensitized to the allergens and Jugendmedizin, DGKJ: Ulrich Umpfen bach), the reacts upon renewed exposure to allergens with Society for Pediatric Pneumology (Gesellscha in ammation of the skin and mucosa. e allergen für Pädiatrische Pneumologie, GPP: Nikolaus extracts rst di use into local tissue, where they are Schwerk), the German Respiratory Society taken up by antigen-presenting cells (APC) [2]. e (Deutsche Gesellscha für Pneumologie, DGP; speed of this process depends on the dose and com- Roland Buhl), the German Association of ENT position of the extracts, particularly when depot Surgeons (Berufsverband der HNO-Ärzte, BV- preparations are used [3]. Following administration, HNO: Doris Hartwig-Bade), the Professional Fed- the allergens are found in local lymph nodes. ey eration of Paediatricians and Youth Doctors arrive there either unbound via free di usion or are (Berufsverband der Kinder- und Jugendärzte, taken up by dendritic (DC) or B cells [4]. At the BVKJ: Frank Friedrichs), Federal Association of same time, immuncomplexes made up of allergens

286 Allergo J Int 2014; 23: 282–319 Speciﬁc immunotherapy Treg IL-10 (high dose) IL-10 Th2 IL-4 B cell Natural exposure (low dose) IgE Ø IL-12 IL-4 IL-4 DC (source: mast cells, basophils, naive T cells?) B cells IL-2, IL-12 IFN-γ IgE

IgG4 IgA IL-3 & IL-10 Treg Th1 Basophil blocking factors IL-5 IL-10 IgG IgE TGF-β IFN-γ Eosinophil IFN-γ Mast cells

B cell Macrophage Inﬂammation TNF-α Anaphylaxis Inﬂammation Necrosis Anaphylaxis Necrosis

Epithelial cells Authors of the guideline ©

Basophil, basophile granulocyte; DC, dendritic cell; Eosinophil, eosinophil granulocyte; IFN, interferon; IgA, immunglobulin A; IgE, immunglobulin E; IgG, immunglobulin G; IL, interleukin; TGF, transforming growth factor; Th, T helper cell; Treg, regulatory T cell

Fig. 1: Complex model of the immunological e ects during AIT

and IgE antibodies may form in the tissue, by which a er 6 months of treatment and have not as yet allergens can be intercepted, mast cells activated or been con rmed in all studies. allergens transported to lymph nodes. At present, 3. Induction of mediators and cytokines that atten- the literature [4, 5, 6, 7, 8, 9] favors the following im- uate local allergic in ammation. Allergens pri- munological mechanisms to explain the e ect of marily activate local APC (e.g., DC). ese release AIT (Fig. 1): IL-10 and TGF-ß in particular. Both cytokines 1. Activation of new and boosting of existing anti- can have a local anti-in ammatory e ect and are bodies that block the allergen-antibody- able to inhibit T-cell proliferation. In addition, mediated immune response. In particular, these the release of IL-10 serves to reinforce the above- include IgG antibodies that are able to prevent mentioned production of blocking IgG antibodies. binding of IgE-allergen complexes to B cells and Cytokines released locally also attenuate local DC. An increase in these antibodies correlates mast cell activity and the activation of other to a certain extent with the success of treatment, e ector cells that contribute to allergic in amma- an e ect that cannot be seen when measuring tion. the total fraction of IgG and IgG4 serum-antibodies. Conclusion: AIT is a therapy with disease-modi-

2. Activation of regulatory T cells (Tregs) that inhibit fying e ects. By administering allergen extracts, the T cell-mediated activation of B cells and the speci c blocking antibodies, tolerance-inducing

speci c T-cell response to the allergen. Tregs mi- cells and mediators are activated. ese prevent grate from their site of formation in the lymph further exacerbation of the allergen-triggered im- nodes back to the area of in ammation and re- mune response, block the speci c immune release IL-10 and TGF-ß, thereby reducing local in- sponse and attenuate the in ammatory response ammation. ese e ects can only be measured in tissue.

Allergo J Int 2014; 23: 282–319 287 Guideline AIT-Guideline

Non-modi ed (native) extracts with unaltered Insect venom allergen conformation and chemically modi ed ex- Aqueous extracts SCIT tracts (allergoids) can be used for SCIT. e concept is that allergoids possess less reactive B-cell epitopes Aqueous extracts Non-modified and thus reduced IgE binding, while their T-cell epi- or allergens extract tablets topes and their immunogenic e ect remain unaltered [14]. In addition to aqueous extracts, which are commonly used as the initial treatment in insect ven- Chemical Depot Adjuvant modification extracts MPL om allergy, depot extracts are primarily used in Formaldehyde Allergoids (physically Europe for SCIT. Here, allergens or allergoids are Glutaraldehyde (polymers) coupled) physically adsorbed to a carrier, such as aluminum Al(OH)3* SLIT Ca3(PO4)2 hydroxide, tyrosine or calcium phosphate (Fig. 2). Allergoids L-tyrosine Carbamylation (monomers) Preparations for SLIT are available with allergens SCIT in unmodi ed conformation or as chemically mod- i ed extracts in the form of aqueous solutions or Aqueous solutions tablets (Fig. 2). Some preparations need to be refrig- Authors of the guideline or tablets © erated, others can be stored at room temperature. *also eff ective as an adjuvant Conclusion: Products for SCIT or SLIT cannot be Al(OH) , aluminum hydroxide; Ca (PO ) , calcium phosphate; MPL, monophosphoryl lipid A 3 3 4 2 compared at present due to their heterogeneous Fig. 2: Allergen extracts available for AIT (see Sect. 3.1 for more details) composition, nor can allergen concentrations given by di erent manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modi ed allergens are used for SCIT in the form of aqueous or physically 3. Allergen extracts: assessment and adsorbed (depot) extracts, as well as chemically marketing authorization modi ed allergens (allergoids) as depot extracts. 3.1. Production and composition of allergen All ergen extracts for SLIT are used in the form of extracts aqueous solutions or tablets. Due to manufacturer-speci c processing, the allergen extracts produced di er in terms of composi- 3.2. Criteria for evaluating subcutaneous or tion and allergen activity and are therefore not com- sublingual administration of speci c parable even if the same allergen sources are used. immunotherapy in clinical studies Standardized allergen extracts should preferentially e e cacy of AIT is measured using symptom be used for AIT, as otherwise extracts vary signi - scores [e. g., individual symptoms, total symptom cantly in their biological activity [10]. e total activ- score (TSS)], medication scores, combined sym- ity of the extracts is determined using in-vitro meth- ptom and medication scores, health-related quality ods [11]. Determining individual allergens (e. g., ma- of life (HRQL) as well as other methods (e. g., visual jor allergens) using standardized, validated methods analog scales, “well” or “severe days”) [15, 16, 17]. It is endorsed in international guidelines [12]. Two re- is essential to record allergy exposure over time combinant major allergens, rBet v 1 from birch pol- (e. g., using pollen counts) as well as to collect safety len (Betula verrucosa, http://crs.edqm.eu/db/4DCGI/ data; moreover, recording laboratory data on IgE, View=Y0001565) and rPhl p 5a from timothy grass IgG and IgG4 is recommended. pollen (Phleum pratense, http://crs.edqm.eu/ Combined symptom and medication scores are db/4DCGI/View=Y0001566), were adopted as refer- frequently used as primary endpoints in AIT trials ence preparations by the European Pharmacopoeia and proposed in multiple variations [18, 19, 20]. e Commission in 2012. ese reference preparations lack of validation of primary and secondary e cacy are intended for the determination of the Bet v 1 and parameters represents a considerable problem in Phl p 5a content in corresponding allergen prepara- terms of the comparability of study results [15, 16, 17]. tions (native and recombinant) [13]. e European Medicines Agency (EMA) primar- e use of these references is voluntary until suit- ily recommends combined symptom and medica- able ELISA systems are available and requested by tion scores for the primary endpoint in AIT trials the European Pharmacopoeia. us, it is not possi- and accepts (in justi ed exceptional cases) a posi- ble at present to compare the allergen concentra- tive study result for both scores, as the consumption tions in various preparations, as manufacturers use of rescue medication also a ects the symptoms. di erent antibodies and measuring systems to de- erefore, the score should re ect both, severity of termine major allergens. symptoms as well as the need for medication [21].

288 Allergo J Int 2014; 23: 282–319 However, the EMA does not provide a precise de - | Table 1 nition for this parameter [21, 22]. Important terms in the German Medicinal Products Act A task force working group of the EAACI recent- (Deutsches Arzneimittelgesetz, AMG) ly published speci c recommendations on clinical www.gesetze-im-internet.de/bundesrecht/amg_1976/gesamt.pdf, endpoints in AIT trials [17]. Particularly worthy of as well as particular features of the Austrian and Swiss drug laws note is that the EAACI Position Paper provides a Finished medicinal products de nition of a homogeneous, standardized combined symptom and medication score (CSMS) as Section 4 Sub-section 1, AMG § 4 (1): „Finished medicinal products are medicinal products primary endpoint with the aim of harmonizing this which are manufactured beforehand and placed on the market in packaging intended for distribution to the consumer or other medicinal products intended for distribution to the outcome measure in future AIT trials [17]. consumer, in the preparation of which any form of industrial process is used or… are pro- It is essential that study results are evaluated, reduced commercially“. presented and published in an appropriate manner. Marketing authorization To this end, standards have been established (Con- solidated Standards of Reporting Trials [CON- Section 21 Sub-section 1, AMG § 21 (1): „Finished medicinal products which are medicinal products as defi ned in Section 2 sub-section 1 or sub-section 2 number 1, may only be SORT]) which, by the use of checklists, are intend- placed on the market within the purview of the present Act, if they have been authorised ed to guarantee minimal yet transparent reporting by the competent higher federal authority…“ of studies (www.consort-statement.org [23]). is includes the evaluation of clinical data in an inten- Individual formulations (NPP) tion-to-treat (ITT) analysis, which takes all patients Section 21 Sub-section 2, AMG § 21 (2): “A marketing authorization (Zulassung) shall not included in a study (even those that withdraw early) be required for medicinal products which ... No. 1g: ... are therapeutic allergens manufac- into account, illustrating the actual e ects of AIT tured to order for individual patients...” under practical conditions [23, 24]. e per-proto- Important Terms in the Austrian Drug Law (Österreichisches Arzneimittelgesetz) col (PP) analysis, on the other hand, is well suited AMG § 7a(1): “Medicinal products containing antigens or half-antigens intended for the de- to estimating maximum e cacy under optimal tection of specifi c antibodies and protective substances for desensitization or hyposensiti- standard conditions. In addition, data on all pa- zation, provided they are not always produced in the same composition and under the tients – even those included in the study without same designation in a defi ned form intended for distribution to the consumer or user, are only permitted to be distributed domestically or held ready for domestic distribution if the ful lling the speci ed inclusion criteria or whose Federal Offi ce for Safety in Healthcare has approved by notifi cation the manufacturing treatment deviated from the study protocol – are re- process including chemical/pharmaceutical documentation, for this medicinal product.“ corded in the analysis of full-analysis-sets (FAS) in Situation in Switzerland order to depict the safety pro le of the treatment. Under the terms of the Swiss Federal Law on Medicinal Products [Heilmittelgesetz, HMG; th Conclusion: e clinical e cacy of AIT is measured Art. 9 (1)] dated December 15 2000, allergen preparations intended for AIT are considered as medicinal products requiring marketing approval (SR812.21, www.admin.ch/opc/ using various scores as primary and secondary de/classifi ed-compilation/20002716/index.html#a9). Allergen preparations used under study endpoints. e EMA stipulates combined the terms of the exemption clause [HMG Art. 9 (2)], for example as individual formulations symptom and medication scores as primary end- (patient-specifi c mixture of allergens, NPP), are exempt from marketing authorization. point. A harmonization of clinical endpoints, e. g., A new regulation came into force in 2010 to simplify the marketing approval process for by using the CSMS recommended by the EAACI, is allergen preparations (Allergenverordnung, AllergV SR812.216.2, www.admin.ch/opc/de/ desirable in the future in order to permit the com- classifi ed-compilation/20060055/index.html). The simplifi cation of the marketing approval procedure consists of the fact that the market authorization documentation can be parison of results from di erent studies. e cur- based on published literature (from scientifi cally recognized sources) or on documentati- rent CONSORT recommendations from the ARIA/ on for other allergen preparations (a reference preparation of the same manufacturer). Al- GALEN group specify standards for the evaluation, lergen preparations containing recombinant allergens or genetically modifi ed organisms are excluded from this simplifi ed marketing authorization procedure. presentation and publication of study results. In cases where marketing authorization has already been granted in a country with compa- 3.3. Relevance of marketing authorization for rable medicinal drug regulations and a comparable marketing authorization process, it is possible, under the terms of Art. 13 of the Swiss HMG to take these results into consideration allergen preparations with regard to marketing authorization in Switzerland. In Germany, marketing authorization is required for allergen preparations in accordance with the German Medicinal Products Act (Arzneimittel- gesetz, AMG). However, there is an exemption excluding individual formulations (named patient products, NPP) of therapy allergens from market- erapy Allergen Ordinance ( erapieallergene- ing authorization. Irrespective of this, all prepara- Verordnung, TAV) [25]. According to the TAV, in- tions are nished medicinal products according to dividual formulations containing at least one ex- the AMG (Tab. 1). tract of an allergen source that frequently triggers Both types of product can be prescribed and are allergies (Tab. 2) require a marketing authorization. tradeable. Individual formulations have been regu- At present, there are marketing authorization ap- lated in Germany since 2008 in addition by the plications for 96 individual formulations of this kind

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ing allergens of this kind and for which no approval | Table 2 A list of therapy allergens requiring marketing was sought needed to be reported to the PEI, re- authorization in Germany* [25] mained tradeable until November 2011 at the latest Species of the Poaceae family excluding Poa mays (grasses excluding maize) for the treatment of patients already on treatment Betula sp. (species of the birch genus) and were then removed from the market [26]. New Alnus sp. (species of the alder genus) regulations related to batch release also came into Corylus sp. (species of the hazel genus) force with the TAV. Before the TAV became e ective, Dermatophagoides sp. (species of the house dust mite genus) only authorized allergen preparations were subject to Bee venom governmental batch release; with the TAV, batch re- Wasp venom lease became mandatory for all reported individual *A list of therapy allergens requiring marketing authorization according to the German Therapy Allergen preparations. In the case of individual formulations Ordinance [25] and which, once transitional regulations have expired, may not be marketed either as (NPP), testing is performed on the bulk allergen ex- individual preparations or as mixtures without marketing authorization. tracts from which the individual formulations are produced (bulk allergen extract batch release), whereas for all other preparations testing is performed primarily on the end product. All other therapy allergens produced as individual | Table 3 formulations (NPPs that do not contain allergens Examples of individual formulations (NPP) for speci c listed in the TAV appendix; see Tab. 3 for examples) immunotherapy using allergen sources not subject to the are still exempt from mandatory marketing autho- German Therapy Allergen Ordinance* [25] rization and are thereby neither subject to o cial Mugwort pollen (Artemisia vulgaris) monitoring on quality, e cacy and safety nor gov- Ash pollen (Fraxinus excelsior) ernmental batch release. With regard to manufac- Alternaria (Alternaria alternata) ture, however, according to the AMG, a manufac- Animal allergens, e.g., from the cat (Felis domesticus) turing license that ful lls all the criteria of good Storage mites (e.g., Acarus siro) manufacturing practice (GMP) is required. *Not mixed with allergen groups subject to the Therapy Allergen Ordinance (Tab. 2), otherwise they would Authorized preparations (www.pei.de/DE/arzneimittel/ subject to the ordinance. allergene/allergene-node.html) can be distinguished from individual formulations (NPP) by their authorization number on the outer packaging and in the summary of product information. In Germany, the PEI is responsible for the market- | Table 4 ing authorization of allergen preparations (Tab. 4) Marketing authorization procedures* for for therapeutic and diagnostic purposes and for medicinal products in the European Union (EU) batch release. Authorization in Austria is regulated National procedure, when marketing authorization is granted for a medicinal product in by the Federal O ce for Safety in Health Care the respective member state only (Bundesamt für Sicherheit im Gesundheitswesen), Mutual recognition procedure, when a preparation already has marketing authorization in one EU member state and this authorization should be extended to other member which serves the Austrian Agency for Health and states Nutrition (Österreichische Agentur für Gesundheit Decentralized procedure, when a medicinal product does not yet have national marketing und Ernährung, AGES-PharmMed). Marketing authorization and seeks parallel marketing authorization in several EU member states authorization for allergens is supervised in Switzer- Central procedure (simultaneous marketing authorization in all EU member states), land by the Swiss Agency for erapeutic Products necessary in the case of medicinal products cited in the Appendix to EU Regulation Swissmedic. e above-mentioned regulations 726/2004 (e.g., medicinal products which are manufactured by using biotechnological processes); can also be used for other medicinal products under certain conditions apply only partially to Austria and Switzerland, especially the TAV applies only for Germany. *All procedures resulting in marketing authorization in several or all European countries are coordinated by the European Medicines Agency (EMA). e application for marketing authorization at the competent authority shall include among others information on the production process of the drug, its quality control, the results of all pre-clinical and clinical studies as well as further medical testing. Medicinal products must ful l the state of pending at the Paul-Ehrlich-Institute (PEI) (as of De- the art requirements valid at the time of authoriza- cember 2014, PEI communication). ese preparation [27]. Today, these include, e. g., GMP, good clin- tions remain equivalent to approved pre parations in ical practice (GCP), the European pharmacopoeia terms of being prescribable and tradeable until the as well as the relevant EMA guidelines (www.ema. decision on their application for marketing authori- europa.eu/docs/en_GB/document_library/Scienti c_ zation. All preparations (more than 6,400) contain- guideline/2009/09/WC500003333.pdf [11], www.ema.

290 Allergo J Int 2014; 23: 282–319 europa.eu/docs/en_GB/document_library/Scientif- Conclusion: According to the TAV, preparations ic_guideline/2009/09/WC500003605.pdf [21]). containing common allergen sources (pollen from Preparations are only authorized for those indi- grasses, birch, alder, hazel, house dust mites, as well cations and patient groups for which safety and as bee and wasp venom) need a marketing authori- e cacy have been proven in clinical trials. zation in Germany. During the marketing authori- Since 1993, and with the exception of bee and zation process, these preparations are examined re- wasp venom preparations, marketing authorization garding quality, safety and e cacy. In the opinion has only been granted if at least one double-blind of the authors, authorized allergen preparations placebo-controlled (DBPC) trial complying with with documented e cacy and safety, or prepara- the relevant state of the art has been successfully tions tradeable under the TAV for which e cacy carried out. Placebo control is not required for and safety have already been documented in clinical hymenoptera venom preparations for ethical rea- trials meeting WAO or EMA standards, should be sons; in such cases, an established equivalent prep- preferentially used. aration is generally used for comparative testing. In Individual formulations (NPP) enable the pre- the case of older authorizations – in accordance scription of rare allergen sources (e.g., pollen from with requirements valid at that time – open stud- ash, mugwort or ambrosia, mold Alternaria, animal ies were sometimes also accepted as evidence of ef- allergens) for speci c immunotherapy. Mixing c a c y . these allergens with TAV allergens is not permitted. Increased requirements set more recently have resulted in a signi cant improvement in the quality 3.4. AIT from a socio-economic perspective of data obtained in clinical studies and thus also in Allergic diseases, such as allergic rhinoconjunctivi- the evidence of safety and e cacy of preparations tis, have a signi cant impact on the individual authorized on the basis of these studies. Although patients as well as on the national economy as a individual formulations that come under the TAV whole [29, 30, 31]. (Tab. 2) are subject to governmental batch release e healthcare system is burdened not only by the on bulk allergen extracts for quality assurance pur- costs caused directly by disease, but also by the in- poses, no o cial inspection of the production pro- direct costs that are o en challenging to measure cess or examination of e cacy and safety is carried [32]. One in ten doctors’ certi cates for work about prior to the authorization process. sence can be attributed to allergy symptoms. e In the opinion of the authors, authorized allergen direct disease costs for allergic rhinoconjunctivitis preparations with documented e cacy and safety, already totalled several hundred million euros in or preparations tradeable under the TAV for which the 1990s [31]. Treatment options consist of symp- e cacy and safety have already been documented tomatic treatment and allergen avoidance, as well in clinical trials meeting WAO or EMA standards, as disease-modifying therapy in the form of AIT. should be preferentially used. A current overview Since AIT is both a somehow curative and a preven- intended as a guide for most of the current clinical tive approach, it is able to a ect the individual dis- trials on AIT approved for implementation can be ease course positively (disease modifying e ect). found in the European Clinical Trials Register at: All ergic rhinitis patients have a 3.5-fold higher rela- www.clinicaltrialsregister.eu. tive risk of developing bronchial asthma within less Manufacturers have the opportunity to report re- than 10 years [33]. In this context, AIT is deemed to sults on e cacy from relevant studies in the sum- have a preventive e ect in terms of allergic progres- mary of product information under Article 5.1; sion (to allergic bronchial asthma) or new sensitiza- however, study quality may vary signi cantly, given tions [24, 34]. the di erences in requirements between 1990 and e scienti c socio-economic evaluation of thera- today. In the case of authorized preparations, this peutic agents is carried out using cost-bene t and information is also examined by the authorities. In cost-e ectiveness analyses, which enable healthcare the case of current marketing authorizations, manu- policymakers to compare di erent methods and facturers use this opportunity, which also o ers products, as well as to identify the advantages and physicians a good chance to inform themselves disadvantages of treatment methods from a socio- about the preparation. economic perspective. e results of this kind of Since authorized nished medicinal products are analysis are taken into consideration in the evalua- not able to cover the full spectrum of allergen ex- tion of medicinals and play an important role today tracts required for AIT, the use of individual formu- in decision-making on the coverage of the treatment lations (named patient products, NPP) is justi ed costs by state health institutions. in cases where the extract needs to be individually e gain in quality of life per year following in- tailored to the allergy needs of a particular patient tervention with AIT is measured using the stan- [28] (see Tab. 3). dardized quality-adjusted life year (QALY) and em-

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ployed for incremental cost-e ectiveness analysis teria. As an example one could only include stud- [35]. Every year of life in perfect health is expressed ies with a minimum of 100 subjects per arm or with a QALY of 1, diminishing according to disease studies on commercially available products. In burden to a QALY of 0.0 for death. By dividing the their analysis through 2009, Calderon et al. evalu- disease course, the di erence in costs for various ated 33 clinical studies on AIT in grass-pollen all- methods or time points in treatment (in this case ergic patients that ful lled prede ned criteria [43]. AIT) by the relevant QALY, one obtains the incre- 28 recent trials were used for a more up-to-date mental cost-e ectiveness ratio (ICER). Recent ex- meta-analysis of studies on SCIT and SLIT in pa- amples show that the ICER for AIT, irrespective of tients with seasonal allergic rhinitis [44]. Another the route of administration, falls within the range recent systematic review of the e cacy and tolera- of treatments accepted in healthcare policy for the bility of SCIT and SLIT in patients with house dust treatment of chronic diseases [36, 37]. Another cost- mite allergy included 44 studies published up to e ectiveness analysis carried out in Germany un- 2013 [45]. derscores the potential of AIT to save costs [38]. In summary, these meta-analyses and reviews If one takes the cumulative ICER per year as a demonstrate a well-documented e cacy for AIT. basis, it becomes clear that the signi cant invest- However, due to the heterogeneity of individual ment made in AIT at the beginning of treatment studies described in all analyses, the authors stress proves to be cost-neutral a er 7 years on average that it is not possible to make a generic recommen- [39]. is is consistent with the fact that the princi- dation about the route of application, but rather that pal advantage of AIT lies in its long-term e ects. It evidence of e cacy and tolerability is required for must be pointed out, however, that these e ects de- individual AIT preparations. pend to a great extent on treatment compliance. It is anticipated that, under the TAV (see Sect. 3.3), Generally speaking, the prices of individual pro- a large number of studies combined with adequate ducts valid at the time (according to the o cial drug evidence on various preparations will be available. price list (LAUER-TAXE®) and at dosage according Tables providing a preparation-speci c list of AIT to the manufacturer‘s recommendations) for a treat- products on the market in Germany, Switzerland ment period of 3 years should be used to compare and Austria can be found on the DGAKI website via the costs of SCIT and SLIT. www.dgaki.de/Leitlinien/s2k-Leitlinie-sit. is list includes all preparations with certain features for Conclusion: Allergic rhinitis and its associated co- some products: morbidities (e. g., bronchial asthma) generate sub- a) studies are available ful lling ve e cacy crite- stantial direct and indirect costs. Treatment options, ria that are modi ed to conform to the recom- in particular AIT, are therefore evaluated using cost– mendations in the WAO consensus paper on the bene t and cost-e ectiveness analyses. From a long- standardization of clinical AIT studies [46]. Since term perspective, AIT is considered to be signi - the e cacy of AIT in view of potential side e ects cantly more cost e ective in allergic rhinitis and and treatment costs should at least be comparable allergic asthma than pharmaco therapy, but is heav- to that of pharmacotherapy, a threshold in e - ily dependent on patient compliance. cacy of 20 % above placebo has been selected as acceptable [46]. e currently most e ective 4. E cacy in clinical studies pharmacotherapy (MP29-02) has an e cacy of 4.1. Systematic reviews and meta-analyses for the 19 % above placebo, thereby justifying this thresh- evaluation of AIT old value [47]. Systematic reviews and meta-analyses are o en re- b) marketing authorization has been granted in ferred to as the highest form of statistical evaluation Germany. of multiple studies. e reliability of their conclu- c) the authorities have granted consent to perform sions depends on the study selection criteria and on clinical trials and the positive vote of the quality control measures as the studies evaluated relevant ethics commission has been submitted are usually highly heterogenous [40]. Although nu- to the competent authorities (from www.clinical merous meta-analyses on AIT have been carried out, trialsregister.eu). recent ones were able to include more studies with e table lists studies in adults and children sepa- large numbers of cases and of higher quality. Re- rately, the year of marketing authorization, the clin- views of published meta-analyses carried out up to ical endpoints used as a basis, the number of pa- and including 2009 can be found in [41] and [42]. tients randomized and evaluated, the evaluation One way to reduce the e ect of heterogeneity on method used (ITT, FAS, PP) for grass pollen –and study results, while enabling conclusions that are birch pollen allergens and house dust mite allergens, relevant in routine practice, is to select the studies as well as the status of consent to conduct clinical to be included strictly according to prede ned cri- trials.

292 Allergo J Int 2014; 23: 282–319 It is important to note that the quality of evidence that was at least equivalent to (purely symptomatic) of e cacy di ers according to the year in which drug treatment [49]. approval was granted (in accordance with the PEI Despite new, methodologically sound DBPC criteria applied in the year of approval) and that trials (for example [50]), there is less data to support approval is independent of the ve e cacy criteria evidence of the clinical e cacy of SCIT in children. discussed here (e.g., a xed percentage improvement above placebo is not endorsed for marketing autho- 4.2.2. E cacy of SCIT in allergic bronchial asthma rization). In contrast to the use of SCIT in allergic rhinoconjunctivitis, the decision to use SCIT in allergic Conclusion: Meta-analyses provide unequivocal bronchial asthma is generally made with greater evidence of the e cacy of SCIT and SLIT for cer- caution [51, 52, 53, 54, 55, 56, 57]. SCIT is not a sub- tain allergen sources and age groups. Data from stitute for adequate anti-asthmatic treatment. On controlled studies di er in terms of scope, quality the basis of numerous studies, SCIT can be recom- and dosing regimens and require product-speci c mended in intermittent (severity according to the evaluation. erefore, evaluating individual prepa- National disease management guideline (NVL) for rations according to clearly de ned criteria is rec- asthma /Global Initiative for Asthma (GINA) I) ommended. A broad transfer of the e cacy of cer- and mild persistent bronchial asthma (severity tain preparations to all preparations administered according to NVL/GINA II) [51, 52, 54, 58]. ese in the same way is not endorsed. recommendations are based on data from a meta- analysis in the Cochrane Library [59], which eval- 4.2. E cacy of SCIT in inhalant allergies uated 88 randomized controlled – yet methodolog- 4.2.1. E cacy of SCIT in allergic rhinoconjunctivitis ically heterogeneous – SCIT studies including al- e documentation on the clinical e cacy of SCIT together 3,459 patients with allergic asthma to in allergic rhinoconjunctivitis is based on numer- house dust mite allergens (42), pollen allergens ous DBPC trials of heterogenous size and quality (27), animal dander allergens (10) and other aller- and which were summarized for seasonal allergens gens. An analysis of all the articles evaluated (e.g., grass pollen, birch pollen) in a systematic re- showed a signi cant reduction in both symptom view and meta-analysis in 2007 [48]. is analysis score and medication use. Furthermore, a slight evaluated 15 studies on SCIT that demonstrated a yet signi cant reduction in non-speci c bronchial reduction in the symptom score (Standardized hyperreactivity was seen. e marked reduction in Mean Di erence (SMD) -0.73; 95 % Con dence In- allergen-speci c bronchial hyperreactivity to terval (CI) -0.97 to -0.50; p < 0.00001) and in the house dust mite allergens as well as pollen aller- medication score (SMD -0.57; 95 % CI -0.82 to -0.33; gens and animal dander allergens in patients treat- p < 0.00001; in 13 studies). ed with SCIT compared with control groups can A current meta-analysis (2013) evaluated 17 clin- be considered as evidence of a lower risk of asthma ical trials (up to April 2011) for e cacy of SCIT in exacerbation on renewed exposure to the relevant patients with seasonal allergic rhinitis [44]. is allergen. However, the 20 studies that included the analysis found a reduction in the symptom scores measurement of lung function parameters showed (SMD -0.65; 95 % CI -0.85 to -0.45; p < 0.00001; all only a trend towards improved lung function, 17 studies), the medication scores (SMD -0.55; 95 % without statistical signi cance [59]. As, there is CI -0.75 to -0.34; p < 0.00001; 16 studies), the com- generally no signi cant reduction in lung function bined symptom and medication scores (CSMS) parameters in patients with intermittent or mild (SMD -0.48; 95 % CI -0.67 to -0.29; p < 0.00001; persistent asthma, this clinical endpoint is not 8 studies) as well as an improvement in the quality- suitable for evaluating the e cacy of AIT. of-life scores (SMD -0.53; 95 % CI -0.66 to -0.39; e incidence of systemic side e ects was 19.9 % p < 0.00001; 8 studies). in the actively treated group versus 8.1 % in patients An evidence-based review of SCIT e cacy based receiving placebo injections. One in nine actively on results from 7 studies on house dust mite-aller- treated patients developed systemic reactions of gic patients was also published in 2013, wherein varying severity to the allergen injections. Unfortu- strong heterogeneity in data on the major allergen nately, this particular Cochrane review did not con- doses used, the evaluation parameters selected and duct a separate analysis for children. the actual study results was seen [45]. e relatively small group of patients with insuf- A comparison of meta-analyses of DBPC SCIT ciently controlled asthma represents a high-risk trials published to date with meta-analyses of group for systemic side e ects, which explains why pharmacotherapy only in seasonal allergic rhinitis here particular caution is required when assessing showed that, even in the rst year of treatment, the indication for AIT and its practical implemen- SCIT resulted in a reduction in allergic symptoms tation [60].

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A recent evidence-based analysis of 19 studies Studies on SCIT using mite extracts in patients (three of which were in children) on the e cacy of with perennial allergic asthma and house dust mite SCIT in patients with (house dust mite) allergic allergy found less symptoms [75, 81, 82, 83], lower asthma found a statistically signi cant bene t in medication use [75, 81, 83, 84], a reduction in aller- SCIT compared with placebo in terms of symptom gen-speci c bronchial hyperreactivity [75, 83] and score or symptom-related scores in only 9 studies improved quality of life [75, 83] compared with pla- [45]. Moreover, there was signi cant heterogeneity cebo. ese ndings were also con rmed in chil- in terms of (major allergen) doses used as well as the dren; SCIT with an allergoid extract of dust mite evaluation parameters and time periods selected resulted in improved asthma control with a signi - [45]. cant reduction in the dose of inhaled corticosteroids One study conducted solely in children with all- required compared with the non-SCIT control ergic asthma in which SCIT was employed using an group (see Sect. 4.2.2 [61]). allergoid extract of house dust mite showed improved asthma control as well as signi cant reduc- 4.2.3.4. Animal allergens tion in the required doses of inhaled corticosteroids To date, a small number of studies have provided compared with the control group not treated with evidence of e cacy primarily for cat allergen ex- SCIT [61]. tracts (with only few for dog allergen extracts) [85, 86, 87, 88, 89]. Only isolated reports are available on 4.2.3. E cacy of SCIT relative to allergen source AIT with allergens from other furry animal species. 4.2.3.1. Grass pollen Numerous clinical studies in the literature highlight 4.2.3.5. Other allergen sources the e cacy of AIT in grass pollen allergic adult pa- Evidence of clinical e cacy in mold allergy is lim- tients (amongst others [62, 63, 64, 65, 66]). Not all ited to a small number of studies using Alternaria approved grass pollen extracts available on the alternata and Cladosporium herbarum extracts [90, market have been tested according to the WAO and 91, 92]. A 3-year DBPC trial in children with Alter- EMA e cacy criteria, and speci c pediatric studies naria alternata allergy showed SCIT to be e ective are lacking for most preparations (see DGAKI table from the second year of treatment onwards [50]. “Trials showing evidence of treatment e cacy: grass pollen” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). 4.2.4. E cacy of AIT in other indications A DBPC trial in 35 children and adolescents with Data on the e cacy of AIT with pollen allergens to seasonal grass pollen-induced asthma aged treat oral allergy syndrome (OAS) are as yet insuf- 3 to 16 years showed that SCIT using a non-modi- cient [93], meaning that further studies are needed ed (native) allergen extract can signi cantly re- before a conclusion is possible. A randomized con- duce asthma symptom–medication scores [67]. trolled trial (on 40 tree pollen allergic patients, 20 of whom were treated with SCIT and 20 treated with 4.2.3.2. Tree pollen SLIT) demonstrated an improvement of the OAS in A number of e cacy studies on birch pollen aller- some of the patients [94]. At present, AIT is not in- gies have shown a reduction in symptoms and/or dicated in exclusively pollen allergen-associated medication use (e. g., [68, 69, 70, 71, 72, 73, 74]). e OAS without airway symptoms. e cacy and safety of most early- owering (fagales) Recent studies show AIT to have clinical e ects tree extracts available on the market have not been in patients with extrinsic atopic dermatitis (AD) as proven in DBPC trials, and relevant speci c pediat- well as corresponding and likely clinically relevant ric studies are lacking (see the DGAKI table “Trials type-I sensitization (e. g., eczema triggered by air- showing evidence of treatment e cacy: tree pollen” borne allergens; reviews in [95, 96]). One random- via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). ized double-blind dose-range- nding SCIT trial on 89 adult patients with a chronic form of AD and sen- 4.2.3.3. House dust mites sitization to house dust mites revealed a signi cant e evaluation of the e cacy of SCIT in house dust improvement of the SCORAD (Scoring Atopic Der- mite-induced rhinoconjunctivitis is based on a matitis) over a one-year therapy-course [97]. In a number of studies (e. g., [75, 76, 77, 78, 79]), but it is more recently published DBPC-Phase-III study true also in this indication that many of the com- (SCIT) on 168 adult patients a signi cant improve- mercially available dust mite extracts have not been ment in the SCORAD was only demonstrated in a investigated for e cacy or safety in DBPC trials, subgroup with severe forms of AD [98]. and only scant speci c pediatric studies (e. g., [80]) A 2013 meta-analysis on the e cacy of AIT in AD, are available (see the DGAKI table “Trials showing in which eight randomized and controlled (six SCIT, evidence of treatment e cacy: house dust mites” via two SLIT) trials were included, found a positive ef- www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). fect [99]. e authors stress, however, the consider-

294 Allergo J Int 2014; 23: 282–319 able heterogeneity between the studies conducted, bis -0,17; p < 0.00001; 35 studies), the combined some of which had small patient numbers, thus symptom and medication scores (SMD -0,40, 95 % limiting the validity of this meta-analysis. However, CI -0.55 to -0.25; p < 0.00001; 6 studies) as well as AD is not a contraindication for AIT in patients improved quality of life scores (SMD -0.37, 95 %-CI with allergic airway diseases requiring treatment. -0.52 to -0.22; p < 0.00001; 7 studies) in SLIT-treated patients compared with placebo [44]. Conclusion: Strong evidence of the e cacy of SCIT An evidence-based review of SLIT e cacy in in pollen allergy-induced allergic rhinoconjunctivi- patients with (house dust mite-induced) allergic tis in adulthood is well-documented in numerous rhinitis found a signi cant di erence in the respec- trials and, in childhood and adolescence, in a few tive symptom score or symptom-related scores in trials. only two of the eight studies considered, whereby E cacy in house dust mite allergy is documented (as with the analysis of SCIT studies in the same by a number of controlled trials in adults and few publication) the authors described signi cant het- controlled trials in children. Only a few controlled erogeneity in terms of the (major allergen) doses trials, independent of age, are available for mold used as well as the evaluation parameters and time allergy (in particular Alternaria). With regard to an- periods selected [45]. imal dander allergies (primarily to cat allergens), Although head-to-head comparisons of studies only small studies, some with methodological de - between SLIT and SCIT in adults show both treat- ciencies are available. Only a moderate and incon- ment methods to be clinically e ective, these studies sistent therapeutic e ect in atopic dermatitis has are methodologically inadequate ([112], reviewed in been observed in the quite heterogeneous studies [41, 44]). Due to scant data and/or methodological conducted to date. de ciencies, it is not possible to draw conclusions SCIT has been well investigated for individual either from meta-analyses on the di erences be- preparations in controlled bronchial asthma (GINA tween SLIT and SCIT in terms of e cacy [41, 44]. 2007 [56]) and intermittent and mild persistent In a recent comparison of DBPC trials in seasonal asthma (GINA 2005 [55]) and it is recommended as allergic rhinitis on SLIT grass tablets and pharma- a treatment option, in addition to allergen avoid- cotherapy-only studies published to date, a reduc- ance and pharmacotherapy, provided there is a clear tion in allergic symptoms by SLIT at least equiva- causal link between respiratory symptoms and the lent to purely symptomatic drug treatment was relevant allergen. found [113].

4.3. E cacy of SLIT in inhalant allergies 4.3.2. E cacy of SLIT in allergic bronchial asthma 4.3.1. E cacy of SLIT in allergic rhinoconjunctivitis Compared with allergic rhinoconjunctivitis, there Due to new controlled trials in adults [100, 101, 102, are only a limited number of studies on the e cacy 103, 104, 105, 106] and children [107, 108, 109], some of SLIT in patients with allergic bronchial asthma. with high patient numbers, good data on the e cacy A grass tablet study showed e cacy for SLIT in of SLIT is also available. As with SCIT, there are sig- bronchial asthma in a subgroup of children with ni cant di erences in the documentation of clinical seasonal allergic asthma [107]. With regard to im- e cacy depending on the product used. While for munotherapy using dust mite extracts, hetero- certain products no randomized and large con- geneous results were found in clinical trials with trolled trials have been published, extensive data is methodological limitations [114, 115, 116, 117]. available for individual preparations and allergens, A recent study included 604 house dust mite- which have been taken into consideration in a re- allergic patients at least 14 years of age with mild to cent Cochrane meta-analysis on SLIT ([110] intend- moderate asthma treated for a 1-year period with ed as an update of [111]). e analysis conducted up SLIT with house dust mite tablets. Compared with to August 2009 included for the symptom scores 23 placebo, actively treated patients exhibited a signif- studies in grass pollen allergic patients (SMD -0.35; icant reduction in the dose of inhaled corticoste- 95 % CI -0.45 to -0.24; p < 0.00001), 9 studies (in- roids required to maintain asthma control over the cluding 2 using birch pollen extract) in tree pollen course of the study period [118]. allergic patients (SMD -0.42; 95 % CI -0.77 to -0,06; p = 0.02) and 9 studies in house dust mite allergic 4.3.3. E cacy of SLIT relative to allergen source patients (SMD -0.97; 95 % CI -1.80 to -0.13; p = 0.02). 4.3.3.1. Grass pollen A meta-analysis published in 2013 on the e cacy e e cacy of SLIT with grass pollen extracts in all- of SLIT in patients with seasonal allergic rhinitis ergic rhinoconjunctivitis with or without concomi- found a reduction in the symptom scores (SMD tant asthma has been documented in a number of -0.33; 95 % CI -0.42 to -0.25; p < 0.00001; 42 studies), large studies conducted in Europe [102, 104] and the in the medication scores (SMD -0,27; 95 % CI -0,37 US [119] (reviewed in [120]) (see the DGAKI table

Allergo J Int 2014; 23: 282–319 295 Guideline AIT-Guideline

children as well as in adults [103, 109, 126, 127]. | Table 5 Factors that increase the clinical e cacy of AITa, b With regard to other grass SLIT preparations, either con icting study results are available or they have Short duration of disease not yet been investigated in DBPC trials. Minor involvement of the lower airways 4.3.3.2. Tree pollen Age (the EMA PDCO recommends that therapy not be commenced before the age of 5 years) A handful of e cacy studies also showed a reduc- Good compliance and adherence tion in symptoms and/or medication use in tree A high cumulative AIT dose pollen allergic patients (e.g.,[105, 112, 128, 129]. An early DBPC trial with a birch pollen extract dem- aThe more of these points that apply, the higher the probability that administration of AIT will reduce symptoms and medication use, as well as decrease the likelihood of allergic march – the development of onstrated a signi cant reduction in symptom and bronchial asthma and broadening of the allergen spectrum. medication scores a er 1 year of treatment com- b only valid for inhalant allergens pared with placebo [112]. A recent study in over 570 birch pollen allergic adults found a statistically signi cant advantage with aqueous tree pollen extract compared with placebo in pre/co-seasonal SLIT over a 2 year period [105] (see the DGAKI | Table 6 table “Trials showing evidence of treatment a Indications for AIT with allergens e cacy: tree pollen” via www.dgaki.de/Leitlinien/ Verifi cation of an IgE-mediated sensitization (preferablyb from skin testing andc/ord in vitro diagnostics) with a clear relationship to clinical symptoms (if indicated, challenge s2k-Leitlinie-sit). testing) However, for numerous aqueous tree pollen Availability of standardized or high-quality allergen extracts (birch or birch/alder/hazel mixtures) SLIT prepara- Proof of effi cacy of the planned AIT for the respective indication and age group tions, either heterogeneous study results are avail- Allergen avoidance not possible or inadequate able or they have not yet been investigated in DBPC Patient age ≥ 5 years trials. E cacy data for birch tablets in SLIT are not aAll points should be fulfi lled. bIn Switzerland, verifi cation of sensitization preferably by skin testing. available. c“And” refers to rare allergens or uncertain results. d“Or” refers to situations in which skin testing is not possible and to diagnostic work-up in children below 5 years. 4.3.3.3. House dust mites Data on the e cacy of SLIT with house dust mite allergens are con icting. A number of SLIT dust mite products currently available have not as yet been subjected for e cacy in clinical studies. “Trials showing evidence of treatment e cacy: grass Most studies have been conducted in patients pollen” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). with mild to moderate asthma (with concomitant e strongest evidence of clinical e cacy (in terms dust mite-induced rhinitis). Besides several positive of the size and methodology of studies) is for the study results (e. g., [130, 131, 117, 114, 132, 133, 134]), sublingual tablets already approved [43, 102, 104]. negative study results also exist (e.g., [116, 135]) (see In a randomized controlled study in 80 children the DGAKI table “Trials showing evidence of treat- comparing the clinical e cacy of a co-seasonal ver- ment e cacy: house dust mites” via www.dgaki.de/ sus a perennial (continuous) schedule, SLIT with an Leitlinien/s2k-Leitlinie-sit). A DBPC trial with a aqueous grass pollen extract demonstrated better modi ed dust mite allergen tablet product proved e cacy of the continuous SLIT during the rst year, e cacy in mild dust mite-induced rhinitis [134]. but the clinical e ects of both schedules were com- A recently published study in 509 adults with parable in the second and third year of treatment house dust mite allergic rhinitis demonstrated a sig- [121]. ni cant improvement in symptom scores following Studies in grass pollen allergic children at least 5 1-year SLIT with dust mite tablets with a carry-over years of age the course of one season showed com- e ect even in the second year of the trial without parable e cacy with grass tablet products to the immunotherapy [106]. Another recently published previously conducted adult studies [107, 108, 122]. study on house dust mite tablets in adolescent (aged As a result, both preparations were approved for use from 14 years) and adult patients with bronchial in children from the age of 5 years. In addition, a asthma also showed clinical e cacy for SLIT (see carry-over e ect could be shown for both grass tab- Sect. 4.3.2. [118]). lets in adults: clinical e cacy was con rmed 1 year [123, 124] to 2 years [125] following completion of a 4.3.3.4. E cacy of SLIT with other allergen 3-year treatment course. extracts In addition, large DBPC trials showed aqueous While individual studies on other inhalant allergen grass SLIT preparations to be clinically e ective in sources (animal dander, molds, weed pollen) are

296 Allergo J Int 2014; 23: 282–319 available, they do not permit a conclusive evalua- | Table 7 tion of treatment e cacy. Allergen components helpful in establishing the indication for AIT (major allergensa versus panallergensb) Conclusion: e e cacy of SLIT in grass pollen-in- Major allergensa duced allergic rhinoconjunctivitis is extensively Bet v 1 ➾ Birch, Betula pendula (formerly Betula verrucosa) documented in adults and children, whilst its e - Phl p 1/5 ➾ Grasses, Phleum pratense (timothy grass) cacy in tree pollen allergy has only been shown in Der p 1/2 ➾ House dust mites, Dermatophagoides pteronyssinus adults. New controlled trials (some with high pa- Alt a 1 ➾ Alternaria, Alternaria alternata tient numbers) on house dust mite allergy provide Ole e 1 ➾ Ash – no actual components instead due to high cross-reactivity: olive tree: evidence of e cacy of SLIT in adults. Olea europaea Compared with allergic rhinoconjunctivitis, Art v 1 ➾ Mugwort, Artemisia vulgaris there are only few studies on the e cacy of SLIT in Amb a 1 ➾ Ragweed, Ambrosia artemisifolia (common ragweed) allergic asthma. In this context, newer studies show an e cacy for SLIT on asthma symptoms in the Components that explain positive skin tests but are not valid in the indications for AIT (panallergensb) subgroup of grass pollen allergic children, adoles- Proﬁ lins: e.g.: Amb a 8 (ragweed), Ara h 5 (peanut), Bet v 2 (birch), Cor a 2 (hazelnut), cents and adults with asthma and e cacy in prima- Hev b 8 (latex), Phl p 12 (grass), Tri a 12 (wheat) ry house dust mite allergy-induced asthma in ado- Polcalcins: e.g.: Aln g 4 (alder), Amb a 9 (ragweed), Art v 5 (mugwort), Bet v 4 (birch), lescents aged from 14 years and in adults. Phl p 7 (grass)

aThe name of an allergen component is derived from the fi rst three letters of the genus and the fi rst letter 4.4. Prevention of asthma and new sensitizations of the species names, e.g., timothy grass Phleum pratense ⇨ Phl p 1. The numbering often follows the For individual products controlled, open studies chronological order of fi rst description; thus, identical numbers unfortunately do not automatically- signify cross-reactivity. Cross-reactivity is so high in some allergen-families that it is not necessary to have shown that, in addition to its primary allergen- determine the individual components separately: Beech-like (PR10 proteins): Bet v 1 (birch) ⇦⇨ Aln a 1 (al- speci c e ect, AIT also has secondary preventive der) ⇦⇨ Cor a 1 (hazelnut); Grasses (grass group 1 allergen): Phl p 1 (timothy) ⇦⇨ Cyn d 1 (Bermuda grass) ⇦⇨ Lol p 1 (ryegrass) ⇦⇨ Tri a 1 (wheat); House dust and fl our mites: cysteine proteases, Der p 1 ⇦⇨ f1, characteristics, thus the potential to have a positive NPC2 family: Der p 2 ⇦⇨ f 2. The up-to-date, international WHO/IUIS list of all allergen components is e ect on the long-term course of allergic disease. available at: www.allergen.org. bDefi nition: a major allergen is an allergen component to which more than 50% of sensitized allergy erefore, young patients with early manifestations suff erers exhibit specifi c IgE (e.g., in grass allergy: major components, Phl p 1, 2, 5, 6; minor component: of allergic symptoms are an important target group Phl p 11). Panallergens are found in many species and are generally clinically insignifi cant, but never- for AIT intervention. theless explain irrelevant positive extract-based skin and/or blood tests, e. g., profi lins from 48 plant species are currently described, and new ones are being added daily; for an up-to-date list see: A SCIT preparation containing birch or grass www.meduniwien.ac.at/allergens/allfam. allergens, or a birch–grass mixture in allergic rhinoconjunctivitis was shown to reduce the risk of developing allergic asthma in an open prospective study (“Preventive allergy treatment (PAT) study” [136, 137]). Moreover, this e ect was detectable 7 years following discontinuation of SCIT com- subsequent follow up-years [146]. Preliminary data pared with the control group that received sympto- are expected in 2016. matic treatment only [34]. e development of new sensitizations can be Conclusion: Aspects of secondary prevention, in reduced in the case of mono- and oligosensitiza- particular the reduction of new sensitizations and tions [138, 139, 140, 141]. reduced asthma risk, are important rationales for Evidence of these and other secondary preventive choosing to initiate treatment early in childhood and e ects were described in an open study up to 12 adolescence. In this context, those products for which years following discontinuation of SCIT with a the appropriate e ects have been demonstrated modi ed allergen preparation compared with an should be considered. untreated control group [139]. A recent SLIT study was able to show a reduction 5. Indications and contraindications in new sensitizations, whereas this e ect was not 5.1. SCIT and SLIT observed in another (also open) study [142, 143]. A number of variables in uences the success of AIT e preventive e ect of SLIT on lower respiratory and should therefore be considered when planning tract involvement (asthma onset) has also been therapy (Tab. 5). demonstrated, but mainly in open studies [142, 144, Tab. 6 contains an overview of the indications for 145]. A multinational prospective DBPC trial is cur- speci c immunotherapy using inhalant allergens. rently being conducted in over 800 children with Fig. 3 outlines the clinical algorithm of the diagnos- grass pollen allergic rhinitis but no evidence of asth- tic work-up for the indication of AIT with seasonal ma, on whether early intervention using grass pol- allergens. len tablets can prevent the development of asthma Tab. 7 outlines the possible advantages of a mo- during the 3 years of treatment, as well as during 2 lecular allergy based diagnostic work-up to estab-

Allergo J Int 2014; 23: 282–319 297 Guideline AIT-Guideline

Seasonal symptoms: e.g. ocular pruritus, sneezing, secretion, nasal obstruction, dyspnea, cough, wheezing

Patient history, clinical examination

Skin testinga pollen, Relevance check: Positive yes Interpretation: yes seasonal corresponding skin test? relevance check mold spores symptoms?

no no

Interpretation: No plausibility check symptoms

yes Determination of Positive speciﬁc IgE, patient history? total IgE

Speciﬁc yes IgE increased?

Suspected local allergy no Provocation- (no positive skin test, yes testingb (nasal, speciﬁc IgE conjunctival) in serum not elevated)?

Positive yes no provocation

Sensitization without Indication No allergy, clinical relevance, for AIT no AIT no AIT

aIn children sensitization can be verified by determination of specific IgE bnot valid for Austria IgE, Immunglobulin E; AIT, allergen-specifi c immunotherapy Authors of the guideline © Fig. 3: Diagnostic work-up for AIT with seasonal allergens (clinical algorithm)

lish the indication for AIT. In some situations In case of a con rmed house dust mite allergy, (polysensitized patients), the use of in vitro com- AIT is an option if measures for mite avoidance ponent-based IgE diagnostics can increase the (mite allergen-proof mattress encasings, washable likelihood of AIT being successful as early on as blankets and further measures to reduce house at the time of making the indication. Patients dust mite allergens) are insu cient (Fig. 4) and no without sensitization to major allergens may re- improvement in symptoms is observed a er 3 ceive less therapeutic bene t from AIT [147]; months of mite avoidance. A meta-analysis pub- although detailed prospective studies on this topic lished in 2008 questioned the e cacy of mite con- are not currently available. Sensitizations solely to trol measures [148]. In only 17 of 54 included stud- pollen-panallergens do not constitute indications ies evaluated a signi cant reduction in the number for AIT. of house dust mites could be documented. Overall,

298 Allergo J Int 2014; 23: 282–319 Perennial symptoms: e.g., ocular pruritus, sneezing, nasal secretion, nasal obstruction, dyspnea, cough, wheezing

Patient history, clinical examination

IgE-mediated Correlation with sensitization (skin yes yes Allergen avoidance yes patient history in test and/or possible? cases of animal speciﬁc IgE)? dander allergies no

Provocationb: nasal, conjunctival, inhalative

Positive yes no provocation?

Sensitization without Aim at allergen avoidance continued allergen clinical relevance, further and consider indication avoidance no diagnostic work-up for AIT (if necessary)

Correlation with patient yes Provocationb: nasal, history inacases conjunctival, inhalative of mite allergies

yes Positive b provocation? Allergen avoidance no Allergen avoidance yes no successful

Observation of the course Sensitization without Optimize allergen of disease, diﬀerential clinical relevance, further avoidance Continued diagnosis, further diagnostic c diagnostic work-up and indication for AIT allergen acoidance work-up (if necessary) (if necessary)

aPerennial symptoms can be caused by molds; in individual cases AIT can be indicated. bIn children, the recommendation for mite-avoidance measures can be given without prior allergen provocation. Before AIT with a house dust mite extract nasal provocation test in children is worthwhile but not mandatory if clinical symptoms are unambiguous and diagnostic work-up corresponds. The allergological societies in Austria do not stipulate organ provocation tests for adults. cIf suspicion for allergy persists: provocation (e.g., mites).

IgE, immunglobulin E; AIT, allergen-speciﬁ c immunotherapy Authors of the guideline © Fig. 4: Diagnostic work-up to establish the indication for AIT with perennial allergens

the intervention measures applied in the investi- ly relevant house dust mite allergy, the aforemen- gated studies were very heterogeneous and no sub- tioned intervention measures are primarily indi- group analysis was carried out for children. Due cated [149, 150]. e German S3 guideline on all- to the methodological de ciencies of this meta- ergy prevention also underscores the value of mite analysis, the conclusion drawn by the authors is control measures for secondary and tertiary aller- questionable. erefore, in patients with a clinical- gy prevention [150].

Allergo J Int 2014; 23: 282–319 299 Guideline AIT-Guideline

In general, seasonal and perennial allergens are | Table 8 Contraindicationsa, d to AIT with allergens not combined in one extract. One reason for this is to avoid an unnecessary reduction in the perennial Subcutaneous administration (SCIT) Sublingual administration (SLIT) allergen fraction during the pollen season. Similar- Partially controlled or uncontrolled Partially controlled or uncontrolled ly, due to enzymatic degradation reactions [152], bronchial asthma (classifi cation according bronchial asthma (classifi cation according mite and animal dander allergens, mite and mold to the GINA guidelines, 2007 or NVL, see to the GINA guidelines, 2007 or NVL, see Tab. 9) Tab. 9) allergens and extracts containing pollen and mold Diseases in which administration of no contraindication allergens should never be combined in one prepara- epinephrine is contraindicated (except in tion. the case of insect venom allergies) Before one opts for SCIT, several contraindica- Treatment with β-blockers (local or preparation-specifi c diff erences, see tions need to be considered (Tab. 8). For safety rea- systemic application)b product information leafl et sons, partially controlled or uncontrolled bronchial severe autoimmune diseasesc, immune severe autoimmune diseasesc, immune defects, immunodefi ciencies, immuno- defects, immunodefi ciencies, immuno- asthma (Tab. 9) (classi cation according to NVL- suppression suppression Asthma [153] or the GINA guidelines, 2007 [56]) malignant neoplastic diseases with current malignant neoplastic diseases with current represents a contraindication to AIT in adults. In disease relevance disease relevance the German NVL, “partially controlled asthma” is serious systemic reactions to AIT in the past serious systemic reactions to AIT in the past de ned more restrictively for the pediatric age acute, severe infl ammatory disorder of the group than for adults; therefore AIT may be per- oral cavity formed in children in case of partially controlled insuffi cient compliance insuffi cient compliance asthma (NVL de nition [153]) – provided they aIn justifi ed individual cases and on the basis of a risk-benefi t analysis, AIT may also be possible even with existing contraindications. rarely experience asthma symptoms. bIn Germany, treatment with ACE inhibitors is also currently a contraindication to SCIT with insect In addition to guideline recommendations, prac- venom. ticioners should also be aware of the product infor- cDiseases not among those severe autoimmune diseases that represent a contraindication to AIT include: Hashimoto thyroiditis, rheumatoid arthritis, ulcerative colitis and Crohn‘s disease, type-1 diabetes mation lea et issued by the product manufacturer. mellitus; see also Sect. 5.2. is information has been approved by the PEI and dWhen evaluating contraindications, the product information leafl et corresponding to the particular product must be consulted. is binding with respect to product-speci c contraindications. GINA, global initiative for Asthma ; NVL, Nationale Versorgungsleitlinie, National disease management guideline; AIT, specifi c immunotherapy Although pregnancy is considered to be a contraindication to initiating AIT, continuation of SCIT in the case of life-threatening allergies to insect venom (bee/wasp venom) is advisable as well in the case of allergies to inhalant allergens, AIT is permissible, Allergen avoidance is the treatment of choice for if the treatment is well tolerated by the patient (and animal dander allergies. If allergen avoidance can- in case it is in accordance with the product infor- not be ensured, SCIT with animal allergen extracts mation lea et) [154, 155]. Only in isolated cases (e. g., can be considered in individual cases (in particular life-threatening insect venom allergy), can SCIT be in the case of a cat allergy; Fig. 4). initiated during pregnancy. In the case of mold allergy, total allergen avoid- Medication with β-blockers (also in topical pre- ance is only possible in exceptional cases. SCIT us- parations, such as eye drops) is listed as a contrain- ing mold allergens can be considered in the case of dication to SCIT in the specialist information. An seasonal mold allergy with a corresponding indica- increased risk of adverse airway reactions (bronchial tion and a well-characterized therapeutic allergen constriction) and the risk that potentially required preparation (Alternaria, Cladosporium) [50, 90, 91]. emergency treatment with epinephrine might be e e cacy of AIT depends on the optimal thera- less e ective [156] are discussed. e decision as to peutic dose of each clinically relevant allergen. Cur- whether it is, under the circumstances, necessary to rent knowledge on the clinical e cacy and immuno- continue therapy with β-blockers has to be made on logical e ects of AIT is based primarily on studies in an individual basis, together with the prescribing which monotherapy with a single allergen extract physician. Although speci c data are lacking, it is was administered. erefore, no di erent (non- logical to assume that treatment with immunosup- homologous) allergen groups should be mixed in an pressants or (immunomodulatory) biologicals may allergen preparation used for therapy, if the use of the reduce the e cacy of AIT [156]. particular combination is not supported by data from Indications and contraindications also need to be clinical trials. A current SCIT DBPC study with a considered with the sublingual application of AIT chemically modi ed mixture of tree pollen and grass (see Tab. 6 and Tab. 8). Systemic adverse events are pollen allergens found signi cant (albeit moderate) observed less frequently with SLIT than with SCIT. clinical e cacy throughout the entire tree and grass Patients with chronic disease of the oral mucosa are pollen season in the second year of treatment [151]. not suitable for SLIT. Furthermore, similar contra-

300 Allergo J Int 2014; 23: 282–319 indications to those for SCIT (Tab. 8) also apply, | Table 9 although the product manufacturer‘s information Level of asthma control lea et must be consulted. (translated by the authors, © of the German version ÄZQ, BÄK, KBV and AWMF 2013, NVL [153], modifi ed according to GINA 2007 [56], www.ginasthma.org) 5.2. AIT despite contraindications Criterion controlled asthma partially controlled uncontrolled In selected cases, immunotherapy can also be initi- (all criteria fulfi lled) asthma (one or two asthma ated despite the existence of relative contraindica- criteria fulfi lled within tions. A typical example of burnt-out autoimmune 1 week) Daytime ≤ 2x per week > 2x per week disease that can be well compensated by drug-based symptoms treatment is Hashimoto‘s thyroiditis. If controlled no yes Restrictions in no yes by drug-based treatment, this disease need not con- activities of daily three or more traindicate AIT. In the case of other autoimmune living criteria of diseases, such as multiple sclerosis, myasthenia gra- Nighttime symp- no yes „partially toms/awakening controlled vis, lupus erythematosus, rheumatoid arthritis and asthma“ fulfi lled Crohn‘s disease, for example, initiating AIT may be Use of reliever ≤ 2x per week > 2x per week within 1 week medication/ no yes judged possible on an individual basis considering emergency activity and course of the disease. treatment An exception among the contraindications listed Lung function normal < 80 % of the predicted in Tab. 8 under immunode ciency is represented by (PEF or FEV1) value (FEV1) or personal acquired immunode ciency in stable, well-con- best value (PEF) 1 trolled HIV (human immunode ciency virus) in- Exacerbation no one or more per year one per week Information relates to any one week within the preceding 4 weeks. fection under highly active antiretroviral therapy green = applies only to adults, red = applies only to children and adolescents, blue = general recommendations (HAART), with negative HIV replication and nor- 1Any exacerbation in 1 week signifi es by defi nition “uncontrolled asthma“. Defi nition of exacerbation: an mal CD4 counts. A case report and one small series episode involving increased dyspnea, coughing, wheezing and/or chest tightness, associated with a of three patients have been described in the litera- deterioration in PEF or FEV1. ture to date [157, 158]. Although SCIT during FEV1, forced expiratory volume in 1 second; NVL, nationale Versorgungsleitlinie, National disease management guideline; PEF, peak expiratory fl ow HAART is safe and does not negatively in uence the disease course, there are currently no data to support the clinical e cacy of SCIT in HIV-positive patients. In the case of a clear indication, SCIT may be initiated in individual HIV-positive patients with stable disease who are undergoing HAART. ciated with reduced mortality [hazard ratio (HR) Because advanced age no longer represents a 0.71; 95 % CI 0.62–0.81), as well as with a lower contra indication to AIT and the incidence of can- incidence of myocardial infarction (HR 0.70; 95 % cer increases with increasing age, there is a growing CI 0.52–0.93) and autoimmune diseases (HR 0.86; population of allergic rhinitis/asthma patients with 95 % CI 0.74–0.99) over a 10-year observation peri- a past history of neoplastic disease. Even relatively od (1997 to 2006) [162]. recent, but currently stable, malignant disease need Although the risk of SCIT causing an autoim- not necessarily represent a contraindication. In a mune disease is probably very low, this risk case study of four patients with melanoma and an should be considered, particularly in light of the insect venom allergy and one patient with breast fact that the therapy lasts several years. Where cancer and seasonal allergic rhinitis, it was possible relevant suspicions are raised, AIT should be in- to complete AIT. Moreover, in most of these pa- terrupted until any possible relation has been tients, no reactivation of malignant disease was ob- ruled out. served even a er more than 5 years of cancer follow-up [159]. Conclusion: SCIT or SLIT with pollen or mite A Swiss case series of 25 patients (with a clear and allergens can be performed in patients with allergic strictly de ned indication for SCIT due to a history rhinoconjunctivitis using allergen extracts that of severe anaphylactic reactions to insect venom) have been proven to be e ective in at least one with cardiac disease who were taking β-blockers ob- double-blind placebo-controlled (DBPC) study. At served no increase in the instance of severe adverse present, clinical trials are underway for the events during SCIT [160]. indication in asthma due to house dust mite allergy, Evidence for the triggering of autoimmune diseases some of the results of which have already been by AIT is based on case studies (15 articles reporting published, whilst others are still awaited (see the 22 cases, of which 12 cases were vasculitis) [161]. DGAKI table “Approved/potentially completed In contrast, a registry-based observational study studies” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit conducted in Denmark showed that SCIT was asso- (according to www.clinicaltrialsregister.eu)).

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When establishing the indication for AIT, factors that favour clinical e cacy should be taken into consideration (Tab. 5). Di erences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justi ably indicated despite the presence of contraindications.

6. Performing speci c immunotherapy AIT is carried out by physicians with a (sub)special- ity in allergy or adequate relevant treatment experience. Furthermore, the treating physician must be capable of dealing with adverse events (including anaphylactic shock and severe asthma attacks) [163, 164]. Since January 1 1996, product information lea ets for desensitization solutions used in Germa- ny are required to include the following warning: “Desensitization injections may be prescribed and administered only by physicians with specialized allergological training or physicians experienced in allergy.” (PEI, communication dated April 5 1995). In Austria, solutions for AIT may be prescribed and administered by physicians specialized or experienced in allergy. e continuation of AIT can then be delegated to a general practitioner. In Switzer- land, AIT can also be performed by primary care physicians, provided an allergological work-up with a specialist has been undertaken before commencing treatment. Before initiating AIT, patients must be informed about the following: the practical procedure, type and duration of treatment; expected e ects; as well as possible risks of and alternatives to treatment [165]. e process of providing patients with this information must be documented (Patients‘ Rights Act of the Ger- man Civil Code [Patientenrechtegesetz des BGB]; §630f BGB: Documentation of Treatment [Dokumen- tation der Behandlung]; available at www.patienten- rechte-gesetz.de/bgb-sgbv/dokumentation.html). Printed information (see “Treatment information sheet”, available as a handout at www.dgaki.de/ Leitlinien/s2k-Leitlinie-sit; Fig. 5 and Fig 6) on how AIT is carried out and how to deal with possible adverse events should be made available to patients. Adequate documentation of patient counseling is obligatory and written informed consent from the patient (or the patient‘s parent or legal guardian, as appropriate) is advisable. In cases where AIT is to be administered or continued by a di erent physician other than the one who initially established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. If necessary, the patient should be referred back to the Fig. 5: Treatment information sheet for subcutaneous physician who originally made the indication. speci c immunotherapy (SCIT), available at If the treatment shows no signs of success a er www.dgaki.de/Leitlinien/s2k-Leitlinie-sit 1 to a maximum of 2 years, it should be critically re-

302 Allergo J Int 2014; 23: 282–319 assessed – if possible by the physician who made the indication. Where indicated a change of preparation or a change from preseasonal to perennial treatment can be considered. Discontinuation of treatment is also an option. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate clinical trial data are available (see Sect. 4.).

6.1. SCIT with inhalant allergens Prior to injection, the patient is interviewed regarding current allergic, or other relevant symptoms: py- rexia or other signs of infection; the tolerability of the last injection; any current or recent illnesses; or new or altered medications or vaccinations. e time interval since the last injection should be checked [165]. Confusion can be avoided by, for example, reading the names of the allergen preparation and of the patient out loud in the patient‘s presence. For AIT injection – which represents a medical task and should thus be performed by the physician – a 1 ml syringe with ne graduation down to 0.01 ml with an injection needle (size 14–18, short bevel, suf- cient length) is used. First, the area of skin where the injection is to be administered is disinfected. e injection is made strictly subcutaneously: following prior or, depending on the injection volume, repeated aspiration, injections are made into a li - ed skin fold a hand‘s width above the olecranon on the extensor side of the upper arms. Details of the injection site and dose are documented. e patient must remain under medical observation for at least 30 min a er injection [165]. During this period, the patient must report any symptoms that may indi- cate an allergic reaction to the medical sta . Once the waiting time has elapsed, the injection site should be examined. If a strong local reaction de- velops, the diameter should be documented, since a dose adjustment according to the product information lea et of the administered SCIT preparation may be required (see Sect 8.1). A er a 3-year transitional period, the national policy for the prevention of injury from sharp/ pointed instruments in hospitals and the health sec- tor came into force in Germany on May 11 2013, within the context of the Biological Agents Act (Biosto verordnung) BGR 250/TRBA 250 (rules of the employers‘ liability insurance association (BG)/ technical rules for biological materials; overview in [166]). is policy regulates the use of, e. g., hypo- dermic needles such as those used for subcutaneous allergen-speci c immunotherapy (SCIT) according to state regulations covering occupational safety and accident prevention. Since the introduction of Fig. 6: Treatment information sheet for sublingual these regulations, the use of injection systems less speci c immunotherapy (SLIT), available at likely to cause injury (including SCIT syringes with www.dgaki.de/Leitlinien/s2k-Leitlinie-sit

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retraction systems, needle shields etc.) is obligatory allergic symptoms at the time of injection. Precise for employees active in the eld of allergy. As an em- clinical documentation is necessary. ployer, the allergist is not only speci cally obliged Due to potential di erences in biological activity to exercise due care personally, but also has a spe- and where stated in the product information lea et, cial obligation to ensure that his employees also a reduction in the intended dose may be necessary exercise due care. It can be assumed that o cial at the beginning of a new batch during treatment checks on the implementation of the Biological continuation. However, preparations which no lon- Agents Act in allergy practices will be heightened in ger require this are now available from various the future. manu facturers. Shortly before and for the remainder of the day of If the injection interval is exceeded, the dose is injection, factors augmenting allergic reactions (e. g., reduced according to the product information leaf- physical exertion, whirlpool or sauna, alcohol) let. e greater the discrepancy between the intend- should be avoided. e time interval between a ed and actual intervals, the more the dose needs to SCIT injection and a planned vaccination should be be reduced [165]. In the case of airway allergies, the at least 1 week [165]. Vaccinations should, therefore, duration of SCIT should be at least 3 years. Although be carried out during the SCIT maintenance phase no controlled studies on parallel immunotherapy and administered between two SCIT injections per- with two di erent allergen extracts administered formed at a 4-week interval. Emergency vaccina- during the same sitting exist, safety considerations tions (e. g., tetanus due to injury) can of course be mandate a time interval of at least 30 min between administered at any time. erea er, SCIT is con- injections/sublingual administrations for safety rea- tinued either according to the product information sons. A er the nal injection, the usual observation lea et, or 2 weeks a er the vaccination using the period of 30 min must be adhered to. previously administered dose (overview in [167]). In patients with allergic bronchial asthma it is Treatment is usually carried out on an outpatient recommended that a peak ow protocol be run basis. In the case of rush desensitization protocols during treatment and that lung function tests are (see below) or high-risk patients (pronounced sys- performed at regular intervals. temic reactions, relative contraindications), it may be appropriate to initiate SCIT in an inpatient set- 6.2. SLIT with inhalant allergens ting. SLIT is performed on an outpatient basis according Allergen extracts for SCIT are mainly applied as to the manufacturer‘s product information lea et. depot solutions. During the dose escalation period Recommendations for practical use can be found in (frequently doubling of the previous dose; see [120, 165]. product information lea et), treatment intervals are Depending on the preparation and the manufac- between 3 and 7 days for aqueous solutions and turer, the initial dose should be administered (and between 1 and 2 weeks for depot solutions. If clus- followed-up) under the supervision of a physician ter or rush titration protocols are applied, several experienced in allergy [120, intended as an update injections are administered on each day of treat- of 171]. With some SLIT preparations, and in accor- ment (reviewed in [168, 169]). Once the maximum dance with their product information lea ets, SLIT tolerated dose has been reached, the injection inter- can be initiated during the pollen season (intra- vals can be increased to 4 to 8 weeks, according to seasonal start). the corresponding product information lea et. In In cases of viral infections of the respiratory tract, the case of seasonal aeroallergens, treatment esca- it may be possible to continue administration based lation to the maximum dose is initiated outside of on a physician‘s recommendation or it may be the allergen season and continued for at least 3 ad- necessary to interrupt treatment (see product infor- ditional years [165]. e general implementation of mation lea et). According to the product informa- purely intra-seasonal dose escalation has recently tion lea et of the particular preparation, adminis- been investigated. is study employed a single trations can then once again be increased to the preparation for which good tolerability to this type maximal dose. No SLIT allergen extracts should be of approach could be demonstrated [170]. Scienti c administered in cases of acute in ammation or in- data on the e cacy of such a strategy are currently jury to the oral or pharyngeal mucosa, signi cant not available in published form; therefore, no gen- surgical interventions (tooth extraction) in the oral eral recommendations for intra-seasonal initiation cavity, acute gastroenteritis or uncontrolled asthma of SCIT in pollen allergic patients can be made at (consult corresponding product information lea et). present. Co-seasonally performed SCIT (continua- Co-seasonally performed SLIT (continuation tion during the allergy season) without dose reduc- during the allergy season) without dose reduction tion is possible where this is in line with the prepa- is possible where this is in line with the prepara- ration‘s product information lea et and there are no tion‘s product information lea et and there are no,

304 Allergo J Int 2014; 23: 282–319 or only minor, allergic symptoms at the time of ad- ter this renders adherence to SCIT than to SLIT is cur- ministration. Precise clinical documentation is rently controversial. ere is a general lack of suitable necessary. Following an unintended break in independent studies addressing the important issue administrations of several days, the dose should be of compliance/adherence under real-life conditions. reduced according to the product information leaf- In a review by Senna, data from clinical studies let. e greater the lapsed interval, the more the on SCIT and SLIT were pooled together [177]. is dose needs to be reduced. review reports adherence rates of approximately Based on experience with SCIT, the duration of 70 % for SCIT and 75 % for SLIT. However, these SLIT should also be at least 3 years. If the treatment results have only limited signi cance, since data is continued in another practice, close cooperation from studies from the US and Europe – with di er- with the physician who made the initial indication ing treatment regimens, indications and patient should be maintained, particularly in the event of groups – were pooled together. questions relating to e cacy and safety. In a randomized controlled trial, 271 patients (age 15 to 65 years) with allergic rhinitis with/without Conclusion: SCIT injections and the initiation of accompanying asthma were to receive SLIT over a SLIT are performed by a physician experienced in course of three years [145]. e authors found in this type of treatment and who is able to administer 72 % of the patients treated over the whole course of emergency treatment in the case of an allergic reac- three years an adherence-rate of more than 80 % tion. Patients must be fully informed about the pro- and in 18 % of the patients an adherence-rate cedure and risks of possible adverse events, and the between 60 % and 80 %. details of this process must be documented (see No di erences in compliance rates between SCIT “Treatment information sheet”, Fig.5 and Fig. 6 ; and SLIT were reported in a comprehensive review available as a handout via www.dgaki.de/Leitlinien/ of Incorvaia et al. [30], independently of the form of s2k-Leitlinie-sit). Treatment should be performed administration compliance rates in recent trials according to the manufacturer‘s product information varied between 75 % and 90 %. However, these data lea et. In cases where AIT is to be performed or con- are from clinical trials and are not likely to predict tinued by a di erent physician to the one who estab- treatment adherence in a real-world setting [120]. lished the indication, close cooperation is required Low treatment adherence oviously jeopardizes in order to ensure that treatment is implemented con- therapeutic success. is conclusion was con rmed sistently and at low risk. by an analysis of real German statutory healthcare In general, it is recommended that SCIT and SLIT insurance SCIT prescription data conducted by should only be performed using preparations for Claes et al. [178]. is study demonstrated persis- which adequate proof of e cacy is available from tence rates (consecutive average prescription rates) clinical trials. that dropped o over the years: in only 24 % of patients treated with established SCIT products was 6.3. Compliance and adherence SCIT continued into the third year. Similarly nega- e term compliance describes a patient‘s passive tive results from Germany and Italy for SLIT over 3 observance of the physician‘s instructions, whereby years have also been published as posters or letters the patient is primarily responsible for the success (13,2 % to 22,7 %) [179, 180, 181]. Another analysis or failure of therapy [172, 173]. e modern concept of real German statutory healthcare insurance pre- of adherence, however, describes the extent of agree- scription data investigated persistence rates among ment between physician and patient on jointly made 1,409 patients treated with market-leading SCIT treatment decisions and therapeutic goals, as well and SLIT products [182]. is analysis found unsat- as the extent to which patients take medications as isfactory persistence rates in the third year of ther- prescribed by their physician on the basis of these apy in 34 % to 51 % of patients. An evaluation of decisions [173, 174]. German statutory healthcare insurance prescrip- Since the success of AIT depends on the duration tion data from 562 children and adolescents aged of appropriately performed treatment, it is particu- between 4 and 18 years demonstrated a persistence larly important that AIT is carried out in accor- rate of 44.1 % in the third year [183]. dance with prescriber’s recommendations. Analo- Following therapy, a study by Sondermann et al. gous to other types of treatment, the likelihood of questioned SCIT and SLIT patients on what they treatment success and adherence to therapy is im- perceived as disadvantageous aspects of the treat- proved by thoroughly informing the patient about ment in order to explain the unsatisfactory adher- the way in which AIT works [165, 175, 176]. ence to therapy [173]. e heavy time demands of As SCIT is administered by a physician, it would the treatment were considered a problem by 69.5 % initially seem that adherence is easier to monitor for of patients, while 62.5 % reported adverse e ects of SCIT than for SLIT. However, exactly how much bet- the therapy as a problem. Furthermore, 60.7 % of

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om allergic patients and between 90 % and 95 % in | Table 10 Reasons for non-compliance in AIT wasp-venom allergic patients. In non-responders an (modi ed from [173]) increased maintenance dose results in a therapeutic Patient information success in almost all the cases [184]. – Patient inadequately informed/motivated For information on indications, contraindica- – no understanding of primary and secondary preventative eff ects of AIT (allergic march, tions, performing treatment, possibilities for moni- new sensitization) toring treatment as well as treatment duration, the Therapeutic procedure reader is referred to the current guideline on “Dia- – Adverse events gnosis and treatment of bee and wasp venom aller- – no reduction in symptoms or self-medication use gy” (S2-AWMF-LL registry number 061-020 [184]). – incorrect patient selection Clinic/Practice Management 8. Safety, risk factors and adverse events – heavy time demands on patients (particularly for SCIT) – treatment insuffi ciently integrated into daily life 8.1. SCIT – no recall system or patient counselling, possibly due to lack of fi nancial resources When administered correctly to properly selected patients, in a medical o ce/hospital with experience in this type of treatment, allergen-speci c immunotherapy with SCIT preparations is safe and well tolerated [165, 185, 186]. Local reactions including redness, swelling or patients experienced no relief of symptoms and itching at the injection site occur very frequently, 53.7 % had not received adequate information about but can be treated using local measures (e. g., cool- the therapy. ing or topical glucocorticoids) or systemic anti- According to these data, reasons for early discon- histamines. tinuation of therapy may be based on inadequate When increased local reactions (redness and/or patient information, on the way in which treatment swelling >10 cm in diameter) occur at the injection is carried out and on practice management (see site, the speci c information contained in the Tab. 10). Patient compliance rates should be in- manu facturer‘s product information lea et for the creased by better organization in the medical o ce corresponding SCIT preparation should be consult- and an attempt to better educate the patient. In or- ed for the dosage of the subsequent injection. How- der to ensure adequate therapeutic adherence and ever, in a retrospective evaluation of their own compliance, recall systems are necessary for both patient data, an American group was able to show SLIT and SCIT. Improvements in AIT adherence that increased local reactions do not predict an in- represent one of the most important goals for the creased individual risk of a systemic reaction [187]. future, in order to ensure success of the therapy. Ad- In the case of Al(OH)-containing SCIT products, ditional motivation and support measures for phy- rarely and particularly with incorrect intradermal sicians (e. g., the “Bavarian Selective Contract”) are administration, but also as a result of Al(OH)-con- desirable. tact allergy, protein contact dermatitis, or a vasculitic in ammatory reaction, granulomas may result from Conclusion: Treatment adherence among AIT pa- a foreign body reaction [188, 189, 190]. In such cases, tients is lower than assumed by physicians, irrespec- is it recommended that treatment continues with an tive of the form of administration. Clearly, adher- allergen extract that does not contain Al(OH). e ence is of vital importance for treatment success. possible systemic risks from adjuvant aluminum Improving AIT adherence is one of the most impor- have been the topic of critical discussion for some tant future goals, in order to ensure e cacy of the time. In response to the increasing number of re- therapy. quests, the PEI published a safety evaluation of aluminum in therapeutic allergens on its website in 2014 7. Subcutaneous immunotherapy with insect (www.pei.de/DE/arzneimittelsicherheit-vigilanz/ venom allergens archiv-sicherheitsinformationen/2014/ablage2014/ A systemic allergic reaction with symptoms of an 2014-01-21-sicherheitsbewertung-von-aluminium- immediate-type allergy (anaphylaxis) occurs in in-therapieallergenen.html). e statement addresses about 3.5 % of the population following a hymenop- not only local tolerability, but also sensitization po- tera sting (e. g., bee, wasp) [184]. tential, toxicity and German pharmacovigilance data. Reactions can occur with various degrees of se- According to this publication, the overall sensitiza- verity, which should be considered when making tion potential of aluminum is to be considered low; the indication for AIT. e success rate of guideline- only isolated cases of sensitization in SCIT patients oriented AIT performed with the standard mainte- have been reported [189, 190, 191]. Toxic e ects de- nance dose lies between 75 % and 85 % for bee-ven- pend on the quantity of aluminum absorbed [191].

306 Allergo J Int 2014; 23: 282–319 e contribution of SCIT to the lifelong accumula- | Table 11 tion of aluminum in the human body is low com- Risk factors for systemic reactions during AIT pared with other sources. e speci c evaluation of (modi ed from [165, 186, 197, 202]) all reports of treatment-related AEs between 1986 Current allergy symptoms and potential allergen exposure and 2013 also raised no alarms regarding the safety Current infections of these preparations. Mast cell disease e PEI concludes that the currently available Hyperthyroidism scienti c data do not suggest that children or adults Unstable or insuﬃ ciently treated asthma are put at risk by undergoing SCIT with aluminum A high degree of sensitization adjuvanted allergens and that, on the basis of cur- Inadequate dose escalation during initiation rent knowledge, there is no reason to reconsider the Pharmaceutical use (β-blockers) use of licensed therapy allergens containing alumi- Inadequate circulatory stress, excessive alcohol consumption, high-intensity physical num adjuvants. exercise, sauna (shortly before and for the rest of the day of injection, augmenting factors Systemic allergic reactions to SCIT can take the should be avoided) form of mild to severe reactions of the skin, gastro- Poor technique of injection intestinal tract, airways or cardiovascular system. Allergen extract overdose In a retrospective analysis of a large patient popula- Manufacturer’s recommendation for dose reduction upon changing to a new production tion (2,206 patients) and a large total number of in- batch was overlooked jections (192,505 injections) over a 10-year observation period, a total of 115 systemic reactions (5.2 % of patients or 0.06 % of all injections) were observed, almost all of which occurred within the 30 min post-injection observation phase (no fatalities) should weigh the risks associated with continuing ([192], reviewed in [186]). A more recent analysis treatment against the urgency of the indication and conducted between 2008 and 2011 by the American possible treatment alternatives (see also Sect. 6.). Academy of Allergy, Asthma and Immunology In order to aid decision-making, the patient (AAAAI), based on an average of 6.3 million injec- should be referred back to the physician who estab- tion visits per year, found systemic reactions in ap- lished the original indication for SCIT where re- proximately 0.1 % of all injection visits. Once again, quired. e risk factors described above should be no fatal reactions were observed [193, 194]. Fatal re- investigated and avoided in relation to SCIT. In cas- actions with clear causal relation to SCIT were esti- es where treatment is continued, it is recommended mated in a survey of American allergists for the pe- that the dose be reduced in accordance with the in- riod of 1990 to 2001 to have a frequency of 1 in 2.5 dividual preparation‘s product information lea et. million injections [195]. Where adverse e ects occur, it is possible to pre- According to PEI data (1991 to 2000), the inci- medicate with an antihistamine in order to reduce dence of severe reactions is calculated to be 0.002 % the frequency and severity of possible systemic re- to 0.0076 % (in terms of injections) for non-modi- actions; however, premedication does not eliminate ed (“native”) allergen extracts and 0.0005 % to the possibility of systemic reactions [156, 168, 169, 0.01 % for chemically modi ed allergen extracts 199, 200]. ( allergoids) [196]. If risk factors are considered, se- e management of severe adverse events is de- vere reactions are sometimes predictable and can scribed in detail in Sect. 9. (“Emergency treatment”). usually be avoided with appropriate care and prophylactic measures [165, 186, 197]. Conclusion: Severe, potentially life-threatening sys- Tab. 11 provides an overview of possible risk temic reactions during SCIT are possible, but – pro- factors that may be related to the occurrence of sys- viding all safety measures are adhered to – these temic reactions during AIT. events are very rare. Most adverse events are mild In 2010, the WAO has published a new standard- to moderate and can be treated well. ized ve-grade classi cation of systemic adverse events in SCIT (Tab. 12 [198]). 8.2. SLIT In the case of recurrent severe reactions or insuf- When administered correctly to patients selected cient compliance (e.g., the patient does not stay in based on the given indications, allergen-speci c the medical o ce long enough, intervals between immunotherapy with SLIT preparations is safe and injections are too long, inappropriate physical exer- well tolerated [110, 120]. tion or avoidable contact with allergens around the Adverse events during SLIT are dose-dependent time of injection), the decision on whether to con- and, depending on the preparation, manifest in tinue or discontinue therapy should be made by an 40 % to 75 % of the cases as temporary local muco- allergist. When making this decision, the allergist sal reactions (pruritus or dysesthesia in the oral

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| Table 12 Grading system of systemic adverse events for subcutaneous immunotherapy (SCIT) according to the World Allergy Organization (WAO) 2010 [198] and for sublingual immunotherapy (SLIT) according to WAO 2013 [205] Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Symptom(s)/sign(s) of one organ system Symptom(s)/sign(s) of Lower respiratory Lower or upper respiratory Death present more than one organ Asthma (e. g., 40 % PEF or FEV1 drop Respiratory failure with or system present not responding to an inhaled without loss of consciousness Cutaneous or bronchodilator) or Generalized pruritus, urticaria, ﬂ ushing, or or sensation of heat or warmtha Lower respiratory Cardiovascular Asthma: cough, wheezing, Upper respiratory Hypotension with or without or shortness of breath (e. g., Laryngeal, uvula, or tongue loss of consciousness Angioedema (not laryngeal, tongue or less than 40 % PEF or FEV1 edema with or without stridor uvular) drop, responding to an or inhaled bronchodilator) Upper respiratory or Rhinitis (e. g., sneezing, rhinorrhea, nasal Gastrointestinal pruritus and/or nasal congestion) Abdominal cramps, or vomiting, or diarrhea Throat-clearing (itchy throat) or or other Uterine cramps Cough perceived to originate in the upper airway, not the lung, larynx, or trachea or Conjunctival Erythema, pruritus or tearing or other Nausea, metallic taste, or headache

Patients may also have a feeling of impending doom, especially in grades 2, 3, or 4. Note: Children with anaphylaxis seldom convey a sense of impending doom and their behavior changes may be a sign of anaphylaxis; eg, becoming very quiet or irritable and cranky. Scoring (grade 1-4) includes a suffi x (a–d or z) that denotes if and when epinephrine is or is not administered in relationship to onset of symptom(s)/sign(s) of the SR:a, ≤ 5 minutes; b, >5 minutes-to ≤ 10 minutes; c: > 10 to 20 minutes; d: > 20 minutes; z, epinephrine not administered. (further details in [198]) The fi nal grade of the reaction will not be determined until the event is over, regardless of the medication administered. The fi nal report should include the fi rst symptom(s)/sign(s) and the time of onset after the subcutaneous allergen immunotherapy injectionb and a suffi x refl ecting if and when epinephrine was or was not administered, e. g., Grade 2a; rhinitis: 10 minutes Final Report: Grade a–d, or z______, First symptom(s)/sign(s)______Time of onset of fi rst symptom______Comments (on reaction and treatment): aThis constellation of symptoms may rapidly progress to a more severe reaction. bSymptoms occurring within the fi rst minutes after the injection may be a sign of severe anaphylaxis. Mild symptoms may progress rapidly to severe anaphylaxis and death.

cavity, swelling of the oral mucusa, throat irritati- contraindications, persisting unaccaptable local ad- on) [120, 201, 202, 203]. ese reactions usually verse events, severe reactions a er administration occur during the initiation of SLIT, are mostly and a lack of clinical response a er two years of mild and generally subside 1 to 3 weeks a er the SLIT are indications for early discontinuation of start of treatment [120]. However, particularly in therapy [165]. the early treatment phase, these reactions can lead In regards to the safety pro le of SLIT, it is im- to self-discontinuation of therapy. It is thus par- portant to note that most adverse events occur at ticularly important that the patient is thoroughly home, where there is no possibility of immediate informed at the start of treatment (see also medical intervention in the (very rare) case of a “treatment information sheet for SLIT”, Fig. 6; systemic reaction. It is therefore important to in- available as a handout at www.dgaki.de/Leitlinien/ form patients – and, when applicable, their par- s2k-Leitlinie-sit). Gastrointestinal symptoms dur- ents – thoroughly on how to react if adverse events ing SLIT are described as occurring at a frequency occur or if administration of the SLIT preparation of 14 % [110]. is forgotten, as well as about situations in which Premedication with antihistamines may also be SLIT should be temporarily interrupted. Exam- suitable for SLIT in order to reduce the extent of ples of the latter include elective maxillofacial sur- local reations. A lack of compliance, newly arising gery, as well as the existence of oropharyngeal in-

308 Allergo J Int 2014; 23: 282–319 | Table 13 Grading system for local adverse events in sublingual immunotherapy (SLIT) according to the WAO (modi ed from [205]) Symptom/sign Grade 1: mild Grade 2: moderate Grade 3: severe unknown severity Pruritus/swelling of mouth, not troublesome troublesome Grade 2 Treatment is discontinued, tongue, or lip; throat and oder and but there is no subjective, irritation*, nausea, abdominal objective, or both description pain, vomiting, diarrhea, no symptomatic treatment requires symptomatic SLIT discontinued because of of severity from the patient/ heartburn, or uvular edema required treatment local side eff ects physician. and and no discontinuation of SLIT no discontinuation of SLIT because of local side eff ects because of local side eff ects

Each local adverse events can be early (< 30 minutes) or delayed, *for example, itchy palate, burning or swelling of the throat (added by guideline authors)

fections and lesions (ulcers, gingivitis, periodon- 8.3. Reporting adverse events from AIT in titis), gastroenteritis and asthma exacerbations Germany, Austria and Switzerland [120]. In Germany, in accordance with §63c (2) of the Although the risk of severe systemic adverse reac- German AMG (www.gesetze-im-internet.de/ tions is lower with SLIT compared with SCIT [120, amg_1976/__63c.html), the marketing authoriza- 196], 11 incidences—in some cases with severe ana- tion holder of a particular drug is legally obliged phylaxis—are described in the literature following to report within 15 days every suspected serious sublingual administration of allergens in droplet or adverse event (SAE) of which he gains knowledge tablet form (reviewed in [202]). However, treatment to the competent higher federal authority and in these cases was not administered according to additionally, in the case of a SAE occurring in the standards that apply today (non-standardized third countries, to the European EudraVigilance extracts, rush protocols, excessive allergen dose, database. Moreover, it is planned that suspected patients in whom SCIT had previously been inter- non-serious adverse events are to be reported to rupted due to severe reactions) [202]. An important the European database by the marketing authori- risk factor for severe systemic adverse events during zation holder within 90 days. SLIT – as is also the case for SCIT – is insu ciently Reporting suspected AEs occurring in daily prac- controlled asthma [202]. tice is of great importance for collecting as much e recommendation of one expert team that pa- data as possible pertaining to the safety of a drug, tients with severe adverse events during SCIT as well as for allowing continued monitoring of its should switch to SLIT [176] cannot be supported: a risk–bene t ratio. Physicians, pharmacists and history of severe systemic reations a er subcutane- other healthcare professionals, as well as patients, ous application of allergens also constitutes a risk parents, legal guardians and other relatives should factor for possible severe systemic reactions during report every suspected AE via the national report- SLIT [204]. ing system (in Germany, for allergen preparations e WAO recommends the adoption of the grad- located at the PEI; in accordance with AMG §11a ing system for systemic reactions on SCIT also for Sect. 1). Patients in Germany can report an AE via SLIT and, moreover, proposes a new, standardized https://verbraucher-uaw.pei.de/fmi/iwp/cgi?- classi cation of local reactions during SLIT (Tab. 13) db=Verbraucher-UAW&-loadframes. [120, 205]. e aim of both classi cation systems is In Austria, the Institute of Pharmacovigilance of to provide a worldwide standardized reporting sys- the Austrian Medicines and Medical Devices Agency tem that should enable the frequency and severity (BASG/AGES Medizinmarktaufsicht) is responsible of adverse events of AIT (SLIT and SCIT) to be more for operational tasks. According to the Austrian Me- precisely de ned. dicinal Products Act and Pharmacovigilance Regu- lations, 2006 (AMG §75j; www.basg.gv.at/ueber-uns/ Conclusion: Dose-dependent adverse local reac- gesetzliche-grundlagen/arzneimittel), members of tions occur frequently in the mouth and throat in the following professions are legally obliged to report SLIT. Systemic reactions have been described in AEs to the Institute of Pharmacovigilance of the Aus- SLIT, but are seen far less o en than with SCIT. In trian Medicines and Medical Devices Agency: phy- terms of anaphylaxis and other severe systemic re- sicians, dentists, veterinarians, midwives, pharma- actions, SLIT has a better safety pro le than SCIT. cists and druggists, as well as tradespersons who are

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AEs covered by this legal obligation are serious or | Table 14 Emergency equipment for the treatment of anaphylactic previously unknown AEs, accumulation of known reactions (S2-AWMF-LL registry number 061–025, 2014 [207]) or previously unknown AEs, quality complaints and unusual constraints on distribution. Manufac- Stethoscope, blood pressure monitor turers are required to send quarterly safety update Tourniquet, syringes, indwelling venous catheters, infusion set reports on each of their approved drugs to the na- Oxygen with face mask/nasal cannula tional competent authority. Guedel-tube, bag valve mask, suction unit, intubation set Adrenaline for injection 9. Emergency treatment H1-antihistamines for intravenous injection Systemic reactions following AIT generally occur infusion solutions (0.9 % NaCl solutions, balances electrolytes/colloids ) within the rst 30 min following administration. Glucocorticoids for intravenous injection erefore, in the case of SCIT, it is essential that Bronchiodilator (rapidly acting β2 adrenoreceptor agonist for inhalation or intravenous patients remain under medical observation for at injection) least 30 min following injection and that they report Automated external deﬁ brillator (optional) immediately any symptoms that may arouse sus- Pulse oximeter (optional) picion of an allergic reaction [165]. NaCl, Sodium chloride Systemic reactions require immediate treatment due to the risk of rapid exacerbation [207, 208]. e personnel involved need to be familiar with the obligatory medications and with the equipment authorized for the manufacture or wholesale of drugs used in an allergic emergency (see Tab. 14) [207]. in accordance with the Austrian Commercial Code Initial measures include: suitable positioning of the of 1994 and the marketing authorization holders of patient, i.m. epinephrine (150 µg for patients weigh- proprietary medicinal products. As in Germany, ing 15 to 30 kg, 300 µg for patients weighing > 30 kg), marketing authorization holders are legally obliged infusion therapy via a large-lumen intravenous ac- to report all information on suspected serious AEs cess as well as O administration. Early use of i.m. arising within the European Economic Area and epinephrine in the acute management of anaphylac- third countries electronically to the European Eudra- tic reactions helps guarantee rapid e cacy of med- Vigilance database within 15 days a er gaining ication (stabilization of the cardiovascular system) knowlegde. Information on all suspected non-serious [208]. For practical reasons, having an epinephrine AEs occurring within the European Economic Area auto-injector available is recommended in order to must be reported electronically by the marketing au- ensure prompt therapeutic intervention. Regular thorization holder to the EudraVigilance Database training in immediate procedures for allergic sys- (AMG §75j Sect. 3] within 90 days a er gaining temic reactions is to be recommended [207]. knowledge. Patients in Austria also have the option Early signs of a severe reaction include: a burning to report AEs electronically via www.basg.gv.at/ sensation and pruritus of the palms and soles; peri- pharmakovigilanz/elektronische-meldung/ anal or perigenital pruritus; an urge to defecate and registrierung/patientangehoeriger. urinate; sneezing attacks and generalized pruritus. Since the introduction of the new Medicinal In addition, further respiratory and/or cardiovas- Products Act (HMG) 2002, medical professionals cular symptoms may occur rapidly. in Switzerland are legally obliged to report particu- Although treatment recommendations for the lar AEs that are fatal or life-threatening, cause se- emergency management of anaphylaxis are based on vere or permanent damage and those which are ei- only limited data from clinical studies, they are none- ther not mentioned in or are inadequately addressed theless consistent on an international, European by drug information (drug compendium) [206]. Re- [209] as well as national level [207] regarding the use ports are made to regional pharmacovigilance cen- of Adrenalin i.m., which is also valid in the acute ters by means of a special form. ese centers take management of emergencies in the AIT setting. over the data entry and electronically forward the e described recommendations also apply in the information (anonymously regarding patient and case of anaphylactic reactions occurring in regard primary reporter) to Swissmedic. Swissmedic ad- to SLIT. ministers the central Swiss AE database and for- wards information on severe and new AEs to the Conclusion: e risk and e ects of adverse systemic relevant pharmaceutical companies. Further to this, reactions in the setting of AIT can be e ectively re- Swissmedic conveys all reports to the World Health duced by training of personnel, adhering to safety Organization (WHO). Marketing authorization standards and prompt use of emergency measures, holders, manufacturers and distributors are also le- including early administration of i.m. epinephrine. gally obliged to report AEs and quality complaints. Details on the acute management of anaphylactic

310 Allergo J Int 2014; 23: 282–319 | Table 15 Requirements on future AIT trials (modi ed according to the ”PRACTALL“ consensus report (EAACI and AAAAI [193] as well as the current ARIA report [221]) Development and – Standardization and validation of clinical endpoints (e.g., CSMS) in AIT studies to ensure future compa- implementation of rability of clinical documentation on diff ering preparations, including independently for children, ado- clinical studies lescents and adults – Clear defi nition of the period during which data on clinical symptoms are recorded (standardized classifi cation of the severity of measured pollen exposure) – Further validation and standardization of the use of allergen exposure chambers, in order that these can be used in AIT not only in phase-II AIT studies – More detailed investigation of underlying immunological mechanisms of AIT Specifi c questions –AIT in polysensitized patients – (Secondary) preventive eff ects, such as preventing allergic march and new sensitizations with which AIT preparations – Long-term eff ects of AIT (adults and children) – Recording and analyzing the safety of AIT in patients that receive AIT in the case of particular co-factors or (relative) contraindications – More data from non-interventional observational trials in order to better assess the effi cacy of AIT under practical conditions – Direct comparison of diff erent preparations [unmodifi ed (native) versus chemically modifi ed], treatment regimens and modes of administration in a direct head-to-head comparison Patient selection for – Development of methods/biomarkers to select patients ideally suited for AIT on the basis of responder clinical studies phenotypes – Phenotyping according to indication (allergic rhinitis, bronchial asthma and atopic dermatitis) Measurement of – Standardization, validation and general acceptance of measuring methods to determine the (major) allergen content in allergen content various extracts Biomarkers – Identifi cation and validation of biomarkers as predictive factors for the success of AIT Effi cacy and safety of AIT – More studies complying with up-to-date quality standards on clinical effi cacy, immunological eff ects at diff erent ages and safety stratifi ed according to age (children, adults, >65 years) New approaches in AIT – Investigation and confi rmation of the effi cacy and safety of AIT by using new adjuvants, synthetically produced peptides, recombinants or modifi ed therapy allergens as well as by means of new modes of allergen administration, such as intralymphatic or epicutaneous immunotherapy Safety and tolerability – Clear international defi nition of contraindications in AIT of AIT – Central register to record systemic reactions to AIT in everyday practice Adherence – Development of further programs to improve patient compliance Socio-economics – Long-term (>3 years) cost-eff ectiveness of AIT

reactions can be found in the current S2 guideline By using allergens at other administration sites on anaphylaxis issued by the AWMF (S2-AWMF- [epidermal immunotherapy (EPIT) or intralym- LL Registry Number 061-025 [207]). phatic immunotherapy (ILIT)], it is possible to achieve similarly good immune responses com- 10. Future perspectives for AIT pared with conventional AIT (with patch applica- By using novel or optimized adjuvants, it is possible tions or only a few (3 to 6) injections) [214]. to achieve stronger stimulation of the immune sys- ese approaches are also undergoing clinical in- tem at otherwise unchanged doses or higher doses vestigation in phase-II and also in early phase-III can be implemented without increased risk [210, trials with altogether promising results to date [215, 211]. With the aid of recombinant allergens, 216, 217]. immunotherapeutics can be produced in precisely Combination therapy, using in particular the de ned concentrations and quality in a highly stan- humanized anti-IgE antibody omalizumab, makes dardized manner [212]. AIT possible in patients with moderate to severe By modifying such allergens, novel preparations bronchial asthma or hymenoptera venom allergy to that also o er potential in terms to optimize e ects/ whom AIT was previously inaccessible due to aller- side e ects pro les can be produced. e rst prod- gic side e ects [218, 219]. ucts of this kind are currently being investigated in phase-II trials [213]. Conclusion: AIT is undergoing some innovative Furthermore, with recombinant allergens, atten- developments in many areas (e. g., allergen charac- tion can also be turned to new indications for AIT, terization, new administration routes, adjuvants, e. g., food allergies. faster and safer dose escalation protocols), some of

Allergo J Int 2014; 23: 282–319 311 Guideline AIT-Guideline

which are already being investigated in clinical man Allergologists (AeDA), the Austrian Society for trials. Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino- 11. Requirements on future AIT trials Laryngology, Head and Neck Surgery (DGHNO-KHC), the Despite the fact that AIT has been used for the dis- German Society of Pediatrics and Adolescent Medicine ease-modifying treatment of type-I allergic diseas- (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Associa- es (such as allergic rhinitis and allergic asthma) for tion of ENT Surgeons (BV-HNO), the Professional Federa- over a century [220], a number of important ques- tion of Paediatricians and Youth Doctors (BVKJ), the tions remain to be answered with large multicenter Federal Association of Pulmonologists (BDP) and the Tab. 15 German Dermatologists Association (BVDD). Allergo J Int trials (see , modi ed according to [193] and 2014;23:282–319 [221]). DOI: 10.1007/s40629-014-0032-2 Final 10th October 2014 (ed: Pfaar), following a consensus process and approval by the guideline authors on 18-07-2014 and by board members of the scienti c medical societies involved and professional associations by 01-10-2014

Co-ordinator Prof. Dr. Oliver Pfaar References

Prof. Dr. Oliver Pfaar 1. Kleine-Tebbe J, Bufe A, Ebner C et al. [Speci c immuno- Center for Rhinology and Allergology Wiesbaden therapy (hyposensitization) for IgE-mediated allergic dis- Department of Otorhinolaryngology, Head and Neck eases. Guideline of the German Society of Allergy and Surgery, University Hospital Mannheim Clinical Immunology (DGAKI), of the Association of Ger- An den Quellen 10 man Allergists (ÄDA) and the Society of Pediatric Allergy 65189 Wiesbaden, Germany and Environmental Medicine (GPA), of the Austrian Society E-Mail: [email protected] of Allergy and Immunology (ÖGAI) and the Swiss Society of Allergy and Immunology]. Allergo J 2009;18:509–37 Disclosure/ Con ict of Interest 2. Bagnasco M, Altrinetti V, Pesce G et al. Pharmacokinetics The information on potential con icts of interest have of Der p 2 allergen and derived monomeric allergoid in been reviewed by a steering-group which did not nd allergic volunteers. Int Arch Allergy Immunol any con icts of interest which may a ect the authors’ 2005;138:197–202 independency in the process of the development of this 3. Martinez-Gómez JM, Johansen P, Erdmann I, Senti G, guideline. The authors’ disclosures are available in a ta- Crameri R, Kündig TM. Intralymphatic injections as a new ble (together with the working-report on this guideline) administration route for allergen-speci c immunothera- on the AWMF-page of the S2k- Guideline on “allergen- py. Int Arch Allergy Immunol 2009;150:59–65 speci c immunotherapy in IgE-mediated allergic diseases” via www.awmf.org/leitlinien/detail/ll/061-004.html. 4. Allam JP, Würtzen PA, Reinartz M et al. Phl p 5 resorption in human oral mucosa leads to dose-dependent and time-dependent allergen binding by oral mucosal Lang- Acknowledgement erhans cells, attenuates their maturation, and enhances The authors and contributing medical and professional their migratory and TGF-beta1 and IL-10-producing societies gratefully acknowledge the translation of this properties. J Allergy Clin Immunol 2010;126:638–45.e1 guideline by Christine Schäfer, BA (Hons) PGDip (in Tech- nical and Specialised Translation), Heidelberg, Germany. 5. Akdis M, Akdis CA. Mechanisms of allergen-speci c im- For careful review of the translated guideline and nal munotherapy. J Allergy Clin Immunol 2007;119:780–91 editorial assistance we gratefully acknowledge native 6. Nouri-Aria KT, Wachholz PA, Francis JN et al. Grass pollen im- speakers Dr. Steve Love, PhD, Laguna Niguel, CA, USA, munotherapy induces mucosal and peripheral IL-10 re- and Dr. Sabine Müller, MD, Allergy Research Group, sponses and blocking IgG activity. J Immunol Department of Dermatology, University Medical Center, 2004;172:3252–9 Freiburg, Germany. 7. Takhar P, Smurthwaite L, Coker HA et al. Allergen drives class switching to IgE in the nasal mucosa in allergic rhi- Cite this as nitis. J Immunol 2005;174:5024–32 Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Fried- 8. Reisinger J, Horak F, Pauli G et al. Allergen-speci c nasal richs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, IgG antibodies induced by vaccination with genetically Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, modi ed allergens are associated with reduced nasal al- Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, lergen sensitivity. J Allergy Clin Immunol 2005;116:347– Sitter H, Umpfenbach U, Wedi B, Wöhrl S, Worm M, Kleine- 54 Tebbe J. Guideline on allergen-speci c immunotherapy in 9. Akdis M, Verhagen J, Taylor A et al. Immune responses in IgE- mediated allergic diseases – S2k Guideline of the Ger- healthy and allergic individuals are characterized by a man Society for Aller gology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environ- ne balance between allergen-speci c T regulatory 1 mental Medicine (GPA), the Medical Association of Ger- and T helper 2 cells. J Exp Med 2004;199:1567–75

312 Allergo J Int 2014; 23: 282–319 10. Li JT, Lockey RF, Bernstein I, Portnoy JM, Nicklas RA. Aller- staatlichen Chargenprü fung (Therapieallergene-Verord- gen immunotherapy: a practice parameter. American nung). Bundesgesetzbl 2008;51:2177–8 Academy of Allergy, Asthma and Immunology. American 26. Englert S, May S, Kaul S, Vieths S. [The therapy allergens College of Allergy, Asthma and Immunology. Ann Allergy ordinance (“Therapieallergene- Verordnung”) – Back- Asthma Immunol 2003;90(1 Suppl 1):1–40 ground and e ects]. Bundesgesundheitsbl Gesundheits- 11. European Medicines Agency; Committee for medicinal forsch Gesundheitsschutz 2012; products for human use (CHMP). Guideline on allergen 55:351–57 products: production and quality issues. EMEA/CHMP/ 27. Kaul S, Jappe U, Vieths S, May S. [Surveillance of allergen BWP/304831/ 2007. London, 20 November, 2008 extracts for speci c immunotherapy: legal regulations 12. Ree R van, Chapman MD, Ferreira F et al. The CREATE and procedures]. Allergo J 2008;17:385–93 project: development of certi ed reference materials for 28. May S, Haustein D. [Named patient products in speci c allergenic products and validation of methods for their immunotherapy. Necessities and sources of error]. quanti cation. Allergy 2008;63:310–26 Bundesgesundheitsbl Gesundheitsforsch Gesundheits- 13. European Directorate for the Quality of Medicines & schutz 2001;44:719–23 HealthCare (EDQM), Council of Europe, eds. Monograph: 29. Incorvaia C, Agostinis F, Amoroso S et al. Pharmacoeco- Allergen Products – Producta Allergenica 07/2014:1063. nomics of subcutaneous allergen immunotherapy. Eur as implemented of 01.07.2014. Strasbourg: Council of Eu- Ann Allergy Clin Immunol 2007;39 Spec No:17–20 rope; 2014:p. 3945–47 30. Incorvaia C, Mauro M, Ridolo E et al. Patient‘s compliance 14. Grammer LC, Shaughnessy MA, Patterson R. Modi ed with allergen immunotherapy. Patient Prefer Adherence forms of allergen immunotherapy. J Allergy Clin Immu- 2008;2:247–51 nol 1985;76:397–401 31. Bocking C, Renz H, Pfe erle PI. Prevalence and socio- 15. Pfaar O, Kleine-Tebbe J, Hörmann K, Klimek L. Allergen- economic relevance of allergies in Germany. Bundes- speci c immunotherapy: which outcome measures are gesundheitsbl Gesundheitsforsch Gesundheitsschutz useful in monitoring clinical trials? Immunol Allergy Clin 2012;55:303–7 North Am 2011;31:289–309 32. Lamb CE, Ratner PH, Johnson CE et al. Economic impact 16. Calderon MA, Eichel A, Makatsori M, Pfaar O. Comparabil- of workplace productivity losses due to allergic rhinitis ity of subcutaneous and sublingual immunotherapy out- compared with select medical conditions in the United comes in allergic rhinitis clinical trials. Curr Opin Allergy States from an employer perspective. Curr Med Res Opin Clin Immunol 2012;12:249–56 2006;22:1203–10 17. Pfaar O, Demoly P, Gerth van Wijk R et al. Recommenda- 33. Shaaban R, Zureik M, Soussan D et al. Rhinitis and onset tions for the standardization of clinical outcomes used of asthma: a longitudinal population-based study. Lan- in allergen immunotherapy trials for allergic rhinocon- cet 2008;372:1049–57 junctivitis: an EAACI Position Paper. Allergy 34. Jacobsen L, Niggemann B, Dreborg S et al. Speci c im- 2014;69:854–67 munotherapy has long-term preventive e ect of season- 18. Grouin JM, Vicaut E, Jean-Alphonse S et al. The average al and perennial asthma: 10-year follow-up on the PAT adjusted symptom score, a new primary e cacy end- study. Allergy 2007;62:943–8 point for speci c allergen immunotherapy trials. Clin Exp 35. Hagen A, Gorenoi V, Schonermark MP. Speci c immuno- Allergy 2011;41:1282–8 therapy (SIT) in the treatment of allergic rhinitis. GMS 19. Didier A, Melac M, Montagut A, Lheritier-Barrand M, Health Technol Assess 2010;6:Doc01 doi: 10.3205/ Tabar A, Worm M. Agreement of e cacy assessments for hta000079 ve-grass pollen sublingual tablet immunotherapy. 36. Ronaldson S, Taylor M, Bech PG, Shenton R, Bufe A. Eco- Allergy 2009;64:166–71 nomic evaluation of SQ-standardized grass allergy im- 20. Clark J, Schall R. Assessment of combined symptom and munotherapy tablet (Grazax(®)) in children. Clinicoecon medication scores for rhinoconjunctivitis immunothera- Outcomes Res 2014;6:187–96 py clinical trials. Allergy 2007;62:1023–8 37. Brüggenjürgen B, Reinhold T, Brehler R et al. Cost-e ec- 21. European Medicines Agency; Commitee for medicinal tiveness of speci c subcutaneous immunotherapy in pa- products for human use (CHMP), eds. Guideline on the tients with allergic rhinitis and allergic asthma. Ann Aller- clinical development of products for speci c immunother- gy Asthma Immunol 2008;101:316–24 apy for the treatment of allergic diseases. CHMP/ 38. Westerhout KY, Verheggen BG, Schreder CH, Augustin M. EWP/18504/2006. London, 20. November 2008 Cost e ectiveness analysis of immunotherapy in patients 22. Bousquet J, Schünemann HJ, Bousquet PJ et al. How to with grass pollen allergic rhinoconjunctivitis in Germany. design and evaluate randomized controlled trials in im- J Med Econ 2012;15:906–17 munotherapy for allergic rhinitis: an ARIA-GA(2)LEN 39. Schädlich PK and Brecht JG. Economic evaluation of spe- statement. Allergy 2011;66:765–74 ci c immunotherapy versus symptomatic treatment of 23. Bousquet PJ, Brozek J, Bachert C et al. The CONSORT allergic rhinitis in Germany. Pharmacoeconomics 2000; statement checklist in allergen-speci c immunotherapy: 17: 37–52 a GA2LEN paper. Allergy 2009;64:1737–45 40. Bachert C. Comparison of solutions for sublingual immu- 24. Brehler R, Klimek L, Kopp MV, Christian Virchow J. Specif- notherapy. Int Arch Allergy Immunol 2007;142:89–90 ic immunotherapy-indications and mode of action. 41. Calderon MA, Casale TB, Togias A, Bousquet J, Durham Dtsch Arztebl Int 2013;110:148–58 SR, Demoly P. Allergen-speci c immunotherapy for respi- 25. Verordnung über die Ausdehnung der Vorschriften ü ber ratory allergies: from meta-analysis to registration and die Zulassung der Arzneimittel auf Therapieallergene, beyond. J Allergy Clin Immunol 2011;127:30–8 die fü r einzelne Personen auf Grund einer Rezeptur herg- 42. Compalati E, Penagos M, Tarantini F, Passalacqua G, Ca- estellt werden, sowie ü ber Verfahrensregelungen der nonica GW. Speci c immunotherapy for respiratory aller-

Allergo J Int 2014; 23: 282–319 313 Guideline AIT-Guideline

gy: state of the art according to current meta-analyses. 62. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. E cacy and Ann Allergy Asthma Immunol 2009;102:22–8 safety of speci c immunotherapy with SQ allergen ex- 43. Calderon M, Mösges R, Hellmich M, Demoly P. Towards tract in treatment-resistant seasonal allergic rhinocon- evidence-based medicine in speci c grass pollen immu- junctivitis. J Allergy Clin Immunol 2006;117:319–25 notherapy. Allergy 2010;65:420–34 63. Corrigan CJ, Kettner J, Doemer C, Cromwell O, Narkus A. 44. Dretzke J, Meadows A, Novielli N, Huissoon A, Fry-Smith A, E cacy and safety of preseasonal-speci c immunother- Meads C. Subcutaneous and sublingual immunotherapy apy with an aluminium-adsorbed six-grass pollen aller- for seasonal allergic rhinitis: a systematic review and indi- goid. Allergy 2005;60:801–7 rect comparison. J Allergy Clin Immunol 2013;131:1361–6 64. Pfaar O, Urry Z, Robinson DS et al. A randomized placebo- 45. Calderon MA, Casale TB, Nelson HS, Demoly P. An evi- controlled trial of rush preseasonal depigmented polym- dence-based analysis of house dust mite allergen immu- erized grass pollen immunotherapy. Allergy 2012;67:272–9 notherapy: a call for more rigorous clinical studies. J 65. Dubuske L, Frew A, Horak F et al. Ultrashort-speci c im- Allergy Clin Immunol 2013;132:1322–36 munotherapy successfully treats seasonal allergic rhino- 46. Canonica GW, Baena-Cagnani CE, Bousquet J et al. Rec- conjunctivitis to grass pollen. Allergy Asthma Proc ommendations for standardization of clinical trials with 2011;32:239– 47 allergen speci c immunotherapy for respiratory allergy. 66. Brewczynski P, Kroon A. [E cacy and safety of immuno- A statement of a World Allergy Organization (WAO) task- therapy with modi ed grasspollen allergens. Results of a force. Allergy 2007;62:317–24 placebo-controlled study]. Allergologie 1999;22:411–20 47. Carr W, Bernstein J, Lieberman P et al. A novel intranasal 67. Roberts G, Hurley C, Turcanu V, Lack G. Grass pollen im- therapy of azelastine with uticasone for the treatment munotherapy as an e ective therapy for childhood sea- of allergic rhinitis. J Allergy Clin Immunol sonal allergic asthma. J Allergy Clin Immunol 2012;129:1282–9.e10 2006;117:263–8 48. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, 68. Arvidsson MB, Löwhagen O, Rak S. E ect of 2-year place- Durham S. Allergen injection immunotherapy for sea- bo-controlled immunotherapy on airway symptoms and sonal allergic rhinitis. Cochrane Database Syst Rev medication in patients with birch pollen allergy. J Allergy 2007;1:CD001936 Clin Immunol 2002;109:777–83 49. Matricardi PM, Kuna P, Panetta V, Wahn U, Narkus A. Sub- 69. Balda BR, Wolf H, Baumgarten C et al. Tree-pollen allergy cutaneous immunotherapy and pharmacotherapy in sea- is e ciently treated by short-term immunotherapy (STI) sonal allergic rhinitis: a comparison based on meta-anal- with seven preseasonal injections of molecular standard- yses. J Allergy Clin Immunol 2011;128:791–9.e6 ized allergens. Allergy 1998;53:740–8 50. Kuna P, Kaczmarek J, Kupczyk M. E cacy and safety of 70. Bødtger U, Poulsen LK, Jacobi HH, Malling HJ. The safety immunotherapy for allergies to Alternaria alternata in and e cacy of subcutaneous birch pollen immunothera- children. J Allergy Clin Immunol 2011;127:502–8.e1–6 py – a one-year, randomised, double-blind, placebo- 51. Bergmann KC. [Speci c immunotherapy in allergic controlled study. Allergy 2002;57:297–305 asthma]. Pneumologie 2003;57:84–90 71. Neerven RJ van, Arvidsson M, Ipsen H, Sparholt SH, Rak S, 52. Bousquet J, Lockey RF, Malling HJ. Allergen immunother- Würtzen PA. A double-blind, placebo-controlled birch al- apy: therapeutic vaccines for allergic diseases. WHO Posi- lergy vaccination study: inhibition of CD23-mediated se- tion paper. Allergy 1998;53(44 Suppl):1–42 rum-immunoglobulin E-facilitated allergen presentation. 53. Buhl R, Berdel D, Criée CP et al. [Guidelines for diagnosis Clin Exp Allergy 2004;34:420–8 and treatment of asthma patients]. Pneumologie 72. Hoiby AS, Strand V, Robinson DS, Sager A, Rak S. E cacy, 2006;60:139–83 safety, and immunological e ects of a 2-year immuno- 54. Gillissen A, Bergmann KC, Kleine-Tebbe J et al. [Speci c therapy with Depigoid birch pollen extract: a random- immunotherapy in allergic asthma]. Dtsch Med Wochen- ized, double-blind, placebo-controlled study. Clin Exp schr 2003;128:204–9 Allergy 2010;40:1062–70 55. Global Initiative for Asthma (GINA), ed. Global strategy 73. Pfaar O, Robinson DS, Sager A, Emuzyte R. Immunothera- for asthma management and prevention (updated 2005). py with depigmented-polymerized mixed tree pollen ex- www.ginasthma.org tract: a clinical trial and responder analysis. Allergy 56. Global Initiative for Asthma (GINA), ed. Global strategy 2010;65:1614–21 for asthma management and prevention (updated 2007). 74. Drachenberg KJ, Heinzkill M, Urban E. [Short-term immu- www.ginasthma.org notherapy with tree pollen allergoids and the adjuvant 57. Walker SM, Durham SR, Till SJ et al. Immunotherapy for monophosphoryl lipid-A – results from a multicentre, allergic rhinitis. Clin Exp Allergy 2011;41:1177–200 placebo-controlled, randomised, double-blind study]. 58. Bousquet J. Speci c immunotherapy in asthma. Allergy Allergologie 2002;25:466–74 1999;54 Suppl 56:37–8 75. Ameal A, Vega-Chicote JM, Fernández S et al. Double- 59. Abramson MJ, Puy RM, Weiner JM. Injection allergen im- blind and placebo-controlled study to assess e cacy munotherapy for asthma. Cochrane Database Syst Rev and safety of a modi ed allergen extract of Dermatopha- 2010;8:CD001186 goides pteronyssinus in allergic asthma. Allergy 60. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal 2005;60:1178–83 reactions to allergen immunotherapy injections. J Aller- 76. Pichler CE, Marquardsen A, Sparholt S et al. Speci c im- gy Clin Immunol 2006;117:169–75 munotherapy with Dermatophagoides pteronyssinus 61. Zielen S, Kardos P, Madonini E. Steroid-sparing e ects and D. farinae results in decreased bronchial hyperreac- with allergen-speci c immunotherapy in children with tivity. Allergy 1997;52:274–83 asthma: a randomized controlled trial. J Allergy Clin Im- 77. Riechelmann H, Schmutzhard J, Werf JF van der, Distler A, munol 2010;126:942–9 Kleinjans HA. E cacy and safety of a glutaraldehyde-

314 Allergo J Int 2014; 23: 282–319 modi ed house dust mite extract in allergic rhinitis. Am J 93. Mari A, Ballmer-Weber BK, Vieths S. The oral allergy syn- Rhinol Allergy 2010;24:e104–9 drome: improved diagnostic and treatment methods. Curr 78. Varney VA, Tabbah K, Mavroleon G, Frew AJ. Usefulness Opin Allergy Clin Immunol 2005;5:267–73 of speci c immunotherapy in patients with severe peren- 94. Mauro M, Russello M, Incorvaia C et al. Birch-apple syn- nial allergic rhinitis induced by house dust mite: a dou- drome treated with birch pollen immunotherapy. Int Arch ble-blind, randomized, placebo-controlled trial. Clin Exp Allergy Immunol 2011;156:416–22 Allergy 2003;33:1076–82 95. Bussmann C, Böckenho A, Henke H, Werfel T, Novak N. 79. Blainey AD, Phillips MJ, Ollier S, Davies RJ. Hyposensitiza- Does allergen-speci c immunotherapy represent a thera- tion with a tyrosine adsorbed extract of Dermatophagoi- peutic option for patients with atopic dermatitis? J Allergy des pteronyssinus in adults with perennial rhinitis. A con- Clin Immunol 2006;118:1292–8 trolled clinical trial. Allergy 1984;39:521–8 96. Novak N. Allergen speci c immunotherapy for atopic der- 80. Yukselen A, Kendirli SG, Yilmaz M, Altintas DU, Karakoc matitis. Curr Opin Allergy Clin Immunol 2007;7:542–46 GB. E ect of one-year subcutaneous and sublingual im- 97. Werfel T, Breuer K, Rue F et al. Usefulness of speci c immunotherapy on clinical and laboratory parameters in munotherapy in patients with atopic dermatitis and aller- children with rhinitis and asthma: a randomized, place- gic sensitization to house dust mites: a multi-centre, ran- bo-controlled, double-blind, double-dummy study. Int domized, dose-response study. Allergy 2006;61:202–5 Arch Allergy Immunol 2012;157:288–98 98. Novak N, Bieber T, Ho mann M et al. E cacy and safety of 81. Olsen OT, Larsen KR, Jacobsan L, Svendsen UG. A 1-year, pla- subcutaneous allergen-speci c immunotherapy with de- cebo-controlled, double-blind house-dust-mite immuno- pigmented polymerized mite extract in atopic dermatitis. therapy study in asthmatic adults. Allergy 1997; 52: 853–9 J Allergy Clin Immunol 2012;130:925–31.e4 82. Wang H, Lin X, Hao C et al. A double-blind, placebo-con- 99. Bae JM, Choi YY, Park CO, Chung KY, Lee KH. E cacy of al- trolled study of house dust mite immunotherapy in Chi- lergen-speci c immunotherapy for atopic dermatitis: a nese asthmatic patients. Allergy 2006;61:191–7 systematic review and meta-analysis of randomized con- 83. Garcia-Robaina JC, Sanchez I, Torre F de la, Fernandez- trolled trials. J Allergy Clin Immunol 2013;132:110–7 Caldas E, Casanovas M. Successful management of mite- 100. Dahl R, Stender A, Rak S. Speci c immunotherapy with SQ allergic asthma with modi ed extracts of Dermatopha- standardized grass allergen tablets in asthmatics with goides pteronyssinus and Dermatophagoides farinae in rhinoconjunctivitis. Allergy 2006;61:185–90 a double-blind, placebo-controlled study. J Allergy Clin 101. Dahl R, Kapp A, Colombo G et al. E cacy and safety of Immunol 2006;118:1026–32 sublingual immunotherapy with grass allergen tablets for 84. Blumberga G, Groes L, Haugaard L, Dahl R. Steroid-spar- seasonal allergic rhinoconjunctivitis. J Allergy Clin Immu- ing e ect of subcutaneous SQ-standardised speci c im- nol 2006;118:434–40 munotherapy in moderate and severe house dust mite 102. Didier A, Malling HJ, Worm M et al. Optimal dose, e cacy, allergic asthmatics. Allergy 2006;61:843–8 and safety of once-daily sublingual immunotherapy with 85. Bucur J, Dreborg S, Einarsson R. Immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Aller- dog and cat allergen preparations in dog-sensitive and gy Clin Immunol 2007;120:1338–45 cat-sensitive asthmatics. Ann Allergy 1989;62:355–61 103. Worm M. E cacy and tolerability of high dose sublingual 86. Hedlin G, Gra -Lonnevig V, Heilborn H et al. Immuno- immunotherapy in patients with rhinoconjunctivitis. therapy with cat- and dog-dander extracts. V. E ects of 3 Allerg Immunol (Paris) 2006;38:355–60 years of treatment. J Allergy Clin Immunol 1991;87:955– 104. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. 64 Sublingual immunotherapy with once-daily grass allergen 87. Hedlin G, Heilborn H, Lilja G et al. Long-term follow-up of tablets: a randomized controlled trial in seasonal allergic patients treated with a three-year course of cat or dog rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802–9 immunotherapy. J Allergy Clin Immunol 1995;96: 879–85 105. Worm M, Rak S, Blay F de et al. Sustained e cacy and safe- 88. Nanda A, O‘Connor M, Anand M et al. Dose dependence ty of a 300IR daily dose of a sublingual solution of birch and time course of the immunologic response to admin- pollen allergen extract in adults with allergic rhinocon- istration of standardized cat allergen extract. J Allergy junctivitis: results of a double-blind, placebo-controlled Clin Immunol 2004;114:1339–44 study. Clin Transl Allergy 2014;4:7 89. Sundin B, Lilja G, Gra -Lonnevig V et al. Immunotherapy 106. Bergmann KC, Demoly P, Worm M et al. E cacy and safety with partially puri ed and standardized animal dander ex- of sublingual tablets of house dust mite allergen extracts tracts. I. Clinical results from a double-blind study on pain adults with allergic rhinitis. J Allergy Clin Immunol tients with animal dander asthma. J Allergy Clin Immunol 2014;133:1608–14.e6 1986;77:478–87 107. Bufe A, Eberle P, Franke-Beckmann E et al. Safety and e - 90. Dreborg S, Agrell B, Foucard T, Kjellman NI, Koivikko A, Nilsson cacy in children of an SQ-standardized grass allergen S. A double-blind, multicenter immunotherapy trial in chil- tablet for sublingual immunotherapy. J Allergy Clin Im- dren, using a puri ed and standardized Cladosporium her- munol 2009;123:167–73.e7 barum preparation. I. Clinical results. Allergy 1986;41:131–40 108. Wahn U, Tabar A, Kuna P et al. E cacy and safety of 91. Horst M, Hejjaoui A, Horst V, Michel FB, Bousquet J. Dou- 5-grass-pollen sublingual immunotherapy tablets in pe- ble-blind, placebo-controlled rush immunotherapy with a diatric allergic rhinoconjunctivitis. J Allergy Clin Immunol standardized Alternaria extract. J Allergy Clin Immunol 2009;123:160–6.e3 1990;85:460–72 109. Wahn U, Klimek L, Ploszczuk A et al. High-dose sublin- 92. Malling HJ, Dreborg S, Weeke B. Diagnosis and immuno- gual immunotherapy with single-dose aqueous grass therapy of mould allergy. V. Clinical e cacy and side pollen extract in children is e ective and safe: a double- e ects of immunotherapy with Cladosporium herbarum. blind, placebo-controlled study. J Allergy Clin Immunol Allergy 1986;41:507–19 2012;130:886–93.e5

Allergo J Int 2014; 23: 282–319 315 Guideline AIT-Guideline

110. Radulovic S, Calderon MA, Wilson D, Durham S. Sublin- randomized trial. J Allergy Clin Immunol 2012;129:717–25. gual immunotherapy for allergic rhinitis. Cochrane Data- e5 base Syst Rev 2010;(12):CD002893 126. Ott H, Sieber J, Brehler R et al. E cacy of grass pollen 111. Wilson DR, Torres LI, Durham SR. Sublingual immuno- sublingual immunotherapy for three consecutive sea- therapy for allergic rhinitis. Cochrane Database Syst Rev sons and after cessation of treatment: the ECRIT study. 2003;(2):CD002893 Allergy 2009;64:179–86 112. Khinchi MS, Poulsen LK, Carat F, Andre C, Hansen AB, 127. Pfaar O, Klimek L. E cacy and safety of speci c immuno- Malling HJ. Clinical e cacy of sublingual and subcutane- therapy with a high-dose sublingual grass pollen prepa- ous birch pollen allergen-speci c immunotherapy: a ran- ration: a double-blind, placebo-controlled trial. Ann domized, placebo-controlled, double-blind, double- Allergy Asthma Immunol 2008;100:256–63 dummy study. Allergy 2004;59:45–53 128. Drachenberg K, Pfei er P, Urban E. [Sublingual immuno- 113. Devillier P, Dreyfus JF, Demoly P, Calderon MA. A meta- therapy – results from a multi-centre, randomised, dou- analysis of sublingual allergen immunotherapy and phar- ble-blind, placebocontrolled study with a standardised macotherapy in pollen-induced seasonal allergic rhino- birch and grass/rye pollen extract].Allergologie conjunctivitis. BMC medicine 2014;12:71 2001;24:525–34 114. Bousquet J, Scheinmann P, Guinnepain MT et al. 129. Horak F, Stübner P, Berger UE, Marks B, Toth J, Jäger S. Sublingual-swallow immunotherapy (SLIT) in patients Immunotherapy with sublingual birch pollen extract. A with asthma due to house-dust mites: a double-blind, short-term double-blind placebo study. J Investig Aller- placebo-controlled study. Allergy 1999;54:249–60 gol Clin Immunol 1998;8:165–71 115. Pajno GB, Morabito L, Barberio G, and Parmiani S. Clinical 130. Tonnel AB, Scherpereel A, Douay B et al. Allergic rhinitis and immunologic e ects of long-term sublingual immuno- due to house dust mites: evaluation of the e cacy of spe- therapy in asthmatic children sensitized to mites: a double- ci c sublingual immunotherapy. Allergy 2004;59:491–7 blind, placebo-controlled study. Allergy 2000;55:842–9 131. Passalacqua G, Albano M, Fregonese L et al. Randomised 116. Hirsch T, Sahn M, Leupold W. Double-blind placebo-con- controlled trial of local allergoid immunotherapy on al- trolled study of sublingual immunotherapy with house lergic in ammation in mite-induced rhinoconjunctivitis. dust mite extract (D.pt.) in children. Pediatr Allergy Im- Lancet 1998;351:629–32 munol 1997;8:21–7 132. Lue KH, Lin YH, Sun HL, Lu KH, Hsieh JC, Chou MC. Clini- 117. Bahceciler NN, Isik U, Barlan IB, Basaran MM. E cacy of cal and immunologic e ects of sublingual immunothera- sublingual immunotherapy in children with asthma and py in asthmatic children sensitized to mites: a double- rhinitis: a double-blind, placebo-controlled study. Pedi- blind, randomized, placebo-controlled study. Pediatr Al- atr Pulmonol 2001;32:49–55 lergy Immunol 2006;17:408–15 118. Mosbech H, Deckelmann R, Blay F de et al. Standardized 133. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. E cacy of quality (SQ) house dust mite sublingual immunotherapy sublingual immunotherapy with high-dose mite extracts tablet (ALK) reduces inhaled corticosteroid use while in asthma: a multi-center, double-blind, randomized, maintaining asthma control: a randomized, double-blind, and placebo-controlled study in Taiwan. Respir Med placebo-controlled trial. J Allergy Clin Immunol 2006;100:1374–83 2014;134:568–75.e7 134. Passalacqua G, Pasquali M, Ariano R et al. Randomized 119. Nelson HS, Nolte H, Creticos P, Maloney J, Wu J, Bernstein double-blind controlled study with sublingual carba- DI. E cacy and safety of timothy grass allergy immuno- mylated allergoid immunotherapy in mild rhinitis due to therapy tablet treatment in North American adults. J Al- mites. Allergy 2006;61:849–54 lergy Clin Immunol 2011;127:72–80.e1–2 135. Guez S, Vatrinet C, Fadel R, Andre C. House-dust-mite 120. Canonica GW, Cox L, Pawankar R et al. Sublingual immuno- sublingual-swallow immunotherapy (SLIT) in perennial therapy: World Allergy Organization position paper 2013 rhinitis: a double-blind, placebo-controlled study. Aller- update. The World Allergy Organization journal 2014;7:6 gy 2000;55:369–75 121. Pajno GB, Caminiti L, Crisafulli G et al. Direct comparison 136. Möller C, Dreborg S, Ferdousi HA et al. Pollen immuno- between continuous and coseasonal regimen for sublin- therapy reduces the development of asthma in children gual immunotherapy in children with grass allergy: a ran- with seasonal rhinoconjunctivitis (the PAT-study). J Aller- domized controlled study. Pediatr Allergy Immunol gy Clin Immunol 2002;109:251–6 2011;22:803–7 137. Niggemann B, Jacobsen L, Dreborg S et al. Five-year fol- 122. Blaiss M, Maloney J, Nolte H, Gawchik S, Yao R, Skoner DP. low-up on the PAT study: speci c immunotherapy and E cacy and safety of timothy grass allergy immunother- long-term prevention of asthma in children. Allergy apy tablets in North American children and adolescents. 2006;61:855–9 J Allergy Clin Immunol 2011;127:64–71.e1–4 138. Eng PA, Reinhold M, Gnehm HP. Long-term e cacy of 123. Didier A, Malling HJ, Worm M et al. Post-treatment e cacy preseasonal grass pollen immunotherapy in children. of discontinuous treatment with 300IR 5-grass pollen sub- Allergy 2002;57:306–12 lingual tablet in adults with grass pollen-induced allergic 139. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. rhinoconjunctivitis. Clin Exp Allergy 2013;43:568–77 Twelve-year follow-up after discontinuation of pre- 124. Durham SR, Emminger W, Kapp A et al. Long-term clinical seasonal grass pollen immunotherapy in childhood. Al- e cacy in grass pollen-induced rhinoconjunctivitis after lergy 2006;61:198–201 treatment with SQ-standardized grass allergy immuno- 140. Purello-D‘Ambrosio F, Gangemi S, Merendino RA et al. therapy tablet. J Allergy Clin Immunol 2010;125:131–8.e1–7 Prevention of new sensitizations in monosensitized 125. Durham SR, Emminger W, Kapp A et al. SQ-standardized subjects submitted to speci c immunotherapy or not. sublingual grass immunotherapy: con rmation of dis- A retrospective study. Clin Exp Allergy 2001;31:1295– ease modi cation 2 years after 3 years of treatment in a 302

316 Allergo J Int 2014; 23: 282–319 141. Pajno GB, Barberio G, De Luca F, Morabito L, and Parm- 158. Randhawa IS, Junaid I, Klaustermeyer WB. Allergen iani S. Prevention of new sensitizations in asthmatic chil- immunotherapy in a patient with human immuno- dren monosensitized to house dust mite by speci c im- de ciency virus: e ect on T-cell activation and viral munotherapy. A six-year follow-up study. Clin Exp Aller- replication. Ann Allergy Asthma Immunol 2007;98:495– gy 2001;31:1392–7 7 142. Di Rienzo V, Marcucci F, Puccinelli P et al. Long-lasting ef- 159. Wöhrl S, Kinaciyan T, Jalili A, Stingl G, Moritz KB. Malig- fect of sublingual immunotherapy in children with asth- nancy and speci c allergen immunotherapy: the results ma due to house dust mite: a 10-year prospective study. of a case series. Int Arch Allergy Immunol 2011;156:313–9 Clin Exp Allergy 2003;33:206–10 160. Müller UR, Haeberli G. Use of beta-blockers during im- 143. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa- munotherapy for Hymenoptera venom allergy. J Allergy lacqua G. Long-lasting e ects of sublingual immuno- Clin Immunol 2005;115:606–10 therapy according to its duration: a 15-year prospective 161. Linneberg A, Madsen F, Skaaby T. Allergen-speci c im- study. J Allergy Clin Immunol 2010;126:969–75 munotherapy and risk of autoimmune disease. Curr Opin 144. Novembre E, Galli E, Landi F et al. Coseasonal sublingual Allergy Clin Immunol 2012;12:635–9 immunotherapy reduces the development of asthma in 162. Linneberg A, Jacobsen RK, Jespersen L, Abildstrom SZ. children with allergic rhinoconjunctivitis. J Allergy Clin Association of subcutaneous allergen-speci c immuno- Immunol 2004;114:851–7 therapy with incidence of autoimmune disease, ischemic 145. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa- heart disease, and mortality. J Allergy Clin Immunol lacqua G. Randomized controlled open study of sublin- 2012;129:413–9 gual immunotherapy for respiratory allergy in real-life: 163. Arzneimittelkommission der deutschen Ärzteschaft clinical e cacy and more. Allergy 2004;59:1205–10 (AkdÄ), ed. Stellungnahme der AkdÄ zur allergenspezi- 146. Valovirta E, Berstad AK, Blic J de et al. Design and recruit- schen Immuntherapie. Dtsch Ärztebl 2007;104: ment for the GAP trial, investigating the preventive ef- A3355–7 fect on asthma development of an SQ-standardized 164. Zylka-Menhorn V. Hyposensibilisierung bald nur noch grass allergy immunotherapy tablet in children with durch "erfahrene Ärzte". Dtsch Ärztebl 1995;92:A-1434 grass pollen-induced allergic rhinoconjunctivitis. Clin 165. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham Ther 2011;33:1537–46 SR, Malling HJ, Valovirta E. Standards for practical al- 147. Schmid-Grendelmeier P. [Recombinant allergens. For rou- lergen-specific immunotherapy. Allergy 2006;61 Suppl tine use or still only science?]. Hautarzt 2010;61:946–53 82:1–20 148. Götzsche PC, Johansen HK. House dust mite control mea- 166. Klimek L. Umsetzung der EU-Richtlinie 2010/32/EU sures for asthma: systematic review. Allergy 2008;63:646–59 fordert verletzungssichere Spritzen: im HNO-Bereich ist 149. Kopp MV, Niggemann B, Forster J. House dust mite aller- hiervon insbesondere auch die subkutane Immunthera- gy: complete removal of the provoking allergen is a pri- pie (SCIT) betro en. HNO-Mitteilungen 2013;63:189 mary therapeutic approach. Allergy 2009;64:1402–3 167. Fischer PJ, Friedrichs F. [Practical parameters of 150. Muche-Borowski C, Kopp M, Reese I et al. [Evidence- hyposensitization]. Monatsschr Kinderheilkd 2013;161:608–15 based and consented guideline on allergy prevention – 168. Calabria CW. Accelerated immunotherapy schedules. update 2009]. Allergo J 2009;18:332–41 Curr Allergy Asthma Rep 2013;13:389–98 151. Pfaar O, Biedermann T, Klimek L, Sager A, Robinson DS. 169. Calabria CW, Cox L. Accelerated immunotherapy sched- Depigmented-polymerized mixed grass/birch pollen ex- ules and premedication. Immunol Allergy Clin North Am tract immunotherapy is e ective in polysensitized pa- 2011;31:251–63, ix tients. Allergy 2013;68:1306–13 170. Pfaar O, Wolf H, Klimek L, Schnitker J, Wüstenberg E. 152. Nelson HS. Speci c immunotherapy with allergen mixes: Immunologic e ect and tolerability of intra-seasonal what is the evidence? Curr Opin Allergy Clin Immunol subcutaneous immunotherapy with an 8-day up-dosing 2009;9:549–53 schedule to 10,000 standardized quality-units: a double- 153. Bundesärztekammer (BÄK), Kassenärztliche Bundesver- blind, randomized, placebo-controlled trial. Clin Ther einigung (KBV), Arbeitsgemeinschaft der Wissen- 2012;34:2072–81 schaftlichen Medizinischen Fachgesellschaften (AWMF), 171. Canonica GW, Bousquet J, Casale T et al. Sublingual im- eds. Nationale Versorgungs Leitlinie Asthma – Langfas- munotherapy: World Allergy Organization Position Paper sung, 2. Au . Version 5, 2009, zuletzt geändert: August 2009. Allergy 2009;64 Suppl 91:1–59 2013. www.leitlinien.de/nvl/asthma/mdb/downloads/ 172. Haynes R. Einleitung. In: Haynes RB, Taylor DW, Sackett nvl/asthma/asthma-2au -vers5-lang.pdf DL. Compliance Handbuch. München: Oldenbourg; 1986. 154. Zuberbier T, Bachert C, Bousquet PJ et al. GA(2) LEN/ p. 11–8 EAACI pocket guide for allergen-speci c immunothera- 173. Sondermann N, Shah-Hosseini K, Henkel K, Schwalfen- py for allergic rhinitis and asthma. Allergy berg A, Mösges R. [Factors of success for adherence in 2010;65:1525–30 hyposensitization]. Allergologie 2011;34:441–6 155. Demoly P, Piette V, Daures JP. Treatment of allergic rhini- 174. Osterberg L, Blaschke T. Adherence to medication. N tis during pregnancy. Drugs 2003;63:1813–20 Engl J Med 2005;353:487–97 156. Wedi B, Rue F. [Pharmacoprophylaxis and co-medica- 175. Baiardini I, Braido F, Bonini M, Compalati E, Canonica GW. tions in allergen-speci c immunotherapy]. Hautarzt Why do doctors and patients not follow guidelines? Curr 2011; 62:663–70 Opin Allergy Clin Immunol 2009;9:228–33 157. Fodeman J, Jariwala S, Hudes G, Jerschow E, Rosenst- 176. Bousquet J, Khaltaev N, Cruz AA et al. Allergic rhinitis and reich D. Subcutaneous allergen immunotherapy in 3 pa- its impact on asthma (ARIA) 2008 update (in collabora- tients with HIV. Ann Allergy Asthma Immunol tion with the World Health Organization, GA(2)LEN and 2010;105:320–1 AllerGen). Allergy 2008;63 Suppl 86:8–160

Allergo J Int 2014; 23: 282–319 317 Guideline AIT-Guideline

177. Senna G, Ridolo E, Calderon M, Lombardi C, Canonica cal Immunology/PRACTALL consensus report. J Allergy GW, Passalacqua G. Evidence of adherence to allergen- Clin Immunol 2013;131:1288–96.e3 speci c immunotherapy. Curr Opin Allergy Clin Immunol 194. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. 2009;9:544–8 AAAAI and ACAAI surveillance study of subcutaneous 178. Claes C, Mittendorf T, Graf von der Schulenburg JM. Per- immunotherapy, year 3: what practices modify the risk of sistence and frequency of prescriptions of subcutaneous systemic reactions? Ann Allergy Asthma Immunol allergen-speci c immunotherapy (SCIT) prescribed with- 2013;110:274–8, 278.e1 in the German statutory health insurance. Med Klin (Mu- 195. Bernstein DI, Wanner M, Borish L, Liss GM, Immunothera- nich) 2009;104:536–42 py Committee AAoAA, and Immunology: Twelve-year sur- 179. Aschemann U, Schulte P, Hecker H. Untersuchung zur vey of fatal reactions to allergen injections and skin test- Compliance eines anwenderfreundlichen Allergoids. ing: 1990-2001. J Allergy Clin Immunol 2004; 113, 1129-36. Allergo J 2010;19(S1):63 (abstract) 196. Lüderitz-Püchel U, Keller-Stanislawski B, Haustein D. [Risk 180. Egert-Schmidt A, Martin E, Müller U, Schulte M, Thum- reevaluation of diagnostic and therapeutic allergen ex- Oltmer S. Patienten-Compliance in der Spezi schen Im- tracts. An analysis of adverse drug reactions from 1991 to muntherapie – Ein Vergleich von SCIT- und SLIT- 2000]. Bundesgesundheitsbl Gesundheitsforsch Gesund- Präparaten. Allergo J 2011;20(S1):S40 (abstract) heitsschutz 2001;44:709–18 181. Senna G, Lombardi C, Canonica GW, Passalacqua G. How 197. Makatsori M, Calderon MA. Anaphylaxis: still a ghost adherent to sublingual immunotherapy prescriptions are behind allergen immunotherapy. Curr Opin Allergy Clin patients? The manufacturers’ viewpoint. J Allergy Clin Immunol 2014; 14(4): 316–22 Immunol 2010;126:668–9 198. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. 182. Sieber J, De Geest S, Shah-Hosseini K, Mösges R. Medica- Speaking the same language: The World Allergy Organi- tion persistence with long-term, speci c grass pollen zation subcutaneous immunotherapy systemic reaction immunotherapy measured by prescription renewal rates. grading system. J Allergy Clin Immunol 2010;125:569– Curr Med Res Opin 2011;27:855–61 74,574.e1–574.e7 183. Eberle P, Schreder H, Shah-Hosseini K, Mösges R. [Medica- 199. Nielsen L, Johnsen CR, Mosbech H, Poulsen LK, Malling tion persistence in children and young people on long- HJ. Antihistamine premedication in speci c cluster im- term, grass pollenspeci c immunotherapy – measured by munotherapy: a double-blind, placebo-controlled study. prescription renewal rates]. Allergologie 2013;36:9–18 J Allergy Clin Immunol 1996;97:1207–13 184. Przybilla B, Rue F, Walker A et al. [Diagnosis and therapy 200. Reimers A, Hari Y, Müller U. Reduction of side-e ects of bee and wasp ven om allergy]. Allergo J 2011;20:318–39 from ultrarush immunotherapy with honeybee venom 185. Cox L, Calderon M, Pfaar O. Subcutaneous allergen im- by pretreatment with fexofenadine: a double-blind, pla- munotherapy for allergic disease: examining e cacy, cebo-controlled trial. Allergy 2000;55:484–8 safety and cost-e ectiveness of current and novel formu- 201. Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Fine- lations. Immunotherapy 2012;4:601–16 gold I, Nelson HS. Sublingual immunotherapy: a compre- 186. Malling HJ. Minimising the risks of allergen-speci c injec- hensive review. J Allergy Clin Immunol 2006;117:1021–35 tion immunotherapy. Drug Saf 2000;23:323–32 202. Calderon MA, Simons FE, Malling HJ, Lockey RF, Moin- 187. Kelso JM. The rate of systemic reactions to immunother- geon P, Demoly P. Sublingual allergen immunotherapy: apy injections is the same whether or not the dose is re- mode of action and its relationship with the safety produced after a local reaction. Ann Allergy Asthma Immu- le. Allergy 2012;67:302–11 nol 2004;92:225–7 203. Passalacqua G, Garelli V, Sclifo F, Canonica GW. Sublin- 188. Vogelbruch M, Nuss B, Körner M, Kapp A, Kiehl P, gual immunotherapy for allergic rhinitis and conjunctivi- Bohm W. Aluminium-induced granulomas after in- tis. Immunotherapy 2013;5:257–64 accurate intradermal hyposensitization injections of 204. Groot H de, Bijl A. Anaphylactic reaction after the rst aluminium-adsorbed depot preparations. Allergy dose of sublingual immunotherapy with grass pollen 2000;55:883–7 tablet. Allergy 2009;64:963–4 189. Netterlid E, Hindsén M, Björk J et al. There is an association 205. Passalacqua G, Baena-Cagnani CE, Bousquet J et al. between contact allergy to aluminium and persistent sub- Grading local side e ects of sublingual immunotherapy cutaneous nodules in children undergoing hyposensitiza- for respiratory allergy: speaking the same language. tion therapy. Contact Dermatitis 2009;60:41–9 J Allergy Clin Immunol 2013;132:93–8 190. Frost L, Johansen P, Pedersen S, Veien N, Ostergaard PA, 206. Swissmedic, ed. Neues Heilmittelgesetz: Meldep icht Nielsen MH. Persistent subcutaneous nodules in children der Fachleute für unerwünschte Arzneitmittelwirkungen. hyposensitized with aluminium-containing allergen Schweiz Ärztezeitung 2002;83:819–22 extracts. Allergy 1985;40:368–72 207. Ring J, Beyer K, Biedermann T et al. Guideline for acute 191. Lopez S, Pelaez A, Navarro LA, Montesinos E, Morales C, therapy and management of anaphylaxis. S2 Guideline Carda C. Aluminium allergy in patients hyposensitized of the German Society for Allergology and Clinical Immu- with aluminium-precipitated antigen extracts. Contact nology (DGAKI), the Association of German Allergolo- Dermatitis 1994;31:37–40 gists (AeDA), the Society of Pediatric Allergy and Environ- 192. Ragusa FV, Passalacqua G, Gambardella R et al. Nonfatal mental Medicine (GPA), the German Academy of Aller- systemic reactions to subcutaneous immunotherapy: a gology and Environmental Medicine (DAAU), the Ger- 10-year experience. J Investig Allergol Clin Immunol man Professional Association of Pediatricians (BVKJ), the 1997;7:151–4 Austrian Society for Allergology and Immunology (ÖGAI), 193. Burks AW, Calderon MA, Casale T et al. Update on allergy the Swiss Society for Allergy and Immunology (SGAI), the immunotherapy: American Academy of Allergy, Asthma German Society of Anaesthesiology and Intensive Care & Immunology/European Academy of Allergy and Clini- Medicine (DGAI), the German Society of Pharmacology

318 Allergo J Int 2014; 23: 282–319 (DGP), the German Society for Psychosomatic Medicine 214. Johansen P, Moos S von, Mohanan D, Kündig TM, Senti G. (DGPM), the German Working Group of Anaphylaxis New routes for allergen immunotherapy. Hum Vaccin Training and Education (AGATE) and the patient organi- Immunother 2012;8:1525–33 zation German Allergy and Asthma Association (DAAB) 215. Senti G, Prinz Vavricka BM, Erdmann I et al. Intralymphat- Allergo J Int 2014;23:96–112 ic allergen administration renders speci c immunothera- 208. Simons FE, Ardusso LR, Bilo MB et al. 2012 Update: World py faster and safer: a randomized controlled trial. Proc Allergy Organization Guidelines for the assessment and Natl Acad Sci U S A 2008;105:17908–12 management of anaphylaxis. Curr Opin Allergy Clin Im- 216. Senti G, Moos S von, Tay F et al. Epicutaneous allergen- munol 2012;12:389–99 speci c immunotherapy ameliorates grass pollen-in- 209. Dhami S, Panesar SS, Rader T et al. The acute and long- duced rhinoconjunctivitis: A double-blind, placebo-con- term management of anaphylaxis: protocol for a system- trolled dose escalation study. J Allergy Clin Immunol atic review. Clin Transl Allergy 2013;3:14 2012;129:128–35 210. Reeve L, Baldrick P, Hewings S, Skinner M. A battery of 217. Senti G, Crameri R, Kuster D et al. Intralymphatic genotoxicity studies with an allergy vaccine adjuvanted immunotherapy for cat allergy induces tolerance after with monophosphoryl lipid A (MPL(R)) for the treat- only 3 injections. J Allergy Clin Immunol 2012;129: 1290–6 ment of grass pollen allergy. J Appl Toxicol 2012;32: 218. Kopp MV. Role of immunmodulators in allergen-speci c 608–16 immunotherapy. Allergy 2011;66:792–7 211. Pfaar O, Cazan D, Klimek L, Larenas-Linnemann D, Calde- 219. Larenas-Linnemann D, Wahn U, Kopp M. Use of omali- ron MA. Adjuvants for immunotherapy. Curr Opin Allergy zumab to improve desensitization safety in allergen im- Clin Immunol 2012;12:648–57 munotherapy. J Allergy Clin Immunol 2014;133:937.e2 212. Jutel M, Solarewicz-Madejek K, Smolinska S. Recombi- 220. Noon L. Prophylactic inoculation against hay fever. Lan- nant allergens: The present and the future. Hum Vaccin cet 1911;1:1572–3 Immunother 2012;8:1534–43 221. Bousquet J, Schünemann HJ, Samolinski B et al. Allergic 213. Patel D, Couroux P, Hickey P et al. Fel d 1-derived peptide Rhinitis and its Impact on Asthma (ARIA): achievements antigen desensitization shows a persistent treatment ef- in 10 years and future needs. J Allergy Clin Immunol fect 1 year after the start of dosing: a randomized, place- 2012;130:1049–62 bo-controlled study. J Allergy Clin Immunol 2013; 131:103–9.e1–7

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