s pecific immunotherapy (hyposensitization) for ige ......former gina guidelines, 2005) and is recom...

Specific Immunotherapy (hyposensitization)for IgE-mediated allergic diseases*Guideline of the German Society of Allergy and Clinical Immunology(Deutsche Gesellschaft für Allergologie und Klinische Immunologie;DGAKI), of the Association of German Allergists (ÄrzteverbandDeutscher Allergologen; ÄDA) and the Society of Pediatric Allergy andEnvironmental Medicine (Gesellschaft für Pädiatrische Allergologie undUmweltmedizin; GPA), of the Austrian Society of Allergy andImmunology (Österreichische Gesellschaft für Allergologie undImmunologie; ÖGAI) and the Swiss Society of Allergy and Immunology(Schweizerische Gesellschaft für Allergologie und Immunologie; SGAI)

J. Kleine-Tebbe1, A. Bufe2, C. Ebner3, P. Eigenmann4, F. Friedrichs5, T. Fuchs6,I. Huttegger7, K. Jung8, L. Klimek9, M. Kopp10, W. Lässig11, H. Merk12,B. Niggemann13, U. Rabe14, J. Saloga15, P. Schmid-Grendelmeier16, H. Sitter17,J.C. Virchow18, M. Wagenmann19, B. Wedi20 and M. Worm21

1Allergie- und Asthma-Zentrum Westend, Berlin, 2Abteilung für experimentellePneumologie, Universitätsklinik Bergmannsheil, Bochum, 3Ambulatorium fürAllergie und klinische Immunologie, Wien, Österreich, 4Allergologie Pédiatrique,Hôpital des Enfants, Hôpitaux Universitaires de Genève, Schweiz, 5Praxis fürKinder- und Jugendmedizin, Laurensberg, 6Abteilung Dermatologie undVenerologie, Universitätsmedizin Göttingen, 7Universitätsklinik für Kinder- undJugendheilkunde, Paracelsus Medizinische Privatuniversität, SalzburgerLandeskliniken, Salzburg, Österreich, 8Praxis für Dermatologie und Immunologie,Erfurt, 9Zentrum für Rhinologie und Allergologie, Wiesbaden, 10Zentrum für Kinder-und Jugendmedizin, Universitätsklinikum Freiburg, 11Klinik für Kinder- undJugendmedizin, Krankenhaus St. Elisabeth und St. Barbara, Halle/Saale,12Universitätshautklinik, Rheinisch-Westfälische Technische Hochschule, Aachen,13Pädiatrische Allergologie und Pneumologie, Hedwig-von-Rittberg-Zentrum,DRK-Kliniken Westend, Berlin, 14Abteilung Pneumologie, Klinik III,Johanniterkrankenhaus im Flämig, Treuenbrietzen, 15Universitätshautklinik,Johannes-Gutenberg-Universität, Mainz, 16Allergiestation, DermatologischeUniversitätsklinik, Zürich, Schweiz, 17Institut für theoretische Chirurgie, UniversitätMarburg, 18Abteilung Pneumologie, Klinik und Poliklinik für Innere Medizin,Universität Rostock, 19Hals-Nasen-Ohren-Klinik, Universitätsklinikum Düsseldorf,20Klinik für Dermatologie, Venerologie und Allergologie, Medizinische HochschuleHannover, 21Allergie-Centrum Charité, Klinik für Dermatologie, Venerologie undAllergologie, Charité – Universitätsmedizin Berlin

Further participants in the consensus process: T. Hering22, A. Koch23, H. Lenders24,H. Müsken25, S. Schnitzer26, B.A. Stuck27, I. Voigtmann28 and W. Wehrmann29

22Lungenarztpraxis Tegel, Berlin, 23Klinik III für Innere Medizin – Herzzentrum,Universitätsklinikum Köln, 24Praxis für HNO-Heilkunde, Schwäbisch Hall,25Praxis für Innere Medizin – Allergologie und Pneumologie, Bad Lippspringe,26Praxis für HNO-Heilkunde, Grevesmühlen, 27HNO-Klinik, Klinikum Mannheim,28Deutscher Allergie- und Asthmabund, Mönchengladbach, 29DermatologischeGemeinschaftspraxis, Münster

Commenting participants and process attendance: S. Kaul30, B. Luther31 andA. Schwalfenberg32

30Abteilung Allergologie, Paul-Ehrlich-Institut, Langen, 31Medizinischer Dienst derKrankenversicherung Hessen, Oberursel, 32Deutscher Allergie- und Asthmabund,Mönchengladbach

Allergologie, Jahrgang 33, Nr. 1/2010, S. 3–34Leitlinie

Guideline

Key words

specific immunotherapy– hyposensitization –guideline – allergen –allergen extract – aller-gic disease – treatment

Stage of developmentS2

Status

September 18, 2009

© 2010Dustri-Verlag Dr. Karl FeistleISSN 0344-5062

Specific immunotherapy (hyposensi-tization) for IgE-mediated allergic diseases

The present guideline on allergen-specificimmunotherapy (SIT) was established byGerman, Austrian and Swiss allergy societiesin conjunction with other scientific and medi-cal societies (dermatology, ear-nose-throat,pediatrics, venerology, lung and airway dis-eases) and a German patient support groupaccording to criteria of the Association of theScientific Medical Societies in Germany(AWMF). Subcutaneous immunotherapy(SCIT) induces long-term tolerance to theapplied allergens after completion due to nu-merous immunologic effects. Regardingimmunologic mechanisms of sublingual im-munotherapy (SLIT), no consistent conceptsexist. In case of preparations with high doses,though, similar systemic immunologic effectshave been observed as with SCIT. Allergenconcentrations and products for SCIT orSLIT cannot be compared at present due totheir heterogeneous composition and variableassay methods of their active components.Non-modified allergens are used as aqueousor physically coupled (depot) allergen ex-tracts; chemically modified allergens (aller-goids) are used as depot extracts for SCIT.Mainly non-modified allergen extracts forSLIT are used as aqueous solutions or tablets.Results from controlled studies differ in ex-tent and in quality, requiring product-specificevaluation of SIT. Systematic reviews dem-onstrate considerable heterogeneity betweenstudy results of SIT, partially explained bydifferent subject groups, the utilized allergenproducts, the duration of treatment, and thetherapeutic dose. Efficacy of SCIT has beendemonstrated for pollen and house dust miteallergens in many controlled studies in pa-tients with allergic rhinoconjunctivitis, andfor animal dander (cat) and mold allergens(Alternaria, Cladosporium) in few studies.SCIT has been well studied in controlledasthma (according to new GINA guidelines,2008) and intermittent and mild persistentIgE-mediated allergic asthma (according toformer GINA guidelines, 2005) and is recom-mended as a therapeutic option besides aller-gen avoidance and pharmacotherapy, particu-larly in case of concomitant allergic rhino-conjunctivitis. Secondary preventive aspects,especially less novel allergic sensitizationsand reduced development of bronchialasthma, are important reasons for an earlystart of SCIT during childhood and adoles-cence. Diagnostic allergy work-up, indica-tion and selection of appropriate allergens forSCIT are, in general, made by a physicianwith allergy training within his/her special-ization or carrying a certified (sub)specialityin allergy. SCIT is indicated in patients withIgE-mediated sensitizations and correspond-ing clinical symptoms to allergens, which do

not or insufficiently permit allergen avoid-ance and which are available as suitable, effi-cacious extracts. Contraindications have to beconsidered on an individual basis. Injectionsof SCIT are administered by a physician ex-perienced in this therapy and who is able toperform emergency treatment in case of an al-lergic adverse event. Apreceding patient’s in-formation is mandatory and should be docu-mented. The therapy should last 3 years. Chil-dren tolerate the SCIT well and benefit nota-bly from its immunomodulatory effects. Se-vere, potentially life-threatening systemic ad-verse events can occur after SCIT, but arevery rare in case of complete adherence tosafety standards. Most adverse events aremild to moderate and easily treatable. Riskfactors for and results of adverse systemic ef-fects can effectively be minimized by trainingthe staff members involved, adhering tosafety standards and immediate emergencytreatment. In case of systemic reactions due tohymenoptera (bee, wasp) venom hypersensi-tivity, SCIT has excellent efficacy and shouldbe continued for at least 3 – 5 years. An ex-tended, sometimes lifelong SCIT is necessaryin some patients. Efficacy of SLIT in grasspollen-induced allergic rhinoconjunctivitishas been proven in several large-scale, con-trolled clinical studies. Applying other aller-gen sources (house dust mites, animal dander,molds), less and in part methodologically in-sufficient studies with contradictory resultsexist so far. Efficacy of SLIT in allergic bron-chial asthma has not enough evidence untilnow. SLIT with efficacious products is an op-tion for adults with allergic rhinoconjunc-tivitis due to pollen allergens, particularly ifSCIT is not suitable. In case of house dustmite allergy or symptoms due to other aller-gen sources and allergic asthma due to inhal-ants, SLIT does not substitute SCIT. SLIT canbe indicated in children and adolescents, ifSCIT is not an option, using a preparationwith proven clinical efficacy in this agegroup. SLIT is started by a physician experi-enced in the therapy of allergic diseases (seeguideline wording) and who is able to per-form emergency treatment in case of an aller-gic adverse event. According to the leaflet ofthe product manufacturer, the patient shouldbe informed about the therapy, usually lasting3 years as pre- and coseasonal or perennialregimen. During this course consultationsshould take place at least every 3 months.Apart from very frequently to frequently oc-curring dose-dependent adverse local oraland pharyngeal symptoms, systemic reac-tions, mostly of mild nature, have rarely beendescribed after SLIT. With regard toanaphylactic and other severe systemic reac-tions SLIT demonstrates a superior safetyprofile compared to SCIT. Additional re-search fields such as allergen characteriza-

Kleine-Tebbe, Bufe, Ebner et al. 4

tion, routes of application, adjuvants, up-dosing regimen and preventive aspects dem-onstrate new developments in SIT are cur-rently being examined for clinical efficacy.

1. Objectives and development

of the guidelines

This guideline for specific immunother-apy with allergens (SIT, hyposensitization)reflects the development that has taken placein the past decades and in which safety and ef-ficacy of SIT have been documented in nu-merous controlled studies (summary in [1, 24,38, 129, 168]). The immunologic mecha-nisms are being better understood [3, 57, 92].At present subcutaneous immunotherapy(SCIT) is considered to be the only treatmentwith a positive causal influence on the courseof allergic diseases by impairing the develop-ment of bronchial asthma [76] and by possi-bly preventing novel allergic sensitizations insome patients with allergic rhinoconjuncti-vitis [127, 148].

This guideline was produced on behalfof and financed by the following allergysocieties: German Society of Allergy andClinical Immunology (Deutsche Gesellschaftfür Allergologie und klinische Immunologie;DGAKI), Association of German Allergists(Ärzteverband Deutscher Allergologen; ÄDA)and Society of Pediatric Allergy and Environ-mental Medicine (Gesellschaft für Pädiatri-sche Allergologie und Umweltmedizin; GPA).It replaces the S2 guideline published in 2006[86]. For the first time the Austrian Society ofAllergy and Immunology (ÖsterreichischeGesellschaft für Allergologie und Immuno-logie; ÖGAI) and the Swiss Society of Al-

lergy and Immunology (SchweizerischeGesellschaft für Allergologie und Immuno-logie; SGAI) were directly involved in the de-velopment of the guideline. When develop-ing the guideline, international (World HealthOrganization (WHO)), European (EuropeanAcademy of Allergology and Clinical Immu-nology (EAACI)) and existing recommenda-tions for sublingual immunotherapy (SLIT)were taken into account [85].

The SIT guideline was developed accord-ing to the methodic requirements for the de-velopment of guidelines for diagnosticwork-up and therapy defined by the Associa-tion of Scientific Medical Societies in Ger-many (Arbeitsgemeinschaft der Wissen-schaftlichen Medizinischen Fachgesellschaf-ten; AWMF) and corresponds, according tothe AWMF’s three-step concept, to a S2guideline, supplemented by stages of recom-mendation and evidence (Table 1) as well asby clinical algorithms (for explanation seeFigure 1) for diagnostic work-up and indica-tion. Statements in the guideline were com-pleted by stages of recommendation and evi-dence established by meta-analyses, clinicaltrials and other scientific investigations.

It is essential to establish a consensus inorder to create acceptance for a guidelineeven if evidence is low in order to support itsdissemination and implementation. To obtainconsensus we used a combination of nominalgroup process and delphi technique involvingauthorized representatives from scientificand medical societies: Wolfgang Wehrmann,Münster, Professional Association of Ger-man Dermatologists (Berufsverband derDeutschen Dermatologen; BVDD), FrankFriedrichs, German Association of Pediatri-cians (Berufsverband der Kinder- und Ju-gendärzte; BVKJ), Thomas Hering, Berlin,German Federal Association of Pneumol-ogists (Bundesverband der Pneumologen;BDP), Andrea Koch, Köln, and HorstMüsken, Bad Lippspringe, German Societyof Pneumology (Deutsche Gesellschaft fürPneumologie, DGP), Heinrich Lenders,Schwäbisch Hall, and Sylvia Schnitzer,Grevesmühlen, German Professional Asso-ciation of Ear, Nose and Throat Doctors(Deutscher Berufsverband der Hals-Nasen-Ohrenärzte; BVHNO), Boris A. Stuck,Mannheim, German Society for Ear, Noseand Throat Medicine, Head and Neck Sur-gery (Deutsche Gesellschaft für Hals-Na-sen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; DGHNOKHC), Joachim Salogaand Bettina Wedi, German Society of Derma-tology, (Deutsche Dermatologische Gesell-schaft, DDG), Ingrid Voigtmann, Mönchen-gladbach, German Allergy and AsthmaAssociation/Patient Organization (DeutscherAllergie- und Asthmabund; DAAB). The fol-

Specific Immunotherapy (hyposensitization) for IgE-mediated allergic diseases 5

Abbreviations

AMG German Medicines ActDBPC double-blind and placebo-controlledFEV1 forced expiratory volume in the

first secondGCP good clinical practiceGMP good manufacturing practiceIg immunoglobulinIL interleukinCI confidence intervalOAS oral allergy syndromPEI Paul-Ehrlich-InstitutSCIT subcutaneous immunotherapySIT specific immunotherapySLIT sublingual immunotherapySMD standardized mean differenceTGF transforming growth factor

lowing persons accompanied the consensusconference and the guideline process as neu-tral observers: Susanne Kaul, Langen, Paul-Ehrlich-Institut (PEI), Department of Aller-gology, Burkhard Luther, Oberursel, MedicalReview Board of the Health Care Providers(Medizinischer Dienst der Krankenversiche-rung; MDK) Hessen, and Anja Schwalfen-berg, Mönchengladbach, DAAB. Followingthe consensus procedure the guideline waspresented to all responsible committees forannotation and recommended for acceptance.

The guideline is addressed to all physi-cians who treat allergic patients and shall beupdated by the authors of the allergy societiesthree years after publication; the first author isresponsible for this. The guideline is pub-lished and distributed by the allergy societiesin their associated organs of publication(Allergo Journal, Pädiatrische Allergologiein Klinik und Praxis) and in the AWMFguideline collection. The guideline is recom-mended to be accepted by other involved so-cieties and is made available for reprint for in-terested journals with allergologic content.

2. Immunologic mechanisms

Most immunologic effects in the contextof SIT have first been described for SCIT. Ac-cording to the current state of knowledgeimmunotherapy causes alterations on thelevel of antigen representation, T cell re-sponse and antibody response, influencingthe effector cells [92]. Current data supportseveral models of the immunologic efficacyof immunotherapy:– SCIT modifies the function of allergen T

cells by activating regulatory CD4+ Tcells that produce interleukin-(IL-)10 andtransforming growth factor-(TGF-)! andmediate tolerance [2, 3, 13, 57, 58, 78,123] (Figure 2). Th2 cells become anergicand their reactivity reduces with decreas-ing cytokine production and proliferationafter stimulation by the T cell receptor[54, 102, 113].

– SCIT causes a shift of the dominant Th2response (e.g., IL-4, IL-5, IL-13) in favorof a more pronounced Th1 response (In-terferon-") [13, 79, 158] (Figure 2).

– SCIT, like vaccinations, induces a new al-lergen-specific immune response charac-terized by a more pronounced productionof allergen-specific IgG antibodies [56,121, 162], particularly of IgG1- and IgG4antibodies [131] which are able to inhibitallergen-specific mast cell degranulation,T cell activation and allergen-inducedboost of the IgE production [23, 62, 112].

– The functions of effector cells, like mastcells and basophil granulocytes or eosino-phil granulocytes, are inhibited [137,142].

Thus, SCIT interferes in the basic immu-nologic mechanisms of all allergic (atopic)disease patterns. This means that SCIT is acausal form of therapy and thus of particularimportance in the therapy of allergic diseases.However, the immunologic effects do not al-ways correlate with the clinical efficacy.

To date there is no common agreementupon the mechanisms involved in SLIT; in


Table 1. Levels of recommendation and evidence for MW guidelines (accor-ding to Centre for Evidence-Based Medicine Oxford) [8].

Level of Level of Evidence byrecommenda- evidencetionA 1a systematic review of RCTs

1b well-planned randomized controlled trial1c all or none principle

B 2a systematic review of well-plannedcohort studies

2b well-planned cohort study, RCT withmoderate follow-up

2c outcome research studies3a systematic review of case

control studies3b individual case control study

C 4 case series (and poor quality cohortand case control studies

D 5 expert opinion without explicit critical appraisal,or based on physiology, laboratory researchor “first principles”

RCT = randomized controlled study.

Figure 1. Standardized terminology for clinical algo-rithms: A clinical algorithm is a procedure formu-lated in a finite number of steps which solves a clini-cal problem using conditional logical statements(if-then-logic). It is usually presented as a graphicusing the nomenclature recommended by the Soci-ety for Medical Decision Making. Status, action anddecision nodes are used. Status and action nodeshave one exit each, decision nodes have exactly 2exits (yes and no).

cases of successful SLIT a local anti-inflam-matory immune response in terms of produc-tion of local cytokines, primarily of IL-10from regulatory T cells, was found [20]. Incurrent studies the increase of factors that in-hibit the binding of IgE to allergens was ob-

served [41, 109]. Under SLIT the increase inallergen-specific IgG-antibodies and IgG4-antibodies can differ [48, 134]. In SLIT with agrass pollen extract in tablet form the aller-gen-specific IgE-antibodies were signifi-cantly increased above the value observedwith natural pollen concentrations (“boost”)[48]. The clinical relevance of this increaseremains unclear.

Conclusion: Subcutaneous immuno-therapy (SCIT) induces long-term toleranceto the applied allergens after completion asdefined by numerous immunologic effects.Regarding immunologic mechanisms ofsublingual immunotherapy (SLIT), no con-sistent concepts exist. In case of prepara-tions with high doses, though, similar sys-temic immunologic effects have beenobserved as with SCIT.

3. Allergen extracts, their

evaluation and marketing

authorization

3.1. Production and compositionof allergen extracts

Due to manufacturer-specific processingthe produced allergen extracts differ concern-ing composition and allergen activity andthus are not comparable even if the same al-lergen sources are used. The total activity ofthe extracts is evaluated by in vitro methodsand is biologically standardized using skintests. For the production of allergen prepara-tions for SIT preferably standardized allergenextracts should be used, because non-stan-dardized extracts vary significantly in termsof biologic activity [94]. The determinationof dominant single allergens (e.g., major al-lergens) using standardized validated meth-ods is recommended by international guide-lines and, if available, will be used morefrequently for important allergen sources[143]. At the moment, however, it is impossi-ble to compare allergen concentrations of dif-ferent preparations, as until now the manu-facturers use different references andmeasuring methods to determine the majorallergens.

For SCIT non-modified (“native”) ex-tracts with unchanged allergen conformationand chemically modified (polymerized) ex-tracts (so-called allergoids) can be used. It isassumed that allergoids possess less reactiveB cell epitopes and thus a reduced IgE bind-ing, while their T cell epitopes and theirimmunogenic effect remain unchanged. Be-sides aqueous extracts, which are commonfor induction therapy in insect venom allergy,


Figure 3. Allergen extracts available for SCIT (forexplanation see Section 3.).

Figure 2. Allergic immune response and mecha-nisms of SCIT: By interleukin (IL-)5 production Type2 T-helper (Th2-) cells induce an allergic inflamma-tion characterized by eosinophil granulocytes(Eos); by IL-4 and IL-13 they induce immunoglobu-lin E (IgE-) synthesis of B-lymphocytes (B). Subcu-taneous specific immunotherapy (SCIT) inhibits thefunction of Th cells by and increased release ofTGF-! (transforming growth factor beta) and IL-10cytokines from regulatory Tr1-like cells (immuno-modulation). Furthermore, a regulatory Th1 im-mune response is induced (immune deviation):IL-12 from antigen-presenting cells (APC) stimu-lates the production of interferon (IFN-)" by TH1cells and thereby inhibits formation of IgE and differ-entiation of Th2 cells. For SLIT, similar mechanismshave been suggested and partially shown for cer-tain products with high allergen contents. Figurecharacteristics: Circle containing +: induced; circlecontaining –: inhibited; red coding: increased aller-gic immune response (immediate-type allergy); yel-low coding: reduced allergic immune response.

mainly depot extracts, in which native ormodified allergens are physically coupled to acarrier (e.g., aluminum hydroxide, tyrosine orcalcium phosphate), are used in Europe, de-pot extracts, in which native or modified al-lergens are physically coupled to a carrier(e.g., aluminum hydroxide, tyrosine or cal-cium phosphate), are most commonly usedwith the exception of insect venom allergy,where aqueous extracts are applied for induc-tion therapy (Figure 3).

Preparations for SLIT are available withallergens in unmodified conformation or asmodified extracts in the form of aqueous solu-tions or tablets. There are preparations thathave to be stored in the refrigerator and othersthat can be stored at room temperature.

Conclusion: Allergen concentrationsand products for SCIT or SLIT cannot becompared at present due to their heteroge-neous composition and variable assay meth-ods of their active components. Non-modi-fied allergens are used as aqueous orphysically coupled (depot) allergen ex-tracts; chemically modified allergens(allergoids) are used as depot extracts forSCIT. Mainly non-modified allergen ex-tracts for SLIT are used as aqueous solutionsor tablets.

3.2. Criteria for evaluation ofspecific immunotherapy insubcutaneous or sublingualapplication

SIT was evaluated by controlled studiesin which efficacy, tolerability and additionaleffects were examined. For this purpose

symptoms and drug use were analyzed usingpreviously defined score-based systems thatalso reflect the patient’s individual diseasemanagement: For example pronouncedsymptoms in association with low drug use orless pronounced symptoms in associationwith high drug use. Symptom and medicationscores, indicated either as separate scores oras a combined symptom/medication score,are linked to each other. Until now, they havenot been validated regarding weighting, dis-tribution and (quantitative) interdependence.They have, however, prospectively beenfixed in the study protocols for double-blind,placebo-controlled (DBPC) trials.

As a result, the outcomes of SIT studiesare hardly comparable due to differences inscore systems, patient cohorts and studydesigns. As preparations (dose, allergen com-position, modifications) and routes of appli-cation (up-dosing regimen, frequency of ap-plication and duration of therapy) also differsignificantly, a general evaluation is difficult.Thus, instead of providing generalized state-ments concerning SIT, SCIT or SLIT, thisguideline is aiming at making product-spe-cific assumptions of successful placebo-con-trolled studies and at evaluating the clinicalrelevance of the results.

This gives a high significance to the scopeand accuracy of the pre-clinical and clinicaldocumentation for a preparation and to itsmarketing authorization, in order to evaluatecertain products and procedures for SIT. Forallergen preparations the reverse is not imper-atively true, i.e., preparations without con-trolled studies are not necessarily ineffective,their clinical efficacy is just not documented.

3.3. Significance of themarketing authorizationof allergen preparations

Preparations of native or modified aller-gen extracts are available as authorized drugsor as individual formulations. According tothe 14th novel of the German Medicines Act(AMG) authorized therapy allergens as wellas individual formulations are ready-to-usemedicinal products (Text box 1). In principle,all ready-to-use medicinal products have tobe authorized. However, the AMG allows ex-ceptions for some drugs, with individual for-mulations for therapy allergens belonging tothis group (Text box 1). Thus, the term ready--to-use medicinal product is no longer appro-priate to distinguish between authorized ther-apy allergens and individual formulations.Basically, both types of products are pre-scribable and negotiable. Until the Regula-tion on Therapy Allergens “Regulation on the


Text box 1. Important terms of the German Medicines Act (AMG).

Finished medicinal product

Section 4 Sub-section 1 AMG [10]: “Finished medicinal products are medicinalproducts which are manufactured beforehand and placed on the market in pack-aging intended for distribution to the consumer or other medicinal products in-tended for distribution to the consumer, in the preparation of which ... an indus-trial process is used or medicinal products which are produced commercially.“

Marketing authorization

Section 21 Sub-section 1 AMG: Finished medicinal products which are medici-nal products as defined in Section 2 sub-section 1 or sub-section 2 no. 1, mayonly be placed on the market within the purview of the present Act, if they havebeen authorized by the competent higher federal authority...”

Individual formulations

Section 21 Sub-section 2 AMG: “A marketing authorization shall not be requiredfor medicinal products which ... 1b: ... are prepared on prescription in the form oftherapy allergens for individual persons …”

expansion of specifications of the marketingauthorization of drugs based on therapy aller-gens prepared on the basis of individual for-mulations for certain persons and regulationon the process control for governmental batchtesting (Therapieallergen-Verordnung)” cameinto effect on November 14, 2008 only autho-rized allergen preparations were subject togovernmental batch tests in Germany. Inthese authorized preparations the batch test-ing is carried out in the end product and/or inthe inter-stage products. Depending on thesize of the primary packaging, they can beidentified by the batch number (Ch.-B.) onthe label or, in any case, by the authorizationnumber (Zul.-Nr.) and the batch designationon the outer package. These characteristicsmake them distinguishable from individualformulations that are not certified by thePaul-Ehrlich-Institut (PEI).

The Regulation on Therapy Allergensstipulates that – with certain transitional regu-lations – therapy allergens that contain at leastone extract of an allergen source that fre-quently causes diseases (Text box 2) have tobe authorized. Individual formulations haveto be reported to the PEI if they contain thosekinds of allergens and an application for au-thorization is to be made. The same is the case

if no marketing authorization is intended, buta therapy that had been started is supposed tobe continued for a maximum of 3 years. Aftera transitional time until final marketing au-thorization or until their negotiability ends,all reported preparations stay negotiable andare subject to batch tests carried out by thePEI. These batch tests are not carried out inthe final product but in the respective parentextracts (parent extract batch testing). All fur-ther therapy allergens produced as individualformulations (those which do not contain al-lergens listed in the appendix of the Regula-tion on Therapy Allergens) continue to be ex-empted and are not subject to governmentalbatch testing. For reasons of pharmaco-vigilance and drug safety, authorized andunauthorized preparations for SCIT aredistributed in a patient-related form directlyby the manufacturer and not via the whole-sale.

In Germany the Paul-Ehrlich-Institut(PEI) is responsible for the marketing autho-rization of allergen preparations (Text box 3)for therapy and diagnosis. In Austria these af-fairs are regulated by the Bundesamt fürSicherheit im Gesundheitswesen (FederalOffice for the Safety in the Public Health Sec-tor) which refers to the ÖsterreichischeAgentur für Gesundheit und Ernährung(Austrian Agency for Health and Nutrition;AGES-PharmMed). In Switzerland the mar-keting authorization of allergens is super-vised by the Swiss medicine institute Swiss-medic. Thus, the above-mentioned regula-tions do not apply for Austria and Switzer-land.

Together with the authorization docu-ments, information on the production processof the drug and on its quality control as well asthe results of all pre-clinical and clinical stud-ies and of further medical testing has to beprovided to the PEI. The documents for cur-rent and recent marketing authorizations haveto comply with the requirements stated in theguidelines for good manufacturing practice(GMP) and in the guidelines for good clinicalpractice (GCP), with the European pharma-copoeia as well as with the respective EMEAguidelines (European Medicines Agency;www.emea.europa.eu/pdfs/human/bwp/30483107enfin.pdf, http://www.emea.europa.eu/pdfs/human/ewp/1850406enfin.pdf). The pre-parations are only authorized for those indica-tions and patient groups for which safety andefficacy have been proven in clinical trials.Apart from bee and wasp venom prepara-tions, since 1993 marketing authorization isonly being granted if at least one dou-ble-blind, placebo-controlled study was car-ried out successfully. For hymenopteravenom preparations placebo control is not re-quired due to ethical reasons. In these cases


Text box 3. Procedure* for marketing authorization of drugs in Germany.

– National procedure by which the medicinal product is authorized for Germanyonly.

– Mutual recognition procedure, if the preparation has already obtained authori-zation in one EU member state and the marketing authorization is supposedto be extended to other EU member states.

– Decentralized procedure, if the medicinal product has not obtained nationalmarketing authorization yet and is supposed to be subject to parallel authori-zation in several EU member states.

– Central procedure (parallel marketing authorization in all EU member states)for medicinal products that are named in the appendix of the EC regulation726/2004 (e.g., medicinal products that have been produced usingbiotechnologic procedures); under certain circumstances this procedure canalso be used for other medicinal products.

*All procedures that result in marketing authorization in several or all EU statesare coordinated by the European Medicines Agency (EMEA).

Text box 2. List of therapy allergens for which market authorization is required*.

– Species of the family poacea except Poa mays (true grasses except maize)– Betula sp. (species of genus birch)– Alnus sp. (species of genus alder)– Corylus sp. (species of genus hazel)– Dermatophagoides sp. (species of the genus house dust mite)– Bee venom– Wasp venom

*List of therapy allergens that have to obtain a marketing authorization accor-ding to the regulation on therapy allergens [163] and that in the future may not bemarketed – neither as single preparations nor as mixtures – without permission.

the new preparation is usually tested by com-paring it to an established comparator prod-uct. Formerly, sometimes also open-labelstudies were accepted as evidence for effi-cacy – corresponding to the standard ofknowledge at that time. Since the GCP regu-lation came into effect in August 2004 clini-cal examinations have to be approved by theresponsible authority beforehand. All GCPcriteria have to be met. This has led to a sig-nificant improvement in the quality of dataobtained in clinical studies and of the evi-dence for safety and efficacy of preparationsauthorized on the basis of these studies. Thus,authorized preparations (www.pei.de > Ärzteund Apotheker > Arzneimittel > Liste zu-gelassener Arzneimittel > Allergene) [81]have been examined in terms of quality, effi-cacy and tolerability in correspondence withthe respective standard of knowledge at thetime of marketing authorization.

This means that those preparations whichwere produced as individual formulations(named patient products) and therapy aller-gens that did not require authorization (Textbox 1) were not officially controlled concern-ing quality, efficacy and tolerability and theywere not subject to governmental batch test-ing. Due to the Regulation on Therapy Aller-gens most individual formulations are subjectto governmental batch testing in the parentsolutions after a transitional period. An offi-cial examination of safety and efficacy is onlyavailable with the final marketing authoriza-tion.

For all other individual formulations (sin-gle or in mixtures) that do not contain ingredi-ents listed in the allergen list (Text box 2) stillno marketing authorization is necessary andthey continue not to be subject to any officialcontrol. Nevertheless, according to the manu-facturers, the parent extracts used for the for-mulations are produced in accordance withthe GMP criteria and are examined on thebasis of internal specifications.

It is estimated that a total of more than50% of therapy preparations of both applica-tion forms (SCIT, SLIT) are available as indi-vidual formulations [104] and thus are not ex-amined by the PEI. Individual formulationsare frequently evaluated in uncontrolled stud-ies – if they are examined at all. This is thereason why hardly any solid data concerningefficacy and tolerability and only sparse dataconcerning tolerability are available. In somecases data might already correspond to thecurrent state of knowledge; these prepara-tions will probably easily be authorized ac-cording to the Regulation on Therapy Aller-gens. As a result of Regulation on TherapyAllergens data will be collected for furtherindividual formulations in the near future.

In our opinion, authorized allergen prepa-rations with documented safety and efficacyshould be preferred as long as the patient’ssensitization spectrum allows for it (D, 5).The manufacturer can present the efficacy re-sults from respective studies in the technicalinformation of the leaflet under Article 5.1.The quality of these studies, however, cansignificantly vary because of the differencesin requirements from 1990 until today. In thecase of authorized preparations these presen-tations are also officially examined. For cur-rent marketing authorizations the manufac-turers use this possibility and make informa-tion on the respective preparation availablefor the physician as part of the leaflet.

As authorized finished medicinal prod-ucts cannot cover the whole spectrum of aller-gen extracts that have to be used for SIT, indi-vidual formulations (named patient products)are still necessary in cases where the extractmust be tailored to the allergologic problemof an individual patient (D, 5) [104].

4. Efficacy in clinical studies

4.1. Systematic reviews andmeta-analyses for evaluation ofspecific immunotherapy

Systematic reviews and meta-analyses areused for a global evaluation of therapies, be-cause they provide the opportunity to carryout a summarized conclusion by “global” sta-tistics. Individual studies examining smallnumbers of cases, have shown trends withoutstatistic significance and have used differentstudy designs or heterogenous products (e.g.,allergen preparations) and differing subjectgroups.

A systematic review of 22 SLIT studiespublished until September 2002 showed asignificant weak-to-moderate clinical effectof verum vs. placebo therapy in the treatmentof allergic (exclusively pollen-induced) rhi-nitis in adults. This applies to the reduction ofsymptoms (standardized mean difference(SMD) –0.42; 95% confidence interval (CI)–0.69 to –0.15; p = 0.002) and to the use ofrescue medication (SMD –0.43; 95% CI–0.63 to –0.23; p = 0.00003) after SLIT [168].In contrast, no sufficient effects were foundfor perennial rhinoconjunctivitis, allergicbronchial asthma in adults and allergic respi-ratory diseases in childhood [168]. The com-prehensive studies concerning SLIT that hadbeen published in the meantime were not yettaken into account in the review published bythe Cochrane Collaboration in 2003.

A systematic review published in 2007 bythe Cochrane Collaboration reporting on 15


studies on SCIT that had been published untilFebruary 2006 shows significant moderate-to-strong effects of verum vs. placebo in thetherapy of seasonal allergic rhinocon-junctivitis. The improvement was related tothe reduction of symptoms (SMD –0.73; 95%CI –0.97 to –0.50; p < 0.00001) and to the re-duced rescue medication use (SMD –0.57;95% CI –0.82 to –0.33; p < 0.00001) [38]. Onthe other hand there was a considerable posi-tive impact of few studies with low numbersof cases on this effect on symptom andmedication scores [38].

Meta-analyses [1, 38, 132, 133, 168] de-pend on the quality of the single studies takeninto account, on their mathematically deter-mined heterogeneity [1, 38, 168] and on thepossible publication bias. The publication ofsystematic reviews and meta-analyses in theCochrane Library [1, 38, 168] is superior tothe publication in expert journals [132, 149],because in the former transparent andstringent evaluation criteria are used.

Conclusion: Systematic reviews dem-onstrate considerable heterogeneity be-tween study results of SIT, partially ex-plained by different subject groups, theutilized allergen products, the duration oftreatment, and the therapeutic dose.

4.2. Efficacy of SCIT

4.2.1. Efficacy of SCIT in allergic

rhinoconjunctivitis

The documentation of the clinical effi-cacy of SCIT in allergic rhinoconjunctivitis isbased on numerous placebo-controlled dou-ble-blind studies that vary in size and qualityand that have been summarized for seasonalallergen sources in a systematic review withmeta-analysis [38]. In these studies a medianreduction of symptoms/drug use of 45 – 60%was described for the comparison verum vs.placebo [38].

The majority of analyzed studies evaluatethe efficacy of specific SCIT in pollen aller-gies. Most of these studies were carried outfor grass pollen allergies using chemicallyunmodified allergen extracts; however, notall available preparations were tested. In al-most all studies a reduction in symptomsand/or drug use of at least 30% in the treat-ment group vs. the placebo group wasobserved (A, 1a) [38].

Efficacy studies for birch pollen allergiesshowed a reduction in symptoms and/or druguse of an average of 45% (A, 1b) [9, 12, 19,120].

The evaluation of efficacy of SCIT inrhinoconjunctivitis caused by house dust mite isbased on several studies. All studies show a re-duction in symptoms and/or drug use of at least30% in the treatment group vs. the placebogroup (A, 1b) [17, 24, 55, 105, 106, 135, 136].

In animal dander allergens efficacy wasonly shown with cat allergen extracts. For otheranimals only few reports exist. In the case ofmold allergies the evidence of clinical efficacyis limited to only a few studies (Alternaria,Cladosporium; B, 2b) [46, 74, 101].

Most SCIT studies that show positive ef-fects were carried out in adults (75%). Onlysix studies involved children. Thus, the evi-dence for a positive effect of SCIT is not com-pletely secured for this age group.

Short-term SCIT is carried out withallergoids (with or without adjuvant) andwith non-modified allergens. The manufac-turers recommend 4 – 8 injections, dependingon the used extract. Nevertheless, modifica-tions are possible according to the patient’stolerability.

Efficacy of short-term SCIT in cases ofseasonal allergic rhinoconjunctivitis was notonly documented in older controlled studies(with or without placebo control [39, 107,130]) but also in more recent publications[12, 40, 45, 161, 172].

Immunologic changes (see 2.) can be ver-ified similarly in short-term SCIT [40, 71, 88,139, 172]. In view of the lower cumulativedose, short-term therapy should only be car-ried out if its clinical efficacy can bedemonstrated in DBPC studies and if the pa-tient is not able to ensure patience for apreseasonal or perennial SCIT (for explana-tion see Text box 4) in which a higher numberof injections of the maximum dose is requiredor if there is only little time left before the pol-len season starts (D, 5). Preventive effects,long-term efficacy, efficacy in children or inbronchial asthma proven by randomized pla-cebo-controlled studies have not been pub-lished until now. Short-term therapy shouldbe carried out until the start of pollen season(D, 5).


Text box 4. Defintions of SCIT with allergens.

Short-term therapy

Limited number of 4 – 7 injections before the seasonal symptoms start.

Preseasonal therapy

Start of treatment in sufficient time before the start of pollen season; weekly in-jections during dose-increase period and monthly injection with the mainte-nance dose until the start of pollen season.

Perennial therapy

Start of therapy with up to 16 weekly injections during the dose-increase periodand monthly injections with the maintenance dose; in case of seasonal allergensources, a reduction of the maintenance dose during the symptom season ac-cording to the manufacturer’s information is possible.

Conclusion: Efficacy of SCIT has beendemonstrated for pollen and house dust miteallergens in many controlled studies in pa-tients with allergic rhinoconjunctivitis, butfor animal dander (cat) and mold allergens(Alternaria, Cladosporium) in few studies.Results from controlled studies differ in ex-tent and in quality, requiring product-spe-cific evaluation of SIT.

4.2.2. Efficacy of SCIT in allergic

bronchial asthma

In order to be able to take into account theasthma criteria used in older studies, the se-verity of asthma is given in terms of the old(2005) [34, 63] as well as in terms of the new(2008) GINA recommendations [64] .

In contrast to the application of SCIT inallergic rhinoconjunctivitis its efficacy in al-lergic bronchial asthma is still discussed con-troversially [14, 61]. SCIT cannot replace anadequate anti-asthma therapy. On the basis ofnumerous studies SCIT can be recommendedfor intermittent (Stage I) and mild persistentbronchial asthma (Stage II) (B, 2a-c) [14, 22,24, 61]. The justification for this is a repeat-edly updated meta-analysis of the CochraneLibrary consisting of 75 controlled, howevermethodologically heterogeneous studies:after SCIT asthma symptoms, drug use anddegree of specific and non-specific hyper-reactivity were reduced compared to placebo,whereas lung function parameters were notimproved (A, 1a) [1, 26]. In patients with pe-rennial allergic asthma and house dust miteallergy SCIT with mite extracts resulted in areduction of symptoms [5, 60, 166], drug use[5, 18, 60] and allergen-specific bronchialhyperreactivity [5, 60] as well as in animproved quality of life [5, 60] compared totreatment with placebo.

Mainly young patients with allergic rhi-noconjunctivitis, mono- or oligosensitizationand a clear association between asthma symp-toms and allergen exposure proven by patienthistory or by provocation can benefit fromSCIT. In contrast, older patients with along-lasting course of asthma, allergen-inde-pendent complaints and minor improvementafter anti-asthma therapy hardly benefit fromSCIT (B, 2a) [22, 26], but carry a high risk foradverse events instead (B, 2a) [25].

Conclusion: SCIT has been well studiedin controlled asthma (according to newGINA guidelines, 2008) and intermittentand mild persisting IgE-mediated allergicasthma (according to former GINA guide-lines, 2005) and is recommended as a thera-peutic option in addition to allergen avoid-ance and pharmacotherapy, particularly incase of concomitant allergic rhinoconjuncti-vitis.

4.2.3. Efficacy of SCIT in other

indications

Data concerning efficacy of SCIT withpollen allergens in the therapy of oral allergysyndrome (OAS) are scarce [103] so that fur-ther studies have to be carried out before a fi-nal assessment can be made. At present, SCITfor OAS without respiratory symptomscaused by pollen allergens is not indicated (D,5).

Current studies show clinical effects ofSCIT in patients with allergic atopic dermati-tis and corresponding, probably clinically rel-evant, Type I sensitization (e.g., eczemas trig-gered by airborne allergens; review in [37,124]). Atopic eczema is not a contraindica-tion for SCIT in cases of allergic respiratorysymptoms requiring treatment (D, 5). Cur-rently further studies are investigatingwhether atopic dermatitis can be a soleindication for SCIT [167].

4.3. Efficacy of SLIT

4.3.1. Efficacy of SLIT in allergic

rhinoconjunctivitis

New controlled studies with higher pa-tient numbers have contributed to providemore data concerning SLIT.

For SLIT the amount of clinical documen-tation varies considerably depending on theproduct. While for some products no random-ized controlled studies have been publishedso far, for some preparations and allergensources (e.g., grass pollen extract) substantialdata from several studies are available thathave led to the European marketing authori-zation as a finished medicinal product for alyophilized orodispersible tablet of a timothypollen extract for the treatment of seasonal al-lergic rhinoconjunctivitis in adults (A, 1b).The lyophilized orodispersible tablet is usedfor SLIT perennially without dose-increaseperiod (review in [108]) and showed a de-crease in symptoms of 30% (mean) and of38% (mean) in medication use compared tothe placebo group in a study with more than600 participants. For this preparation efficacydata from several pollen seasons are available[43]. A similar tablet product based on lac-tose, which is also authorized in Germany,containing a mixed pollen extract of 5 vernalgrasses is used, after a short dose-increase pe-riod, approximately 4 months prior to the startof pollen season for pre- and coseasonal SLITin adults: In a study with more than 600 par-ticipants for higher doses a reduction insymptoms of 37% (median) and in drug use(46%, median) compared to the placebogroup could be shown (A, 1b) [44].


A high-dosed liquid single-dose prepara-tion with a mixed pollen extract from 6grasses is used, after a 30-minute titrationphase, for at least 3 months before the pollenseason starts for perennial as well as for pre-and coseasonal SLIT in adults. In a study with185 participants the combined symptom andmedication score of the 104 analyzed subjectswas reduced by 46% (mean) compared to theplacebo group (A, 1b) [134, 169].

Studies involving children with allergicrhinoconjunctivitis caused by grass pollen al-lergens showed a similar efficacy similarefficacy as in the adult study for the period ofone season: Using the lyophilized orodisper-sible tablet a reduction in symptoms of 24%(median) and a reduction in drug use of 34%(median) [32] was achieved. The use of theproduct based on lactose resulted in a reduc-tion in symptoms of 28% (mean) and in a re-duction in medication use of 24% (mean)compared to placebo [165]. In Germany, bothpreparations are authorized for children of 5years and older. Until now, only efficacy datafor the period of one pollen season are avail-able for these grass pollen tablets when usedin childhood and adolescence.

For other preparations heterogeneousdata are available (review in [42, 99, 168]),probably because of the dose and composi-tion of these preparations as well as for meth-odological reasons.

Studies comparing SLIT and SCIT inadults [118, 141] only show the clinical effi-cacy of both therapies and are methodologi-cally deficient [100]. Due to the small numberof cases in the only existing study comparingboth forms of SIT [83], it is impossible tomake a statement on the differences of SLITand SCIT with regard to efficacy. However, inthe case of SLIT, contrary to SCIT, no adversesystemic reactions were observed. In contrastto SCIT [47], long-term effects [145] and pre-ventive effects with regard to lower airwayinvolvement (development of asthma) [125]of SLIT are less well documented due tomethodological deficiencies. SLIT with a liq-uid pollen extract from 5 vernal grasses, usingan identical composition and dose as theproduct based on lactose, showed a trend ofsustained efficacy (“carry-over” effect in thecombined symptom/medication score withsignificantly less symptoms) compared toplacebo during the pollen season after a3-year period of coseasonal treatment [126].SLIT continues to be examined with regardsto these open questions and will represent afurther option for treating allergic diseases.Nevertheless, some questions (Text box 10)have to be answered for numerous prepara-tions before SLIT can be considered as anadequate alternative for SCIT.

Conclusion: Efficacy of SLIT in grasspollen-induced allergic rhinoconjunctivitishas been proven in several large-scale, con-trolled clinical studies. Applying other aller-gen sources (house dust mites, animal dan-der, molds), less and in part methodologi-cally insufficient studies with contradictoryresults exist so far.

4.3.2. Efficacy of SLIT in allergic

bronchial asthma

For the use of SLIT in cases of allergicbronchial asthma less data are available as forallergic rhinoconjunctivitis [93, 168]. Therewas hardly any investigation on the efficacyof SLIT in bronchial asthma. The results areinconsistent so that SCIT should not be rou-tinely used for treatment of allergic bronchialasthma (D).

Conclusion: Efficacy of SLIT in allergicasthma does not currently have enough evi-dence to suggest its use.

4.4. Prevention of asthma andnovel allergic sensitization

Studies in children and adolescents showthe prophylactic value of SCIT for certainpreparations (A, 1b). In cases of allergicrhinoconjunctivitis the risk of the develop-ment of asthma symptoms and bronchialhyperreactivity can be reduced in the longterm (A, 1b) [110, 122]. These effects are stillverifiable 7 years after SCIT completioncompared to the untreated control group [76],which led to an extension of the indication forthis preparation by the regulatory authorities.In cases of mono- and oligosensitizations thefrequency of novel allergic sensitizations canbe reduced (B, 2c) [51, 127, 140, 148]. Until12 years after completion of SCIT with amodified allergen preparation there was evi-dence for this and other secondary preventiveeffects compared to an untreated controlgroup [50].

So far, no evidence for a reduction in sen-sitization rate was found for the sublingualroute of application [125, 145]. In one study areduction of primary asthma diagnosis wasdescribed, nevertheless the high rate of dis-continuations and significant inter-center dif-ferences limit the result of this study [125].

Conclusion: Secondary preventive as-pects, especially the reduction in novel al-lergic sensitizations and reduced develop-ment of bronchial asthma, are importantreasons for an early start of SCIT duringchildhood and adolescence.


5. Indications and

contraindications

Diagnostic work-up, indication (Figure 4)and the selection of appropriate allergensshould, in general, be carried out independ-ently of the route of application (subcutane-ous or sublingual) by a physician with allergytraining within his/her specialization (derma-tology, otorhinolaryngology, pediatrics, pul-monology or internal medicine with focus onpneumology) or carrying a certified (sub)speciality in allergy.

In Austria the indication for immuno-therapy can only be made by specialized al-lergy centers (allergologic outpatient clinics)or by physicians specialized in dermatology,otorhinolaryngology, pediatrics or pulmon-ology. Accordingly, the package “initial treat-ment” can only be prescribed by these spe-cialists; “continuation treatment” can also beprescribed by a general practitioner.

In Switzerland initial treatment may onlybe carried out after prior allergologic work-up; otherwise, the health insurances can re-

fuse to meet the costs. The SGAI recom-mends that a physician or specialist withallergy training (dermatology, otorhino-laryngology, pediatrics, pulmonology) shouldcarry out the evaluation and indication. Con-tinuation treatment can also be prescribed bya general practitioner.

For the indication of SIT other therapeuticmeasures have to be taken into account (aller-gen avoidance, pharmacotherapy and educa-tion of patients). SCIT is indicated in patientswith proven clinically relevant IgE-mediatedsensitization against immediate-type aller-gens when exposure to or provocation withthese allergens causes clinical symptoms (al-lergic rhinoconjunctivitis, bronchial asthma)and allergen avoidance is not possible or notsufficiently effective (Text box 6) (A, 1a; A,1b) [1, 24, 38]. The same indication is alsovalid for SLIT (Text box 8) (B, 1a; B, 1b);there are, however, limitations concerning theselection of allergens and patients (see 5.2.).When seasonal allergic symptoms newly de-velop, the following season should be fol-lowed before SIT is indicated on the basis ofat least two anamnestically secured observa-


Figure 4. Diagnostic work-up for SIT with seasonal allergens (clinical algorithm).

tional periods. In patients with minor com-plaints who only sporadically require anti-allergic therapy the benefit of SIT has to bethoroughly weighed against its costs.

Sensitizations without clinical symptomsare no indication for SIT.

Conclusion: Diagnostic allergy work-up, indication and selection of appropriateallergens for SCIT are, in general, made by aphysician with allergy training withinhis/her specialization or carrying a certified(sub)speciality in allergy.

5.1. Indications andcontraindications of SCIT

Several variables are suspected to influ-ence the success of SCIT and thus should beconsidered when a therapy is planned (Textbox 5).

Broken down into allergen sources theindications given in Text box 6 are valid with-out limitation for SCIT with pollen allergens(A, 1b). In cases of confirmed house dust miteallergy SCIT can be carried out if measuresfor mite avoidance (mite allergen-proof mat-tress encasings, washable blankets and fur-ther measures for reduction of house dustmite allergens) are not sufficient (Figure 5)and if symptoms do not improve after 3months of mite avoidance (D, 5). A meta-analysis published in 2008 questions the effi-cacy of control measures against mites [70].In evaluated studies only 17 of 47 showed asignificant reduction of house dust mites. Inthe investigated studies the interventionalmeasures were very heterogeneous and nosubgroup analysis of children was carried out.Due to methodological deficiencies of thismeta-analysis the authors’ conclusion is notcomprehensible. Thus, the above-mentionedinterventional measures are primarily indi-cated in patients with clinically relevant al-lergy against house dust mites [90, 155]. Incases of allergies against animal dander aller-gen avoidance is the treatment of choice (D,5). If allergen avoidance is not possible, SCITwith animal dander allergens might be con-sidered in some cases (especially cat dander)(D, 5) (Figure 5). In cases of mold allergy to-tal allergen avoidance is only possible in ex-ceptional cases. Obvious allergen sources,like mold contaminations in living or workingareas, should be removed. SCIT with peren-nial mold allergens is only rarely carried out.If a seasonal mold allergy and the correspond-ing indication are present and if well-characterized extracts (Alternaria, Clado-sporium) are available, a therapy with moldallergens can be considered (B, 1b) [46, 74].

The effectiveness of SIT depends on theoptimal therapeutic dose of each clinicallyrelevant allergen. The knowledge concerningefficacy and immunologic effects of SIT ismainly based on studies in which mono-therapy with an allergen extract was carriedout. Thus, as few different allergen groups aspossible should be mixed in an allergen prep-aration used for therapy. In general, seasonaland perennial allergens are not mixed to-gether in one extract. One reason for this is toavoid an unnecessary reduction of the frac-tion of perennial allergens during pollen sea-son [17, 24, 55, 106]. Due to enzymatic reac-tions, mite and animal dander, mite and mold


Text box 6. Indications for SCIT with allergens.

– Verification of IgE-mediated sensitization (preferably* using skin testand**/or*** in vitro diagnosis) and unambiguous relation to clinical symptoms(if applicable, provocation testing).

– Availability of standardized or high-quality allergen extracts.– Proof of efficacy of the planned SCIT for the respective indication.– Allergen avoidance impossible or insufficient.

*In Switzerland, verification of sensitization preferably by skin testing; **”and” re-fers to rare allergens or diagnostically doubtful results. ***”or” refers to diagnos-tic work-up in children.

Text box 5. Success predictors* of SCIT.

– Dominating pollen allergy– No sensitization against perennial allergen sources– Narrow allergen spectrum– Short duration of disease– Minor involvement of the lower airways– Young age– Perennial treatment

*The more of these predictors apply, the higher the probability for a reduction ofsymptoms and medication use as well as for the prevention of disease progres-sion including the development of bronchial asthma and a broadening of the al-lergen spectrum (D).

Text box 7. Contraindications* for SCIT with allergens.

– Partially controlled or uncontrolled bronchial asthma (classification accordingto the current GINA recommendations 2008) as well as a moderate or severepersisting bronchial asthma (classification according to the older GINA rec-ommendations 2005) with a FEV1 of less than 70% of the predicted value de-spite adequate pharmacotherapy.

– Cardiovascular disease with increased risk of side effects after epinephrineadministration (except insect venom allergy).

– Treatment with !-blockers (local, systemic)**.– Severe autoimmune diseases, immunodeficiencies.– Malignant neoplastic diseases with current disease relevance.– Insufficient compliance.

*In justified individual cases specific immunotherapy is possible despite existen-ce of contraindications. **In Germany ACE inhibitor therapies are also sugge-sted as contraindication for insect venom SCIT.

allergens, or extracts with pollen and moldallergens (C, 5) should not be combined inone preparation.

In order to be able to make a decision forSCIT some contraindications have to be con-sidered (Text box 7). For safety reasons, apartially controlled or uncontrolled bronchialasthma (classification according to the cur-rent GINA recommendations 2008 [64]) aswell as a moderate (forced expiratory volumein the first second (FEV1) < 80% until > 60%of the expected value, Stage III) or severe(FEV1 < 60% of the expected value, Stage IV)persisting bronchial asthma (classificationaccording to the older GINA recommenda-tions 2005 [34, 63]) are contraindications forSCIT, specifically SCIT should not be used, ifthe FEV1 is lower than 70% of the expectedvalue (B, 2a) [25].

Although pregnancy is considered to be acontraindication for the start of SCIT, a con-tinuation of SCIT in cases of life-threatening

allergies against insect venom (bee, wasp) isrecommendable if the therapy is well toler-ated by the patient; SCIT with airborne aller-gens is possible when the dose is significantlyreduced (e.g., 1/10) (D, 5). For safety reasonsSCIT should not be started during pregnancy(only exception: life-threatening indication).

Clinical experience shows that the for-merly used age limit is no longer justified; anage of 50 years and older is no longer a con-traindication for SIT (D, 5). The use of !blockers (also locally applied, like ophthal-mics) under SCIT increases the risk of ad-verse airway reactions (bronchial obstruc-tion) and carries the danger that an adrenalintherapy that might me necessary in a case ofan emergency is less effective. The decisionwhether it is necessary to continue the therapywith these substances has to be made on anindividual basis.

Conclusion: SCIT is indicated in pa-tients with IgE-mediated sensitizations and


Figure 5. Diagnostic work-up for the indication of SCIT with perennial allergens.

corresponding clinical symptoms to aller-gens, which do not or insufficiently permitallergen avoidance and which are availableas suitable, efficacious extracts. Diagnosticallergy work-up, indication and selection ofappropriate allergens should only be madeby a physician with allergy training withinhis/her specialization or carrying a certified(sub)speciality in allergy (according to thetext of the guidelines). Contraindicationshave to be considered on an individual basis.

5.2. Indications andcontraindications of SLIT

In cases of allergic rhinoconjunctivitiswith seasonal allergen basis using prepara-tions for which clinical efficacy was provenin DBPC studies SLIT can be used in adults(B, 1a) (Text box 8). Particularly when SCITis not a treatment option, SLIT can be consid-ered. Reasons would, for example, be phobiaof syringes, general refusal of subcutaneousinjections, fear of (rare) systemic anaphy-lactic reactions or lacking time for therepeated injections.

When perennial symptoms caused byhouse dust mite allergens were present, SLITshowed heterogenous results so that it shouldonly be used cautiously for this indication(D). In Switzerland all physicians are allowedto prescribe SLIT by grass tablets or solutionsas long as the requirements presented in Sec-tion 5 are fulfilled.

Patients with chronic diseases of the oralmucosa are not suitable for SLIT. Further-more, apart from the use of ! blockers, con-traindications (Text box 9) are similar to thosefor SCIT . The application of SLIT in childrenand adolescents is presented in Section 7.2.

Conclusion: SLIT with efficaciousproducts is an option for adults with allergicrhinoconjunctivitis due to pollen allergens,particularly if SCIT is not suitable. In case ofhouse dust mite allergy or symptoms due toother allergen sources and allergic asthmadue to inhalants, SLIT cannot substituteSCIT.

6. Procedure of

specific immunotherapy

SIT should only be carried out by a physi-cian with allergy training within his/her spe-cialization, carrying a certified (sub)special-ity in allergy or who is skilled in these kinds oftherapy and able to deal with adverse drug re-actions (systemic allergic reactions up toanaphylactic shock, severe asthma attacks)(D, 5) [11, 24]. Before starting SIT patientshave to be informed about method and dura-tion of treatment, expected effects, possiblerisks and existing therapy options. This infor-mation should be documented (D, 5) [157].

If SIT is carried out or continued after theindication was set by another physician, aclose cooperation is essential in order to war-rant a consistent and low-risk implementationof SIT. This applies in particular to the occur-rence of adverse events; if necessary, the pa-tient has to be referred back to the same physi-cian who originally decided on the indicationfor SIT. Changing preparations during thecourse of therapy must be avoided.

If the treatment is not successful after amaximum of 2 years, it has to be critically in-vestigated and, if necessary, discontinued.For allergens like house dust mites the pa-tient’s environment has to be organized in away that warrants the least possible allergenexposure.

6.1. SCIT

Before injection the patient has to be in-terviewed for current allergic or other rele-


Text box 8. Indications for SLIT with allergens.

– Verification of IgE-mediated sensitization (preferably* using skin testand**/or*** in vitro diagnosis) and unambiguous relation to clinical symptoms(if applicable, provocation testing), particularly if treatment with SCIT is not ap-plicable.

– Availability of standardized and high-quality allergen extracts.– Proof of efficacy of the planned SLIT for the respective indication– Age of patients with grass pollen allergy # 5 years.– Age of patients preferably # 18 years****.

*In Switzerland, verification of sensitization preferably by skin testing; **”and” re-fers to rare allergens or diagnostically doubtful results; ***“or“ refers to condi-tions that impede skin testing and to diagnosis in children; ****better/more stu-dies available for adults than for children and adolescents.

Text box 9. Contraindication* for SLIT with allergens.

– Partially controlled or uncontrolled bronchial asthma (classification accordingto the current GINA recommendations 2008) as well as a moderate or severepersisting bronchial asthma (classification according to the older GINA rec-ommendations 2005) with a FEV1 of less than 70% of the predicted value de-spite adequate pharmacotherapy.

– Severe autoimmune diseases, immunodeficiencies, immunosuppression.– Malignant neoplastic diseases with current disease relevance.– Insufficient compliance.– Inflammations of the oral cavity with severe symptoms.

*In justified individual cases specific immunotherapy is possible despite existen-ce of contraindications.

vant symptoms (fever, general condition),tolerability of the last injection, current infec-tions, new or modified medication and vacci-nations, and the interval from the last injec-tion has to be checked. Confusing prepara-tions should be avoided by all means, e.g., byreading the allergen preparation and the pa-tient’s name aloud to the patient.

For injection, which is the physician’stask and should not be delegated, a 1 ml sy-ringe with graduation intervals of 0.01 mlwith an injection needle (size No. 14 – 18,short bevel) is used. The injections are carriedout strictly subcutaneously into a lifted skinfold after previous or, depending on the injec-tion volume, repeated aspiration, preferablysix inches above the olecranon on theextensor side of the upper arms and are docu-mented indicating injection site and dose. Thepatient has to stay under medical control for atleast 30 minutes after injection. The patientshould be advised to communicate all symp-toms pointing to an allergic reaction to thestaff. If a strong local reaction develops, it hasto be controlled and documented by the phy-sician, because a dose adjustment might benecessary for the following injection (seeSection 9.2.).

Shortly before and on the rest of the dayof injection augmenting factors for allergicreactions (e.g., physical exercise, sauna, alco-hol etc.) should be avoided (D, 5). The timeinterval between an SCIT injection and a vac-cination that can be planned should be 1 weekat least. Thus, vaccinations should be carriedout during the SCIT maintenance phase andadministered between two SCIT injectionswhich are applied in a 4-week interval. Vacci-nations that have to be given immediately(e.g., tetanus after injuries) can be carried outat any time. Afterwards, SCIT can be contin-ued according to the product insert or 2 weeksafter vaccination with the previouslyadministered dose.

6.2. SCIT with inhalant allergens

This therapy is mainly carried out on anoutpatient basis. For high risk patients (strongsystemic reactions, relative contraindica-tions) an inpatient start of SCIT should beconsidered.

Allergen extracts for SCIT are mainly ap-plied as depot solutions. During the escala-tion period (frequently doubling of the previ-ous dose) the therapy intervals are between 3– 7 days for aqueous solutions and 1 – 2weeks for depot solutions. If cluster or rushescalations schedules are applied, several in-jections are administered depending on theday of treatment. After the maximum toler-ated dose is reached, the injection intervals

can be increased to 4 – 8 weeks, if the productinsert permits this. In cases of seasonal aeroallergens therapy is started before the allergenseason and continued for 2 further yearspreseasonally. It can also be continued peren-nially. In this case it can be reduced during al-lergen season on an individual basis or de-pending on the extract (C, 4). For onepreparation intraseasonal updosing with agrass pollen extract up to 10,000 SQ-U with a1- to 3-day injection interval was authorizedby the PEI for Germany. After the end of pol-len season the dose can be further increased tothe maximum dose of 100,000 SQ-U with aninjection interval of 7 (– 14) days. Anintraseasonal start of SIT in pollen allergycannot be recommended because no scientificfindings concerning safety and efficacy ofsuch procedure have been published untilnow. Coseasonal SCIT (continuation duringthe respective season) without dose reductionis possible, if the product insert permits it, ifno allergic symptoms are present and ifclinical documentation is carefully carriedout.

Only half of the scheduled dose should beapplied for continuation treatment when anew lot is used (according to the product in-sert) because the biologic activity can differ.When the injection interval was exceeded, thedose has to be reduced according to the prod-uct insert. The longer the time was, the morethe dose has to be reduced. In cases of airwayallergies the duration of SCIT should at leastbe 3 years. Although controlled studies con-cerning parallel immunotherapy with two dif-ferent allergen extracts administered at thesame time are lacking, clinical experienceshows that it is beneficial to have a time inter-val of at least 15 minutes between the injec-tions (D, 5). After the last injection, theprevailing observation period of 30 minuteshas to be kept.

In patients receiving SCIT due to allergicbronchial asthma the peak flow should bemeasured before and 30 minutes after each in-jection. Furthermore, it is recommended torecord the peak flow measurements duringthe complete duration of therapy and to carryout regular lung function measurements.

Conclusion: Injections of SCIT are ad-ministered by a physician experienced inthis therapy and who is able to performemergency treatment in case of an allergicadverse event. Preceding information of thepatients is mandatory and should be docu-mented. The therapy should last 3 years.

6.3. SLIT with inhalant allergens

SLIT is carried out on an outpatient basisaccording to the product inserts enclosed by


the manufacturer. These recommendationsdeveloped by the manufacturer should becarefully adhered to, because there are sev-eral variants concerning galenics, storage andapplication of products as well as handlingthem in particular situations.

Depending on the preparation used, on themanufacturers’ instructions and on the evalu-ation of the patient’s individual tolerability,the application of the first dose should be ob-served by a physician with experience inallergology (for definition see 5.). The dropsor tablets are administered at the same time ofday to the fasted patient and applied under thetongue where they should be kept for 2 – 3minutes before the saliva is swallowed. Whenpreparations with direct allergen contact areused it can be useful to wash hands after ap-plication in order to avoid ophthalmic or nasalsymptoms by indirect carry-over of allergens[4]. During the first 5 minutes after appli-cation the patient should not drink or brushteeth.

If recommended by the manufacturer, theintroduction period with e.g. doubling of thedose is between 1 and 14 days. After this, thedrops or tablets are applied daily or every sec-ond day. Depending on the manufacturer’srecommendations no or only short introduc-tion periods exist, culminating in ultra rush ti-tration where the maximum dose is reachedon the first day after several dose increases in20-minute intervals. When lyophilized aller-gen tablets are used, an immediate adminis-tration of the maximum dose is possible sothat no dose escalation period is necessary.

After the tolerated or recommended maxi-mum dose has been reached the intervals ofadministration are kept in the original fre-quency. When febrile diseases, especially air-way infections, occur, the administration hasto be stopped and afterwards the dose has tobe increased again to the maximum dose ac-cording to the product insert. Depending onthe product insert the allergen extract forSLIT should also not be administered in thefollowing cases: acute inflammations or inju-ries of the oral or pharyngeal mucosa, surgicalinterventions in the oral cavity, acute gastro-enteritis, asthma exacerbations, reduction ofpeak flow below 70% or 80% of the personaloptimum values, simultaneous vaccinationwith an antiviral vaccine [4]. When vaccina-tions and SLIT are carried out on differentdays, it is easier to allocate side effects to therespective application. When new impairingoropharyngeal symptoms occur, the therapycan be discontinued or reduced, depending onthe extract used. The same is true for productswith seasonal allergen sources that, if neces-sary, can be reduced during season on an indi-vidual basis and depending on the preparation(C, 4). Coseasonal SCIT (continuation during

the respective season) without dose reductionis possible, if the product insert permits it, ifno allergic symptoms are present and if clini-cal documentation is carefully carried out.When the administration was discontinuedfor more than 7 – 14 days, the dose has to bereduced according to the product insert. Thelonger the time was, the more the dose has tobe reduced.

Based on the experience with SCIT forairway allergens the duration of SLIT shouldbe at least 3 years (D). The reasons for a pre-mature discontinuation of SLIT can be: badcompliance, newly developing contraindica-tions, persisting inacceptable local side ef-fects, repeated systemic reactions and miss-ing clinical reactions after 2 years [4]. Parallelimmunotherapy with two different allergenextracts should be applied at different timesof day (e.g., one in the morning, the other onein the evening) (D). Based on current dataSLIT can only be recommended for adultswhen preparations with proven efficacy areused. When treatment is continued in anothermedical practice, there should be close coop-eration with the physician who originallymade the indication, especially regardingsafety and efficacy.

Conclusion: SLIT is started by a physi-cian experienced in the therapy of allergicdiseases (see guideline wording) and who isable to perform emergency treatment in caseof an allergic adverse event. According tothe leaflet of the product manufacturer, thepatient should be informed about the ther-apy, usually lasting 3 years as pre- andcoseasonal or perennial regimen. Duringthis course consultations should take placeat least every 3 months.

7. Characteristics of specific

immunotherapy in children

7.1. SCIT in children

There are several reasons that support theindication of specific SCIT in children (C, 4):– Frequently, the disease has not yet led to

secondary alterations.– The risk for the progression of the disease

is reduced.– The risk for possible further sensitizations

is reduced.

Basically, indication in children is not dif-ferent from that in adults. However, preven-tive aspects should be considered as well.These consist of the possible prevention of aprogression of the disease (development ofbronchial asthma when rhinoconjunctivitis ispresent; A, 1b) as well as to the positive ef-


fects on the development of new sensiti-zations (B, 2b; see 4.4.). There is no generallyrecommended lower age limit: while there isin principle no age limitation in cases of po-tentially life-threatening insect venom al-lergy, SCIT against inhalants is better toler-ated when the child is at least approximately 6years old – this is due to psychological factorsrather than to immunologic reasons (D, 5).Furthermore, indication for SCIT is normallymore reliable when a child is older than ap-proximately 6 years. When an appropriate in-dication is present, the risks of SCIT in chil-dren can be considered as low. The rate ofsystemic reactions is below 0.1% ofinjections (B, 2b) [36].

Conclusion: Children tolerate the SCITwell and benefit notably from its immu-nomodulatory effects.

7.2. SLIT in children

Recent studies on SLIT in children showless methodologic deficiencies and includedhigher numbers of children [32, 33, 75, 128,151, 165]. Despite weak partial effects in sub-groups, some of these studies did not showclinically relevant efficacy of SLIT in chil-dren with the respective preparations whenselectively evaluated clinical criteria were ap-plied or when certain time points werecompared.

Two recent independent studies on tabletproducts (lyophilized orodispersible tablet,tablet based on lactose; see above) for thetreatment of rhinoconjunctivitis with concur-rent asthma have shown clinically relevantimprovement: After 4-months treatment withgrass pollen allergens symptoms and drug usein children were significantly reduced [32,165].

The long-term effects of SLIT were notplacebo-controlled [145] and the preventiveeffects with regard to asthma developmentwere only investigated in an open study[125].

Based on current data, an application ofSLIT in children and adolescents can only berecommended if efficacy is proved and ifSCIT is not possible (B, 1b). The final recom-mendation on SLIT in children and adoles-cents is postponed until further study resultsare available.

One parent should stay near the child dur-ing the intake of the preparation and shortlyafter. As the rate of side effects is relativelyhigh in the beginning of SLIT, particularly inchildren low compliance has to be suspected.It is recommended to inform the patient aboutthe risk of side effects and to follow them upmore closely.

Conclusion: SLIT can be indicated inchildren and adolescents, if SCIT is not anoption, using a preparation with provenclinical efficacy in this age group.

8. Subcutaneous

immunotherapy with

insect venom allergens

8.1. Efficacy

Between 0.8% and 5% of people are af-fected by systemic hypersensitivity reactionsafter hymenoptera stings (e.g., bee, wasp) (C,2b) [69, 156]. In children these reactions arerare and mainly mild, while in beekeepersthey occur more frequently [7, 15, 66]. Al-most all of these cases are IgE-mediated withsymptoms of an immediate-type allergy. Thereactions can be classified according to theirdegree of severity [147] that has to be consid-ered for the indication of SIT: skin symptomsonly (systemic skin reactions exceeding in-creased local reactions; Stage I), skin symp-toms and/or airway symptoms and/or drop inblood pressure and tachycardia (Stage II),bronchospasm, unconsciousness, shock (StageIII), respiratory and cardiac arrest (Stage IV).Allergies against bee and wasp venom can oc-cur independently from each other.

Between 30% and 60% of patients with ahistory of general reaction after an insectsting again develop a systemic hypersensitiv-ity reaction after the next sting (B, 3b) [21,66]. In patients with severe reactions the riskof recurrence is higher. Adulthood, repeatedstings in short time intervals, severe previousreactions and comorbidity are considered tobe risk factors [15].

SCIT is a highly effective treatment forhymenoptera venom allergies (C, 4; B, 3b)[68, 111, 115, 138] and is more effective thanSCIT in allergies against inhalants. Its effi-cacy is better for wasp venom than for beevenom allergies (C, 4) [114, 115]. With thestandard maintenance dose of 100 µg efficacyis approximately 75 – 95%; with an increaseddose (in most cases 200 µg are sufficient) effi-cacy is almost 100% (C, 4) [154]. Long-termefficacy after completion of SCIT was provenparticularly in children (A, 1b) [67].

8.2. Indication

Indication for SCIT is based on patienthistory, skin tests and in vitro examinations.Positive skin testing or specific IgE againstinsect venom without a history of systemic re-actions (e.g., exclusive occurrence of an in-


creased local reaction) is not an indication forSCIT (C, 4) [69, 156]. When severe systemicreactions occur, the indication for hypo-sensitization treatment with insect venom isobligatory (Stage III – IV; C, 2b) [15, 21, 117,138]. When systemic reactions are notlife-threatening (Stage I – II) further factorslike potential masking of more pronouncedsymptoms by early therapy, high exposure(e.g., beekeepers), increased risk of severeanaphylaxis (e.g., mastocytosis, increased se-rum tryptase), concomitant cardiovasculardiseases or psychologic factors (fear, qualityof life) have to be considered for the indica-tion [15, 21, 117, 138]. In Germany SCITwith insect venom is already indicated inStage II, independently from concomitantfactors.

In children with a systemic reaction that islimited to the skin (Stage I) hyposensitizationis only recommended in exceptional cases,because severe symptoms after a new stingare rare (C, 2b) [67, 138]. In older adults sys-temic reactions are more often severe so thatSCIT with insect venom is frequently indi-cated in those persons [15, 138].

Titrated skin tests are carried out withcommercially available bee and wasp venomextracts in the form of prick and/or intra-cutaneous testing. In case of doubt (systemicreaction despite missing skin test reaction andnegative specific IgE) diagnosis can be com-pleted by basophil allergen stimulation test(histamine release, leukotriene production,activation marker CD63 or CD203c) for indi-rect (cellular) IgE detection (C, 4). IgE anti-bodies against cross-reactive carbohydratedeterminants (CCD) that are responsible for80% of cross-reactions with unclear clinicalrelevance can make diagnosis difficult, espe-cially in atopics, due to nonspecific IgE reac-tivity against insect venom (D, 5) [15, 77].Double-sensitizations can be clarified usingthe reciprocal IgE inhibition test. In somecases diagnostic work-up with recombinantallergens can be useful [116].

At least in the case of severe reactions tostings mast cell tryptase should be analyzed,because the risk is particularly high andlife-long SCIT is recommended when serumtryptase levels are increased (> 11.4 µg/l)and/or mastocytosis is present (D, 5) [97,138].

In addition and taking into account con-traindications, the patient should be providedan “emergency kit” for self-medication withepinephrine in an autoinjector. If respiratorysymptoms have to be expected, the patientshould further have an inhalable !2-sym-pathomimetic preparation, a glucocorticoidand a H1-antihistamine (in solution or in arapidly soluble form) that can be taken orally[146].

8.3. Procedure

Therapy can be started either on an inpa-tient or on an outpatient basis. For the formerthe patient should stay in hospital for severaldays; therapy is started with aqueous com-mercial extracts using different dose increaserecommendations (C, 4) [16]. In the lattercase therapy is initially carried out in weeklyintervals. The so-called conventional rushSCIT, which is the prevailing method in Ger-many, in which the maximum dose is reachedafter several days or one week (C, 4) [159]and ultra rush methods in which the maxi-mum dose is reached within 2 – 3 days (C, 4)[28, 29, 49] have to be started on an inpatientbasis and have the advantage that the mainte-nance dose is reached early having a corre-sponding protective effect which is especiallybeneficial during the insect season and incases with severe reactions.

Subsequently, therapy is continued withan (authorized) aqueous or depot preparationapplying a maintenance dose of 100 µg of in-sect venom extract, the injection intervals areincreased to 4 weeks (C, 4) [138]. In cases ofbee and wasp venom allergy in which the pa-tient is highly exposed to the allergens or issubject to an increased risk for severeanaphylaxis a maintenance dose of 200 µg isrecommended (B, 2b) [138].

Furthermore, in Switzerland ultra rushprocedures with a duration of approximately4 hours are carried out to start therapy [80,144, 152] either on an inpatient or on an out-patient basis. The subsequent after-treatmentwith the maintenance dose is carried out ac-cording to the usual schedules in 4- to 6-weekintervals.

8.4. Duration of therapy,tolerability and monitoring

SCIT with insect venoms is carried out forat least 3 or ideally 5 years (A, 1b) [65, 138,153]. If a high exposure or an increased indi-vidual risk for severe reactions (guideline oninsect venom allergy [138]) is present, itshould be carried out even longer. In patientswith extremely high risks (e.g., mastocytosis)a longer and sometimes even life-long SCITare recommended (D, 5) [65, 138]. Discon-tinuation of SCIT with insect venoms shouldbe decided on an individual basis; details havebeen presented extensively [21, 117, 138].

For SCIT with bee venom systemic sideeffects have been observed more frequentlythan for SCIT with wasp venom (D, 5) [27,171].

Therapy failure can be demonstrated by acontrolled sting under clinical conditions. For


sting provocation, ideally carried out 6 – 12months after start of treatment, individual riskfactors have to be considered, because a miss-ing protection would result in an increasedrisk when the patient is stung by an insect inthe future. Apart from sting provocation thereare generally no accepted parameters forevaluating therapeutic success at the moment.Concerning this topic we refer to the currentDGAKI guideline [138].

If no adequate protection can be obtainedunder 100 µg of insect venom, the mainte-nance dose should be increased from 100 µgto 200 µg (A, 1b) [153]. Also for patients withbee venom allergy and high exposure (e.g.,beekeepers) or increased risk for severeanaphylaxis (e.g., mastocytosis) an increaseddose is recommended (D, 5) [138, 153]. If af-ter treatment there is again a systemic reactionafter an insect sting, SCIT should be startedagain [138].

Conclusion: In case of systemic reac-tions due to hymenoptera (bee, wasp)venom hypersensitivity, SCIT has excellentefficacy and should be continued for at least3 – 5 years. An extended, sometimes life-long SCIT is necessary in some patients.

9. Safety, risk factors and

adverse events

9.1. Safety and risk factors inSCIT

Severe, life-threatening systemic reactionsare very rare, i.e., they occur in less than 1 of10.000 cases (classification according toguideline “Summary of Product Characteris-tics (SPC)”: very frequent # 10%, frequent #1% to < 10%, occasional # 0.1% to < 1%, rare# 0.01% to < 0,1%, very rare < 0.01%; A, 1a)[98]. On the basis of data provided by the PEI(1991 – 2000) an incidence of 0.002 –0.0076% (of injections) for non-modified al-lergen extracts and of 0.0005 – 0.01% forchemically modified allergen extracts(allergoids) was calculated (C, 4) [96]. Dataobtained in the context of authorization exten-sions between 2001 and 2005 do not indicatechanges in the incidence of severe adverseevents as compared to data published in 2001[Lüderitz-Püchel, PEI, personal communica-tion]. When risk factors are considered (A, 1a)[98] severe reactions are sometimes foresee-able and avoidable by caution and prophylaxis(Text box 11) (D, 5). If severe reactions de-velop, they mainly occur as severe bronchialobstruction and only rarely as anaphylacticshock (A, 1a) [98]. In particular, severe reac-tions can occur in cases of asthma exacerba-tion, simultaneous administration of !-blockers, inappropriate dose increase (e.g., de-spite adverse events when the previous injec-tion was administered), non-observance of the30-minute waiting period or subsequent circu-latory stress (Text box 11) (A, 1a) [25, 98]. Incases of repeated insufficient compliance (e.g.,patient does not stay long enough in the doc-tor’s office, interval is exceeded, inappropriatephysical strain or avoidable allergen contactshortly before or after injection) the treatmentshould be discontinued.

When adverse reactions occur premedi-cation with an antihistamine is possible (B,2b) [30, 144]. Nevertheless, systemic reac-tions cannot be excluded.

9.2. Side effects of SCIT

When increased local reactions (rednessand/or swelling > 10 cm in diameter) at the in-


Text box 11. Risk factors for SCIT.

– Current allergy symptoms and potential allergen exposure.– Unstable or insufficiently treated asthma (FEV1 less than 70% of the predicted

value).– High degree of sensitization.– Inadequate dose increase during induction therapy.– Drug use (!-blockers).– Inadequate circulatory stress, physical exercise, sauna (shortly before and for

the rest of the day of injection augmenting factors should be avoided).– Inadequate technique of injection.– Allergen extract overdose.– Manufacturer’s recommendation for dose reduction in case of changing to a

new package (production batch) was overlooked.

Text box 10. Open questions concerning SLIT* (modified according to [168]).

– Optimal single or cumulative dose**? Frequency of application** and durationof treatment? Identical for all allergens – seasonal or perennial?

– Magnitude of symptomatic improvement compared to SCIT?– Modified immune response by SLIT? Long-lasting, persisting effect of treat-

ment? Course after withdrawal of active treatment?– Safety profile for routine practice?– Influence of co-factors on safety (e.g., application of !-blockers)?– Compliance in controlled trials comparable to compliance in routine applica-

tion at home over a period of 3 years?– Reasons for less convincing proof of efficacy in children**?

*Some of these questions are also applicable for SCIT products. **For certainproducts (grass pollen allergen tablets) these questions cannot be applied orhave already been answered in controlled studies.

jection site occur, it is recommended not to in-crease the dose or to go back – according tothe product insert – to a dose that was alreadytolerated before it is increased again (D, 5).Delayed (6 – 12 hours) increased local reac-tions do not represent an increased individualrisk for systemic reactions [82].

When systemic reactions occur, the deci-sion for continuation or discontinuation of thetherapy should be made by an allergologisttaking into consideration the risks of continu-ation, the urgency of indication and treatmentalternatives. For this purpose the patient hasto be referred to the physician who initiallymade the indication for SCIT if necessary.Possible reasons for the systemic reaction(e.g., additional allergen exposure, drug in-take, infections, physical strain, other stresssituations or diseases) should be analyzed andavoided for future allergen injections. If thetherapy is continued the dose should neces-sarily be significantly reduced by at least 2 – 3stages (when the dose was doubled before) orto 1/4 – 1/8 of the last dose taking intoconsideration the product insert of therespective preparation (D, 5).

Circulating immune complexes can de-velop during the course of SCIT; their clinicalrelevance, however, remains unclear (C, 4).The frequency of granulomas depends on theextract or on the method of application (e.g.,not deep enough subcutaneously) (B, 2c)[164, 171] and can rather be attributed to for-eign body reactions (C, 4) [59].

Conclusion: Severe, potentially life-threatening systemic adverse events can oc-cur after SCIT, being very rare in case ofcomplete adherence to safety standards.Most adverse events are mild to moderateand easily treatable.

9.3. Safety, risk factors and sideeffects in SLIT

Side effects in SLIT depend on the doseand appear, depending on the preparation, astemporary local mucosal reactions (pruritusor dysesthesia in the oral cavity, swelling ofthe oral mucosa, throat irritation) in 30 – 70%of affected patients. These side effects aremainly mild and diminish in a period of 1 – 3weeks after start of therapy. Nevertheless, dueto their anatomic localization pronounced lo-cal reactions can be potentially life-threaten-ing (e.g., uvular or laryngeal edema).

Based on present experience the risk forsevere adverse events in SLIT is lower than inSCIT [96]. While for SCIT there is a very lowrisk for anaphylactic potentially life-threaten-ing reactions (0.0004% per injection; data of1981 – 2000 [96]), this was not assumed ac-

cordingly for SLIT, and the frequency ofsevere non-life-threatening reactions was in-dicated with 0.0011% of intakes, this numbersumming up several studies [6].

An analysis of severe adverse events dur-ing SLIT showed 1 reaction in 285 patients(0.35%) or 1.4 reactions in 100,000 adminis-trations (0.0014%), respectively. Very fewcase reports, with varying documentationquality, on systemic or anaphylactic reactionsduring SLIT have been published. It has to betaken into account that in most of these casespolysensitized patients with allergic bron-chial asthma were affected. Furthermore,gastrointestinal symptoms during SLIT canoccur in up to 30% of patients [6]. Post-marketing observations for a grass pollenproduct (lyophilized orodispersible tablet)show that severe adverse events are rare (4 se-vere adverse events in 4,500 sold packings)and occur mainly in the form of swellings ofthe tongue or asthma exacerbation (ALK-Abelló, drug safety; data on file). Pre-medication with non-sedating antihistaminesis potentially apt to reduce the degree of localreactions (D, 5). It must, however, be consid-ered that allergen intake is carried out withoutsupervision by a physician and thus side ef-fects cannot be treated immediately. There-fore, the patient should receive simple, easilyunderstandable instructions on how to behavein the case of adverse events and be urged tocall a physician as soon as possible whensystemic reactions occur.

Based on present data the risk factors forsevere allergic reactions during SLIT are thesame as for SCIT: uncontrolled allergicasthma and polysensitization. It remains to beanalyzed to which extent augmentation fac-tors for anaphylaxis, like physical strain, ex-cessive alcohol consumption, infections and!-blockers, are also relevant in SLIT. If se-vere reactions develop, they mainly occur asbronchial obstruction.

Conclusion: Apart from very frequentlyto frequently occurring dose-dependent un-wanted local oral and pharyngeal symp-toms, systemic reactions, mostly of mild na-ture, have rarely been described after SLIT.With regard to anaphylactic and other se-vere systemic reactions SLIT demonstratesa superior safety profile compared to SCIT.

10. Emergency therapy

Systemic reactions after SIT occur mainlywithin the first 30 minutes after allergen ap-plication. Therefore, in the case of SCIT, pa-tients have to be monitored under medical re-sponsibility for at least 30 minutes afterinjection and should report any symptom that


could point to an allergic reaction. Systemicreactions can begin within a few minutes afterinjection. Due to the risk of rapid aggravationthey must be treated immediately (D, 5)[146]. Thus, the responsible staff has to be fa-miliar with the handling of obligatory drugs(D, 5) [87] and equipment for an allergologicemergency (D, 5) [146]. First measures in-volve the adequate positioning of the patient,epinephrine (i.m.), an infusion therapy via alarge-bore intravenous access site and the ad-ministration of O2. Attending physician andpractice team have to be trained in cardio-pulmonary resuscitation. Epinephrine is es-pecially useful for the therapy of anaphylacticreactions so that an early administration shouldbe considered. If applicable, autoinjectors fori.m. injection can be used.

Systemic reactions have to be recognizedearly and treated immediately. The signals forlife-threatening side effects involve burningsensation and pruritus of palms and soles,sneezing attacks, generalized pruritus of theskin and generalized urticaria, swelling oftongue and larynx/pharynx, dyspnea, tachy-cardia, bradycardia, nausea and hypotonia.Mainly skin symptoms and pruritus are thefirst symptoms that occur. Symptoms can de-velop consecutively. Occasionally, biphasiccourses have been observed.

Due to ethical reasons hardly any con-trolled studies concerning therapeutic recom-mendations for the emergency treatment areavailable. Clinical experience and consider-ations based on pathophysiologic relationshave led to the guideline for the acute therapyof anaphylactic reactions [146] which was re-vised by the respective scientific medical so-cieties and which is also valid for the acutetherapy of a SIT emergency.

These recommendations are also valid foranaphylactic reactions occurring during SLIT.

When Stage IV anaphylactic reactions oc-cur, the recommendations for cardiopulmo-nary resuscitation published by the GermanMedical Association (www.aerzte blatt.de/v4/archiv/artikel.asp?src=suche&id=50906oder www.inm-online.de/pdf/Wis sen/Reani-mation/deutsches_aerzteblatt.pdf) based onthe German translation [53] of the interna-tional guideline published by the EuropeanResuscitation Council (ERC; www.erc.edu)[52] and available via the German Interdisci-plinary Organization for Intensive Care andEmergency Medicine (DIVI) (www.divi-org.de/Leitlinien-des-European-Resusc.49.0.html)are valid.

Conclusion: Risk factors for and resultsof unwanted systemic effects can effectivelybe minimized by training the staff membersinvolved, adhering to safety standards andimmediate emergency treatment.

11. Future prospects

Despite the success achieved, innovationsand advancements are desirable in order to in-crease the efficacy of SIT, particularly forspecial, complex allergen sources, to lowerthe rate of side effects and to raise patients’compliance. Some approaches seem to be ofparticular interest and thus, several of themare clinically tested (Phase I/II):– Diagnostic work-up and monitoring: re-

combinant allergens, so-called marker al-lergens, could turn out to be valuable in-struments for facilitating patient selectionfor SIT and permitting documentation ofthe immune response to the administeredpreparation (immune monitoring).

– Optimization of application without in-jections: development of mucosal toler-ance by higher allergen doses, improvedgalenics or addition of specific adjuvantsseems to be possible. This opens up newperspectives for oral or local routes ofapplication.

– Accelerated dose increase: like in SCITwith insect venom allergens, the dose canalso be increased more quickly in case ofinhalants. Some SLIT protocols alreadystart with the maximum dose. Allergenmodification e.g. by formaldehyde orglutaraldehyde (allergoidization) allowsfor a quick dose increase.

– Allergen characterization: the use of puri-fied or biotechnologically manufacturedand molecularly characterized allergenswould allow for the composition of opti-mized allergen preparations containingthe allergens that are most important forthe respective therapy. Particularly in thecase of complex allergen mixtures, likemolds or food, it is possible to manufac-ture preparations that could not be pro-duced by extraction only. In addition, it iseasier to maintain the same qualitystandards.

– Improved efficacy: by identifying the mo-lecular mechanisms of SIT new opportu-nities for therapy optimization by combi-nation of allergens and allergen extractswith newly identified immune modulatorswill open up. These molecules frequentlyare of microbial origin and interact at theinterface between native and acquired im-munity; they are either toll-like receptoragonists or so-called nonspecific immunemodulators.

– Less side effects: the combination of aller-gens with other molecules like in the caseof the additional use of anti-IgE or the de-velopment of allergen fragments, foldingvariants or multimeres from allergensopens up new therapy options with poten-tially less side effects. Combining subcu-


taneous allergen application with anti-IgE(omalizumab) can possibly increase thesafety and efficacy of SCIT in allergicrhinoconjunctivitis. Due to economicconsiderations, this combination wouldonly be taken into account for individualcases (D, 2b) [89, 91, 150], particularlysince anti-IgE is not authorized for thispurpose at the moment. The scientificevaluation of this combination seems tobe interesting in cases of allergicbronchial asthma.

– Use of SCIT or SLIT for allergy preven-tion: studies have proven that SIT pre-vents further sensitization and the devel-opment of asthma. Further analyses, alsoinvolving other preparations, have to becarried out to prove this potentially inter-esting indication.

Conclusion: Various research fields likeallergen characterization, routes of applica-tion, adjuvants, updosing regimen and pre-ventive aspects demonstrate new develop-ments in SIT being currently examined forclinical efficacy.

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PD Dr. Jörg Kleine-TebbeAllergy & Asthma Center WestendOffice Hanf, Herold and Kleine-TebbeSpandauer Damm 130, Haus 9D-14050 Berlin, Germanye-mail: [email protected]

Acknowledgment

The authors and contributing medical andprofessional societies gratefully acknowl-edge the translation of this guideline – origi-nally published in German – by Ms. VeronikaLuger (Dustri-Verlag; Dr. Karl Feistle GmbH& Co. KG; Deisenhofen-Munich, Germany)and final proof reading by Mrs. Sophie Wirth(Clinical Research Center for Dermatology,Allergy & Asthma, UZDAA, Berlin, Ger-many). For careful review of the translatedguideline we gratefully acknowledge Dr.Miya O. Paterniti, MD, and Prof. Dr. Peter S.Creticos, MD (Division of Allergy and Clini-cal Immunology, Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA).


s pecific immunotherapy (hyposensitization) for ige ......former gina guidelines, 2005) and is recom...

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