Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases

S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of 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)

Summary

The present guideline (S2k) on allergen-specific immunotherapy (AIT) was established by the German, Austrian and Swiss professional associations for allergy in consensus with the scientific specialist societies and professional associations in the fields of otolaryngology, dermatology and venereology, pediatric and adolescent medicine, pneumology as well as a German patient organization (German Allergy and Asthma Association; Deutscher Allergie- und Asthmabund, DAAB) according to the criteria of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF).

AIT is a therapy with disease-modifying effects. By administering allergen extracts, specific blocking antibodies, toler-ance-inducing cells and mediators are activated. These prevent further exacerbation of the allergen-triggered immune response, block the specific immune response and attenuate the inflammatory response in tissue.

Products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients. Non-modified allergens are used for SCIT in the form of aqueous or physically adsorbed (depot) extracts, as well as chemically modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets.

The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints. The EMA stipulates combined symptom and medication scores as primary endpoint. A harmonization of clinical endpoints, e. g., by using the combined symptom and medication scores (CSMS) recommended by the EAACI, is desirable in the future in order to permit the comparison of results from different studies. The current CONSORT recommendations from the ARIA/GA2LEN group specify standards for the evaluation, presentation and publication of study results.

According to the Therapy allergen ordinance (TAV), preparations containing common allergen sources (pollen from grasses, birch, alder, hazel, house dust mites, as well as bee and wasp venom) need a marketing authorization in Germany. During the marketing authorization process, these preparations are examined regarding quality, safety and efficacy. In the opinion of the authors, authorized allergen preparations with documented efficacy and safety, or preparations tradeable under the TAV for which efficacy and safety have already been documented in clinical trials meeting WAO or EMA standards, should be preferentially used. Individual formulations (NPP) enable the prescription of rare allergen sources (e.g., pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted.

Allergic rhinitis and its associated co-morbidities (e. g., bronchial asthma) generate substantial direct and indirect costs. Treatment options, in particular AIT, are therefore evaluated using cost-benefit and cost-effectiveness analyses. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy, but is heavily dependent on patient compliance.

Meta-analyses provide unequivocal evidence of the efficacy of SCIT and SLIT for certain allergen sources and age groups. Data from controlled studies differ in terms of scope, quality and dosing regimens and require product-specific evaluation. Therefore, evaluating individual preparations according to clearly defined criteria is recommended. A broad transfer of the efficacy of certain preparations to all preparations administered in the same way is not endorsed. The website of the German Society for Allergology and Clinical Immunology (www.dgaki.de/leitlinien/s2k-leitlinie-sit; DGAKI: Deutsche Gesellschaft für Allergologie und klinische Immunologie) provides tables with specific information on available products for AIT in Germany, Switzerland and Austria. The tables contain the number of clinical studies per product in adults and children, the year of market authorization, underlying scoring systems, number of randomized and analyzed subjects and the method of evaluation (ITT, FAS, PP), separately given for grass pollen, birch pollen and house dust mite allergens, and the status of approval for the conduct of clinical studies with these products.

Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis in adulthood is well-documented in numerous trials and, in childhood and adolescence, in a few trials. Efficacy in house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. Only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date. SCIT has been well investigated for individual preparations in controlled bronchial asthma as defined by the Global Initiative for Asthma (GINA) 2007 and intermittent and mild persistent asthma (GINA 2005) and it is recommended as a treatment option, in addition to allergen avoidance and pharmacotherapy, provided there is a clear causal link between respiratory symptoms and the relevant allergen.

The efficacy of SLIT in grass pollen-induced allergic rhinoconjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. New controlled trials (some with high patient numbers) on house dust mite allergy provide evidence of efficacy of SLIT in adults.

Compared with allergic rhinoconjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen allergic children, adolescents and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults.

Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. In this context, those products for which the appropriate effects have been demonstrated should be considered.

SCIT or SLIT with pollen or mite allergens can be performed in patients with allergic rhinoconjunctivitis using allergen extracts that have been proven to be effective in at least one double-blind placebo-controlled (DBPC) study. At present, clinical trials are underway for the indication in asthma due to house dust mite allergy, some of the results of which have already been published, whilst others are still awaited (see the DGAKI table “Approved/potentially completed studies” via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit (according to www.clinicaltrialsregister.eu)). When establishing the indication for AIT, factors that favour clinical efficacy should be taken into consideration. Differences between SCIT and SLIT are to be considered primarily in terms of contraindications. In individual cases, AIT may be justifiably indicated despite the presence of contraindications.

SCIT injections and the initiation of SLIT are performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction. Patients must be fully informed about the procedure and risks of possible adverse events, and the details of this process must be documented (see “Treatment information sheet”; available as a handout via www.dgaki.de/Leitlinien/s2k-Leitlinie-sit). Treatment should be performed according to the manufacturer‘s product information leaflet. In cases where AIT is to be performed or continued by a different physician to the one who established the indication, close cooperation is required in order to ensure that treatment is implemented consistently and at low risk. In general, it is recommended that SCIT and SLIT should only be performed using preparations for which adequate proof of efficacy is available from clinical trials.

Treatment adherence among AIT patients is lower than assumed by physicians, irrespective of the form of administration. Clearly, adherence is of vital importance for treatment success. Improving AIT adherence is one of the most important future goals, in order to ensure efficacy of the therapy.

Severe, potentially life-threatening systemic reactions during SCIT are possible, but – providing all safety measures are adhered to – these events are very rare. Most adverse events are mild to moderate and can be treated well.

Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Systemic reactions have been described in SLIT, but are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT.

The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of i. m. epinephrine. Details on the acute management of anaphylactic reactions can be found in the current S2 guideline on anaphylaxis issued by the AWMF (S2-AWMF-LL Registry Number 061-025).

AIT is undergoing some innovative developments in many areas (e. g., allergen characterization, new administration routes, adjuvants, faster and safer dose escalation protocols), some of which are already being investigated in clinical trials.

Cite this as Pfaar O, Bachert C, Bufe A, Buhl R, Ebner C, Eng P, Friedrichs F, Fuchs T, Hamelmann E, Hartwig-Bade D, Hering T, Huttegger I, Jung K, Klimek L, Kopp MV, Merk H, Rabe U, Saloga J, Schmid-Grendelmeier P, Schuster A, Schwerk N, Sitter H, Umpfenbach U, Wedi B, Wöhrl S, Worm M, Kleine-Tebbe J. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases – S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of 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). Allergo J Int 2014;23:282–319

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Abbreviations

AAAAI:

American Academy of Allergy, Asthma & Immunology

ACE:

Angiotensin converting enzyme

AD:

Atopic dermatitis

ADR:

Adverse drug reactions

AGES:

Austrian Agency for Health and Nutrition, Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH

AIT:

Allergen-specific immunotherapy

Al(OH)3:

Aluminum hydroxide

AMG:

Arzneimittelgesetz, Medicinal Products Act

APC:

Antigen-presenting cells

BASG:

Austrian Medicines and Medical Devices Agency, Bundesamt für Sicherheit im Gesundheitswesen (Österreich)

Baso:

Basophile granulocyte

BGB:

Bundesgesetzbuch, german civil code

BGR:

professional association regulations, Berufsgenossenschaftsregeln

Ca3(PO4)2:

Calcium phosphate

CI:

Confidence interval

CONSORT:

Consolidated standards of reporting trials

CSMS:

Combined symptom and medication score

DAAB:

German Allergy and Asthma Association, Deutscher Allergie- und Asthmabund

DBPC:

Double-blind placebo-controlled

DC:

Dendritic cells

DELBI:

German instrument for methodological guideline appraisal, Deutsches Leitlinien-Bewertungsinstrument

EAACI:

European Academy of Allergy and Clinical Immunology

EMA:

European Medicines Agency

Eos:

Eosinophile granulocyte

EPIT:

Epidermal immunotherapy

FAS:

Full analysis set

FEV1:

Forced expiratory volume in 1 second

GCP:

Good clinical practice

GINA:

Global Initiative for Asthma

GKV:

Statutory health insurance, Gesetzliche Krankenversicherung

GMP:

Good manufacturing practice

HAART:

Highly active antiretroviral therapy

HIV:

Human immunodeficiency virus

HMG:

Medicinal Products Act (Switzerland), Heilmittelgesetz (Schweiz)

HR:

Hazard ratio

HRQL:

Health-related quality of life

ICER:

Incremental cost-effectiveness ratio

IFN:

Interferon

IgA:

Immunglobulin A

IgE:

Immunglobulin E

IgG:

Immunglobulin G

IL:

Interleukin

ILIT:

Intralymphatic immunotherapy

ITT:

Intention to treat

MPL:

Monophosphoryl lipid A

NaCl:

Sodium chloride

NPP:

Named patient product

NVL:

National disease management guideline, Nationale Versorgungsleitlinie

O2:

Oxygen

OAS:

Oral allergy syndrome

PAT:

Preventive allergy treatment

PDCO:

Paediatric Committee

PEF:

Peak expiratory flow

PP:

Per protocol

QALY:

Quality-adjusted life year

SCIT:

Subcutaneous immunotherapy

SCORAD:

Scoring Atopic Dermatitis

SLIT:

Sublingual immunotherapy

SMD:

Standardised mean difference

TAV:

Therapy allergen ordinance, Therapieallergene-Verordnung

TGF:

Transforming growth factor

Th:

T helper cell

TRBA:

Technical regulations for biological agents

Treg:

Regulatory T cell

TSS:

Total symptom score

VAS:

Visual analogue scale

WAO:

World Allergy Organization

WHO:

World Health Organization

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Correspondence to Prof. Dr. Oliver Pfaar.

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Disclosure/ Conflict of Interest

The information on potential conflicts of interest have been reviewed by a steering-group which did not find any conflicts of interest which may affect the authors’ independency in the process of the development of this guideline. The authors’ disclosures are available in a table (together with the working-report on this guideline) on the AWMF-page of the S2k- Guideline on “allergen-specific immunotherapy in IgE-mediated allergic diseases” via www.awmf.org/leitlinien/detail/ll/061-004.html.

Acknowledgement

The authors and contributing medical and professional societies gratefully acknowledge the translation of this guideline by Christine Schäfer, BA (Hons) PGDip (in Technical and Specialised Translation), Heidelberg, Germany. For careful review of the translated guideline and final editorial assistance we gratefully acknowledge native speakers Dr. Steve Love, PhD, Laguna Niguel, CA, USA, and Dr. Sabine Müller, MD, Allergy Research Group, Department of Dermatology, University Medical Center, Freiburg, Germany.

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Pfaar, O., Bachert, C., Bufe, A. et al. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. Allergo J Int 23, 282–319 (2014). https://doi.org/10.1007/s40629-014-0032-2

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Key words

  • allergen-specific immunotherapy
  • AIT
  • Hyposensitization
  • guideline
  • allergen
  • allergen extract
  • allergic disease
  • allergic rhinitis
  • allergic asthma