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Sub-lingual Immunotherapy: World Allergy Organization Position

Paper 2009

Chair: G Walter Canonica

CoChairs:Jean Bousquet, Thomas Casale, Richard F Lockey, Carlos E Baena-Cagnani, Ruby Pawankar,

Paul C Potter

Authors:Philippe J Bousquet, Linda S Cox, Stephen RDurham, Harold S Nelson, Giovanni Passalacqua, Dermot P

Ryan, Jan L Brozek, Enrico Compalati, Ronald Dahl, Luis Delgado, RoyGerth vanWijk, Richard GGower,Dennis K Ledford, Nelson Rosario Filho, Erkka J Valovirta, OsmanMYusuf, Torsten Zuberbier

Co-Authors:

Wahiduzzaman Akhanda, Raul Castro Almarales, Ignacio Ansotegui, Floriano Bonifazi, Jan Ceuppens,Tomas Chivato, Darina Dimova, Diana Dumitrascu, Luigi Fontana, Constance HKatelaris, Ranbir Kaulsay,

Piotr Kuna, Desiree Larenas-Linnemann, Manolis Manoussakis, Kristof Nekam, Carlos Nunes, RobynO’Hehir, Jose M Olaguibel, Nerin Bahceciler Onder, JungWon Park, Alfred Priftanji, Robert Puy, Luis Sar-miento, Glenis Scadding, Peter Schmid-Grendelmeier, Ester Seberova, Revaz Sepiashvili, Dirceu Sole, Alkis

Togias, Carlo Tomino, Elina Toskala, Hugo Van Beever, Stefan Vieths*

Acknowledgement

World Allergy Organization acknowledges Ronald LRabin for reviewing this Position Paper. Ken Rainey,Medical Writer, and Karen Henley, WAO Global ProjectDirector, are acknowledged for their assistance in editingand co-ordinating the manuscript.This supplement is co-published as an article: Canonica

GW,Bousquet J, Casale T, LockeyRF, Baena-Cagnani CEet al. Sublingual Immunotherapy: World Allergy Organi-zation Position Paper 2009. World Allergy OrganizationJournal, 2009; 2(11):233-281. www.WAOJournal.org

Societies/Organisations Attending the Paris Meeting

Regional Member Societies

Asia Pacific Association of Allergology and ClinicalImmunology.

Commonwealth of Independent States (CIS).European Academy of Allergy and Clinical Immunology(EAACI).Latin American Society of Allergy and Immunology.

Affiliate Member Societies

Interasma (International Association of Asthmology).

National Member Societies

AlbanianSociety ofAllergology andClinical Immunology.Allergy Society of South Africa.AmericanAcademyofAllergy,AsthmaandImmunology.AmericanCollege ofAllergy, Asthma and Immunology.Argentine Association of Allergy and Immunology.Australasian Society of Clinical Immunology and Allergy.Bangladesh Society of Allergy and Immunology.Belgian Society of Allergology and Immunology.Brazilian Society of Allergy and Immunopathology.British Society for Allergy and Clinical Immunology.

Allergy 2009: 64 (Suppl. 91): 1–59 � 2009 The AuthorsJournal compilation � 2009 World Allergy Organization

ALLERGY

1

Correspondence: G. Walter Canonica, MD, Allergy and RespiratoryDiseases, DIMI, Department of Internal Medicine, University ofGenoa, Largo Rosanna Benzilo, Genoa 1-16132, ItalyEmail: [email protected]

Bulgarian National Society of Allergology.China Allergology Society and Chinese Allergists.Cuban Society of Allergology.Czech Society of Allergology and Clinical Immunology.Finnish Society ofAllergology andClinical Immunology.French Society ofAllergology andClinical Immunology.GermanSocietyforAllergologyandClinicalImmunology.*HellenicSocietyofAllergologyandClinical Immunology.HungarianSocietyofAllergologyandClinicalImmunology.ItalianAssociation of Territorial andHospital Allergists.Italian Society forAllergology andClinical Immunology.Japanese Society of Allergology.Korean Academy of Allergy, Asthma and ClinicalImmunology.Malaysian Society of Allergy and Immunology.Mexican College of Clinical Immunology and Allergy(CMICA).Mexican College of Clinical Immunology and Allergy(CMICA).Mexican College of Pediatricians Specialized in Allergyand Clinical Immunology.Portuguese Society of Allergology and Clinical Immunol-ogy.RomanianSocietyofAllergologyandClinicalImmunology.Singapore Society of Immunology, Allergy and Rheuma-tology.Spanish Society ofAllergology andClinical Immunology.Swiss Society of Allergology and Immunology.Singapore Society of Immunology, Allergy & Rheumatol-ogy.Turkish National Society of Allergy and ClinicalImmunology.Venezuelan Society of Allergy and Immunology.

Contributing Non-Member Society

Southern European Allergy Society.

Non-Governmental Organizations

Allergic Rhinitis and Its Impact on Asthma (ARIA).European Federation of Allergy and Airway DiseasesPatients Association (EFA).International Primary Care Respiratory Group (IPCRG).Global Allergy and Asthma European Network(GA2LEN).National Institutes of Health (NIH).

Ratification by WAO Member Societies not attending theParis meeting

Approved by:

Colombian Allergy, Asthma, and Immunology Associa-tion.

Egyptian Society of Allergy and Clinical Immunology.Egyptian Society of Pediatric Allergy and Immunology.Icelandic Society of Allergy and Immunology’’.IndianCollege ofAllergy,Asthma andApplied Immunology.Mexican College of Allergy, Asthma and Clinical Immu-nology.Mongolian Society of Allergology.Norwegian Society of Allergology and Immuno-pathology.Peruvian Society of Allergy and Immunology.RussianAssociationofAllergologyandClinical Immunology.Allergy and Immunology Society of Thailand.

Abbreviations

AAAAI: American Academy of Allergy and Clinical ImmunologyACAAI: American College of Allergy and Clinical ImmunologyADR: Adverse Drug ReactionAE: Adverse EventAMP: Adenosine MonophosphateARIA: Allergic Rhinitis and its Impact on AsthmaAUC: Area Under CurveBHR: Bronchial HyperresponsivenessCHMP: Committee for Human Medicinal ProductsCIS: Commonwealth of Independent StatesCMD: Cumulative Monthly DoseCONSORT: Consolidated Standards of Reporting TrialsDBPCFC: Double-blind placebo-controlled food challengeDBPC-RCT: Double-blind, placebo-controlled – randomized clinical

trialEAACI: European Academy of Allergy and Clinical ImmunologyEBM: Evidence-Based MedicineECP: Eosinophil Cationic ProteinEFA: European Federation of Allergy and Airway Diseases

Patients AssociationEMEA: European Medicines AgencyEU: European UnionFDA: (US) Food and Drug AdministrationFeNO: Fraction of exhaled Nitric OxideFEV1: Forced Expiratory Volume in One SecondFVC: Forced Vital CapacityGA2LEN: Global Allergy and Asthma European NetworkGP: General PractitionerGRADE: Grading Recommendations, Assessment, Development

and EvidenceHCP: Health Care ProfessionalHDM: House Dust MiteICAM-1: Intercellular Adhesion Molecule-1ICER: Incremental Cost-Effectiveness RatioIDO: Indoleamine 2,3-dioxygenaseIg: ImmunoglobulinIL: InterleukinInterasma: International Association of AsthmologyIPCRG: International Primary Care Respiratory GroupIT: ImmunotherapyLLR: Large Local ReactionsMedDRA: Medical Dictionary for Regulatory ActivitiesMHC: Major Histocompatibility ComplexmRNA: Messenger Ribonucleic AcidNIH: National Institutes of HealthPAT: Preventive Allergy Treatment (study)PEF: Peak Expiratory Flow

2 � 2009 World Allergy Organization

G. Walter Canonica

QoL: Quality of LifeRCT: Randomised Controlled TrialRQLQ: Rhinoconjunctivitis Quality of Life QuestionnaireSAE: Serious Adverse EventSCIT: Subcutaneous ImmunotherapySCORAD: Score in Atopic DermatitisSCUAD: Severe Chronic Upper Airway DiseasesECP: Serum Eosinophil Cationic ProteinSIT: (allergen-) Specific ImmunotherapySLIT: Sublingual ImmunotherapySMD: Standardized Mean DifferencesSPT: Skin Prick TestSR: Systemic ReactionT regs: Regulatory T CellsTGF: Transforming Growth FactorTh: T Helper cellsVAS: Visual Analogue ScaleWAO: World Allergy OrganizationWHO: World Health Organisation

Preface

Sublingual immunotherapy (SLIT) has gained wide accep-tance in many European countries and has raised the levelof interest in immunotherapy among practicing allergistsand primary care physicians. Large pivotal double-blind,placebo-controlled, randomized clinical trials have con-firmed the efficacy and safety of SLIT, although somenegative trials have also been published. In 2008, theWorldAllergy Organization (WAO) Board of Directors decidedthat it was important and timely to advise our globalconstituents on the current State of theArt onSLIT, to offerconsensus on its use based on currently available evidenceand expert opinion, and to develop practice parameters.Unmet needs would be identified by analysis of recent andongoing SLIT clinical trials, then recommendations forfurther studies needed, and suggestions for the appropriatemethodology to conduct them, would be offered.To ensure a truly global consensus on SLIT, a meeting

was held on 22 - 23 January 2009 in Paris, France. WAOinvited its Regional, National and Affiliate MemberSocieties to participate actively by sending representativesto the meeting. Non-Governmental Organizations work-ing in the field of allergy were also invited to attend, andARIA, EFA, IPCRG, Interasma, GA2LEN et al wererepresented.Themeeting and its outcomes remain totally independent

from the interest/influence/funding of the pharmaceuticalor the allergen extract/vaccine industry.

Regulatory Perspective

Historical perspective:

Before the 1980s there was no allergen standardization;this resulted in marked variations in allergenic strength

among allergen vaccine batches produced in differentphases.

Until 1991 allergen vaccines were considered ‘‘Galenic’’drugs, because they were prepared upon request of thephysician for a specific patient. Specific immunotherapywas administered through the injective route only, and theavailable allergen preparations were used both in diagnosisand therapy. Most firms produced batches of ready-to-prepare extracts and the final phase of production consistedof matching the name of a patient with a specific pre-prepared vaccine. Leading up to 1991, the companies activein the allergen manufacturing sector noticed that physi-cians had changed their prescribing patterns, and were nowrequesting single specific allergens for immunotherapy,rather than the allergen mixtures that had previously beensupplied.

In the 1990s, when sub-lingual immunotherapy firstappeared on the market, the available vaccines for SLITwere only single allergen preparations, as required by thefirst guideline in this field. It immediately became evidentto the regulatory authorities that documents pertaining tothe production of allergens and their standardizationmethod were needed; it is important not only to prepareextracts that are always equivalent between differentbatches, but also to prepare an initial reference extract(the standard extract) which is allergenically/biologicallyactive, to provide a comparison with subsequent produc-tion batches.

Current situation

According to Guideline 2001/83/EC, allergens are immu-nological medicinal products and therefore, in general,require a marketing authorization. However, in severalcountries national regulations are implemented that stillallow marketing of allergen products as ‘‘named patientpreparations’’ (NPPs) without a marketing authorization.For example, in Germany it has been estimated thatapproximately 50% of the market for allergen productsare NPPs. This market segment includes the majority ofallergen products for SLIT.

From the regulatory point of view, there is no differencebetween allergen products for SLIT and SCIT. By contrasta clear difference exists between the requirements onnaturalallergen extracts versus recombinant allergens, in particularregarding acceptance criteria for product quality (1–3). InGermany, four products for SLIT were authorized up tomid-2009, while more than 200 allergen products for SCIThad a marketing authorization. Of the SLIT products, onegrass pollen allergen tablet successfully passed a mutualrecognition procedure and is available in themajority ofEUcountries.

Recent Phase III clinical trials performed with two grasspollen tablets involved hundreds of patients in each trialand were performed according to an adequate DBPC-RCT design. These studies and others showed that

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Sub-lingual immunotherapy

particularly for SLIT, parameters such as determinationof an adequate pre-treatment period in seasonal rhino-conjunctivitis trials, and exploratory studies for determi-nation of the dose resulting in the most favorablerisk:benefit ratio, are of major importance. A recentWAO statement (4) and the EMEA Guideline (5) definefor the first time the regulatory requirements for clinicaltrials in SIT, and will lead to improved harmonization ofassessments by regulatory agencies of data obtained fromclinical trials.Increased availability of authorized allergen products

with proven quality, safety and efficacy will lead to animproved benefit for allergic patients and may alsoimprove the general acceptance of SIT as an establishedtreatment by regulatory agencies.Sub-lingual vaccines appear to have heralded a new

era in specific allergen desensitization; because of theirefficacy and safety, they have been considered eligiblefor submission for registration by many regulatoryauthorities. New products registered for respiratoryallergopathologies approach this pathology in an etio-logic way; they may act as real biological modifiers, andhave long-lasting effects. This benefit is interesting notonly clinically, but also in terms of their pharmaco-economic profile.

Why sub-lingual immunotherapy vaccines should belicensed

For the physician

• The prescription of non-authorized products weak-ens the role of the allergy specialist, and may havecontributed to the current paucity of allergy spe-cialists available to treat the estimated figure of 20%of the world population that suffers from allergies.

• The prescription of products not sold in pharmaciescreates difficulties for the global management ofvaccines (from the point of ordering, up to receiptand storage).

For the patient

• The use of products, which are not distributedin pharmacies weakens, the credibility of the productitself; it precludes any patient interaction with thepharmacist (a traditional counselor of patients) andweakens the image of the product, which has to beused for years.

• An authorized pharmaceutical product offers thepatient more guarantees, consequently increasingcompliance with treatment (at present only 30% ofvaccinated patients complete at least 3 years oftreatment in accordance with the recommendedguidelines for duration of therapy).

For the industry

• A non-regulated sector makes possible the use of‘‘low quality’’ products, and fails to give adequaterecognition to the ethical manufacturers who con-duct scientific research and employ good manufac-turing practices. A more regulated sector attracts theincreasing interest of ethical and qualified investors.

For the regulatory agencies

• Marketing of non-regulated products precludescorrect pharmacovigilance and, in consequence,precludes all the activities connected with an openand transparent dialogue among the stakeholders,eg, pre- and post-registration clinical trials, profes-sional training, and congress activities.

References, Preface1. Lorenz AR, Luttkopf D, Seitz R, Vieths S. The regulatory system

in Europe with special emphasis on allergen products. Int ArchAllergy Immunol. 2008;147:263–275.

2. Guideline on Allergen Products: Production and Quality Issues.EMEA, CHMP/BWP/304831/2007 adopted by CHMP Novem-ber 20, 2008.

3. European Pharmacopoeia 6.6, Allergen Products, 01/2010/1063.4. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ,

Lockey RF, Malling HJ, et al. Recommendations for standard-ization of clinical trials with Allergen Specific Immunotherapy forrespiratory allergy. A statement of a World Allergy Organization(WAO) taskforce. Allergy 2007;62:317–324.

5. Guideline on the Clinical Development of Products for SpecificImmunotherapy for the Treatment of Allergic Diseases. EMEA,CHMP/EWP/18504/2006, adopted by CHMP November 20,2008.

Chapter 1: Introduction and

historical background to

sublingual immunotherapy

• Subcutaneous immunotherapy (SCIT) currentlyrepresents the standard immunotherapy modality,with well ascertained clinical efficacy.

• The first SLIT randomized double-blind, placebo-controlled trial (DBPC-RCT) was published in1986. The rationale proposed for SLIT was toimprove the safety and to make the treatment moreconvenient.

• The first DBPC-RCT trial with tablets was publishedin 1986.

• SLIT was firstly accepted as a viable alternative toSCIT in the WHO position paper, published in 1998,and then included in the ARIA guidelines.


G. Walter Canonica

• Since 1986, 60 DBPC-RCT trials have been pub-lished.

• The available meta-analyses are in favour of SLIT(rhinitis in adults, asthma and rhinitis in children),although the conclusions are limited by the greatheterogeneity of the studies.

• Adequately powered, well-designed DBPC-RCTsinvolving hundreds of patients, published in the last3 years have clearly confirmed the efficacy and thedose dependent effect of SLIT for grass allergens inboth adults and children.

Allergen-specific immunotherapy (SIT), or allergen vac-cination is the practice of administering to allergicsubjects increasing amounts of allergen(s) (the allergenicextract or vaccine) to achieve hyposensitization, that isto reduce the symptoms occurring during the naturalexposure to the allergen(s) itself. The history of SITbegan in first years of the twentieth century, based onthe idea of the vaccination against infectious agents. Infact, Leonard Noon (1) aimed at achieving a vaccina-tion against �airborne toxins�, and for this reason hechose the subcutaneous route of administration.Although the theoretical background was incorrect,SIT was immediately found to be effective in reducingsymptoms of hay-fever, its use spread rapidly, and thesubcutaneous route (SCIT) remained therefore thestandard practice.Indeed, the idea of administering the allergenic extracts

via non injection routes is not as recent as commonlybelieved. The first descriptions of the �oral� route ofadministration also appeared in the early 1900s (2) andthe first clinical attempts with this administration werecarried out only few years later (3, 4). Subsequently,other routes of administration were proposed, that is,local bronchial during the 1950s (5, 6) and local nasal (7,8) during the 1970s. The overall rationale of theseattempts was of course that of finding a safer and moreconvenient route of administration for SIT. Those routeshave been variously named, that is, alternative, non-parenteral, non-injection or local routes. Presently, it isagreed that the most proper terms are local and non-injection, which are equivalent; whereas the word alter-native has been abandoned since it might generateconfusion with other unconventional medicines. The oralroute was investigated in several clinical trials performedduring the 1980s (9–12), but the clinical results werecontroversial and, in some cases, important gastrointesti-nal adverse events were reported. For these reasons, oraladministration was gradually abandoned. In 1986, theBritish Committee for the Safety of Medicines (13)reported several deaths caused by SCIT, and raisedserious concerns about the safety and the risk/benefitratio of SIT, also because cheaper and effective drugs(e.g. oral H1-antihistamines and topical corticosteroids)

had become available for the treatment of respiratoryallergy. In this scenario, the interest in non-injectionroutes of IT increased again (14), and in 1986 the firstrandomized controlled trial with the sublingual route(SLIT) was published (15). This study was conductedwith very low doses of a mite extract. The original ideasupporting SLIT was to achieve a prompt absorption ofthe vaccine through the sublingual mucosa as happens,for instance with nitroglycerine or nifedipine. Indeed, tenyears later, biodistribution studies with radiolabelledallergens in humans (16, 17), consistently showed thatthe direct absorption of the extract through the oralmucosa is absent or negligible, and that the clinical effectshould be rather ascribed to the interaction of theallergen with the mucosal immune system. Nonetheless,from a clinical point of view, SLIT was confirmed to beeffective in several controlled studies utilizing either dropsor tablets (18, 19), and the first paediatric study appearedin 1990 (18).

In the subsequent years, the number of DBPC-RCTsof SLIT rapidly increased, and SLIT began to bementioned in official documents. In 1993 the EuropeanAcademy of Allergy and Clinical Immunology (EAACI)stated in its position paper that SLIT could be regardedas a �promising route� for desensitization (14). Five yearslater, the World Health Organization (WHO), based onthe results of 8 DBPC-RCTs, stated that SLIT �may beconsidered as a viable alternative to the injection routein adults� (20). In the same year, EAACI produced aposition paper on non-injection routes, stating thatthe use of SLIT in clinical practice is justified because ofthe ascertained efficacy and the favourable safety profile(21). In 2001, the ARIA position paper accepted the useof SLIT in adults and children, as a valid alternative toSCIT (22) and this was confirmed by the ARIA updatein 2008 (23). In SLIT, the allergen extract (preparedas drops or tablets) is kept under the tongue for1–2 minutes and then swallowed: thus this route is alsocalled sublingual-swallow. In some studies a differentmethod was adopted: the allergen was kept underthe tongue and then spat out (sublingual-spit) (24).Presently, only the sublingual-swallow route is used,therefore the acronym SLIT refers to the sublingual-swallow modality.

Nowadays, more than 50 DBPC-RCTs are availablein the literature (25). Their results were also pooled andevaluated in several meta-analyses, which concluded thatSLIT is significantly efficacious compared to placebo forrhinitis and asthma in adults and children (26–29). Inthe last 2 years, some adequately powered, well-designedDBPC-RCTs with grass drops (30) or tablets (31–33)including hundreds of patients, were published. Thesestudies have confirmed the efficacy of SLIT for theseallergens and, more importantly, have demonstrated adose-effect relationship. In parallel to the clinical trials,post-marketing surveys (34), mechanistic investigations(35, 36), prevention studies (37, 38) and pharmaco-



economic assessments (39) were also published in thelast 10 years, so that several aspects of SLIT weregradually clarified. Concerning safety, all clinical trialsand post-marketing surveys have consistently agreedthat SLIT is safe, and the majority of side effects arelocal and mild. In more than 20 years of clinical trialsand everyday use, only six cases of anaphylaxis withSLIT have been reported, some of which were withmixtures of multiple unrelated allergens using non-standardized extracts, but two patients had a severereaction following the first dose of a grass tablet. It hasalso been reported that use of multiple allergens forSLIT does not increase the rate of side effects inchildren (40). Furthermore, it has been suggested (41)that the safety profile of SLIT does not differ inchildren below the age of five years (a relative contra-indication to SCIT).SLIT is currently commercialized and used in most

European and South American countries, as well as inAustralia and Asian countries, but not in the USA. Afteran initial scepticism, due to the paucity of data, the USAscientific community also acknowledged the efficacy andsafety of SLIT (42). Nevertheless, because there is so farno FDA-approved product for SLIT, this modality is notcurrently recommended in clinical practice in the USA,where the Practice Parameter states that �…there is noUS Food and Drug Administration (FDA)-approvedformulation for sublingual or oral immunotherapy in theUnited States. Therefore sublingual and oral immuno-therapy should be considered investigational at this time.�(43) Clinical trials for FDA registration in the USA arecurrently ongoing.

There are several aspects of SLIT still needing inves-tigation and confirmation, including the optimal dose,the long-lasting effect, the preventive action and theexact mechanisms of action. This relative lack ofinformation is not surprising if we consider that thehistory of SLIT is only 20 years in duration, and thatthe majority of studies were aimed at demonstrating theefficacy and safety of the treatment. Moreover, despitethe number of clinical trials available, the value of SLITin paediatric patients was a matter of debate (44), untilthe new positive adequately powered, well-designedDBPC-RCTs in children were reported (45, 46). Themost important concern that still remains is to determinethe optimal dose of allergen for SLIT, since thetreatment has been shown effective over a very largerange of doses (from 5 to 300 times the dose used forSCIT). However, it is clear that the effective doses ofallergens for SLIT must be higher than for SCIT (in fact,we commonly speak of high-dose SLIT). On the otherhand, the recently published large trials have indicatedthe correct direction for research; that is, dose-findingstudies, standardization and uniformization of adminis-tration schedules, and the use of no-updosing regimens,which are more simple and patient-friendly. In themeantime, new opportunities are being explored withSLIT, including the possibility of using it in conditionsother than respiratory allergy, namely food allergy (47)or Hymenoptera venom allergy (48) and the use ofadjuvants and mucoadhesive substances. Other issuesconcern the indication of SLIT since there is no studyassessing its efficacy in patients uncontrolled despiteoptimal pharmacotherapy (Slide 1).

Slide 1: History of sublingual immunotherapy.


G. Walter Canonica

References, Chapter 1

1. Noon L. Prophylactic inoculation against hay fever. Lancet1911;i:1572–1573.

2. Curtis HH. The immunizing cure of hayfever. Med News (NY)1900;77:16–18.

3. Black JH. The oral administration of pollen. J Lab Clin Med1927;12:1156.

4. Black JH. The oral administration of pollen: clinical report. JLab Clin Med 1928;13:709.

5. Herxeimer H. Bronchial hypersensitization and hyposensitiza-tion in man. Int Arch Allergy Appl Immunol 1951;40:40–57.

6. Herxeimer H, Prior EN. Further observations in induced asth-ma and bronchial hyposensitization. Int Arch Allergy ApplImmunol 1952;3:159–161.

7. Metha SB, Smith JM. Nasal hyposensitization and hayfever.Clin Allergy 1975;5:279–284.

8. Taylor G, Shivalkar PR. Local nasal desensitization in allergicrhinitis. Clin Allergy 1972;2:125–126.

9. Rebien W, Wahn U, Puttonen E, Maasch HG. Comparativestudy of immunological and clinical efficacy of oral and subcu-taneous hyposensitization. Allergologie 1980;3:101–109.

10. Taudorf E, Weeke B. Orally administered grass pollen. Allergy1983;38:561–564.

11. Urbanek R, Gehl R. Wirksaimkeit oral hiposensibilisierung beihausstabmilbenallergie. Monatssch Kinderheilkd 1982;130:150–152.

12. Taudorf E, Laursen L, Lanner A, Bjorksten B, Dreborg S,Weeke B. Specific IgG IgE and IgA antibody response to oralimmunotherapy in birch pollenosis. J Allergy Clin Immunol1989;83:589–594.

13. Committee on the safety of medicines. CSM update. Desensi-tizing vaccines. Br Med J 1986;293:948.

14. Malling H, Weeke B eds. Immunotherapy. Position Paper of theEuropean Academy of Allergy and Clinical Immunology. Al-lergy 1993;48(Suppl 14):9–35.

15. Scadding GK, Brostoff J. Low dose sublingual therapy in pa-tients with allergic rhinitis due to dust mite. Clin Allergy1986;16:483–491.

16. BagnascoM,MarianiG, PassalacquaG,MottaC,BartolomeiM,Falagiani P, Mistrello G et al. Absorption and distributionkinetics of the mayor Parietaria allergen administered by nonin-jectable routes to healthy human beings. J Allergy Clin Immunol1997;100:121–129.

17. Bagnasco M, Passalacqua G, Villa G. Pharmacokinetics of anallergen and a monomeric allergoid for oromucosal immuno-therapy in allergic volunteers. Clin Exp Allergy 2001;31:54–60.

18. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-notherapy in patients with rhinitis and asthma due to house dustmite. A double-blind study. Allergol Immunopathol1990;18:277–284.

19. Sabbah A, Hassoun S, Le Sellin J, Andre C, Sicard H. A double-blind placebo-controlled trial by the sublingual route of immu-notherapy with a standardized grass pollen extract. Allergy1994;49:309–313.

20. Bousquet J, Lockey R, Malling HJ eds. World Health Organi-zation Position Paper. Allergen immunotherapy: therapeuticalvaccines for allergic diseases. Allergy 1998;53:1–42.

21. Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, Bjorksten B,Bousquet J, Caillot D et al. EAACI Position Paper on localimmunotherapy. Allergy 1998;53:933–944.

22. Bousquet J, Van Cauwenberge P eds. Allergic Rhinitis and itsImpact on Asthma. J Allergy Clin Immunol 2001;108(Suppl5):S147–S334.

23. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,Togias A et al. Allergic Rhinitis and its Impact on Asthma(ARIA) 2008 update (in collaboration with the World HealthOrganization, GA(2)LEN and AllerGen). Allergy 2008;86:8–160.

24. Nelson H, Oppenheimer J, Vatsia G, Buchmeier A. A double-blind, placebo-controlled evaluation of sublingual immuno-therapy with standardized cat extract. J Allergy Clin Immunol1993;92:229–236.

25. Passalacqua G, Durham SR. Allergic rhinitis and its impact onasthma update: allergen immunotherapy. J Allergy ClinImmunol 2007;119:881–891.

26. Wilson DR, Torres L, Durham SR. Sublingual immunotherapyfor allergic rhinitis. Allergy 2005;60:3–8.

27. Penagos M, Compalati E, Tarantini F et al. Efficacy of sublin-gual immunotherapy in the treatment of allergic rhinitis inchildren. Meta analysis of randomized controlled trials. AnnAllergy Asthma Immunol 2006;97:141–148.

28. Calamita Z, Saconato H, Bronhara Pela A et al. Efficacyof Sublingual immunotherapy in asthma. Systematic reviewof randomized clinical trials. Allergy 2006;61:1162–1172.

29. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,Orozco S, Pedroza A et al. Metaanalysis of the efficacy ofsublingual immunotherapy in the treatment of allergic asthmain pediatric patients, 3 to 18 years of age. Chest 2008;133:599–609.

30. Pfaar O, Klimek L. Efficacy and safety of specific immuno-therapy with a high-dose sublingual grass pollen preparation: adouble-blind, placebo-controlled trial. Ann Allergy AsthmaImmunol 2008;100:256–63.

31. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S.Sublingual immunotherapy with once-daily grass-allergentablets: a randomised controlled trial in seasonal allergicrhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802–809.

32. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S,Emminger W et al. Efficacy and safety of sublingualimmunotherapy with grass allergen tablets for seasonalallergic rhinoconjunctivitis. J Allergy Clin Immunol2006;118:434–440.

33. Didier A, Malling HJ, Worm M, Horak F, Jager S, MontagutA et al. Optimal dose, efficacy, and safety of once-dailysublingual immunotherapy with a 5-grass pollen tablet forseasonal allergic rhinitis. J Allergy Clin Immunol2007;120:1338–1345.

34. Passalacqua G, Guerra L, Fumagalli F, Canonica GW. Safetyprofile of sublingual immunotherapy. Treat Respir Med2006;5:225–234.

35. Cosmi L, Santarlasci V, Angeli R, Liotta F, Maggi L, FrosaliF et al. Sublingual immunotherapy with Dermatophagoidesmonomeric allergoid down-regulates allergen-specificimmunoglobulin E and increases both interferon-gamma-and interleukin-10-production. Clin Exp Allergy 2006;36:261–272.

36. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance,and immune deviation. J Allergy Clin Immunol 2007;120:707–713.

37. Novembre E, Galli E, Landi F et al. Coseasonal sublingualimmunotherapy reduces the development of asthma in childrenwith allergic rhinoconjunctivitis. J Allergy Clin Immunol2004;114:851–857.



38. Marogna M, Tomassetti D, Bernasconi A, Colombo F, MassoloA, Businco AD et al. Preventive effects of sublingual immuno-therapy in childhood: an open randomized controlled study.Ann Allergy Asthma Immunol 2008;101:206–210.

39. Berto P, Frati F, Incorvaia C. Economic studies of immuno-therapy: a review. Curr Opin Allergy Clin Immunol 2008;8:585–590.

40. Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C,Canonica GW et al. The safety of sublingual immunotherapywith one or multiple pollen allergens in children. Allergy2008;63:1637–1639.

41. Di Rienzo V, Minelli M, Musarra A, Sambugaro R, Pecora S,Canonica WG et al. Post-marketing survey on the safety of sub-lingual immunotherapy in children below the age of 5 years. ClinExp Allergy 2005;35:560–564.

42. Cox L, Linneman D, Nolte H, Weldon D, Finegold I, NelsonHS. Sublingual immunotherapy: a comprehensive review.J Allergy Clin Immunol 2006;117:1021–1035.

43. Allergen immunotherapy: a practice parameter second update.J Allergy Clin Immunol 2007;120(Suppl 3):S25–S85.

44. Roder E, BergerMY, deGrootH, vanWijkRG. Immunotherapyin children and adolescents with allergic rhinoconjunctivitis: asystematic review. Pediatr Allergy Immunol 2008;19:197–207.

45. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, de Beau-mont O et al. Efficacy and safety of 5-grass-pollen sublingualimmunotherapy tablets in pediatric allergic rhinoconjunctivitis.J Allergy Clin Immunol 2009;123:160–166.

46. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M,Klimek L et al. Safety and efficacy in children of an SQ-stan-dardized grass allergen tablet for sublingual immunotherapy.J Allergy Clin Immunol 2009;123:167–173.

47. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella Ret al. Sublingual immunotherapy for hazelnut food allergy: arandomized, double-blind, placebo-controlled study with astandardized hazelnut extract. J Allergy Clin Immunol2005;116:1073–1079.

48. Severino MG, Cortellini G, Bonadonna P, Francescato E,Panzini I, Macchia D et al. Sublingual immunotherapy for largelocal reactions caused by honeybee sting: a double-blind,placebo-controlled trial. J Allergy Clin Immunol2008;122:44–48.

Chapter 2: Allergen specific

immunotherapy

An update on subcutaneous immunotherapy, otherroutes of immunotherapy administration, differentallergens and impact of immunotherapy on the naturalhistory of disease.

• Many double-blind, placebo-controlled studies con-firm the efficacy of subcutaneous immunotherapy fortreatment of allergic rhinitis, allergic asthma, andHymenoptera venom hypersensitivity.

• Studies are lacking that support immunotherapywith fungal extracts, other than for Alternaria andCladosporium, and with cockroach extracts.

• Although limited in number, some controlled studieshave demonstrated efficacy of subcutaneousimmunotherapy with multiple allergen mixes. How-ever, there have also been negative studies.

• There appear to be two distinct and perhapssequential immunological responses to immuno-therapy, generation of regulatory T-cells (T regs)secreting (IL)-10 and (TGF)-b and immune devia-tion from TH2 to TH1 responses.

• Subcutaneous immunotherapy has reduced thedevelopment of new sensitizations in monosensitizedpatients and, in a few studies, has reduced thedevelopment of asthma in children who only haveallergic rhinitis

• The beneficial effects of subcutaneous immunother-apy persist for years after discontinuation

• The use of subcutaneous immunotherapy is limitedby the occurrence of local and systemic reactions(SRs) and the prolonged period required for build-up to maintenance dosing

Historical development

Subcutaneous administration of increasing doses of agrass-pollen extract to treat allergic rhinitis was intro-duced by Leonard Noon in 1911 (1), with completion ofhis studies by John Freeman (2). Timothy grass wasadministered preseasonally or seasonally. This treatmentwas subsequently extended to other seasonal and peren-nial allergens and to the treatment of allergic asthma aswell as rhinitis (3). Perennial administration largelyreplaced preseasonal treatment. While immunotherapywas initially used based on the clinical impression ofefficacy, in the 1960s, definitive double-blind studies usingragweed pollen extract established that this was aneffective form of treatment (4, 5).

Clinical efficacy

Many double-blind, placebo-controlled studies confirm theefficacy of subcutaneous injection allergen specific immu-notherapy (SCIT) for treatment of both allergic rhinitis (6)and allergic asthma (7). These studies showed efficacy withextracts of various pollens, animal danders, house dustmites and fungi. For most classes of allergens, resultssupport efficacy. However, although a few small size studiesreport positive results treating patients with Cladosporium(8) and Alternaria (9), studies supporting immunotherapywithmany of the other available fungal allergen extracts arelacking (10).

Most controlled studies included in SCIT meta-analysesthat show clinical efficacy of SCIT for allergic rhinitis andasthma include only a single allergen extract. Although


G. Walter Canonica

there are controlled studies that demonstrate efficacy formultiple allergens mixes for treatment of both allergicrhinitis (4) and allergic asthma (11), the studies are over40 years old and there are no recent studies.

Mechanisms of action

Along with evidence of the efficacy has come an under-standing of the probable mechanisms by which SCITalters the disease processes. The earliest objective evidenceof an immune response was the observation by Noon thatimmunotherapy reduced conjunctival sensitivity to timo-thy grass extract (1). Subsequent observations confirm areduction of sensitivity to the injected allergen in the skin,or topical allergen on the conjunctivae, nasal mucosa andlungs (12, 13). Humoral responses were also observed,with first an increase and later a decline in specific IgE (14)and the generation of a blocking IgG antibody (15).However, studies failed to correlate these responses withclinical improvement (16).Research today is focused on changes in T-lymphocyte

responses and two distinct patterns of change, which mayoccur sequentially. An event that occurs within 7 days athigh allergen doses (17) and 2–4 weeks at low allergendoses (18, 19) is the generation of regulatory T-cellssecreting IL-10 and TGF-b(19) accompanied by suppres-sion of allergen-induced late cutaneous responses (17, 18).This is followed at 6–12 weeks after initiating therapy bycorresponding elevations in allergen-specific IgG4 andIgA at that parallel a more delayed suppression ofallergen-induced early cutaneous responses (18, 19). Asecond and probably later immunologic response isimmune deviation with a shift in the allergen specific T-cell response from predominantly TH2 to TH1 (20).

Impact on natural history

Considering the profound effect on the immune responseto the administered allergen, it is not surprising that SCITalters the natural course of allergic diseases. Severalstudies have demonstrated that SCIT, when administeredto monosensitized patients, reduces the likelihood ofdeveloping new sensitivities (21–23). Moreover, the reduc-tion in new sensitivities persists for at least 3 yearsfollowing discontinuation of treatment (22, 23). A similarinhibitory effect occurs for the progression to asthma inchildren suffering from only allergic rhinitis (24). Timothyor birch pollen SCIT reduced the development of newonset asthma during the course of three years of treatment(25) and reduced the incidence of asthma with little loss ofeffect over 7 years of post-treatment observation. Thebeneficial effects of SCIT on allergy symptoms persist foryears following its discontinuation. In a prospective,placebo-controlled trial, subjects who discontinued timo-

thy grass SCIT after 3–4 years of treatment had the samelevel of symptoms during the next three grass pollenseasons as did the group who continued on monthlymaintenance injections (26).

Alternative approaches to immunotherapy

Despite its clinical and disease-modifying efficacy, SCIThas some disadvantages: it is not �patient friendly� becauseof the regular injections, which may arouse fear amongstchildren and some adults, and it has some indirect costse.g. travel to the doctor�s office and lost work/schoolhours. The use of SCIT is also limited by the prolongedtime for build-up required to reach maintenance levels oftreatment and by adverse reactions. Attempts to improvethe former have lead to trials with accelerated treatmentschedules, while the latter has been addressed by modi-fying the allergen extracts or administering them by routesother than injection. Alternatives to the weekly build-upinclude administering clusters of 2 or 3 injections, usually30 min apart, during a single clinic visit with visits spreadover several weeks (27). This cluster schedule is notassociated with an increased incidence of adverse reac-tions (28). However, a more rapid build-up, in whichmaintenance is achieved in just one or a few days, isassociated with an increased incidence of reactions evenwhen treatment subjects are premedicated (29). Extractmodification includes adsorption of the extract to alu-minium to achieve a depot effect (30) and modifying theextracts with formaldehyde (31) or glutaraldehyde (32) toreduce reactivity with specific IgE. Recombinant technol-ogy is currently being used to produce altered proteins(33) or peptides (34, 35) that retain T-cell epitopes but areno longer recognized by the specific IgE. Anotherapproach is to combine the allergen with products, mostextensively with monophosphoryl lipid A (36) or CpGmotifs (37), that stimulate the innate immune systemthereby favouring a TH1 response.

Another approach is to administer the extracts by analternative route, for example, orally (38) or sublingually(39) slowing absorption and presenting the extract to adifferent component of the immune system. Other alter-native approaches are to administer the extract directly onto the respiratory mucosa, either into the upper or lowerrespiratory tracts (40, 41). This approach can induceallergic respiratory symptoms, therefore, either modifiedextracts with decreased allergenicity are utilized (42) orcromolyn sodium is applied to the mucosa before theallergen is administered to block the allergic reaction (43).


1. Noon L. Prophylactic inoculation against hay fever. Lancet1911;i:1572–1573.



2. Freeman J. Further observations on the treatment of hay feverby hypodermic inoculations of pollen vaccine. Lancet1911;ii:814–817.

3. Cohen SG, Evans R III. Allergen immunotherapy in historicalperspective. In: Lockey RF, Ledford DK, eds. Allergens andallergen immunotherapy, 4th edn. New York: Informa Health-care, 2008:1–29.

4. Lowell FC, Franklin W. A double-blind study of the effective-ness and specificity of injection therapy in ragweed hay fever. NEngl J Med 1965;273:675–679.

5. Norman PS, Winkenwerder WL, Lichtenstein LM. Immuno-therapy of hay fever with antigen E: comparisons with wholepollen extract and placebo. J Allergy 1968;42:93–108.

6. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A,Durham S et al. Allergen injection immunotherapy for sea-sonal allergic rhinitis. Cochrane Database Syst Rev2007;1:CD001936.

7. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapyfor asthma. Cochrane Database Syst Rev 2003;4:CD001186.

8. Malling H-J, Dreborg S, Weeke B. Diagnosis and immuno-therapy of mould allergy. V. Clinical efficacy and side effects ofimmunotherapy with Cladosporium herbarum. Allergy1986;41:507–519.

9. Horst M, Hejjaoui A, Horst V et al. Double-blind, placebo-controlled rush immunotherapy with a standardized Alternariaextract. J Allergy Clin Immunol 1990;85:460–472.

10. Salvaggio JE, Burge HA, Chapman JA. Emerging concepts inmold allergy: what is the role of immunotherapy. J Allergy ClinImmunol 1993;92:217–222.

11. Johnstone DE, Crump L. Value of hyposensitization therapy forperennial bronchial asthma in children. Pediatrics 1961;27:39–44.

12. Bousquet J, Maasch H, Martinot B et al. Double-blind, pla-cebo-controlled immunotherapy with mixed grass pollen al-lergoids. II. Comparison between parameters assessing theefficacy of immunotherapy. J Allergy Clin Immunol1988;82:439–446.

13. Hedlin G, Graf-Lonnevig L, Heilbron H et al. Immunotherapywith cat and dog dander extracts: V. Effects of three years oftreatment. J Allergy Clin Immunol 1991;87:955–964.

14. Sherman WB, Stull A, Cooke RA. Serologic changes in hayfever cases treated over a period of years. J Allergy 1940;11:225–244.

15. Cooke RA, Barnard JH, Hebald S, Stull A. Serological evidenceof immunity with coexisting sensitization in a type of humanallergy (hay fever). J Exp Med 1935;62:733–750.

16. Alexander HL, Johnson MC, Bukantz SC. Studies on correla-tion between symptoms of ragweed hay fever and titer of ther-mostable antibody. J Allergy 1948;19:1–8.

17. Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, AkdisM. In vivo switch to IL-10-secreting T regulatory cells in highdose allergen exposure. J Exp Med 2008;205:2887–2898.

18. Francis JN, James LK, Paraskevopoulos G, Wong C, CalderonMA, Durham SR et al. Grass pollen immunotherapy: IL-10induction and suppression of late responses precedes IgG4inhibitory antibody activity. J Allergy Clin Immunol2008;121:1120–1125.

19. Jutel M, Akdis M, Budak F et al. IL-10 and TGF-b cooperate inthe regulatory T cell response to mucosal allergens in normalimmunity and specific immunotherapy. Eur J Immunol2003;33:1205–1214.

20. Hamid QA, Schotman E, Jacobson MR et al. Increases in IL-12messenger RNA+ cells accompany inhibition of allergen-in-duced late skin responses after successful grass pollen immu-notherapy. J Allergy Clin Immunol 1997;99:254–260.

21. Des Roches A, Paradis L, Menardo J-L et al. Immunotherapywith a standardized Dermatophagoides pteronyssinus extract.VI. Specific immunotherapy prevents the onset of newsensitizations in children. J Allergy Clin Immunol 1997;99:450–453.

22. Pajno GB, Barberio G, De Luca F et al. Prevention of new sen-sitizations in asthmatic children monosensitized to house dustmite by specific immunotherapy. A Six-year follow-up study. ClinExp Allergy 2001;31:1392–1397.

23. Purello-D�Ambrosio F, Gangemi S, Merendino RA et al. Pre-vention of new sensitizations in monosensitized subjects submit-ted to specific immunotherapy or not. A retrospective study. ClinExp Allergy 2001;31:1295–1302.

24. Jacobsen L, Niggemann B, Dreborg S et al. Specific immuno-therapy has long-term preventive effect on seasonal and peren-nial asthma: 10-year follow-up on the PAT study. Allergy2007;62:943–948.

25. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, JacobsenL et al. Pollen immunotherapy reduces the development ofasthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–256.

26. Durham SR, Walker SM, Varga E-M et al. Long-term clinicalefficacy of grass-pollen immunotherapy. N Engl J Med1999;341:468–475.

27. Nanda A, O�Connor M, Anand M et al. Dose dependence andtime course of the immunologic response to administration ofstandardized cat allergen extract. J Allergy Clin Immunol2004;114:1339–1344.

28. Tabar AI, Echechipia S, Garcia BE et al. Double-blind com-parative study of cluster and conventional immunotherapyschedules and Dermatophagoides pteronyssinus. J Allergy ClinImmunol 2005;116:109–118.

29. Portnoy J, Bagstad K, Kanarek H et al. Premedication reducesthe incidence of systemic reactions during inhalant rush immu-notherapy with mixtures of allergenic extracts. Ann Allergy1994;73:409–418.

30. Corrigan CJ, Kettner J, Doemer C, Cromwell O. Efficacy andsafety of preseasonally-specific immunotherapy with an alumi-num-adsorbed six-grass pollen allergoid. Allergy 2005;60:801–807.

31. Norman PS, Lichtenstein LM, Marsh DG. Studies on allergoidsfrom naturally occurring allergens. IV. Efficacy and safety oflong-term allergoid treatment of ragweed hay fever. J AllergyClin Immunol 1981;68:460–470.

32. Casanovas M, Martin R, Jimenez C et al. Safety of immuno-therapy with therapeutic vaccines containing depigmented andpolymerized allergen extracts. Clin Exp Allergy 2007;37:434–440.

33. Niederberger V, Horak F, Vrtala S et al. Vaccination withgenetically engineered allergens prevents progression of allergicdisease. Proc Natl Acad Sci U S A 2004;101:14677–14682.

34. Norman PS, Ohman JL Jr, Long AA et al. Treatment of catallergy with T-cell reactive peptides. Am J Respir Crit Care Med1996;154:1623–1628.

35. Verhoef A, Alexander C, Kay AB, Larche M. T cell epitopeimmunotherapy induces a CD 4+ T cell population with regu-latory activity. PLoS Med 2005;2:253–261.

36. Drachenberg KJ, Wheeler AW, Stuebner P, Horak F. A well-tolerated grass pollen-specific allergy vaccine containing a noveladjuvant, monophosphoryl lipid A, reduces allergic symptomsafter only four preseasonal injections. Allergy 2001;56:498–505.

37. Creticos PS, Schroeder JT, Hamilton RG et al. Immunotherapywith a ragweed-Toll-like receptor 9 agonist vaccine for allergicrhinitis. N Engl J Med 2006;355:1445–1455.


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38. Taudorf E, Laursen C, Lanner A et al. Oral immunotherapy inbirch pollen hay fever. J Allergy Clin Immunol 1987;80:153–161.

39. Wilson DR, Lima MT, Duuham SR. Sublingual immunother-apy for allergic rhinitis. Allergy 2005;60:1–2.

40. Passalacqua G, Albano M, Ruffoni S et al. Nasal Immuno-therapy to Parietaria: evidence of reduction of local allergicinflammation. Am J Respir Crit Care Med 1995;152:461–466.

41. Tari MG, Mancino M, Monti G. Immunotherapy by inhalationof allergen in powder in house dust allergic asthma. A double-blind study. J Invest Allergo Clin Immunol 1992;2:59–67.

42. Georgitis JW, Nickelsen JA, Wypych JI et al. Local intranasalimmunotherapy with high-dose polymerized ragweed extract.Int Archs Allergy Appl Immunol 1986;81:170–173.

43. Andri L, Senna G, Bettel C et al. Local nasal Immunotherapyfor Dermatophagoides-induced rhinitis: efficacy of a powderinhaler. J Allergy Clin Immunol 1993;91:987–996.

Chapter 3: Mechanisms of


• Allergen immunotherapy provides an opportunity tostudy antigen-specific tolerance in man.

• Subcutaneous immunotherapy suppresses allergic�TH2-mediated� inflammation and increases antigen-specific IgG probably by induction of T regs, im-mune deviation (TH2 fi TH1) and/or apoptosis ofT cells.

• Oral mucosa is a natural site of immune tolerance(Langerhans cells, Fc�R1, IL-10, IDO [indoleamine2,3-dioxygenase]).

• Sublingual immunotherapy in optimal doses iseffective and may induce remission after discontin-uation and prevent new sensitizations, featuresconsistent with induction of tolerance.

• Sublingual immunotherapy is associated with:

s retention of allergen in sublingual mucosa forseveral hours.

s marked early increases in antigen-specific IgE,blunting of seasonal IgE.

s modest increases in antigen-specific IgG4 and IgE-blocking activity.

s inhibition of eosinophils, reduction of adhesionmolecules in target organ.

s some evidence of increase in peripheral T cellIL-10.

• SLIT induces modest systemic changes consistentwith SCIT, but additional local mechanisms in oralmucosa and/or regional lymph nodes are likelyimportant.

Immunotherapy provides a unique opportunity to studythe evolution of antigen-specific tolerance in man. Under-standing the underlying mechanisms may lead to the

development of vaccines with greater efficacy and allowthe identification of biomarkers that may predict theclinical response to treatment. Whereas there is consider-able knowledge concerning mechanisms of SCIT,information on the mechanisms of SLIT (1, 2) is lesswell-advanced.

Subcutaneous immunotherapy

Subcutaneous immunotherapy in patients with pollenrhinitis is associated with transient increases in allergen-specific IgE, blunting of seasonal increases in IgE (3),and increases in allergen-specific IgG, particularly IgG4(3–5), and IgA (5, 6). Serum antibody concentrationsappear to relate more to the dose of allergen adminis-tered rather than correlate with clinical improvement (7).Immunoreactive IgG populations include antibodies witha wide range of clonality and/or affinity. In contrast,functional assays of IgG are more likely to representthat proportion of circulating IgG that is biologically(and therefore clinically) relevant. For example, serumobtained following SCIT has been shown to inhibitallergen-IgE binding to B-cells (8), an effect mediatedlargely by IgG4. This system has provided an in vitroassay of the ability of �blocking� antibodies to inhibitIgE-facilitated antigen presentation. Similarly, basophilhistamine release can be used to measure the functionalability of IgG to inhibit IgE-dependent activation andmediator release (9), either via competition with IgE forallergen and/or by stimulation of surface IgG-inhibitoryreceptors present on basophils and mast cells (10).Whereas post-immunotherapy serum IgA is unable toblock allergen-IgE binding to B cells, by triggeringsurface IgA receptors on monocytes, IgA releases theinhibitory cytokine IL-10 (6). Subcutaneous immuno-therapy has been shown to decrease the numbers ofeffector cells at mucosal sites, both during seasonalallergen exposure (11) and after allergen challenge (12),as well as reducing effector cell reactivity in vitro (9).

It has been suggested that allergic disease may resultfrom a relative imbalance between the effects of regula-tory T cells and Th2 cells (13). Regulatory T cells can bedivided into �naturally occurring�, thymus derived CD4+CD25+ cells, which are positive for the transcriptionfactor Foxp3, and �adaptive� regulatory cells, either Tr1IL-10 secreting cells, or TH3 TGF-b secreting cells (14).Subcutaneous immunotherapy in patients with grasspollen (15) and mite (5) allergy results in increased IL-10 in allergen-stimulated peripheral T cell cultures.Additionally, subcutaneous immunotherapy has beenassociated with immune deviation in favour of TH1responses (16, 17). However, changes in T cell responsesto allergen have not been universally observed in cellsderived from peripheral blood (18, 19). Studies of localnasal T cell responses have identified skewing of cytokineprofiles in favour of TH1 responses (20, 21) and local



increases in IL-10+ (3) and TGF-b+ T cells (6) andFoxp3+ phenotypic T regs (22) within the nasal mucosa.

The oral mucosa as a tolerogenic organ

The local environment in the mouth is regarded as a site ofnatural immune tolerance (2). Despite continued exposureto micro-organisms and multiple foreign substances, theoralmucosa remains non-inflamedwith a relative paucity ofeffector cells compared to other mucosal sites. The presenceof a sophisticated network of Langerhans cells epithelialcellsandmonocytescapableofproducingIL-10,TGF-bandactivins (23–26) may play a role in the maintenance of oraltolerance. Local secretory IgA may also have an anti-inflammatory effect (6).Human oral Langerhans cells constitutively express

Fc�R1, Major Histocompatibility Complex (MHC) class Iand II and co-stimulatory and co-inhibitorymolecules (27),properties consistent with highly efficient antigen presen-tation to T cells. Cross-linking of Fc�R1 on monocytesinduces production of IL-10 (28) and indoleamine 2, 3-dioxygenase (29), the latter associated with reduced tryp-tophan levels and consequent impaired T-cell stimulatorycapacity. Human oral mucosal Langerhans cells producesubstantial IL-10. Ligation of Toll-like receptor 4 onisolated human oral Langerhans cells enhanced IL-10production (30) and in co-culture experiments decreased T-cell proliferation (in mixed lymphocyte reactions) with aparallel induction of T-cells with a regulatory phenotype.One hypothesis is that innate receptors enhance thetendency toward tolerance to antigens presented in themicrobe-rich oral environment. Interaction between den-dritic cells, Langerhans cells and T cells may occur locallywithin the oral mucosa (27, 30), whereas animal studies (26)imply that the principle site for such interactions is withinthe regional lymph nodes. It is possible that oral Langer-hans cells interact with naıve T-cells, resulting in thegeneration of allergen-specific regulatory T-cells. Alterna-tively, interaction with allergen-specific memory TH2 cellsmay result in down regulation of function or redirection to aregulatory or TH1 phenotype. Downstream events, as insubcutaneous immunotherapy, may include B-cell class-switch to IgG4 and IgA rather than IgE, and downregulation of mucosal effector cells. It remains to bedetermined whether such mechanisms operate in vivoduring sublingual immunotherapy.

Immunological effects of sublingual immunotherapy in man

Clinical studies of sublingual immunotherapy are hetero-geneous, involving different allergens, doses and durationsof therapy. A wide range of laboratory techniques hasbeen used to measure putative immunological mecha-nisms: this may explain, at least in part, the variability ofresults obtained. Tracer studies of radio-iodine labelled

allergen have shown that allergen may be retained withinthe oral mucosa for at least 2 hours (31) and up to 18–20 hours (32) following sublingual administration, afford-ing opportunities for both local as well as systemic effectson the immune system.

Specific antibody levels

During pollen SLIT, increases in allergen-specific IgE occurwithin weeks although do not appear to be associated withadverse events. These early increases are followed byblunting of seasonal rises in IgE. There follows an increasein allergen-specific IgG/IgG4. These elevations are bothtime- and allergen-dose dependent (33) and progressive forat least 2 years (34) although of lower magnitude thanobserved during SCIT (3, 35). Some studies have shownincreases in specific IgG4 in the absence of demonstrableefficacy (36), whereas others have shown no difference inIgG levels, likely related to the lower allergen dosesemployed (37), particularly in relation to mite SLIT (38–41). These findings raise the issue of causality versesbystander effects. In functional assays, sera obtained aftergrass pollen SLIT was able to inhibit IgE-binding in vitro(34).

Effector cells

Sublingual mite immunotherapy (42) was associated withdecreases in conjunctival eosinophils, neutrophils andepithelial expression of intercellular adhesion molecule-1(ICAM-1) and accompanied by a reduction in circulatingeosinophil cationic protein (ECP). Similarly, SLIT inParietaria-sensitive patients reduced eosinophils, neu-trophils and ICAM-1 expression in the nasal mucosa (43).Decreases in ECP (42, 44) and eosinophils have beenobserved in several but not all (40) studies. One studyinvestigated the effects of high dose grass pollen SLIT onimmune cells within the sublingual mucosa (45). Nodifferences in total T-cells, CD1a+ dendritic cells ormacrophages were detectable and no differences in IL-12messenger ribonucleic acid (mRNA)+ cells, whereas the Treg phenotype was not assessed. Interestingly, mast cellsand eosinophils are present, albeit in low numbers, withinthe buccal/sublingual mucosa (46, 47) and correspondingactivation markers such as tryptase and ECP are detectablewithin salivary secretions (48), providing a plausibleexplanation for local itching and swelling that may occurafter sublingual allergen administration.

T cells and cytokines

Studies of peripheral T cell responses to inhalant aller-gens, before/after SLIT have been highly variable.Decreased T cell proliferative responses in birch (49) andgrass-treated (50) patients have been observed in some butnot other studies (37, 51) and even less convincing trendsfor house dust mite-treated patients (52, 53). Similarly


G. Walter Canonica

results for T cell cytokine production at both messengerRNA and protein levels have been highly variable, withsome studies showing an increase in interferon gammaand/or decreases in TH2 cytokines (49, 51, 53–55) whereasothers show no changes (37, 41, 50). A more consistentfinding (as in SCIT) has been increases in peripheral T cellIL-10 production which have been observed at protein(49, 56, 57) and mRNA levels (54) in several, but not all,studies (37). An elegant study by Bohle (49) on smallnumbers of birch-treated patients showed a reduction inproliferative responses to Bet v1 that was accompanied byincreases in IL-10. This suppression was reversed by anti-IL-10 or depletion of CD25+ cells from the cultureswhich implied involvement of regulatory T cells. Furtherimmunological studies on larger numbers of subjects usingvalidated clinical protocols are needed. One such recentlypublished DBPC-RCT evaluated HDM SLIT in 30HDM-allergic subjects for more than 12 months. Thestudy reported suppression of IL-5 production andallergen specific CD4+ T cell proliferation via TGF-b,transient increase in CD4+ CD25+ Foxp3+/CD127lo Tregs with functional suppressor activity and allergenspecific antibody isotype switching to IgG4 in clinicallyeffective HDM SLIT (58).

Conclusion

A consensus is emerging that SLIT may involve similarmechanisms to SCIT with allergen-driven altered T cellresponses underlying suppression of allergic inflammationand the modest changes observed in circulating antibodylevels, particularly allergen-specific IgG4. Although re-sults vary, the underlying event is likely to involveinduction of a population of IL-10 producing regulatoryT cells. Alternative mechanisms include immune deviationin favour of TH1 responses and apoptosis and/or anergyof antigen-specific T cells. Studies of local T cell responsesin the allergic mucosa may yield more definitive informa-tion. In contrast to murine studies, it is difficult to assess inman the likely additional local mechanisms involvingT cell-dendritic cell interactions within the oral mucosaand/or local lymph nodes.


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9. Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, KrauthMT, Majlesi Y et al. Allergen-specific immunotherapy with amonophosphoryl lipid A-adjuvanted vaccine: reducedseasonally boosted immunoglobulin E production andinhibition of basophil histamine release by therapy-inducedblocking antibodies. Clin Exp Allergy 2003;33:1198–1208.

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11. Wilson DR, Irani AM, Walker SM, Jacobson MR, Mackay IS,Schwartz LB et al. Grass pollen immunotherapy inhibits sea-sonal increases in basophils and eosinophils in the nasal epi-thelium. Clin Exp Allergy 2001;31:1705–1713.

12. Furin MJ, Norman PS, Creticos PS, Proud D, Kagey-SobotkaA, Lichtenstein LM et al. Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity. J AllergyClin Immunol 1991;88:27–32.

13. Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Ar-bery J et al. Relation of CD4+ CD25+ regulatory T-cell sup-pression of allergen-driven T-cell activation to atopic status andexpression of allergic disease. Lancet 2004;363:608–615.

14. Robinson DS, Larche M, Durham SR. Tregs and allergic dis-ease. J Clin Invest 2004;114:1389–1397.

15. Francis JN, Till SJ, Durham SR. Induction of IL-10+ CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy ClinImmunol 2003;111:1255–1261.

16. Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U,Schenk S et al. Immunological changes during specific immu-notherapy of grass pollen allergy: reduced lymphoproliferativeresponses to allergen and shift from TH2 to TH1 in T-cell clonesspecific for Phl p 1, a major grass pollen allergen. Clin ExpAllergy 1997;27:1007–1015.

17. Jutel M, Pichler WJ, Skrbic D, Urwyler A, Dahinden C, MullerUR Bee venom immunotherapy results in decrease of IL-4 andIL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol 1995;154:4187–4194.

18. Till S, Walker S, Dickason R, Huston D, O�Brien F, Lamb Jet al. IL-5 production by allergen-stimulated T cells followinggrass pollen immunotherapy for seasonal allergic rhinitis. ClinExp Immunol 1997;110:114–121.



19. Wachholz PA, Nouri-Aria KT, Wilson DR, Walker SM, Ver-hoef A, Till SJ et al. Grass pollen immunotherapy for hayfeveris associated with increases in local nasal but not peripheralTh1:Th2 cytokine ratios. Immunology 2002;105:56–62.

20. Durham SR, Ying S, Varney VA, Jacobson MR, SudderickRM, Mackay IS et al. Grass pollen immunotherapy inhibitsallergen-induced infiltration of CD4+ T lymphocytes and eo-sinophils in the nasal mucosa and increases the number of cellsexpressing messenger RNA for interferon-gamma. J AllergyClin Immunol 1996;97:1356–1365.

21. Klimek L, Dormann D, Jarman ER, Cromwell O, RiechelmannH, Reske-Kunz AB. Short-term preseasonal birch pollenallergoid immunotherapy influences symptoms, specific nasalprovocation and cytokine levels in nasal secretions, but notperipheral T-cell responses, in patients with allergic rhinitis. ClinExp Allergy 1999;29:1326–1335.

22. Radulovic S, Jacobson MR, Durham SR, Nouri-Aria KT.Grass pollen immunotherapy induces Foxp3-expressing CD4+CD25+ cells in the nasal mucosa. J Allergy Clin Immunol2008;121:1467–1472.

23. Zemann B, Schwaerzler C, Griot-Wenk M, Nefzger M, MayerP, Schneider H et al. Oral administration of specific antigens toallergy-prone infant dogs induces IL-10 and TGF- betaexpression and prevents allergy in adult life. J Allergy ClinImmunol 2003;111:1069–1075.

24. Akbari O, DeKruyff RH, Umetsu DT. Pulmonary dendritic cellsproducing IL-10 mediate tolerance induced by respiratoryexposure to antigen. Nat Immunol 2001;2:725–731.

25. Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F,Groux H. Characterization of dendritic cells that induce toler-ance and T regulatory 1 cell differentiation in vivo. Immunity2003;18:605–617.

26. Van Wilsem EJ, Van Hoogstraten IM, Breve J, Scheper RJ,Kraal G. Dendritic cells of the oral mucosa and the induction oforal tolerance. A local affair. Immunology 1994;83:128–132.

27. Allam JP, Novak N, Fuchs C, Asen S, Berge S, Appel T et al.Characterization of dendritic cells from human oral mucosa: anew Langerhans� cell type with high constitutive Fc-epsilon RIexpression. J Allergy Clin Immunol 2003;112:141–148.

28. Novak N, Bieber T, Katoh N. Engagement of Fc epsilon RI onhuman monocytes induces the production of IL-10 and preventstheir differentiation in dendritic cells. J Immunol 2001;167:797–804.

29. von Bubnoff D, Matz H, Frahnert C, Rao ML, Hanau D, de laSalle H et al. Fc-epsilonRI induces the tryptophan degradationpathway involved in regulating T cell responses. J Immunol2002;169:1810–1816.

30. Allam JP, Peng WM, Appel T, Wenghoefer M, Niederhagen B,Bieber T et al. Toll-like receptor 4 ligation enforces tolerogenicproperties of oral mucosal Langerhans cells. J Allergy ClinImmunol 2008;121:368–374.

31. Bagnasco M, Passalacqua G, Villa G, Augeri C, Flamigni G,Borini E et al. Pharmacokinetics of an allergen and a mono-meric allergoid for oromucosal immunotherapy in allergic vol-unteers. Clin Exp Allergy 2001;31:54–60.

32. Bagnasco M, Mariani G, Passalacqua G, Motta C, BartolomeiM, Falagiani P et al. Absorption and distribution kinetics of themajor Parietaria judaica allergen (Par j 1) administered bynoninjectable routes in healthy human beings. J Allergy ClinImmunol 1997;100:122–129.

33. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut Aet al. Optimal dose, efficacy, and safety of once-daily sublingualimmunotherapy with a 5-grass pollen tablet for seasonal allergicrhinitis. J Allergy Clin Immunol 2007;120:1338–1345.

34. Dahl R, Kapp A, Colombo G, de Monchy JGR, Rak S,Emminger W et al. Sublingual grass allergen tablet immuno-therapy provides sustained clinical benefit with progressiveimmunologic changes over 2 years. J Allergy Clin Immunol2008;121:512–518.

35. Frew AJ, Powell RJ, Corrigan CJ, Durham SR; UK Immuno-therapy Study Group. Efficacy and safety of specific immuno-therapy with SQ allergen extract in treatment-resistant seasonalallergic rhinoconjunctivitis. J Allergy Clin Immunol2006;117:319–325.

36. Lue KH, Lin YH, Sun HL, Lu KH, Hsieh JC, Chou MC.Clinical and immunologic effects of sublingual immunotherapyin asthmatic children sensitized to mites: a double-blind, ran-domized, placebo-controlled study. Pediatr Allergy Immunol2006;17:408–415.

37. Rolinck-Werninghaus C, Kopp M, Liebke C, Lange J, Wahn U,Niggemann B. Lack of detectable alterations in immune re-sponses during sublingual immunotherapy in children seasonalallergic rhinoconjunctivitis to grass pollen. Int Arch AllergyImmunol 2005;136:134–141.

38. Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical andimmunologic effects of long-term sublingual immunotherapy inasthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy 2000;55:842–849.

39. Tonnel AB, Scherpereel A, Douay B, Mellin B, Leprince D,Goldstein N et al. Allergic rhinitis due to house dust mites:evaluation of the efficacy of specific sublingual immunotherapy.Allergy 2004;59:491–497.

40. Bahceciler NN, Arikan C, Taylor A, Akdis M, Blaser K, BarlanIB et al. Impact of sublingual immunotherapy on specific anti-body levels in asthmatic children allergic to house dust mites. IntArch Allergy Immunol 2005;136:287–294.

41. Dehlink E, Eiwegger T, Gerstmayr M, Kampl E, Bohle B, ChenKW et al. Absence of systemic immunologic changes duringdose build-up phase and early maintenance period in effectivespecific sublingual immunotherapy in children. Clin Exp Allergy2006;36:32–39.

42. Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C,Mela GS et al. Randomised controlled trial of local allergoidimmunotherapy on allergic inflammation in mite-induced rhi-noconjunctivitis. Lancet 1998;351:629–632.

43. Passalacqua G, Albano M, Riccio A, Fregonese L, Puccinelli P,Parmiani S et al. Clinical and immunologic effects of a rushsublingual immunotherapy to Parietaria species: a double-blind,placebo-controlled trial. J Allergy Clin Immunol 1999;104:964–968.

44. Ippoliti F, De Santis W, Volterrani A, Lenti L, Canitano N,Lucarelli S et al. Immunomodulation during sublingual therapyin allergic children. Pediatr Allergy Immunol 2003;14:216–221.

45. Lima MT, Wilson D, Pitkin L, Roberts A, Nouri-Aria K, Jac-obson M et al. Grass pollen sublingual immunotherapy forseasonal rhinoconjunctivitis: a randomized controlled trial. ClinExp Allergy 2002;32:507–514.

46. Allam JP, Stojanovski G, Friedrichs N, Peng W, Bieber T,Wenzel J et al. Distribution of Langerhans cells and mast cellswithin the human oral mucosa: new application sites of allergensin sublingual immunotherapy? Allergy 2008;63:720–727.

47. Marcucci F, Sensi L, Incorvaia C, Di Cara G, Moingeon P, FratiF. Oral reactions to sublingual immunotherapy: a bioptic study.Allergy 2007;62:1475–1477.

48. Marcucci F, Sensi L, Frati F, Senna GE, Canonica GW, Par-miani S et al. Sublingual tryptase and ECP in children treatedwith grass pollen sublingual immunotherapy (SLIT): safety andimmunologic implications. Allergy 2001;56:1091–1095.


G. Walter Canonica

49. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance,and immune deviation. J Allergy Clin Immunol 2007;120:707–713.

50. Fanta C, Bohle B, Hirt W, Siemann U, Horak F, Kraft Det al. Systemic immunological changes induced by adminis-tration of grass pollen allergens via the oral mucosa duringsublingual immunotherapy. Int Arch Allergy Immunol1999;120:218–224.

51. Cosmi L, Santarlasci V, Angeli R, Liotta F, Maggi L, FrosaliF et al. Sublingual immunotherapy with Dermatophagoidesmonomeric allergoid down-regulates allergen-specificimmunoglobulin E and increases both interferon-gamma-and interleukin-10-production. Clin Exp Allergy 2006;36:261–272.

52. Fenoglio D, Puppo F, Cirillo I, Vizzaccaro A, Ferrera A, ToscaMA et al. Sublingual specific immunotherapy reduces PBMCproliferations. Eur Ann Allergy Clin Immunol 2005;37:147–151.

53. Savolainen J, Jacobsen L, Valovirta E. Sublingual immuno-therapy in children modulates allergen-induced in vitro expres-sion of cytokine mRNA in PBMC. Allergy 2006;61:1184–1190.

54. Savolainen J, Nieminen K, Laaksonen K, Laiho T, Jacobsen L,Lahesmaa R et al. Allergen-induced in vitro expression of IL-18,SLAM and GATA-3 mRNA in PBMC during sublingualimmunotherapy. Allergy 2007;62:949–953.

55. Ippoliti F, De Santis W, Volterrani A, Lenti L, Canitano N et al.Immunomodulation during sublingual therapy in allergic chil-dren. Pediatr Allergy Immunol 2003;14:216–221.

56. Ciprandi G, Cirillo I, Fenoglio D, Marseglia G, Tosca MA.Sublingual immunotherapy induces spirometric improvementassociated with IL-10 production: preliminary reports. Int Im-munopharmacol 2006;6:1370–1373.

57. Ciprandi G, Fenoglio D, Cirillo I, Vizzaccaro A, Ferrera A,Tosca MA et al. Induction of interleukin 10 by sublingualimmunotherapy for house dust mites: a preliminary report. AnnAllergy Asthma Immunol 2005;95:38–44.

58. O�Hehir RE, Gardner LM, de Leon MP, Hales BJ, Biondo M,Douglass JA et al. House dust mite sublingual immunotherapy –the role for TGF-beta and functional regulatory T cells. Am JRespir Crit Care Med 2009;180:936–947.

Chapter 4: Clinical efficacy of


• Up to June 2009, there were 60 DBPC-RCTs ofSLIT, of which 41 conducted with grass or HDMextracts. The majority of these studies is heteroge-neous for allergen dose, duration and patients�selection.

• 48 trials provided overall positive results and 12 weretotally or almost totally negative.

• The literature suggests that overall, SLIT is effective,although differences exist among allergens.

• The available meta-analyses are in favour of SLIT(rhinitis in adults, asthma and rhinitis in children),although the conclusions are limited by the greatheterogeneity of the studies.

• The clinical efficacy and dose dependency have beendemonstrated, in adequately powered, well-designedDBPC-RCTs, for rhinoconjuntivitis due to grasspollen.

• Dose finding trials and large studies with properlydefined outcomes and sample size are needed for theother relevant individual allergens.

General aspects

As in the case of SCIT, the evaluation of the clinicalefficacy of SLIT relies on the assessment of symptomseverity and rescue medication use during the naturalexposure to allergens. This requires the adoption of arigorous methodological design, which is the DBPC-RCT.Moreover, as suggested by WAO (1), an ideal studyshould include:

• only monosensitized patients• a baseline assessment (i.e. a run-in pollen season)• adequate pollen counts in trials on pollen-allergicsubjects

• a sample size calculation for adequate power of thestudy

• a balanced symptom/medication score evaluation• an adequate duration and allergen dose

For practical (time consumption, budget, and rarity ofmonosensitized subjects) and historical reasons (the ear-liest studies were performed more than 10 years ago), onlyfew recent trials fulfil the above mentioned criteria.Therefore, the majority of the published RCTs can beconsidered as suggestive, rather than demonstrative.Nonetheless, the RCTs taken together provide relevantand reliable information.

DBPC-RCTs (Table 4-1)

The number of DBPC-RCTs is increasing: as shown inTable 4-1, there were 60 DBPC-RCTs performed since1986 (2–61), when the first controlled trial appeared (2).Of these, 26 were performed with grass extracts, 15 withmite, five with Parietaria, three with cat and the remaining11 trials with other pollen extracts. The duration of thetrials ranged between 4 months and 4 years, 19 of thembeing of 6 months duration or less. The majority ofstudies was conducted in patients with rhinitis or rhinitisplus asthma. Only a few studies (15, 21, 31, 38, 44, 46, 61)were specifically designed to evaluate the efficacy inasthma, and one study dealt with allergic conjunctivitis(28). When stated, the dose used in the clinical trialsranged between five and 375 times that used in anequivalent SCIT course, but the monthly and cumulativedoses of major allergen(s) was largely variable from trial



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coun

t.

Med

icat

ion

scor

e,Oc

ular

scor

e

Yuks

elet

al.(

19),

1999

5–15

21/1

8N

SGr

ass

4m

onth

sCu

mul

at21

0lg

Dac

g5

Glyc

-er

osal

ine

NS

RAST

AAn

tihis

tam

ine

(<0.

05),

Rhin

itis

scor

e(<

0.01

),Ov

eral

leffi

cacy

byph

ysi-

cian

(P=

0.04

)

Beta

2us

e,As

thm

asc

ores

,PE

F

Aria

noet

al.(

23),

2001

19–5

010

/10

0/0

Cypr

ess

8m

onth

s30

000

RU/m

onth

,Cu

mul

at30

000

0,Gl

ycer

o-Aq

ua

5RA

ANA

Sym

ptom

san

dm

edic

atio

nssc

ore

(<0.

05)

Bahc

ecile

ret

al.

(24)

,200

17–

158/

70/

0HD

M6

mon

ths

72lg

Der

p1/

mon

th;

Cum

ul:

0.56

mg

Aque

ous

NS

RAST

AAs

thm

asc

ore

(P=

0.05

),Be

ta2

(P=

0.02

8),

PEF

(P=

0.04

9),

Exac

erba

tion(

P=

0.00

7)

Nas

alsy

mpt

omsc

ore,

ICS

(P=

0.06

),N

CSvs

plac

ebo

Volto

lini

etal

.(25

),20

01(s

econ

dye

arop

en)

15–5

215

/15

first

,24

/10

seco

nd0/

1Bi

rch

24m

onth

s90

lgBe

tv

1/m

onth

Glyc

erop

heno

l

5RA

ALK

Sym

ptom

svs

base

line

(P=

0.00

1);d

rugs

vsba

selin

e(P

=0.

007)

.sec

ond

year

:com

bine

dsc

ores

vsba

selin

ean

dpl

aceb

o

Sym

ptom

san

ddr

ugs

scor

esvs

plac

ebo

Sanc

hez

etal

.(26

),20

0118

–50

20/2

00/

0Ca

t1

year

0.3

lgFe

ld1/

day

Glyc

ero-

salin

e

NS

RACB

FSy

mpt

omsc

ore

(<0.

01)

Med

icat

ion

not

asse

ssed


G. Walter Canonica

Tabl

e4-

1(C

ontin

ued)

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

prep

arat

ion

Dos

evs

SCIT

Dis

ease

�M

anuf

ac-

ture

rM

ain

posi

tive

resu

ltsN

och

ange

Lim

aet

al.(

27),

2002

16–4

826

/23

2/1

Gras

s18

mon

ths

0.9

mg

Phlp

5/m

onth

Glyc

erin

ate

50R

ALK

Patie

ntas

sess

men

t(P

=0.

02)

Resc

uem

eds,

Sym

ptom

scor

e

Mor

tem

o-us

que

etal

.(28

),20

03

6–60

26/1

94/

11HD

M24

mon

ths

Cum

ulat

:2.

2m

gDe

rp

1, Glyc

ero-

aque

-ou

s

NS

CST

ACo

njun

ctiv

alpr

ovoc

atio

n,Co

njun

ctiv

alsc

ore,

Nas

alsc

ore

Andr

eet

al.(

29),

2003

6–55

48/5

17/

4Ra

gwee

d3

dose

s7

mon

ths

1.4–

4.0

mg

Amb

a1/

mon

thSo

lutio

n/ta

b-le

ts

NS

RST

AOn

lyhi

ghes

tdo

se:

Rhin

itis

scor

e(P

=0.

05),

Ocul

arsc

ore

(P=

0.04

),Or

alst

eroi

ds(P

=0.

05)

Inal

ldos

egr

oups

:sy

mpt

oms

and

drug

sco

mbi

ned

Ippo

litie

tal

.(30

),20

035–

1247

/39

0/0

HDM

6m

onth

s10

.4l

gDe

rp

1/m

onth

Cum

ulat

:57

lg

Glyc

er-

ophe

nol

5AR

ALK

Asth

ma

scor

e(<

0.01

),Rh

initi

ssc

ore

(<0.

01),

FEV 1

(<0.

01),

Drug

sno

tas

sess

ed

Pajn

oet

al.(

31),

2003

(vs

plac

ebo

and

cont

rol)

8–14

15/1

51/

2Pa

rieta

riaAd

don

toIC

S

13m

onth

s1.

56l

gPa

rj1

/m

onth

Cum

ulat

:23

lg

Glyc

eros

alin

e

NS

RAC

ALK

Ocul

arsc

ore

0.02

5vs

cont

rols

;VAS

(P=

0.03

7)vs

plac

ebo

Bron

chia

l,na

sal

scor

es

Wut

hric

het

al.(

32),

2003

6–13

10/1

24/

2Gr

ass

2ye

ars

6l

g/m

onth

Glyc

erop

heno

lN

SRA

ALK

Drug

scor

ese

cond

year

(0.0

5)Dr

ugsc

ore

first

year

,Sym

ptom

scor

e

Tonn

elet

al.(

33),

2004

7–45

15/1

75/

9HD

M2

year

s53

lg

Der

p1/

mon

thCu

mul

at:

57l

gSo

lutio

n-ta

b-le

ts

NS

RST

ARh

initi

ssc

ore

first

year

(<0.

03):

seco

ndye

ar(<

0.02

)

Drug

scor

e

Bufe

etal

.(3

4),2

004

6–13

68/7

40/

10Gr

ass

1ye

ar+

2ye

ars

open

273

lg

Phlp

5/m

onth

Cum

ulat

:9.

6m

gSo

lutio

n

10RA

HAL

Sym

ptom

+dr

ugsc

ore

P=

0.04

6vs

plac

ebo:

only

third

year

and

only

mos

tse

vere

grou

p

Sym

ptom

+dr

ugsc

ores

Smith

etal

.(35

),20

0418

–60

491

year

,46

2ye

ars,

46pl

aceb

o

35Gr

ass

1ye

ar2

year

s32

9l

gDa

cg

5/m

onth

Solu

tion-

tabl

ets

300

RST

ASe

cond

year

:sne

ezin

g(0

.05)

and

rhin

orrh

ea(0

.001

)

Nas

alsc

ore

first

year

:Dru

gsc

ores

alls

tudy



Tabl

e4-

1(C

ontin

ued)

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

prep

arat

ion

Dos

evs

SCIT

Dis

ease

�M

anuf

ac-

ture

rM

ain

posi

tive

resu

ltsN

och

ange

Rolin

ck-

Wer

ning

haus

etal

.(36

),20

04

3–14

39/3

81/

1Gr

ass

3ye

ars

6l

gm

ajor

/m

onth

Glyc

erop

heno

l

NS

RAAL

KDr

ugsc

ore

(0.0

25)

Sym

ptom

+dr

ugsc

ore

(0.0

49)

Ocul

ar,n

asal

,bro

n-ch

ials

ympt

omsc

ore

Bow

enet

al.(

37),

2004

6–52

36/4

08/

11Ra

gwee

d3

dose

s4

mon

ths

3.1–

9.4

mg

Amb

a1/

mon

thSo

lutio

n

NS

RST

ASn

eezin

gan

ditc

hing

(0.0

4);i

nves

tigat

or�s

eval

uatio

n

Drug

scor

e,Co

njun

ctiv

itis

scor

e

Durh

amet

al.(

41),

2006

18–6

656

9/28

639

/26

Gras

s3

dose

s6

mon

ths

15l

g(1

36pt

s)15

0l

g(1

39pt

s)45

0l

g(2

94pt

s)Ph

lp

5/m

onth

sTa

blet

s

NS

RAL

KDr

ugsc

ore

–28

%(0

.012

):Sy

mpt

oms

–21

%(0

.002

):Qo

L,On

lyhi

ghes

tdo

se

Sym

ptom

san

ddr

ugsc

ores

for

the

2lo

wdo

ses

Pass

alac

qua

etal

.(40

),20

06

14–5

634

/34

6/6

HDM (mon

oid)

2ye

ars

8.00

0AU

/m

onth

Tabl

ets

10R

LOF

Firs

tye

ar:t

otal

sym

ptom

s(0

.03)

,ob

stru

ctio

n(0

.05)

,m

edic

atio

n(0

.03)

.Se

cond

year

:med

icat

ions

(0.0

3);

Gene

ralw

ellb

eing

Sym

ptom

scor

ean

dob

stru

ctio

nat

seco

ndye

ar.S

at-

isfa

ctio

npr

ofile

.

Niu

etal

.(3

8),2

006

6–12

56/5

47/

6HD

M6

mon

ths

320

lg

Derp

1/m

onth

Cum

ulat

,1.

7m

gGl

ycer

osal

ine

100

AST

AN

ight

time

(0.0

02),

dayt

ime

(0.0

09),

tota

l(0.

01)a

sthm

asc

ore;

FEV 1

,FVC

vsba

selin

e(<

0.05

).Gl

obal

asse

ssm

ent

Oral

ster

oids

PEF

(0.0

7),

FEV1

and

FVC

betw

een

grou

ps

Dahl

etal

.(3

9),2

006

18–6

474

/40

13/8

Gras

s5

mon

ths

450

lg

Phlp

5/m

onth

,Cu

mul

at.

2.7

mg,

Tabl

ets

NS

RCA

ALK

RCsy

mpt

om–3

7%(0

.004

),RC

drug

s–4

1%(0

.03)

,W

elld

ays

–52%

(0.0

04)

Asth

ma

sym

ptom

san

dm

edic

atio

ns

Valo

virta

etal

.(42

),20

066–

1465

/33

8/6

Haze

lnut

,birc

h,el

m(tw

odo

-se

s)

18m

onth

sW

eekl

ydo

seof

maj

oral

lerg

ens,

Grou

p1

3.6

lg,

Grou

p2:

30l

g

NS

RCAL

KW

ithhi

gher

dose

:to

tals

ympt

oms

(0.0

01),

nose

,lun

g,ey

esy

mpt

oms

durin

gbi

rch

seas

on(<

0.05

)

Tota

ldru

gsc

ore,

Met

hach

olin

e,Sk

inte

st


G. Walter Canonica

Tabl

e4-

1(C

ontin

ued)

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

prep

arat

ion

Dos

evs

SCIT

Dis

ease

�M

anuf

ac-

ture

rM

ain

posi

tive

resu

ltsN

och

ange

Dahl

etal

.(43

),20

0623

–35

316/

318

42/4

6Gr

ass

6m

onth

s45

0lg

Phlp

5/m

onth

s,Cu

mul

at:

2.7

mg,

Tabl

ets

NS

RCAL

KRC

sym

ptom

–30%

(0.0

01),

RCdr

ugs

)38

%(0

.001

),W

elld

ays

–52%

(0.0

04),

VAS

Lue

etal

.(4

4),2

006

6–12

10/1

00/

0HD

M8

mon

ths

Cum

ulat

:1.

7m

gDe

rp

1,Gl

ycer

osal

ine

NS

AST

AN

ight

sym

p(0

.04)

vspl

Day

sym

p(0

.04)

,FE

V 1,

drug

s(0

.01)

vsb/

line

Day

sym

ptom

s,dr

ugs,

FEV 1

,PEF

vspl

aceb

o

Palm

a-Ca

rlos

etal

.(45

),20

06

19–4

317

/16

4/9

Gras

s(m

onoi

d)2

year

8000

AU/m

onth

Tabl

ets

NS

RCLO

FCo

njun

ctiv

itis,

rhin

orrh

ea,

snee

zing

(<0.

05)

atth

ese

cond

year

;na

salr

eact

ivity

(0.0

3)at

the

seco

ndye

ar

Sym

ptom

san

dna

-sa

lrea

ctiv

ityat

the

first

year

Pham

-Ti

etal

.(46

),20

07

5–11

55/5

611

/8HD

M18

mon

ths

810

lgDe

rp1/

mon

thCu

mul

at6.

9m

g,Gl

ycer

osal

ine

NS

AST

ASP

T(P

=0.

01),

QoL

(P<

0.01

)As

thm

asy

mpt

oms,

Asth

ma

med

icat

ion,

Asth

ma

free

days

,(lo

w:b

oth

grou

ps)

Verv

loet

etal

.(48

),20

07

19–6

038

/38

2/4

Juni

per

4m

onth

s,2

seas

ons

6m

gJu

na

1/m

onth

,Gl

ycer

o-aq

ue-

ous

NS

AST

AFi

rst

and

seco

ndse

ason

:N

asal

ster

oids

(0.0

1),

Tota

lmed

icat

ions

(0.0

4),I

gEan

dIg

G4

Both

seas

ons:

Tota

land

sing

lesy

mpt

omsc

ores

.Si

ngle

med

icat

ion

Roed

eret

al.(

47),

2007

6–18

108/

9626

/24

Gras

s2

year

s16

8lg

Lolp

5/m

onth

Cum

ulat

:4.

5m

gSo

lutio

n

NS

RCAR

TUM

ean

daily

scor

e,Sy

mpt

om-fr

eeda

ys,

Med

icat

ion

free

days

,Qo

L

Alva

rez-

Cues

taet

al.(

49),

2007

16–5

125

/25

8/9

Cat

1ye

arCu

mul

at:

17.1

lgFe

ld1, Gl

ycer

osal

ine

2RC

CBF

Bron

chia

l,na

sal,

conj

unct

i-va

lsym

ptom

san

dPE

Fvs

base

line

(<0.

05)a

tro

omch

alle

nge



Tabl

e4-

1(C

ontin

ued)

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

prep

arat

ion

Dos

evs

SCIT

Dis

ease

�M

anuf

ac-

ture

rM

ain

posi

tive

resu

ltsN

och

ange

Didi

eret

al.(

50),

2007

25–4

747

2/15

659

/10

Gras

s,3

dose

s6

mon

ths

240

lg

(157

pt)/

mon

th,

750

lg

(155

pt)/m

onth

,1.

2m

g(1

60pt

)/mon

thTa

blet

s

NS

RCST

AFo

r30

0&

500

IR,

Tota

l/ind

ivid

uals

ympt

om/

drug

scor

es(<

0.00

1);

RQLQ

;med

icat

ion-

free

days

Horig

uchi

etal

.(51

),20

0718

–50

43/2

42/

2Ja

pce

dar

7m

onth

s6

lg

Cry

j1/m

onth

Solu

tion.

Spit

100

RCTO

RISy

mpt

oms

+dr

ugs

(<0.

05);

snee

zing,

obst

ruct

ion,

rhin

orrh

ea(P

<0.

05).

IgG4

DeBl

ayet

al.(

52),

2007

12–4

161

/57

8/8

Gras

s10

mon

ths

250

lg

grou

p5/

mon

thCu

mul

at:

2.5

mg,

Solu

tion

NS

RCAL

BM

edic

atio

ns(0

.02)

;sym

p-to

ms

inpa

tsw

ithou

tas

thm

a(0

.01)

:QoL

;IgG

4

Glob

alsy

mp

scor

e,Gl

obal

med

icat

ion

scor

e

Mor

eno

etal

.(53

),20

0714

–55

51/4

911

/9Ol

ive

+Gr

ass

10m

onth

s60

lg

grou

p5

90l

gOl

ee

1/m

onth

,So

lutio

n

NS

RCAL

Kvs

first

seas

on:e

ye,n

ose,

lung

and

tota

lsym

ptom

(<0.

01);

sym

ptom

+dr

ugs

(0.0

2)VA

S(0

.01)

;QoL

(0.0

1)

Sym

ptom

and

drug

activ

evs

plac

ebo

Mos

ges

etal

.(54

),20

0718

–50

48/5

36/

5Gr

ass

9m

onth

sCu

mul

ativ

e3.

5m

gPh

lp5

NS

RCST

AN

asal

+oc

ular

sym

ptom

s–3

7%(0

.03)

Eye

sym

ptom

s–4

7%(0

.003

)

Nas

alsy

mpt

oms

(0.0

8),

IgE,

IgG4

Panz

eret

al.(

55),

2008

15–5

045

/30

4/0

Gras

sSL

ITor

supr

alin

g

1ye

ar38

lg

Lol

p5/

mon

thCu

mul

at:

456

lg

Solu

tion

NS

RCSE

VASy

mpt

oms

–38%

(sup

ralin

gual

);–6

7%SL

IT;d

rugs

–67%

IgE;

SPT

Okub

oet

al.(

56),

2008

25–5

538

/23

1/1

Ceda

r5

mon

ths

2000

JAU

NS

RCTO

RISy

mpt

oms

and

med

bette

rin

SLIT

in4

days

ofse

ason

;QoL

Over

alls

easo

nsy

mpt

oms

and

med

icat

ions

Pfaa

ran

dKl

imek

(57)

,200

817

–59

94/9

117

/9Gr

ass

2ye

ars

1.2

mg/

mon

thSo

lutio

nN

SRC

AAL

PSy

mpt

oms

+m

edsc

ores

AUC

(<0.

01),

VAS

Wah

net

al.(

58),

2008

4–17

139/

139

4/8

Gras

s8

mon

ths

600

lg

maj

oral

lerg

en/

mon

th,

Tabl

ets

NS

RCST

ARh

initi

ssc

ore

–28%

(0.0

1);M

eds

–24%

(0.0

06);

Med

.fre

eda

ys(0

.01)


G. Walter Canonica

to trial. The majority of the clinical trials used thetraditional symptom score assessment (graded from 0 to3) plus recording of doses of rescue medications. In sometrials, other evaluation parameters were applied, includingvisual analogue scale (VAS), combined score, symptom-free days and medication-free days. Out of 60 DBPC-RCTs, 18 enrolled more than 100 patients (9, 17, 34, 35,38, 39, 41, 43, 46, 47, 50, 52, 57–60). Of these, ten had aformal sample size calculation (41, 43, 46, 47, 50, 52, 57–60). Twenty DBPC-RCTs involved only paediatric sub-jects (<18 years of age). As shown in Table 4-1, in themajority of the trials, the results were overall positive forone or more of the parameters investigated. On the otherhand, there were four totally negative studies (4, 20, 47,56) and eight trials reported only partial or negligibleclinically efficacy (8, 9, 11, 27, 34, 36, 46, 52).

During the last three years, adequately powered, well-designed DBPC-RCTs involving several hundreds ofpatients and using standardized grass pollen tablets, werepublished (39, 41, 43, 50, 58–60). In those studies themagnitude of the effect, defined as the reduction in diarysymptoms and rescue medication scores compared toplacebo was reported as 16% and 28% (41), 30% and38% (43), 35% and 46% (50), 28% and 24% (58), 24%and 34% (60) respectively. All these trials followed theestablished methodological criteria, had a power calcula-tion and clearly defined outcomes and statistical analyses.So far, these large trials represent the best evidenceavailable on the efficacy of SLIT. According to thesetrials, a dose-dependency of the efficacy of SLIT wasobserved, and the optimal monthly maintenance dose forgrasses was identified as about 600 lg of the majorallergen(s). One large DBPC-RCT (47) of grass extract,with 164 patients from general practice, screened andselected by researchers and specialists from a universityallergy department, failed to demonstrate any differencebetween active and placebo. In another large trial withgrass extract (52), a significant difference in rhinitis scorescould be seen only for those patients without asthma. Thevast majority of the DBPC-RCTs were designed to assessthe efficacy of SLIT in rhinoconjunctivitis, and asthmawas sometimes evaluated as a secondary outcome. Onlyeight studies were specifically designed to assess the effectof SLIT in asthma (15, 21, 31, 38, 39, 44, 46, 61), and themajority confirmed a significant effect on symptoms and/or medication intake. In the three asthma studies thatreported negative results (39, 44, 46), the patients werealmost completely free of asthma symptoms at enrolmentand remained so during the trial, so that the absence ofefficacy is not substantiated. Only two DBPC-RCTsassessed the efficacy of multiple non cross-reacting aller-gens (53, 62). The first one used grass and olive extracts,and confirmed the efficacy of SLIT in rhinitis. The secondone compared the efficacy of SLIT with grass alone orwith grass plus nine other pollens and found that thetreatment with a single allergen had more effect onimmunological parameters than that with multiple aller-Ta

ble

4-1

(Con

tinue

d)

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

prep

arat

ion

Dos

evs

SCIT

Dis

ease

�M

anuf

ac-

ture

rM

ain

posi

tive

resu

ltsN

och

ange

Ott

etal

.(5

9),2

009

20–5

014

2/67

3/1

Gras

s5

year

s,4

seas

ons

Cum

ulat

ive

1.5

mg

maj

oral

lerg

en/

seas

on

NS

RCST

ACo

mbi

ned

and

sym

ptom

ssc

ore

sig.

redu

ced

from

first

seas

on.S

ympt

oms

decr

ease

from

–33%

to47

%(th

irdse

ason

)

Med

icat

ion

scor

eal

lse

ason

s

Bufe

etal

.(60

),20

095–

1612

6/12

712

/7Gr

ass

6m

onth

s45

0l

gPh

lp5/

mon

thN

SRC

ALK

Sig

redu

ctio

nin

RCsy

mp-

tom

ssc

ore

()24

%),

asth

-m

asc

ore

()64

%),

RCm

eds

()34

%),

wel

lday

s(+

28%

).Al

lP<

0.03

Stel

mac

het

al.(

61),

2009

6–17

25/2

55/

10Gr

ass

6m

onth

s,2

seas

ons

3.65

mg

Phlp

5cu

mu-

lat.

NS

AST

ASi

gre

duct

ion

inas

thm

asc

ore

()40

%),

asth

ma

med

()10

%)

Eye

sym

ptom

s



gens. Because of the low pollen count, no clinicaldifference between the two groups and placebo was seenin this study.

Meta-analyses

The first meta-analysis of SLIT for allergic rhinitisincluded 22 trials and 979 patients up to September2002. It concluded that SLIT was significantly moreeffective than placebo (63), but the studies in allergicasthma were too few to perform a meta-analysis. A meta-analysis in asthma was recently repeated, including 25trials (either open or blinded) and involving more than1000 adults and children (64). This meta-analysis demon-strated a significant effect of SLIT for most of theconsidered outcomes (symptoms + medications, pulmo-nary function, overall improvement), with the exceptionof asthma symptoms alone. Another meta-analysis (65) ofSLIT for allergic rhinitis in paediatric patients (aged 4–18 years) involved 10 trials and 484 subjects. It showedthat SLIT was significantly more effective than placebo, asassessed by the reduction in both symptom scores andrescue medications usage. Although all the studies were ofhigh methodological quality, there was a relevant heter-ogeneity (I2 > 80%), because of the large variability instudy design, duration, outcome measures and inclusioncriteria. Finally, a meta-analysis was also performed forasthma in paediatric patients (66). This review includednine DBPC trials and 441 patients, and found a significanteffect of SLIT on both asthma symptoms and rescuemedication usage. Also in this case, the heterogeneity ofthe trials was very large (I2 > 90%). The meta-analysesmentioned pooled together all the allergens, whereas asystematic evaluation of the efficacy of one specificallergen is available only for house dust mite (67), withpositive results. In summary, the available meta-analysesinvolve very heterogeneous trials, often without a propersample size calculation: publication biases and discrepan-cies in data collection are additional concerns (68). Thus,meta-analyses provide only suggestive evidence.

Other controlled studies (Table 4-2)

There are eight randomised open controlled trials (69–76)assessing the clinical efficacy of SLIT, mostly comparedwith control groups receiving drugs only. All these studiesprovided positive results for clinical scores and/or med-ication intake, and two of them (71, 74) also demonstrateda significant reduction in non-specific bronchial hyperre-sponsiveness. One trial (75) was specifically designed toevaluate the safety of a no-updosing regimen, rather thanthe efficacy, and another (76) demonstrated that SLITwith two non cross-reacting allergens (birch and grass) isoverall more effective than SLIT with the single allergensin both pollen seasons.


Tabl

e4-

2Ra

ndom

ised

cont

rolle

dno

tdo

uble

-blin

d

Aut

hor

(ref

),ye

arD

escr

iptio

nA

ge rang

ePa

tient

sA

llerg

enD

urat

ion

Dos

ePr

epar

atio

nD

isea

seM

anu-

fact

urer

Mai

nre

sults

D�Am

bros

ioet

al.(

69),

1996

Rand

omis

edop

en.

Cont

rols

with

drug

son

ly

18–5

620

SLIT

20Co

ntro

lPa

rieta

ria6

mon

ths

NS

RAL

KLo

wer

sym

ptom

scor

e(P

=0.

032)

and

drug

+sy

mpt

omsc

ore

(P=

0.03

7)

Goza

loet

al.(

70),

1997

Rand

omis

edop

en.

Cont

rols

with

drug

son

ly

18–5

035

SLIT

19Co

ntro

lGr

ass

2ye

ars

NS

RAL

KLe

esm

edic

atio

nsin

SLIT

grou

pin

first

(0.0

5)an

dse

cond

(0.0

1)po

llen

seas

on

Lom

bard

iet

al.(

71),

2001

Rand

omis

edop

en.

Cont

rols

with

drug

son

ly

18–5

526

SLIT

25Co

ntro

lGr

ass

6m

onth

s3

seas

ons

8000

AU/m

onth

Alle

rgoi

dRA

LOF

Decr

ease

drh

initi

s/as

thm

am

edic

atio

n(0

.01)

,rhi

nitis

/ast

hma

scor

es(0

.01)

,non

-spe

cific

bron

chia

lrea

ctiv

ity(0

.01)

G. Walter Canonica


Tabl

e4-

2(C

ontin

ued)

Aut

hor

(ref

),ye

arD

escr

iptio

nA

gera

nge

Patie

nts

Alle

rgen

Dur

atio

nD

ose

Prep

arat

ion

Dis

ease

Man

ufac

ture

rM

ain

resu

lts

Mar

ogna

etal

.(72

),20

04

Rand

omis

ed,o

pen

cont

rolle

d18

–62

390

SLIT

192

Cont

rol

HDM Gras

sPa

rieta

riaBi

rch

3ye

ars

32l

gDe

rp

1/m

onth

5.8

lg

Phlp

1/m

onth

5.8

lg

Par

j1/m

onth

8.3

lg

Bet

v1/m

onth

RCAN

ACl

inic

alsc

ores

impr

ovem

ent

at1,

2an

d3

year

svs

base

line

and

cont

rols

(<0.

01).

New

sens

itiza

tions

at3

year

sin

5.9%

SLIT

and

38%

cont

rols

(<0.

01)

Mar

cucc

iet

al.(

73),

2005

Rand

omis

ed,o

pen,

two

diffe

rent

dose

s6–

1410

0IR

=32

300I

R=

42Gr

ass

6m

onth

s10

0IR

300

IRGl

ycer

osal

ine

RCST

AHi

gher

dose

bette

rfo

rov

eral

lsco

re(P

=0.

024)

,sy

mpt

oms

(0.0

3),

and

med

icat

ions

(0.0

4)du

ring

peak

polle

n.N

och

ange

inIg

E

Mar

ogna

etal

.(74

),20

05

Rand

omis

edop

en.

Cont

rols

with

drug

son

ly

18–6

539

SLIT

40Co

ntro

lBi

rch

5ye

ars

5se

ason

s8.

5l

gBe

tv

1gl

ycer

inat

edRA

ANA

From

seco

ndse

ason

:re

duct

ion

asth

ma/

rhin

itis

sym

ptom

s(0

.01)

,sal

buta

mol

inta

ke(0

.001

),m

etha

chol

ine

reac

tivity

(0.0

1).N

och

ange

inth

efir

stse

ason

.

Guer

raet

al.(

75),

2006

Rand

omis

ed,o

pen.

Com

paris

ontra

ditio

nalv

sno

updo

sing

18–4

510

tradi

tion

10no

updo

sing

Parie

taria

3m

onth

s90

lg

Par

j1cu

mul

ativ

eSo

lutio

n

RAL

KN

odi

ffere

nce

insi

deef

fect

sbe

twee

nth

etw

ore

gim

ens

Mar

ogna

etal

.(76

),20

07Ra

ndom

ised

open

.Fo

urgr

oups

:bi

rch,

gras

s,bi

rch

+gr

ass,

cont

rols

19–4

311

birc

h,12

gras

s,13

birc

h+

gras

s12

Cont

rol

Birc

hGr

ass

2se

ason

sSe

cond

and

Four

thye

ar

100

lg

Bet

v180

lg

Phlp

1RA

ANA

Sing

leal

lerg

ens

effe

ctiv

eon

sym

ptom

san

dm

edic

atio

nsc

ores

inth

esp

ecifi

cse

ason

and

othe

rse

ason

.Co

mbi

ned

SLIT

sign

ifica

ntly

mor

eef

fect

ive

inbo

thse

ason

s.



Tabl

e4-

3Co

mpa

rison

sbe

twee

nSL

ITan

dSC

IT

Aut

hor

(ref

),ye

arD

esig

nPa

tient

sA

llerg

enD

urat

ion

Dos

eM

anuf

actu

rer

Mai

nre

sults

Quiri

noet

al.

(77)

,199

6Ra

ndom

ised

DBdo

uble

-dum

my

with

out

plac

ebo

arm

10SL

IT10

SCIT

Gras

s12

mon

ths

6.4

lgm

ajor

alle

rgen

/m

onth

for

SCIT

.SL

IT=

3X

SCIT

ALK

Sign

ifica

ntre

duct

ion

insy

mpt

oman

ddr

ugin

take

scor

e(P

<0.

01)i

nbo

thgr

oups

ver-

sus

base

line.

No

chan

gein

IgE.

Incr

ease

inIg

Gan

dre

duct

ion

ofsk

inre

activ

ityon

lyin

SCIT

grou

p

Bern

ardi

set

al.

(79)

1996

Rand

omis

ed,o

pen,

with

out

plac

ebo

SCIT SLIT

Alte

rnAL

K

Piaz

zaan

dBi

zzar

ro(8

0),

1993

Rand

omis

ed,

open

,SLI

Tan

dSC

ITvs

nasa

lIT

and

cont

rols

17SC

IT14

SLIT

12LN

IT14

Cont

rols

HDM

2ye

ars

SCIT

:4.8

lg/

mon

thSL

IT:1

2l

g/m

onth

LNIT

:32

ng/

mon

th

ALK

SLIT

:dec

reas

ein

sym

ptom

sat

3m

onth

s(0

.01)

but

not

12–2

4m

onth

s.SC

IT:d

ecre

ase

insy

mpt

oms

at3,

12,2

4m

onth

s(<

0.01

).Ig

E,Ig

Gan

dIg

G4ch

ange

don

lyin

SCIT

.N

och

ange

atal

lin

LNIT

Mun

gan

etal

.(8

1),1

999

Rand

omis

edop

en,p

la-

cebo

-SL

ITco

ntro

lled

15SL

IT10

SCIT

11Pl

aceb

o

HDM

1ye

arDe

rp

1SL

IT:2

1.6

lg/

mon

thSC

IT:0

.6l

g/m

onth

STA

Redu

ctio

nin

rhin

itis

scor

efo

rSL

IT(<

0.01

)and

SCIT

(<0.

05).

Asth

ma

scor

ere

duct

ion

only

SCIT

(<0.

05).

Redu

ctio

ndr

ugsc

ore

for

both

SLIT

and

SCIT

.Re

duct

ion

SPT

diam

eter

only

inSC

IT.

Khin

chie

tal

.(7

8),2

002

Rand

omis

edDB

doub

le-d

umm

ypl

aceb

oco

ntr.

21SC

IT18

SLIT

19Pl

aceb

o

Birc

h2

seas

ons

Bet

v1/

mon

thSC

IT:3

.28

lg

SLIT

:738

lg

STA

Redu

ctio

nof

rhin

itis

scor

ein

SLIT

(0.3

6)an

dSC

IT(0

.75)

.No

sign

ifica

ntdi

ffere

nce

betw

een

treat

men

ts,b

oth

supe

rior

topl

aceb

o(P

=0.

002)

.Med

ica-

tion

scor

esSL

ITan

dSC

ITvs

plac

ebo

(P=

0.02

).N

och

ange

inQo

L.

Mau

roet

al.

(82)

,200

7Ra

ndom

ised

open

SLIT

vsSC

IT19

SCIT

15SL

ITBi

rch

4m

onth

sCu

mul

ativ

e50

.65

IRSC

IT46

53.1

IRSL

IT

STA

Durin

gpo

llen

seas

on,n

odi

ffer-

ence

SLIT

-SCI

Tin

sym

p-to

ms

+dr

ugsc

ores

.Spe

cific

IgG4

sign

ifica

ntly

incr

ease

sw

ithSC

ITon

ly

G. Walter Canonica


Tabl

e4-

4DB

PC-R

CTs

inDi

seas

esot

her

than

Resp

irato

ryAl

lerg

y

Aut

hor

(ref

),ye

arA

gera

nge

Patie

nts

A/P

*D

ropo

utA

/P*

Alle

rgen

Dur

atio

nD

ose

Dis

ease

Man

ufac

ture

rM

ain

resu

lts

Enriq

ueet

al.(

83),

2005

19–5

312

/11

1/0

Haze

lnut

6m

onth

s18

8lg

Cor

a1/d

ayFo

od alle

rgy

Sign

ifica

ntin

crea

sein

the

food

chal

leng

epr

ovoc

atio

ndo

se(P

=0.

02).

50%

activ

esu

bjec

tsto

lera

ted

max

imum

dose

.No

chan

geIg

G4an

dsk

inte

st.

Fern

ande

zRi

vas

etal

.(84

),20

09

20–4

037

/19

4/3

Peac

h6

mon

ths

300

lgPr

up

3/m

onth

Food

alle

rgy

ALK

Sign

ifica

ntin

crea

se(3

–5tim

es)

ofth

epr

ovoc

atio

ndo

seat

DBPC

FC

Bern

ardi

ni(8

5),

2006

5–14

12/1

40/

0La

tex

1ye

arSk

in,r

espi

rato

ryan

dor

alal

lerg

ydu

eto

late

x

ALK

Activ

egr

oup:

Impr

ovem

ent

glov

ete

stat

3m

onth

san

d1

year

(P<

0.01

).Re

duct

ion

oral

alle

rgy

syn-

drom

e

Pajn

oet

al.(

87),

2007

5–16

28/2

82/

6M

ite18

mon

ths

3.3

lg

Der

p1/

wee

kAt

opic

derm

atiti

sAN

AOn

lyin

mild

-mod

erat

esu

bjec

ts:

Redu

ctio

nSC

ORAD

star

ting

from

mon

th9

(P=

0.02

5).

Redu

ctio

nre

scue

med

icat

ions

(P0.

02)

Net

tiset

al.

(86)

,200

718

–47

20/2

02/

3La

tex

12m

onth

s12

00lg

/mon

thLa

tex

alle

rgy,

urtic

aria

,ast

hma

ALK

Activ

egr

oup:

Decr

ease

dre

activ

itygl

ove

test

(P<

0.05

),De

crea

sed

bron

chia

lrea

ctiv

ityto

late

x(<

0.05

),Sy

mpt

oms

and

resc

uem

edic

a-tio

nsc

ores

at6

and

12m

onth

s

Seve

rino

etal

.(8

8),2

008

18–6

515

/15

1/3

Hone

ybe

e6

mon

ths

525

lgve

nom

/m

onth

Hym

enop

tera

alle

rgy,

Larg

elo

calr

eact

ions

ANA

Redu

ctio

npe

akdi

amet

erLL

R(P

=0.

014)

atst

ing

chal

leng

e.In

crea

sesp

ecifi

cIg

G4(0

.03)

*Act

ive/

Plac

ebo;

�Rhi

nitis

,Ast

hma,

Conj

unct

iviti

s.AL

K,Al

k-Ab

ell�

;AN

A,An

alle

rgo;

ALB,

Alle

rBio

;AL

P,A

llerg

opha

rma;

ART,

Artu

Biol

ogic

als;

CBF,

CBF

Leti;

HS,H

ollis

ter-S

tier;

LOF,

Lofa

rma;

STA,

Stal

lerg

enes

;SEV

A,Se

vaPh

arm

a;TO

RI,T

orii

Phar

mac

eutic

als.


Comparison with SCIT (Table 4-3)

When comparing two different routes of administration,the gold standard methodology is the use of a double-blind, double-dummy design. One double-dummy study,although without a placebo group, conducted in grasspollen allergic patients, showed that the clinical efficacyof SLIT (symptoms and medication use) was equivalentto that of SCIT (77). Another rigorous double-blind,double-dummy, placebo-controlled trial with birch pol-len extract, compared SLIT and SCIT. Symptoms andmedication use were reduced by about one-third in theSLIT group and by one-half in the SCIT group, withno significant difference evident between treatments.However, there were six grade 3 and 4 adverse reactionsin the SCIT group and none in the SLIT group (78).Four other comparative studies have been published,but they were all conducted in an open fashion.Bernardis et al. (79) performed an open comparative12 months study in Alternaria tenuis allergic patientsand found a clinical improvement in symptoms (mainlyrhinitis) and medication use in both groups with astatistically significant difference in favour of SLIT. Inanother study (80), the clinical efficacy of SLIT, SCITand nasal immunotherapy was assessed in 43 patientswith rhinitis due to mites. This study considered onlythe immunological changes, which were significant onlyfor SCIT. An open comparison (81), again in mite-allergic patients, showed that the clinical improvementwas more prompt with SCIT, especially for asthmasymptoms, although SLIT controlled rhinitis symptomswell. Finally, Mauro et al. (82), compared SCIT andSLIT in 47 patients with birch allergy and found nodifference between the two treatments in seasonalsymptom score, although specific IgG4 significantlyincreased only with SCIT.

DBPC-RCTs of SLIT in other diseases (Table 4-4)

The efficacy of SLIT was investigated, as proof ofconcept, in DBPC-RCTs in diseases other than respira-tory allergy, namely food allergy (83, 84), latex allergy(85, 86), atopic dermatitis (87), and Hymenopteravenom allergy (88). The results of all these trials wereclearly in favour of SLIT. Enrique (83) found that SLITwas able to significantly increase the oral provocationthreshold in patients with hazelnut allergy and the samewas shown by Fernandez et al. with peach (84). Pajnoet al. (87) showed that in patients allergic to mites andwith mild-moderate atopic dermatitis SLIT after9 months significantly reduced the SCORAD score.Severino et al., in 30 patients with honeybee allergy,demonstrated that a 6-month course of SLIT with amaintenance dose of 525 lg venom significantly reducedthe severity of large local reactions to sting challenge(88).

Unmet needs

• Recent large trials with grass extracts have identified theoptimal dose for this allergen: similar studies (dose-finding, DBPC-RCT) are mandatory for the other rel-evant allergens, that is, house dust mite (HDM),Parietaria, ragweed and cat dander, but should takeinto account the variability of potency of extractsamong manufacturers (89).

• According to press releases and one abstract (90), someUS clinical trials failed to reach the primary outcome,thus, FDA approval is still pending. Possible reasonsfor those results, including inappropriate patient selec-tion and low pollen counts, have been extensivelyanalysed by a WAO task force (91), who also providedrecommendations for future trials.

• Current data on the clinical efficacy of SLIT in asthmaare controversial: it is essential that RCTs with appro-priate sample sizes are conducted in patients symp-tomatic for asthma under natural allergen exposure.Symptom and rescue medication intake scores are areasonable outcome measure, but objective parameters(FEV1, PEF) should be included as co-primary end-points.

• Experimental data on mixtures of unrelated allergensare very scarce, thus properly conducted clinical trialsevaluating this are needed (the safety aspect is of pri-mary relevance). Since the European Agency for Med-ications (EMEA) recommends against mixing differentallergens in a single preparation (92), there may beproblems with the feasibility of clinical studies with suchmixtures.

• Other relevant questions are the optimal duration of aSLIT course, the duration of the preseasonal inductionand the efficacy/safety of the no-build up regimens.

• Oral allergy symptoms are commonly reported in manystudies and it is not possible to control for this side-effect. This fact could influence results.

• Although positive results on the use of SLIT in latexallergy, food allergy, atopic dermatitis and Hymenop-tera venom allergy have been reported, these should beconsidered as investigational: further data on efficacyand safety are needed.

• No clinical data are available for nickel-induced sys-temic reactions (SRs).


1. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ,Lockey RF, Malling HJ et al. Recommendations for standard-ization of clinical trials with Allergen Specific Immunotherapyfor respiratory allergy. A statement of a World Allergy Orga-nization (WAO) taskforce. Allergy 2007;62:317–324.

2. Scadding GK, Brostoff J. Low dose sublingual therapy in pa-tients with allergic rhinitis due to dust mite. Clin Allergy1986;16:483–491.


G. Walter Canonica

3. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-notherapy in patients with rhinitis and asthma due to house dustmite. A double-blind study. Allergol Immunopathol1990;18:277–284.

4. Nelson H, Oppenheimer J, Vatsia GA, Buchmeier A. A double-blind, placebo-controlled evaluation of sublingual immuno-therapy with standardized cat extract. J Allergy Clin Immunol1993;92:229–236.

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14. Passalacqua G, Albano M, Riccio AM, Fregonese L, PuccinelliP, Parmiani S et al. Clinical and immunological effects of a rushsublingual immunotherapy to Parietaria species: a double-blindplacebo-controlled trial. J Allergy Clin Immunol 1999;104:964–968.

15. Bousquet J, Scheinmann P, Guinnepain MT, Perrin-Fayolle M,Sauvaget J, Tonnel AB et al. Sublingual swallow immunother-apy (SLIT) in patients with asthma due to house dust mites: adouble-blind placebo-controlled study. Allergy 1999;54:249–260.

16. Purello D�Ambrosio F, Gangemi S, Isola S, La Motta N, Puc-cinelli P, Parmiani S et al. Sublingual immunotherapy: a double-blind placebo-controlled trial with Parietaria judaica extractstandardized in mass units in patients with rhinoconjunctivitis,asthma or both. Allergy 1999;54:968–973.

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24. Bahceciler NN, Isik U, Barlan IB, Basaran N. Efficacy of sub-lingual immunotherapy in children with asthma and rhinitis: adouble-blind, placebo-controlled study. Pediatr Pulmonol2001;32:49–55.

25. Voltolini S, Modena P, Minale P, Bignardi D, Troise C, Puc-cinelli P, Parmiani S. Sublingual immunotherapy in tree pollenallergy. Double-blind, placebo-controlled study with a biologi-cally standardized extract of tree pollen (alder, birch and hazel)administered by a rush schedule. Allergol Immunopathol2001;29:103–110.

26. Sanchez Palacios A, Schamann F, Garcia JA. Sublingualimmunotherapy with cat epithelial extract. Personal experience.Allergol Immunopathol (Madr) 2001;29:60–65.

27. Lima MT, Wilson D, Pitkin L et al. Grass pollen sublingualimmunotherapy for seasonal rhinoconjunctivitis: a randomizedcontrolled trial. Clin Exp Allergy 2002;32:507–514.

28. Mortemousque B, Bertel F, De Casamayor J, Verin P, Colin J.House-dust mite sublingual-swallow immunotherapy in peren-nial conjunctivitis: a double-blind, placebo-controlled study.Clin Exp Allergy 2003;33:464–469.

29. Andre C, Perrin-Fayolle M, Grosclaude M et al. A double-blindplacebo-controlled evaluation of SLIT with a standardizedragweed extract in patients with seasonal rhinitis. Int Arch Al-lergy Immunol 2003;131:111–118.

30. Ippoliti F, De Sanctis W, Volterrani A, Lenti L, Canitano N,Lucarelli S et al. Immunomodulation during sublingual ther-apy in allergic children. Pediatr Allergy Immunol 2003;14:216–221.

31. Pajno G, Vita D, Parmiani S, Caminiti D, La Grutta S, BarberioG. Impact of sublingual immunotherapy on seasonal asthmaand skin reactivity in children allergic to Parietaria pollentreated with inhaled fluticasone propionate. Clin Exp Allergy2003;33:1641–1647.

32. Wuthrich B, Bucher Ch, Jorg W, Bircher A, Eng P, Schneider Yet al. Double-blind, placebo-controlled study with sublingualimmunotherapy in children with seasonal allergic rhinitis tograss pollen. J Investig Allergol Clin Immunol 2003;13:145–148.




34. Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P, Ge-hlhar K, Holland-Letz T et al. Efficacy of sublingual swallowimmunotherapy in children with severe grass pollen allergicsymptoms: a double-blind placebo-controlled study. Allergy2004;59:498–504.

35. Smith H, White P, Annila I, Poole J, Andre C, Frew A. Ran-domized controlled trial of high-dose sublingual immunother-apy to treat seasonal allergic rhinitis. J Allergy Clin Immunol2004;114:831–837.

36. Rolinck-Werninghaus C, Wolf H, Liebke C, Baars JC, Lange J,Kopp MV et al. A prospective, randomized, double-blind, pla-cebo-controlled multi-centre study on the efficacy and safety ofsublingual immunotherapy (SLIT) in children with seasonalallergic rhinoconjunctivitis to grass pollen. Allergy2004;59:1285–1293.

37. Bowen T, Greenbaum J, Charbonneau Y, Hebert J, FildermanR, Sussman G et al. Canadian trial of sublingual swallowimmunotherapy for ragweed rhinoconjunctivitis. Ann AllergyAsthma Immunol 2004;93:425–430.

38. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy ofsublingual immunotherapy with high-dose mite extracts inasthma: a multi-center, double-blind, randomized, andplacebo-controlled study in Taiwan. Respir Med 2006;100:1374–1383.

39. Dahl R, Stender A, Rak S. Specific immunotherapy with SQstandardized grass allergen tablets in asthmatics with rhino-conjunctivitis. Allergy 2006;61:185–190.

40. Passalacqua G, Pasquali M, Ariano R, Lombardi C, Baiardini I,Majani G et al. Randomized double-blind controlled study withsublingual carbamylated allergoid immunotherapy in mild rhi-nitis due to mites. Allergy 2006;61:849–854.

41. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S.Sublingual immunotherapy with once-daily grass-allergentablets: a randomised controlled trial in seasonal allergicrhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802–809.

42. Valovirta E, Jacobsen L, Savolainen A. Clinical efficacy andsafety of sublingual immunotherapy with tree pollen extract inchildren. Allergy 2006;61:1177–1183.

43. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S,Emminger W et al. Efficacy and safety of sublingualimmunotherapy with grass allergen tablets for seasonalallergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;118:434–440.


45. Palma-Carlos AG, Santos AS, Branco-Ferreira M, Pregal AL,Palma-Carlos ML, Bruno ME et al. Clinical efficacy and safetyof preseasonal sublingual immunotherapy with grass pollencarbamylated allergoid in rhinitic patients. A double-blind,placebo-controlled study. Allergol Immunopathol (Madr)2006;34:194–198.

46. Pham-Thi N, Scheinmann P, Fadel R, Combebias A, Andre C.Assessment of sublingual immunotherapy efficacy in childrenwith house dust mite-induced allergic asthma optimally con-trolled by pharmacologic treatment and mite-avoidance mea-sures. Pediatr Allergy Immunol 2007;18:47–57.

47. Roder E, Berger MY, Hop WC, Bernsen RM, de Groot H,Gerth van Wijk R. Sublingual immunotherapy with grass pollenis not effective in symptomatic youngsters in primary care. JAllergy Clin Immunol 2007;119:892–898.

48. Vervloet D, Birnbaum J, Laurent P, Hugues B, Fardeau MF,Massabie-Bouchat YP et al. Safety and efficacy of Juniperusashei sublingual-swallow ultra-rush pollen immunotherapy incypress rhinoconjunctivitis. A double-blind, placebo-controlledstudy. Int Arch Allergy Immunol 2007;142:239–246.

49. Alvarez-Cuesta E, Berges-Gimeno P, Mancebo EG, Fernandez-Caldas E, Cuesta-Herranz J, Casanovas M. Sublingual immu-notherapy with a standardized cat dander extract: evaluation ofefficacy in a double-blind placebo-controlled study. Allergy2007;62:810–817.


51. Horiguchi S, Okamoto Y, Yonekura S, Okawa T, YamamotoH, Kunii N et al. A randomized controlled trial of sublingualimmunotherapy for Japanese cedar pollinosis. Int Arch AllergyImmunol 2007;146:76–84.

52. de Blay F, Barnig C, Kanny G, Purohit A, Leynadier F, Tunonde Lara JM et al. Sublingual-swallow immunotherapy withstandardized 3-grass pollen extract: a double-blind, placebo-controlled study. Ann Allergy Asthma Immunol 2007;99:453–461.

53. Moreno-Ancillo A, Moreno C, Ojeda P, Domınguez C, Bara-sona MJ, Garcıa-Cubillana A et al. Efficacy and quality of lifewith once-daily sublingual immunotherapy with grasses plusolive pollen extract without updosing. J Investig Allergol ClinImmunol 2007;17:399–405.

54. Mosges R, Buning HJ, Hessler G, Gotz G. SLIT in pollen in-duced seasonal rhinitis and conjuncivitis: a randomized con-trolled trial. Acta Dermatovenerol Alp Panonica Adriat2007;16:143–150.

55. Panzner P, Petras M, Sykora T, Lesna I. Double-blind, placebo-controlled evaluation of grass pollen specific immunotherapywith oral drops administered sublingually or supralingually.Respir Med 2008;102:1296–1304.

56. Okubo K, Gotoh M, Fujieda S, Okano M, Yoshida H, Mor-ikawa H et al. A randomized double-blind comparative study ofsublingual immunotherapy for cedar pollinosis. Allergol Int2008;57:265–275.

57. Pfaar A, Klimek L. Efficacy and safety of specific immuno-therapy with a high-dose sublingual grass pollen preparation: adouble-blind, placebo-controlled trial. Ann Allergy AsthmaImmunol 2008;100:256–263.

58. Wahn U, Tabar A, Kuna P, Halken S, Montagut A, De Beau-mont O. Efficacy and safety of 5 grass pollen subllingualim-munotherapy in pediatric allergic rhinoconjunctivitis. J AllergyClin Immunol 2009;123:160–166.

59. Ott H, Sieber J, Brehler R, Folster-Holst R, Kapp A, Klimek Let al. Efficacy of grass pollen sublingual immunotherapy forthree consecutive seasons and after cessation of treatment: theECRIT study. Allergy 2009;64:179–186.

60. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig F,Klimek L et al. Safety and efficacy in children of an SQ-stan-dardized grass allergen tablet for sublingual immunotherapy. JAllergy Clin Immunol 2009;123:167–173.

61. Stelmach I, Kaczmarek-Wozniak J, Majak P, Olszowiec-Chlebna M, Jerzynska J. Efficacy and safety of high-dosessublingual immunotherapy in ultra-rush scheme in childrenallergic to grass pollen. Clin Exp Allergy 2009;39:401–408.

62. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O�Brien H, NelsonH. Response to sublingual immunotherapy with grass pollenextract: monotherapy versus combination in a multiallergenextract. J Allergy Clin Immunol 2009;124:150–156.


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63. Wilson DR, Torres L, Durham SR. Sublingual immunotherapyfor allergic rhinitis. Allergy 2005;60:3–8.

64. Calamita Z, Saconato H, Bronhara Pela A, Nagib Atallah A.Efficacy of sublingual immunotherapy in asthma. Systematicreview of randomized clinical trials. Allergy 2006;61:1162–1172.

65. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Hu-erta J, Passalacqua G et al. Efficacy of sublingual immuno-therapy in the treatment of allergic rhinitis in children. Metaanalysis of randomized controlled trials. Ann Allergy AsthmaImmunol 2006;97:141–148.

66. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,Orozco S, Pedroza A et al. Metaanalysis of the efficacy of sub-lingual immunotherapy in the treatment of allergic asthma inpediatric patients, 3 to 18 years of age. Chest 2008;133:599–609.

67. Compalati E, Passalacqua G, Bonini M, Canonica GW. Theefficacy of sublingual immunotherapy for house dust mitesrespiratory allergy: results of a GA2LEN meta-analysis. Allergy2009;64:1570–1579.

68. Nieto A, Mazon A, Pamies R, Bruno M, Navarro M, MontanesA. Sublingual immunotherapy for allergic respiratory diseases:an evaluation of meta-analyses. J Allergy Clin Immunol2009;124:157–161.

69. D�Ambrosio FP, Ricciardi L, Isola S, Savi E, Parmiani S, Puc-cinelli P et al. Rush sublingual immunotherapy in Parietariaallergic patients. Allergol Immunopathol (Madr) 1996;24:146–151.

70. Gozalo F, Martın S, Rico P, Alvarez E, Cortes C. Clinicalefficacy and tolerance of two year Lolium perenne sublingualimmunotherapy. Allergol Immunopathol (Madr) 1997;25:219–227.

71. Lombardi C, Gargioni S, Venturi S, Zoccali P, Canonica GW,Passalacqua G. Controlled study of preseasonal immunotherapywith grass pollen extract in tablets: effect on bronchial hyp-erreactivity. J Investig Allergol Clin Immunol 2001;11:41–45.

72. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa-lacqua G. Randomized controlled open study of sublingualimmunotherapy for respiratory allergy in real-life: clinical effi-cacy and more. Allergy 2004;59:1205–1210.

73. Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F. Dosedependence of immunological response to sublingual immuno-therapy. Allergy 2005;60:952–956.

74. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa-lacqua G. Clinical, functional, and immunologic effects of sub-lingual immunotherapy in birch pollinosis: a 3-year randomizedcontrolled study. J Allergy Clin Immunol 2005;115:1184–1188.

75. Guerra L, Compalati E, Rogkakou A, Pecora S, Passalacqua G,Canonica G. Randomized open comparison of the safety ofSLIT in a no-updosing and traditional updosing schedule inpatients with Parietaria allergy. Allergol Immunopathol (Madr)2006;34:82–83.

76. Marogna M, Massolo A, Spadolini I, Zanon P, Berra D, Pas-salacqua G. Efficacy of sublingual immunotherapy with singe ormultiple allergens in polysensititzed patients. Ann AllergyAsthma Immunol 2007;98:274–280.

77. Quirino T, Iemoli E, Siciliani E, Parmiani S, Milazzo F. Sub-lingual vs injective immunotherapy in grass pollen allergic pa-tients: a double-blind double-dummy study. Clin Exp Allergy1996;26:1253–1261.

78. Khinchi S, Poulsen LK, Carat F, Andre C, Malling HJ. Clinicalefficacy of sublingual swallow and subcutaneous immunother-apy in patients with allergic rhinoconjunctivitis due to birchpollen. A double-blind double-dummy placebo-controlled study.Allergy 2004;59:45–53.

79. Bernardis P, Agnoletto M, Puccinelli P, Parmiani S, PozzanM. Injective VS sublingual immunotherapy in Alternariatenuis allergic patients. J Investig Allergol Clin Immunol 1996;6:55–62.

80. Piazza I, Bizzarro N. Humoral response to subcutaneous, oraland nasal immunotherapy for allergic rhinitis due todermatophagoides pteronyssinus. Ann Allergy 1993;71:461–469.

81. Mungan D, Misirligil Z, Gurbuz L. Comparison of theefficacy of subcutaneous and sublingual immunotherapy inmite sensitive patients with rhinitis and asthma: a placebo-controlled study. Ann Allergy Asthma Immunol 1999;82:485–490.

82. Mauro M, Russello M, Incorvaia C, Gazzola GB, Di Cara G,Frati F. Comparison of efficacy, safety and immunologic effectsof subcutaneous and sublingual immunotherapy in birch polli-nosis: a randomized study. Eur Ann Allergy Clin Immunol2007;39:119–122.

83. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella Ret al. Sublingual immunotherapy for hazelnut food allergy: arandomized, double-blind, placebo-controlled study with astandardized hazelnut extract. J Allergy Clin Immunol2005;116:1073–1079.

84. Fernandez-Rivas M, Garrido Fernandez S, Nadal JA, AlonsoDıaz de Durana MD, Garcıa BE, Gonzalez-Mancebo E et al.Randomized double-blind, placebo-controlled trial of sublingualimmunotherapy with a Pru p 3 quantified peach extract. Allergy2009;64:876–883.

85. Bernardini R. Sublingual immunotherapy with a latex extract inpaediatric patients: a double-blind, placebo-controlled study.Curr Med Res Opin 2006;22:1515–1522.

86. Nettis E, Colanardi MC, Soccio AL, Marcandrea M, Pinto L,Ferrannini A et al. Double-blind, placebo-controlled study ofsublingual immunotherapy in patients with latex-inducedurticaria: a 12-month study. Br J Dermatol 2007;156:674–681.

87. Pajno GB, Caminiti L, Vita D, Barberio G, Salzano G, Lom-bardo F et al. Sublingual immunotherapy in mite-sensitizedchildren with atopic dermatitis: a randomized, double-blind,placebo-controlled study. J Allergy Clin Immunol 2007;120:164–170.

88. Severino M, Cortellini G, Bonadonna P, Macchia D, CampiP, Spadolini I et al. Sublingual immunotherapy for largelocal reactions. due to honeybee sting. Double-blind placebo-controlled trial. J Allergy Clin Immunol 2008;122:44–48.

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90. Esch RE, Bush RK, Skoner D, Gentile D, McLaughlin A, Fa-sano MB. Parallel randomized double-blind placebo-controlleddose response phase IIB trial in adults for short ragweed sub-lingual oral immunotherapy [abst]. J Allergy Clin Immunol2008;121:S127.

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92. Committee for medicinal prducts for human use (CPMP).Guideline on allergen products: production and qualityissues. EMEA/CPMP/BWP/304831/2007. London, November28th.



Chapter 5: Safety of sublingual

immunotherapy

• SLIT appears to be better tolerated than SCIT.• SLIT should only be prescribed by allergy-trainedphysicians.

• Specific instructions should be provided to patientsregarding the management of adverse reactions,unplanned interruptions in treatment and situationswhen SLIT should be withheld.

• The majority of SLIT adverse events appears to oc-cur during the beginning of treatment.

• A few cases of SLIT-related anaphylaxis have beenreported but no fatalities.

• Risk factors for the occurrence of SLIT severe ad-verse events have not yet been established.

• There is a need for a generally accepted system ofreporting adverse reactions/anaphylaxis.

Classification and frequency of SLIT adverse events

One of the purported advantages of SLIT over SCIT isgreater safety, which may allow for administration ofthis treatment outside of the medical setting. In acomprehensive review of 104 articles on SLIT, therewere 66 studies that provided some information onsafety and tolerance, representing 4378 patients whoreceived approximately 1 181 000 SLIT doses (1). Theamount of information on the adverse events (AE) inthese studies varied greatly, ranging from generalsummary statements, such as �no relevant side effects,�to a detailed analysis of the AEs. One considerationwith SLIT is that the majority of doses are administeredoutside of the clinic setting with no direct medicalsupervision, and the accuracy of the AE reporting isdependent on the patient and/or family�s interpretationof the event and recall. The vast heterogeneity inclassifying and reporting immunotherapy (SCIT andSLIT) AEs in the published clinical trials makescomparisons and analysis of safety difficult. Recognizingthe need for a more uniform classification of immuno-therapy AEs, a Joint Task Force (representing membersof the American College of Allergy and ClinicalImmunology [ACAAI], American Academy of Allergyand Clinical Immunology [AAAAI], EAACI, and WAOimmunotherapy committees) was formed with thepurpose of developing a uniform classification systemfor anaphylaxis. This grading system is referred to asthe World Allergy Organization Subcutaneous Immu-notherapy Systemic Reaction Grading System, and a

paper is in press in the Journal of Allergy and ClinicalImmunology.

Only ten studies in this review classified the severity of theAEaccording to varying criteria. Three studies classified thereactions according to the recommendations of EAACI,which have subsequently beenmodified andwere originallyintended as a classification system for SCIT reactions (2).Oral-mucosal reactions, considered a SLIT local reaction,were relatively common, affecting up to 75% of patients,and seen most frequently in the build-up phase. In thestudies that specified the type of reaction, 169 of 314 959(0.056% of doses administered) were classified as systemicreactions (SR). There were 244 moderate AEs requiringdose adjustment or causing withdrawal from the study in2939 patients treated for 4586 treatment years with 810 693doses of SLIT (50 studies). The majority of these reactionswere gastrointestinal symptoms, rhinoconjunctivitis, urti-caria or some combination of these symptoms.

In the 38 placebo-controlled studies, there were approx-imately 282 894 SLIT doses administered to 1688 patients,which resulted in 353 (21%) patients reporting 823 AEs(2.9 per 1000 doses) and 226 261 placebo doses adminis-tered to 1302 patients, resulting in 152 (11.7%) patientsreporting 207 AEs (0.9 per 1000 doses). AEs accounted forwithdrawal in 3% of the SLIT patients compared with1.4% of the placebo-treated patients. To provide someperspective, in one review of 38 SCIT studies, the systemicreaction rate with non-accelerated schedules (single doseincrease per visit) ranged between 0.05–3.2% of injectionsand 0.8–46.7% of patients (mean, 12.92%) (3).

SLIT serious adverse events

In the SLIT comprehensive review, there were no fatalitiesor events described as anaphylaxis, although there were 14probable SLIT-related serious adverse events (SAE) in 3984patients treatedwith a total of 1 019 826 doses in 58 studies.This represents 1.4 SAEs per 100 000 SLIT doses and oneSLIT-related SAE per 384 treatment years or 285 patients.The most common SLIT-related SAEs were asthmaticreactions (7), one of which required hospitalization: theothers were abdominal pain/vomiting (3), uvula oedema(1), and urticaria lasting 48 hours. Subsequent to thisreview, there have been four case reports of SLIT-associ-ated anaphylaxis:

• One occurred on the third day of build-up with a multi-allergen SLIT extract in a 31-year-old woman withallergic rhinitis and asthma (4).

• One occurred in a 11-year-old girl with allergic rhinitisand asthma shortly after administration of mixed pollenSLIT at the height of pollen season, 1 month afterbeginning maintenance (5).

• One occurred on the fourth day of a latex rush protocol(6).


G. Walter Canonica

• One occurred after a 3-week gap in maintenance treat-ment after taking a dose six times higher than pre-scribed HDM SLIT (60 drops of 100 IR instead of 10drops) in a 16-year-old girl with allergic rhinitis andasthma. She had two previous episodes of wheezingrelated to SLIT within the first 3 months of mainte-nance. This reaction resulted in loss of consciousnessand admission to the intensive care unit (7).

• Two cases of anaphylaxis occurring with the first doseof a sublingual grass tablet have recently been reported(8). Both of these individuals had previously discon-tinued grass-pollen SCIT because of systemic reactions.One reaction was urticaria in a 13-year-old boy withallergic rhinitis, who developed periorbital angioedemaand urticaria within 15 min of administering the grasstablet. The other case involved a 27-year-old womanwith allergic rhinitis and asthma, who began to experi-ence asthma symptoms, generalized itching, faintnessand abdominal cramps immediately after the first grasstablet dose. She was wheezing and hypotensive (bloodpressure 90/50) when she arrived in her general practi-tioner�s (GP’s) office, where she was treated with sub-cutaneous epinephrine.

• In comparision, SCIT fatalities, although rare, havebeen reported at a rate of one in 2–2.5 million injectionsin three surveys of AAAAI members that date from1945 to 2001 (9–11). The most recent survey also as-sessed the frequency of SCIT near-fatal reactions, de-fined as severe respiratory compromise and/or fall inblood pressure requiring emergency treatment withepinephrine (12). The incidence of unconfirmed near-fatal reactions during the period of 1990–2001 was 23per year or 5.4 events per one million injections.

Risk factors for SLIT adverse events

No clear predictors for SLIT AEs have been identifiedalthough some of the factors in the SLIT anaphylaxis casereports are recognized as risk factors for SCIT: i.e. heightof season (12), history of previous SRs (13), dose (14) andaccelerated schedules (15). In addition, most of thepatients with SLIT-related SAEs or anaphylaxis hadasthma, which has been identified as a risk factor (16).

Dose and adverse reaction rate

There does not appear to be a consistent correlationbetween the adverse reaction rate or severity and theadministered SLIT dose. In an 18-month study of 58asthmatic children with dust mite allergy treated withrelatively low-dose SLIT (1.2 mg of Der p 1 three times aweek or 15.4 mg of Der p 1 cumulative monthly dose[CMD]), there were 32 SRs in approximately 6933administered doses (0.46% per dose) (17). Seventeen of

these reactions were classified as severe and because ofexceeding �maximum tolerated dose�. In contrast, amulticentre study of 97 dust-mite allergic children withmild-to-moderate asthma who received high-dose SLIT(20 drops of 300 IR/ml = approximately 783 mg CMDof mixed mites), there were no incidences of serious SLIT-related AEs or a significant difference in the incidence ofAEs between the SLIT and placebo groups (18). TheCMD dose in this study was about 50 times the dose usedin the study that reported 17 severe dose-related reactions,and the daily dose appeared to be equal to the amounttaken by the16-year-old, who developed anaphylaxis aftertaking six times her usual dose after a 3-week gap intreatment. However, in some large dose response studies,a relationship between dose and frequency and severity ofAE has been demonstrated (19, 20).

Induction schedule

Unlike SCIT, which appears to be associated with agreater incidence of AEs during some accelerated induc-tion schedules such as rush, there does not appear to be arelationship between the type of induction schedule andAEs with SLIT. Rush, ultra-rush and no-inductionschedules appear to be equally well tolerated with SLIT.In a study of 679 patients with allergic rhinitis, asthma, orboth, who underwent a 20- to 25-minutes ultra-rush SLITinduction, during which increasing doses of allergen wereadministered every 5 minutes, the cumulative allergendoses achieved after half an hour were in the range of 4.7–525 lg of major allergens (21). All patients were reportedto have tolerated the treatment well, with 17.96% ofpatients reporting mild local symptoms, primarily oralpruritis. Two patients experienced urticaria 2 and 3 hoursafter the ultra-rush induction and one patient hadurticaria and rhinitis 3 hours later.

In two large multi-centre dose response studies of 855and 628 patients with grass-pollen allergic rhinitis, treatedwith grass tablets containing up to 15 lg of Phl p 5 (22) or41 lg of the group 5 major allergens (20), respectively,administered with no induction phase, there was only oneserious SLIT-related AE. One patient in the middle-dosetreatment group (�5 lg Phl p 5) was hospitalized forobservation with �mild uvula edema� (22): the patientcontinued the study without any further complications.

Although the induction phase does not appear toinfluence the SLIT AE rate, many studies reported thatthe majority of AEs occurred during the induction phaseas compared with the maintenance phase.

SLIT in young children

SCIT is not generally prescribed to young children,primarily because of safety concerns (23). It has been



suggested that children under 5 years of age may havedifficulty cooperating in an immunotherapy program,particularly, in communicating symptoms of systemicreactions (24). It has also been suggested that injectionscan be traumatic to very young children.Three studies, two observational and one post-mar-

keting survey, specifically designed to assess the safetyof SLIT in young children, included a total of 231children younger than 5-years-old, who were treatedwith various pollen and mite allergens (33 patientsreceived allergoid) (25–27). AEs were reported in 5–15%of patients in a total of 68 975 doses with rates of0.268, 0.0766, and 1.767 AEs per 1000 doses in thethree studies. Most reactions appeared to be mild ormoderate and resolved without treatment. Dose reduc-tion by changing from a sublingual-swallow to asublingual-spit method controlled gastrointestinal reac-tions in one study (27). One further RCT with HDMSLIT in 138 children aged 2–5 years with asthmaor rhinitis showed only mild to moderate local AEs(28).

Multi-allergen SLIT

Two of the case reports of SLIT anaphylaxis involvedmulti-allergen SLIT and the vast majority of SLIT studiesemployed single allergens. Two studies have investigatedthe safety of multi-allergen SLIT in adults and children(29, 30). There was no significant difference in AEs in astudy of 159 adult patients with allergic rhinitis ± asthma(age 16–59 years), who were treated with either a singleallergen (n = 76) or multiple allergens (n = 83), with 45AEs occurring in 42 patients who received 7296 singleallergen doses and 51 AEs reported in 47 patients, whoreceived 8051 multi-allergen doses (29). Similar resultswere found in a study of 355 children (age 3–18 years)who received either single allergen SLIT (n = 179) ormulti-allergen SLIT (n = 254) with 76 AEs reported inthe single allergen group (42.46% patients, 4.43/1000doses) and 102 AEs in the multi-allergen group (40.3%patients, 4.42/1000 doses) (P = NS) (29).

SLIT safety: special considerations

Because this treatment is administered at home withoutdirect medical supervision, patients should be providedwith specific instructions regarding: how to manageadverse reactions, unplanned treatment interruptions,when and what to report to the prescribing physician,situations when SLIT should be withheld (e.g. oropha-ryngeal infection, oral abrasion, acute gastroenteritis,asthma exacerbation, etc.) (2). Careful considerationshould also be given to the ability of the patient and/ortheir family to adhere to these instructions and thetreatment regimen.

SLIT safety summary

In general, SLIT appears to be associated with fewerand less severe AEs than SCIT. Oropharyngeal reac-tions are the most common AEs but other reactions,such as asthma, urticaria and abdominal pain have beenreported with SLIT. There have been a few case reportsof anaphylaxis with SLIT, including two reports ofanaphylaxis with the first dose. Risk factors for SLITAEs have not been clearly established. Some studiessuggest a greater frequency of AEs during the inductionphase compared to the maintenance phase, but theredoes not appear to be a relationship between inductionschedule and SLIT AEs, with ultra-rush and no-induc-tion schedules reported as being well tolerated in severalstudies.

Further studies are needed to identify and characterizeSLIT risk factors and patients who should initially receivethis treatment in a medically supervised setting.

Unmet needs• The safety of SLIT in moderate to severe asthmatics.• The safety of SLIT in patients who have had systemicreactions with SCIT.

• The safety of SLIT with multiple allergens.• Interruptions in treatment: how long between doses is itsafe to administer usual dose?

- This might also include treatments with no inductionphase: once treatment has begun and there is a gap intreatment, the response to reintroduction is not known.

- Can someone stop e.g. daily grass tablets for a fewweeks then restart and stop periodically as patientsoften do in real life?

- If sowould it be safe to startmid-season if they aremostsymptomatic in season?

• Is it safe to administer SLIT with no induction with allformulations? Or do some require an updosing phase?

• Are oropharyngeal infections or lesions (e.g. ulcers, gin-givitis, paradentosis) risk factors for SLIT systemicreactions?

• Under which clinical situations should an SLIT dose bewithheld (e.g. recent respiratory tract infection, recentexacerbation of asthma, gastroenteritis)?

• The safety of SLIT in pregnant or breast or feeding wo-men.

• The safety of SLIT in patients on beta-blockers.• Are there any risk factors that identify which patientsmay experience a systemic reaction with SLIT?


1. Cox LS, Larenas-Linnemann D, Nolte H, Weldon D, FinegoldI, Nelson HS. Sublingual immunotherapy: a comprehensive re-view. J Allergy Clin Immunol 2006;117:1021–1035.


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2. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR,Malling HJ, Valovirta E. Standards for practical allergen-spe-cific immunotherapy. Allergy 2006;61(Suppl. 82):1–20.

3. Stewart GE 2nd, Lockey RF. Systemic reactions from allergenimmunotherapy. J Allergy Clin Immunol 1992;90:567–578.

4. Dunsky EH, Goldstein MF, Dvorin DJ, Belecanech GA. Ana-phylaxis to sublingual immunotherapy. Allergy 2006;61:1235.

5. Eifan AO, Keles S, Bahceciler NN, Barlan IB. Anaphylaxis tomultiple pollen allergen sublingual immunotherapy. Allergy2007;62:567–568.

6. Antico A, Pagani M, Crema A. Anaphylaxis by latex sublingualimmunotherapy. Allergy 2006;61:1236–1237.

7. Blazowski L. Anaphylactic shock because of sublingual immu-notherapy overdose during third year of maintenance dose.Allergy 2008;63:374.

8. de Groot H, Bijl A. Anaphylactic reaction after the first dose ofsublingual immunotherapy with grass pollen tablet. Allergy2009;64:963–964.

9. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TA. Surveyof fatalities from skin testing and immunotherapy 1985-1989. JAllergy Clin Immunol 1993;92:6–15.

10. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatal-ities from immunotherapy (IT) and skin testing (ST). J AllergyClin Immunol, 1987;79:660–677.

11. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-yearsurvey of fatal reactions to allergen injections and skin testing:1990-2001. J Allergy Clin Immunol 2004;113:1129–1136.

12. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatalreactions to allergen immunotherapy injections. J Allergy ClinImmunol 2006;117:169–175.

13. Moreno C, Cuesta-Herranz J, Fernandez-Tavora L, Alvarez-Cuesta E. Immunotherapy safety: a prospective multi-centricmonitoring study of biologically standardized therapeutic vac-cines for allergic diseases. Clin Exp Allergy 2004;34:527–531.

14. Dolz I, Martinez-Cocera C, Bartolome JM, Cimarra M. Adouble-blind, placebo-controlled study of immunotherapy withgrass-pollen extract Alutard SQ during a 3-year period withinitial rush immunotherapy. Allergy 1996;51:489–500.

15. Cox L. Advantages and disadvantages of acceleratedimmunotherapy schedules. J Allergy Clin Immunol 2008;122:432–434.

16. Simons FER, Anthony JF, Ignacio JA, Bruce SB, David BKG,Fred DF et al. Risk assessment in anaphylaxis: current and fu-ture approaches. J Allergy Clin Immunol 2007;120:S2–S24.

17. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-notherapy in patients with rhinitis and asthma due to house dustmite. A double-blind study. Allergol Immunopathol (Madr)1990;18:277–284.

18. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy ofsublingual immunotherapy with high-dose mite extracts inasthma: a multi-center, double-blind, randomized, and placebo-controlled study in Taiwan. Respir Med 2006;100:1374–1383.

19. Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standar-dised grass allergen tablet for sublingual immunotherapy: arandomized, placebo-controlled trial. Allergy 2006;61:181–184.

20. Larsen TH, Poulsen LK, Melac M, Combebias A, Andre C,Malling HJ. Safety and tolerability of grass pollen tablets insublingual immunotherapy–a phase-1 study. Allergy2006;61:1173–1176.

21. Rossi RE, Monasterolo G. A pilot study of feasibility of ultra-rush (20–25 minutes) sublingual-swallow immunotherapy in 679patients (699 sessions) with allergic rhinitis and/or asthma. Int JImmunopathol Pharmacol 2005;18:277–285.

22. Durham S, Yang W, Pedersen M, Johansen N, Rak S. Sublin-gual immunotherapy with once-daily grass allergen tablets: arandomized controlled trial in seasonal allergic rhinoconjuncti-vitis. J Allergy Clin Immunol 2006;117:802–809.

23. Bousquet J, Lockey R, Malling HJ, Alvarez-Cuesta E, Can-onica GW, Chapman MD et al. Allergen immunotherapy:therapeutic vaccines for allergic diseases. World HealthOrganization. American academy of Allergy, Asthma andImmunology. Ann Allergy Asthma Immunol 1998;81(5Pt 1):401–405.

24. Joint Task Force on Practice Parameters; American Academy ofAllergy, Asthma and Immunology; American College of Al-lergy, Asthma and Immunology; Joint Council of Allergy,Asthma and Immunology. A practice parameter second update.J Allergy Clin Immunol 2007;120:S25–S85.

25. Agostinis F, Tellarini L, Canonica GW, Falagiani P, Passa-lacqua G. Safety of sublingual immunotherapy with amonomeric allergoid in very young children. Allergy2005;60:133–134.

26. Fiocchi A, Pajno G, La Grutta S, Pezzuto F, Incorvaia C, SensiL et al. Safety of sublingual-swallow immunotherapy in childrenaged 3 to 7 years. Ann Allergy Asthma Immunol 2005;95:254–258.

27. Rienzo VD, Minelli M, Musarra A, Sambugaro R, Pecora S,Canonica WG et al. Post-marketing survey on the safety of sub-lingual immunotherapy in children below the age of 5 years. ClinExp Allergy 2005;35:560–564.

28. Rodriguez-Santos O. Sublingual immunotherapy for Allergicrhinitis and asthma in children from two to five years of age withmite allergy. Revista Alergia Mexico 2008;55:71–75.


30. Lombardi C, Gargioni S, Cottini M, Canonica GW, Passalac-qua G. The safety of sublingual immunotherapy with one ormore allergens in adults. Allergy 2008;63:375–376.

Chapter 6: Impact of sublingual

immunotherapy on the natural

history of respiratory allergy

• Allergen specific immunotherapy may alter the nat-ural history of respiratory allergy by preventing theonset of new skin sensitizations and/or reducing therisk of asthma onset.

• There are two randomised open controlled studiessuggesting that SLIT reduces the risk of asthmaonset in children with rhinitis.

• Two open randomised studies show that SLITreduces the onset of new allergen sensitizations.

• One DBPC-RCT and one nonrandomised prospec-tive study suggest the persistence of the clinicaleffects for 3–5 years after discontinuation.



Introduction

Respiratory allergy (allergic rhinitis, allergic asthma,united airways disease) is not a static entity, but maychange in its clinical presentation over time. Apart fromchanges in environmental exposure, which can modify theseverity and presentation of the disease, there seems to bea �natural history� of the disorder. One of the paradigmaticexamples of this is the so-called �atopic march� in children(1). It is also well known, for instance, that allergic rhinitisis an independent risk factor for developing asthma andthat allergic rhinitis often precedes asthma. It has beenshown that 16% to about 40% of subjects with rhinitisdevelop asthma later in life (2–5), that the relative risk ofrhinitis patients developing asthma varies from 2.2 to 5.4(review in Ref. 6) and that rhinitis independent of atopy isa good predictor of adult onset asthma (7). Identically,prospective studies have shown that allergic rhinitis mayprecede the development of bronchial hyperresponsive-ness (BHR) (8, 9). On the other hand, it has been shownthat in children, asthma may precede rhinitis (10).Another well recognized aspect of the natural history ofrespiratory allergy is the trend to develop new skinsensitization over time (9), and this has been consistentlydemonstrated in both adults and children. On one hand,this development testifies for an evolution of the immuneresponse to allergens; on the other hand, it has relevantclinical implications, since the severity of the diseasedirectly correlates in part with the number and size ofpositive skin tests (11, 12).Interventions that can alter the natural history of

respiratory allergy may reduce the risk of developingasthma or prevent the onset of new allergen sensitiza-tions. Presently, none of the currently available medica-tions, including H1-antihistamines and inhaled steroids,display such properties (13–16). Conversely, the disease-modifying effect of subcutaneous immunotherapy (SCIT)was described more than 40 years ago. In an observa-tional study, Johnstone (17) observed that a significantlysmaller proportion of children receiving SCIT developedasthma, versus children treated with medications only,over a period of 14 years. Subsequently, the PreventiveAllergy Treatment (PAT) (18) study suggested thepreventive effect of SCIT on the development of asthmain children with rhinitis, and this effect was shown topersist 7 years after discontinuation (19). In parallel, itwas consistently shown that SCIT was able to reduce theonset of new sensitizations in both adults and children(20, 21). The long-lasting persistence of the clinicaleffects of SCIT after discontinuation is an additionalindirect confirmation of the effect on the natural history(22–25).The disease-modifying effects of SLIT have only been

apparent in the past 10 years because the previous clinicaltrials were aimed at demonstrating the clinical efficacy andthe safety of the treatment. Moreover, studies assessinglong-term and preventive effects require several years of

follow-up of the patients. Nonetheless, there are someinteresting and promising data on the preventive effects ofSLIT.

Prevention of asthma

The first study showing that SLIT may prevent the onsetof asthma in children with rhinitis was published in 2004(26). This randomised, open, controlled study involved113 children aged 5–14 years suffering from seasonalrhinitis due to grass pollen at enrolment. Of thesechildren, 54 were randomly allocated to drug treatmentplus SLIT and 59 to standard symptomatic therapy alone.After 3 years, 99 children were re-evaluated: developmentof asthma was 3.8 times more frequent (95% CI, 1.5–10.0)in the control subjects. Another randomised, open,controlled trial (27) involved 216 children (age 5–17 years)suffering from allergic rhinitis with or without intermittentasthma. They were randomly allocated 2 : 1 to drugs plusSLIT or drugs only, and followed for 3 years. Symptomsand medication scores were recorded yearly during theperiod of exposure, whereas the presence of persistentasthma was assessed at 3 years. There was a significantreduction of symptom-medication scores only in the SLITgroup throughout the study. One hundred and ninety-sixpatients were evaluated at 3 years, and the occurrence ofpersistent asthma was 2/130 (1.5%) in the SLIT group and19/66 (30%) in the control group, with a number to treatof four. Overall, the rate of prevention of the onset ofasthma in children, as reported in the aforementionedtrials, is quite similar to that described for SCIT in thePreventive Allergy Treatment (PAT) study.

Concerning bronchial hyperresponsiveness (BHR), Pa-jno et al. (28) demonstrated in a double-blind placebo-controlled study of 30 children with Parietaria-inducedasthma, that SLIT was capable of preventing the onset ofbronchial hyperresponsiveness to methacholine during theParietaria pollen season. In an open randomised con-trolled study (29) of 52 birch-monosensitized patients (29SLIT + 23 controls; followed for five pollen seasons)with allergic rhinitis and asthma, there was a significantand progressive increase in the methacholine provocationdose in the SLIT group (that become near normal at thefifth pollen season), with no change in the control group.As for the PAT study, the severity of asthma in the controlgroups was never presented.

Prevention of new skin sensitizations

There is no double-blind study with SLIT specificallydesigned to study the preventive effect on the developmentof new allergen sensitizations. However, some randomisedcontrolled open trials have suggested this preventive effectwith SLIT. Marogna et al. (30) assessed the onset of newallergy skin test sensitizations after 3 years in 511 patients,


G. Walter Canonica

randomly allocated to SLIT (319 subjects) or drugs alone(192 subjects). SLIT was given for mites (166), grass (89)or trees (64). At the end of the study, new sensitizations,compared with baseline, appeared in 64/170 (38%) ofcontrols and 16/271 (5.9%) of SLIT patients (P < 0.001).In the study mentioned earlier, conducted in children (27),at the third year of follow-up, the rate of onset of newsensitizations was 4/130 in the SLIT group and 23/66 inthe control group.

Long-lasting effect

Few studies have investigated the long-term effect of SLIT.DiRienzo et al. (31), in aprospective controlled open study,followed 60 children (mean age 8.5 years) with asthma/rhinitis due to dustmites for 10 years. Theywere subdividedinto two matched groups with 35 subjects undergoing 4–5-years of SLIT and 25 subjects receiving only drug therapy.The patients were evaluated at baseline, at the end of SLITand 4–5 years after SLIT discontinuation. In the SLITgroup there was a significant difference compared withbaseline for the presence of asthma (P £ 0.001), whereasno difference was observed in the control group. Thisdifference was also seen 5 years after the SLIT discontin-uation.A 15-year follow-up of mite-allergic patients treated

with SLIT for 3, 4 or 5 years has suggested that a 4-yearcourse represents the best combination of clinical efficacyand long-term effect (32). Patients who received 4 years ofSLIT had significantly better monthly symptom scores7 years after discontinuation compared with the groupsthat were treated with 1 or 3 years of SLIT and theuntreated control group. Again, a retrospective study on59 patients allergic to HDM (33) suggested that 4 years ofSLIT achieved a long-lasting effect of 7–8 years, whereasthis effect was lost with shorter courses of treatment.Tahamiler et al. (34), in a 6-year randomised prospectivetrial, evaluated two groups of patients up to 3 years afterSLIT discontinuation. One group of 67 patients receivedSLIT for 2 years and placebo in the subsequent year. Theother group (70 patients) received SLIT for 3 years.Symptoms and specific nasal reactivity improved in bothgroups during treatment. The improvement was main-tained 3 years after stopping SLIT, although the 3-yeargroup displayed a more pronounced, long-term effect.

Unmet needs

• The available experimental data suggest that SLIT canexert some effects on the natural history of respiratoryallergy, resembling those of SCIT. These studies can beconsidered suggestive, but not conclusive, due to therelatively small number of subjects and the methodo-logical problems.

• In particular, the long-term effect of SLIT after itsdiscontinuation needs to be confirmed in randomisedcontrolled trials, possibly double-blinded in the firstyears, and involving large numbers of patients (35).

• The demonstration of a preventative effect on the onsetof asthma would also require DBPC-RCTs, whereobjective respiratory parameters are assessed.

• The severity of asthma in patients on placebo needs tobe assessed.

• Specific factors that can predict those patients that areprotected against new sensitizations and new develop-ment of asthma, need to be identified: this issue alsoapplies to SCIT.


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2. Guerra S, Sherrill DL, Baldacci S, Carrozzi L, Pistelli F, Di PedeF et al. Rhinitis is an independent risk factor for developingcough apart from colds among adults. Allergy 2005;60:343–349.

3. Lombardi C, Passalacqua G, Gargioni S, Senna G, Ciprandi G,Scordamaglia A et al. The natural history of respiratory allergy:a follow-up study of 99 patients up to 10 years. Respir Med2001;95:9–12.

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5. Toren K, Olin AC, Hellgren J, Hermansson BA. Rhinitis in-crease the risk for adult-onset asthma – a Swedish population-based case-control study (MAP-study). Respir Med2002;96:635–641.

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8. Townley RG, Ryo UY, Kolotkin BM, Kang B. Bronchial sen-sitivity to methacholine in current and former asthmatic andallergic rhinitis patients and control subjects. J Allergy ClinImmunol 1975;56:429–442.

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16. Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, BoehmerSJ, Szefler SJ et al. Long-term inhaled corticosteroids in pre-school children at high risk for asthma. An important studyof inhaled corticosteroids in childhood asthma showing nopreventive potential after cessation of treatment. N Engl JMed 2006;354:1985–1997.

17. Johnstone DE, Dutton A. The value of hyposensitization ther-apy for bronchial asthma in children–a 14-year study. Pediatrics1968;42:793–802.

18. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, JacobsenL et al. Pollen immunotherapy reduces the development ofasthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251–256.

19. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S,Høst A et al; (The PAT investigator group). Specific immuno-therapy has long-term preventive effect of seasonal and peren-nial asthma: 10-year follow-up on the PAT study. Allergy2007;62:943–948.

20. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S.Prevention of new sensitizations in asthmatic children mono-sensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy 2001;31:1392–1397.

21. Purello-D�Ambrosio F, Gangemi S, Merendino RA, Isola S,Puccinelli P, Parmiani S et al. Prevention of new sensitizationsin monosensitized subjects submitted to specific immunotherapyor not. A retrospective study. Clin Exp Allergy 2001;31:1295–1302.

22. Limb SL, Brown KC, Wood RA, Eggleston PA, Hamilton RG,Adkinson NF Jr. Long-term immunologic effects of broad-spectrum aeroallergen immunotherapy. Int Arch AllergyImmunol 2006;140:245–251.

23. Durham SR, Walker SM, Varga EM, Jacobson MR, O�brien F,Noble W et al. Long-term clinical efficacy of grass-pollenimmunotherapy. N Engl J Med 1999;341:468–475.

24. Eng PA, Reinhold M, Gnehm HP. Long-term efficacy of pre-seasonal grass pollen immunotherapy in children. Allergy2002;57:306–312.

25. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after discontinuation of preseasonal grass pollenimmunotherapy in childhood. Allergy 2006;61:198–201.

26. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, DeMarco E et al. Coseasonal sublingual immunotherapy reducesthe development of asthma in children with allergic rhinocon-junctivitis. J Allergy Clin Immunol 2004;114:851–857.

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29. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa-lacqua G. Clinical, functional, and immunologic effects of sub-lingual immunotherapy in birch pollinosis: a 3-year randomizedcontrolled study. J Allergy Clin Immunol 2005;115:1184–1188.

30. Marogna M, Spadolini I, Massolo A, Canonica GW, Passa-lacqua G. Randomized controlled open study of sublingualimmunotherapy for respiratory allergy in real-life: clinical effi-cacy and more. Allergy 2004;59:1205–1210.

31. Di Rienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F,Sensi L et al. Long-lasting effect of sublingual immunotherapyin children with asthma due to house dust mite: a 10-year pro-spective study. Clin Exp Allergy 2003;33:206–210.

32. Marogna M, Spadolini I, Massolo A et al. Long lasting effectaccording to the duration of SLIT: a 15-year prospective study[abst]. XXVI EAACI Meeting, Goteborg 2007:276.

33. Marogna M, Bruno M, Massolo A, Falagiani P. Long-lastingeffects of sublingual immunotherapy for house dust mites inallergic rhinitis with bronchial hyperreactivity: a long-term(13-year) retrospective study in real life. Int Arch AllergyImmunol 2007;142:70–78.

34. Tahamiler R, Saritzali G, Canakcioglu S. Long-term efficacy of sublingual immunotherapy in patients withperennial rhinitis. Laryngoscope 2007;117:965–969.

35. Committee for medicinal products for human use. Guideline onthe clinical development of products for specific immunotherapyfor the treatment of allergic diseases. CHMP/EWP/18504/2006.London, European Medicines Agency. Pre-authorisation eval-uation of medicines for human use. 20 November 2008.

Chapter 7: Sublingual

immunotherapy in children

• SLIT is effective in allergic rhinitis in children‡5 years of age.

• SLIT may be safe in allergic rhinitis in children‡3 years of age.

• SLIT can be used for allergic rhinitis in children withasthma.

• SLIT should not be suggested as monotherapy fortreating asthma.

• There are many unmet needs with SLIT in children.• More studies are needed with SLIT in children inlarge randomised trials.

The first study on SLIT in children was published in1990 (1): since then many studies have been publishedshowing the efficacy and safety of SLIT in allergicchildren with rhinitis (rhino-conjunctivitis) and somesporadic papers of SLIT in children with other allergicdiseases.

Rhinitis

Tari�s study (1) was the first showing the efficacy of SLITin reducing the symptom score for rhinitis and signifi-cantly increasing nasal patency measured by rhinometry.Some studies have been published since then and a recentmetanalysis of 10 DBPC-RCT (that met the metanalysiscriteria out of 70 studies reviewed) found a significant


G. Walter Canonica

improvement in those children receiving standardizedallergen extract compared to placebo, as well as a decreasein medication use (2), even though the heterogeneityamong the studies was high and the dosages used diverse.However, a systematic review of the literature reportedthat there was no evidence of effect for SLIT in terms ofefficacy in rhinitis in the paediatric age group (3), but thestudies analysed in this review were those published upuntil 2005, when study design and dosing were still notoptimal (4).The first evidence of the effect of SLIT in children came

from an 18-month study of two different doses of SLIT fortree-pollen allergy in 88 children suffering seasonal allergicrhinitis, confirmed by skin prick test, specific serum IgEand conjunctival allergen challenge. Eighteen months ofSLIT with tree pollen extract provided dose-dependentbenefits in terms of significantly reduced symptoms andmedication use (5).Two adequately powered, well-designed DBPC-RCTs

have now been published, both showing a clear effect ofallergen tablets in childhood. A statistically significantreduction in rhinitis symptoms (28%) and medication(64%) score was shown during the pollen season in 114children receiving active grass allergen tablets (with15 lg Phl p 5) compared to 120 children in the placebogroup (6). The other DBPC-RCT evaluated the efficacyof five-grass tablets (with 25 lg group 5 major allergen)administered pre- and co-seasonally to 227 children withseasonal allergic rhino-conjunctivitis. In those receivingthe five-grass tablets a significant improvement wasfound in symptom and medication scores (7). All thesestudies performed by specialists clearly show the efficacyof SLIT in reducing the symptom score during pollenseason in children with rhinitis; moreover there was alsoa significant reduction in medication use. On thecontrary a study of SLIT in a primary care settingdid not show any differences at all for symptoms, rescuemedication-free days, and disease-specific QoL betweenactive and placebo groups, not even when sub-groupanalysis were carried out (8). The studies suggest thatSLIT is effective for the management of rhinitis inchildren selected and followed up by specialists.The allergens that have been used with success in SLIT

in the paediatric age group for rhinitis are pollen fromPhleum pratense, 5-grass mix, Parietaria and Betulaceaepollens and HDM. SLIT with olive pollen showed onlyimprovement in symptoms (9) and one grass study wasnegative (10).

Asthma

Tari�s study also looked at the effect of SLIT in asthmain children. SLIT induced an improvement in bothspecific and non specific bronchial hyperreactivity (1).An Italian double-blind, placebo-controlled study eval-uated the efficacy and safety of SLIT after 2 years of

treatment: there was a significant decrease in symptomsof asthma (P = 0.0001) and medication use(P = 0.0001) in the active group (n = 12) comparedto the placebo group (n = 12). The visual analoguescore on overall asthma symptoms improved in theSLIT group (P = 0.0001), but not in the placebo group(11). Other studies have been published showing theefficacy and safety of SLIT in HDM sensitive childrenwith asthma (12). A study in 97 HDM-sensitive asthmachildren from Taiwan has shown that SLIT waseffective in improving not only day and night symptomscore but also lung function (13). However two otherDBPC studies of HDM SLIT in children were negative(14, 15). In olive pollen sensitive children the dyspnoeascore, but not the medication score, improved withSLIT (9). More recently a meta-analysis of DBPC-RCTof SLIT in asthma in children was published (16).Symptom scores and the use of rescue medication werecalculated with standardized mean differences (SMDs)using the random-effects model. The statistical softwarepackage (RevMan, 4.2.8; The Cochrane Collaboration;Oxford, UK) was used to perform the meta-analysisfollowing the recommendations of the Cochrane Col-laboration and the Quality of Reporting of Meta-analyses guidelines. Overall, there was a significantreduction in both symptoms (P = 0.02) and medicationuse (P = 0.007) following SLIT compared with placebo.However, all of these studies were small in size (totalnumber of patients 441) and the size of effect was atbest moderate.

One of the recent large trials on SLIT has assessed theeffect of the grass-tablets on asthma in children 5–16 yearsof age. Asthma symptoms (coughing, wheezing, shortnessof breath and exercise-induced symptoms) were signifi-cantly reduced, whereas use of rescue medication wasreduced, but not significantly (6). There is no clearconsensus as to the use of SLIT in allergic children withasthma symptoms, particularly those with pollen allergyand concomitant allergic rhinitis (17, 18). The allergensthat have been used with success in SLIT in the paediatricage group for allergic asthma are pollen from Phleumpratense and Betulaceae pollen; pollen extract fromParietaria did not show efficacy (19). Furthermore,Moreover, none of the studies reported objective param-eters, and the clearcut diagnosis of pollen asthma in thesepatients is questionnable.

SLIT in other allergic processes in children

A single study in children with atopic dermatitis (20)and a preliminary report in those with IgE-mediatedcow milk allergy (21) suggested that SLIT had givenpositive results. A DBPC-RCT study showed efficacy inchildren with cutaneous and respiratory symptomsinduced by natural rubber latex (22). At 1 year, latexSLIT reduced the symptom score in treated patients and



prevented reactions induced by cross-reacting fruits. Allof these studies open an avenue to study the efficacyand safety of SLIT in children suffering allergic symp-toms beyond traditional seasonal or perennial aeroal-lergens. However, more studies are needed in order toconfirm further clinical indications.

Safety in children

The sublingual route was introduced with the aim ofreducing side effects and increasing the safety of immu-notherapy. This aspect has been reviewed recently. Thereis no difference in the incidence of AEs between childrenand adults (23) and SLIT has been shown to be safe. Themost frequently reported AEs (mostly self-limiting) arelocal in the oral mucosa (itching and swelling) and of thedigestive system. Just a few cases were considered mod-erate/severe and requiring medical intervention. Experi-ence must be gained in the use of single vs multiple-allergens. SLIT with a single allergen is the most commonpractice in Europe whereas multiple allergens are usedmainly in USA, Latin America and some other parts ofthe world. In adults, in one study, use of SLIT withmultiple allergens was reported to be as safe as SLIT witha single allergen (24).

Unmet needs of SLIT in children

Although recent adequately powered, well-designedDBPC-RCTs with grass tablets in children have shownefficacy, there is no dose-ranging study and the optimaldose is still a matter of debate. Recent metanalysesindicate that SLIT has a significant effect on symptomsand medications use in allergic rhinitis as well as asthmaand the treatment is shown to be safe, though severe AEsmay occur (see section on SLIT safety). There are stillunmet needs for SLIT in children:

• Optimal dose and dosing frequency of allergen admin-istration

• Efficacy in patients unresponsive to pharmacotherapy• Drops vs tablets• Duration of treatment• Long-term efficacy• Preventive capacity• Other allergic process beyond respiratory allergy• SLIT in preschool children


1. Tari MG, Mancino M, Monti G. Efficacy of sublingual immu-notherapy in patients with rhinitis and asthma due to house dustmite. A double-blind study. Allergol Immunopathol (Madr)1990;18:277–284.

2. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R,Huerta J, Passalacqua G et al. Efficacy of sublingual immu-notherapy in the treatment of allergic rhinitis in pediatricpatients 3 to 18 years of age: a meta-analysis of randomized,placebo-controlled, double-blind trials. Ann Allergy AsthmaImmunol 2006;97:141–148.

3. Roder E, Berger MY, de Groot H, van Wijk RG. Immuno-therapy in children and adolescents with allergic rhinoconjunc-tivitis: a systematic review. Pediatr Allergy Immunol2008;19:197–207.

4. Larenas-Linnemann D. Sublingual immunotherapy in children:more optimism today. Pediatr Allergy Immunol 2009;20:399–400.

5. Valovirta E, Jacobsen L, Ljorring C, Koivikko A, Savolainen J.Clinical efficacy and safety of sublingual immunotherapy withtree pollen extract in children. Allergy 2006;61:1177–1183.

6. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M,Klimek L et al. Safety and efficacy in children of an SQ-stan-dardized grass allergen tablet for sublingual immunotherapy. JAllergy Clin Immunol 2009;123:167–173.



9. Vourdas D, Syrigou E, Potamianou P, Carat F, Batard T,Andre C et al. Double-blind, placebo-controlled evaluation ofsublingual immunotherapy with standardized olive pollenextract in pediatric patients with allergic rhinoconjunctivitisand mild asthma due to olive pollen sensitization. Allergy1998;53:662–672.

10. Bufe A, Ziegler-Kirbach E, Stoeckmann E, Heidemann P,Gehlhar K, Holland-Letz T et al. Efficacy of sublingualswallow immunotherapy in children with severe grass pollenallergic symptoms: a double-blind placebo-controlled study.Allergy 2004;59:498–504.

11. Pajno GB, Morabito L, Barberio G, Parmiani S. Clinical andimmunologic effects of long-term sublingual immunotherapy inasthmatic children sensitized to mites: a double-blind, placebo-controlled study. Allergy 2000;55:842–849.

12. Bahceciler NN, Isik U, Barlan IB, Basaran MM. Efficacy ofsublingual immunotherapy in children with asthma and rhinitis:a double-blind, placebo-controlled study. Pediatr Pulmonol2001;32:49–55.

13. Niu CK, Chen WY, Huang JL, Lue KH, Wang JY. Efficacy ofsublingual immunotherapy with high-dose mite extracts inasthma: a multi-center, double-blind, randomized, andplacebo-controlled study in Taiwan. Respir Med 2006;100:1374–1383.

14. Hirsch T, Sahn M, Leupold W. Double-blind placebo-con-trolled study of sublingual immunotherapy with house dust miteextract (D.pt.) in children. Pediatr Allergy Immunol 1997;8:21–27.


16. Penagos M, Passalacqua G, Compalati E et al. Metaanalysisof the efficacy of sublingual immunotherapy in the treatmentof allergic asthma in pediatric patients, 3 to 18 years of age.Chest 2008;133:599–609.


G. Walter Canonica

17. Baena-Cagnani CE, Passalacqua G, Gomez M, Zernotti ME,Canonica GW. New perspectives in the treatment of allergicrhinitis and asthma in children. Curr Opin Allergy Clin Immu-nol 2007;7:201–206.

18. Cox L. Sublingual immunotherapy in pediatric allergic rhinitisand asthma: efficacy, safety, and practical considerations. CurrAllergy Asthma Rep 2007;7:410–420.

19. Pajno GB, Vita D, Parmiani S, Caminiti L, La Grutta S,Barberio G. Impact of sublingual immunotherapy on seasonalasthma and skin reactivity in children allergic to Parietariapollen treated with inhaled fluticasone propionate. Clin ExpAllergy 2003;33:1641–1647.


21. de Boissieu D, Dupont C. Sublingual immunotherapy for cow�smilk protein allergy: a preliminary report. Allergy 2006;61:1238–1239.

22. Bernardini R, Campodonico P, Burastero S, Azzari C, No-vembre E, Pucci N et al. Sublingual immunotherapy with a latexextract in paediatric patients: a double-blind, placebo-controlledstudy. Curr Med Res Opin 2006;22:1515–1522.

23. Passalacqua G, Guerra L, Compalati E, Canonica GW. Thesafety of allergen specific sublingual immunotherapy. Curr DrugSaf 2007;2:117–123.


Chapter 8: Guidelines and

recommendations on sublingual

immunotherapy

• Several adequately powered, well-designed, rando-mised clinical trials have been published on sublin-gual immunotherapy.

• High-dose sublingual specific immunotherapy iseffective in carefully selected patients with rhinitis,conjunctivitis and/or asthma caused by pollen and/or house dust mite (HDM) allergy.

• Randomised clinical trials have confirmed that sub-lingual immunotherapy is safe. However, many pa-tients report local side effects.

• Systemic reactions (SRs) have only been reportedrarely.

Many consensus and guidelines for immunotherapy havefollowed the WHO consensus meeting on immunotherapy(1), the first EAACI guidelines on immunotherapy (2), andthe WHO Position Paper on immunotherapy (3). In all ofthese articles, SLIT was not recognized as an effective and/

or safe treatment of allergic diseases. In 1998, an EAACIconsensus on local immunotherapy (4) suggested that SLITmay be effective but its safety was questioned. Only fourtrials met the requirements for inclusion in this document.The first ARIA guidelines (5) found that 12 trials could beanalysed and proposed use of SLIT both in children andadults. However, SLIT was still a matter of debate, inparticular in the USA (6), and is not FDA approved. Intheir review for the ARIA 2008 Update (7, 8), Passalacquaand Durham listed 23 new RCTs (7). Other RCTs havebeen reported more recently (9–13).

Guideline development: from evidence-based medicine topatients' views

A consensus is �a document that represents the collectiveopinionof a convened expert panel�. Theopinions expressedin the statement do not reflect a formal evidence review andwere not developed in accordance with the process outlinedfor evidence-based clinical practice guidelines. Early guide-lines were predominantly derived from such unsystemati-callycompiledopinionsofexpertsbasedonclinical trialsandmechanisticapproaches (Opinion-basedmedicine) (14).Theterms �recommendation�, �evidence-based� and �guideline�should not be used in the context of consensus statements.

The development of evidence based clinical guidelines,on the contrary, follows transparent processes (15).�Evidence-based-medicine� (EBM) has become an essentialcomponent in the preparation of guidelines. It is theability to track down, critically appraise (for validity andusefulness) and incorporate data obtained from the bestavailable evidence (ideally DBPC-RCTs) in order toestablish the clinical bases for diagnosis, prognosis andtherapeutics (16, 17). Evidence-based medicine attemptsto provide a logical, transparent and applicable frame-work from which the quality and relevance of clinicalstudies may be assessed in an unbiased manner (18).Systematic reviews contribute to resolving uncertaintywhen original research, reviews and editorials disagree(19).

The efficacy of SLIT has been assessed in randomisedcontrolled trials (RCTs). Around 50 SLIT RCTs havebeen carried out. Systematic reviews and meta-analyseshave been completed (20–23). However, their results aredifficult to interpret for many reasons (Table 8–1).

Although there is increasing agreement upon the com-ponents of proper clinical practice guidelines and whatconstitutes high quality evidence, it is also clear that thehighest quality evidence from DBPC-RCTs is often basedon selected patients. Therefore, they may fall short ofrepresenting the entire population (24). However, RCTsoffer the most methodological rigorous approach toestablishing cause and effect, thereby providing the highestquality evidence. A number of approaches have been usedto grade the quality of evidence and the resulting strengthof recommendations (25, 26). The large number of systems



for measuring the quality of evidence and recommenda-tions is confusing (27) and all previously used approachesfor grading levels of evidence and the strength of recom-mendations have important shortcomings (14, 25).At present, the identification, interpretation, and

reporting of harmful effects is incomplete in RCTs (28,29). Thus, there is a need to obtain better evidence aboutside effects (risks) (27). Evidence is required throughoutthe entire spectrum of the treatment life cycle, from thepre-marketing to the post-marketing phase. Drug safetyand effectiveness need to be assessed in the real world,where outcomes may differ from those of controlledclinical trials that provide pre-market test results. Drugregulatory initiatives include data mining, active adversedrug reaction (ADR) surveillance, independent, multidis-ciplinary evaluation of suspected ADRs and formalpharmaco-epidemiology studies.More recently, the �Guidelines for WHO guidelines�

recommended using a specific, uniform grading system(30). The GRADE (Grading of Recommendations Assess-

ment, Development and Evaluation) approach is one ofthe recommended systems (26) and is being used increas-ingly by a number of organizations. The GRADEworking group has published the results of its work (31).It grades recommendations in two levels – strong andweak – and quality evidence into four categories – high,moderate, low and very low (26, 27) based on theevidence, the quality of evidence, safety, costs andpatients� views.

Guidelines and consensus in sublingual immunotherapy

The first guidelines on immunotherapy were opinion-based (3). Then, most guidelines and consensus used theShekelle et al. method (32) (Table 8–2).

The ARIA guidelines were the first to develop anevidenced-based model (5, 8). Adequately powered, well-designed DBPC-RCTs have been performed with SCIT(35) and SLIT (10, 36–38) in patients suffering frompollen induced allergic rhinitis. In the populationselected, they confirmed the efficacy of immunotherapy(Evidence A) (32). In children, one systematic reviewsuggested that SLIT is not effective (22), but a largeRCT in birch pollen allergy (39) and two very recentadequately powered, well-designed DBPC-RCTs in grasspollen allergy convincingly showed efficacy (40, 41).More studies are however needed to demonstrate theefficacy of SLIT to other allergens in rhinitis and SLIT inasthma (42). The methodology of RCTs is critical (43,44) and only trials following an optimal study designshould be considered (45, 46). Practice parameters forimmunotherapy have been published by EAACI (47, 48)and AAAAI/ACAAI (34).

SLIT is safer than SCIT although some rare severereactions may occur (49–51). SLIT is administered athome and patients should be educated on how torecognize and treat a reaction if it occurs. It is alsoimportant to improve the study of the time course ofsevere reactions after immunotherapy (52). The safety ofSLIT in preschool children needs more attention beforebeing widely used (53) or proposed in guidelines. Post-marketing surveillance studies are needed to compare thesafety of different forms of immunotherapy.

The costs of treatment are key factors in the thera-peutic decision. They should include short-term effects aswell as long term effects and the preventive effect ofimmunotherapy which is always difficult to assess or tomodel (54). Some large carry-over studies assessing theeffect after treatment interruption will soon be available.SLIT was proposed to be cost-effective (55–57) but theseanalyses suggest a very high annual cost and there are

Table 8–1 Points to consider for inclusion of SLIT RCTs in meta-analyses

• The number of patients needed to enrol should be clearly stated in the protocolconsidering expected effect size and drop-out rates. Analysis should be doneaccording to the intention to treat principle.

• Most RCTs carried out before 2005 were underpowered and could only beconsidered as proof-of-concept studies.

• Extracts may not be compared between manufacturers and the labelled contentmay not be the exact content in lg of major allergen.

• Vehicles differed and there may be large pharmacokinetic differences betweendrops and tablets and between tablets themselves. Appropriate analyses ofthis difference is required.

• The allergens may differ for a given indication. Some manufacturers use asingle allergen whereas others a mixture of a few major grass pollens.

• The raw materials, preparation and standardization of allergens differ widelybetween manufacturers.

• A number of standardized allergens, allergoids and others have been studied.• The dosing schedule is specific to each manufacturer: maintenance dose,

weekly dose, total cumulative dose, pre- and co-seasonal administration.• Primary and secondary outcomes may differ between trials.• Emphasis should be placed on registered trials (when started after registries

were available) and publication biases should be evaluated carefully.

Table 8–2 Evidence models of guidelines in sublingual immunotherapy

YearEvidence

model

SLIT

RCT No.* Recommendation

WHO consensus (1) 1988 None 0 NoneEAACI 1988 guidelines (2) 1988 None 0 NoneEAACI 1992 guidelines (33) 1992 None 0 NoneWHO Position Paper (3) 1998 None 2 NoneEAACI Local

Immunotherapy (4)1998 None 4 Suggested in adults

ARIA (5) 2001 Shekelle(32)�

12 Recommendedin adults, suggestedin children

AAAAI/ACAAI Practiceparameters (34)

2007 Shekelle(32)�

18 SLIT as investigational(in the USA,not FDA approved)

ARIA Update (8) 2008 Shekelle(32)�

36 Recommended in adultsand children

*number of DBPC-RCTs considered in the paper.�The Shekelle et al. (32) grading system only considers efficacy.


G. Walter Canonica

some concerns (58). Moreover, there may be somemisconceptions about immunotherapy cost-effectiveness.Many studies are now using the quality-adjusted-lifeyears to make pharmacoeconomic decisions (59). It isusually accepted that for severe and/or life-threateningdiseases the ICER (incremental cost-effectiveness ratio)threshold is up to 50 000 € per year. This is the case foromalizumab in severe asthma or many biologicals incancer or neurodegenerative diseases (60). Thus, someauthors have proposed that a similar ICER thresholdmay be used for immunotherapy (60). However, themajority of patients suffering from allergic diseases havea mild to moderate form of the disease and cost-effectiveness needs to take into consideration thepreventive effect of immunotherapy using models suchas Markov (54, 60).One of the remaining problems is that the selection of

patients for immunotherapy RCTs does not necessarilyreflect the current suggestions (5, 8) (Table 8–3). Forallergic rhinitis, immunotherapy is commonly indicatedin patients who have long-lasting symptoms during theyear and/or who were not well controlled by optimalpharmacotherapy (SCUAD: Severe Chronic Upper

Airway Disease) and/or who have had side effectsfrom pharmacotherapy and/or who do not wishpharmacotherapy (5, 8). However, these patient charac-teristics are not included in the published RCTs. Onestudy approached these recommendations and showedthat SLIT can reduce medication needs in patientsreceiving immunotherapy while maintaining diseasecontrol (61).

The age of the patients is still a matter of debate.New adequately powered, well-designed DBPC-RCTshave found that SLIT is effective in school children (41,42, 62). However, there is no study in preschoolchildren. The guidelines on immunotherapy recommendstarting the treatment after the age of 5 years (3). Inpreschool children, safety has to be evaluated in Phase Itrials before large RCTs are started. Moreover, thediagnosis of allergy in preschool children may needsome attention (64).

Unmet needs

• SCUAD patients should be tested using chamberstudies to show that SLIT can add efficacy to currenttreatment in patients uncontrolled despite intranasalcorticosteroids and oral H1-antihistamines.

• If the above study shows that SCUAD patients areimproved by SLIT, an appropriate RCT should becarried out.

• Studies in asthma should be done. In order to get reg-istration for asthma, objective measures should be used(FEV1, PEF) as co-primary or major secondary out-comes. The definition of �seasonal asthma� needs bettercharacterization.

• Studies on prevention should be started (see preventionand methodology).

• After analysis of HDM studies, new studies are neededwith improved or different outcomes.


1. Current status of allergen immunotherapy. Shortened version of aWorld Health Organisation/International Union of Immunolog-ical SocietiesWorking Group Report. Lancet 1989;1:259–261.

2. Malling H. Immunotherapy. Position paper of the EAACI.Allergy 1988;43(Suppl 6):9–33.

3. Bousquet J, Lockey R, Malling HJ, Alvarez-Cuesta E, CanonicaGW, Chapman MD et al. Allergen immunotherapy: therapeuticvaccines for allergic diseases. World Health Organization.American academy of Allergy, Asthma and Immunology. AnnAllergy Asthma Immunol 1998;81:401–405.

4. Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, Bjorksten B,Bousquet J, Caillot D et al. Local immunotherapy. Allergy1998;53:933–944.

5. Bousquet J, Van Cauwenberge P, Khaltaev N. Allergic rhinitisand its impact on asthma. J Allergy Clin Immunol 2001;108(5Suppl):S147–S334.

Table 8–3 Recommendations to minimize risk and improve efficacy of immuno-therapy [From EAACI (63), GINA (62) and ARIA (5, 8)]

Considerations for initiating immunotherapy (Updated from the WHOPosition Paper on Allergen Vaccines) (3)

1. Presence of a demonstrated IgE-mediated disease:• Positive skin tests and serum specific IgE to an allergen concordant to clinical

symptoms.2. Documentation that specific sensitivity is involved in symptoms:

• Exposure to the allergen(s) determined by allergy testing related to appearanceof symptoms.

• If required, allergen challenge with the relevant allergen(s) (optional).3. Severity and duration of symptoms:

• Subjective symptoms for rhinoconjunctivitis: patients should have symptoms ofsufficient severity and duration.

• For asthma: control questionnaire should not show uncontrolled asthma.• Objective parameters e.g. work loss, school absenteeism.• In asthmatics pulmonary function (essential): exclude patients with severe

asthma.• Monitoring of pulmonary function.

4. Availability of standardized or high quality vaccines• Specific immunotherapy needs to be prescribed by specialists.• SCIT needs to be administered by physicians trained to manage systemic

reactions if anaphylaxis occurs.• SLIT is administered at home and patients should be informed of possible risks

and how to control eventual side effects.• Patients with multiple sensitivities may not benefit from specific immuno-

therapy as much as patients with a single sensitivity. More data are necessary.• Patients with non-allergic triggers will not benefit from specific immunotherapy.• It is essential, for safety reasons, that asthmatic patients should be asymp-

tomatic at the time of the injections because lethal adverse reactions are moreoften found in asthma patients with severe airways obstruction.

• In asthmatics, FEV1 with pharmacological treatment should reach at least 70%of the predicted values, for both efficacy and safety reasons.



6. Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I,Nelson HS. Sublingual immunotherapy: a comprehensivereview. J Allergy Clin Immunol 2006;117:1021–1035.

7. Passalacqua G, Durham SR. Allergic rhinitis and its impact onasthma update: allergen immunotherapy. J Allergy ClinImmunol 2007;119:881–891.

8. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,Togias A et al. Allergic Rhinitis and its Impact on Asthma(ARIA) 2008 update (in collaboration with the World HealthOrganization, GA2LEN and AllerGen). Allergy 2008;63(Suppl86):8–160.

9. Pham-Thi N, Scheinmann P, Fadel R, Combebias A,Andre C. Assessment of sublingual immunotherapy efficacy inchildren with house dust mite-induced allergic asthmaoptimally controlled by pharmacologic treatment andmite-avoidance measures. Pediatr Allergy Immunol2007;18:47–57.


11. Pfaar O, Klimek L. Efficacy and safety of specific immuno-therapy with a high-dose sublingual grass pollen preparation:a double-blind, placebo-controlled trial. Ann Allergy AsthmaImmunol 2008;100:256–263.

12. Mosges R, Bruning H, Hessler HJ, Gotz G, KnaussmannHG. Sublingual immunotherapy in pollen-induced sea-sonal rhinitis and conjunctivitis: a randomized controlledtrial. Acta Dermatovenerol Alp Panonica Adriat 2007;16:143–148.

13. de Blay F, Barnig C, Kanny G, Purohit A, Leynadier F, Tunonde Lara JM et al. Sublingual-swallow immunotherapy withstandardized 3-grass pollen extract: a double-blind, placebo-controlled study. Ann Allergy Asthma Immunol 2007;99:453–461.

14. Bousquet J, Clark TJ, Hurd S, Khaltaev N, Lenfant C, O�ByrneP et al. GINA guidelines on asthma and beyond. Allergy2007;62:102–112.

15. Bousquet J, Bieber T, Fokkens W, Humbert M, KowalskiML, Niggemann B et al. Consensus statements, evidence-based medicine and guidelines in allergic diseases. Allergy2008;63:1–4.

16. Sackett DL, Rosenberg WM. The need for evidence-basedmedicine. J R Soc Med 1995;88:620–624.

17. Elstein AS, Schwarz A. Clinical problem solving and diagnosticdecision making: selective review of the cognitive literature.BMJ 2002;324:729–732.

18. Barton S. Which clinical studies provide the best evidence? Thebest RCT still trumps the best observational study. BMJ2000;321:255–256.

19. Petticrew M, Wilson P, Wright K, Song F. Quality of Cochranereviews. Quality of Cochrane reviews is better than that of non-Cochrane reviews. BMJ 2002;324:545.

20. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Hu-erta J, Passalacqua G et al. Efficacy of sublingual immuno-therapy in the treatment of allergic rhinitis in pediatric patients 3to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol2006;9:141–148.

21. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,Orozco S, Pedroza A et al. Metaanalysis of the efficacy ofsublingual immunotherapy in the treatment of allergic asthmain pediatric patients, 3 to 18 years of age. Chest 2008;133:599–609.


23. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy ofsublingual immunotherapy in asthma: systematic review ofrandomized-clinical trials using the Cochrane Collaborationmethod. Allergy 2006;61:1162–1172.

24. Herland K, Akselsen JP, Skjonsberg OH, Bjermer L. Howrepresentative are clinical study patients with asthma or COPDfor a larger ‘‘real life’’ population of patients with obstructivelung disease? Respir Med 2005;99:11–19.

25. Atkins D, Briss PA, Eccles M, Flottorp S, Guyatt GH, HarbourRT et al. Systems for grading the quality of evidence and thestrength of recommendations II: pilot study of a new system.BMC Health Serv Res 2005;5:25.

26. Schunemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA,Ernst A et al. An official ATS statement: grading the quality ofevidence and strength of recommendations in ATS guidelinesand recommendations. Am J Respir Crit Care Med2006;174:605–614.

27. Guyatt G, Vist G, Falck-Ytter Y, Kunz R, Magrini N,Schunemann H. An emerging consensus on grading recom-mendations. Available at: http://www. evidence-basedmedi-cine.com 2005; Module 37. Topic 2011:189.

28. Cuervo LG, Clarke M. Balancing benefits and harms in healthcare. BMJ 2003;327:65–66.

29. Ernst E, Pittler MH. Assessment of therapeutic safety insystematic reviews: literature review. BMJ 2001;323:546.

30. Global Programme on Evidence for Health Policy. Guidelinesfor WHO guidelines. EIP/GPE/EQC/2003.1. Geneva, WorldHealth Organization; 2003. 2003.

31. Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp Set al. Grading quality of evidence and strength of recommen-dations. BMJ 2004;328:1490.

32. Shekelle PG, Woolf SH, Eccles M, Grimshaw J. Clinicalguidelines: developing guidelines. BMJ 1999;318:593–596.

33. Malling H, Weeke B. Immunotherapy. Position Paper of theEuropean Academy of Allergy and Clinical Immunology. Al-lergy 1993;48(Suppl 14):9–35.

34. Coifman RE, Cox LS. 2006 American Academy of Allergy,Asthma & Immunology member immunotherapy practice pat-terns and concerns. J Allergy Clin Immunol 2007;119:1012–1013.

35. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy andsafety of specific immunotherapy with SQ allergen extract intreatment-resistant seasonal allergic rhinoconjunctivitis. J Al-lergy Clin Immunol 2006;117:319–325.

36. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emm-inger W et al. Efficacy and safety of sublingual immunotherapywith grass allergen tablets for seasonal allergic rhinoconjuncti-vitis. J Allergy Clin Immunol 2006;118:434–440.

37. Durham SR, Riis B. Grass allergen tablet immunotherapy re-lieves individual seasonal eye and nasal symptoms, includingnasal blockage. Allergy 2007;62:954–957.

38. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S.Sublingual immunotherapy with once-daily grass allergentablets: a randomized controlled trial in seasonal allergicrhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802–809.

39. Valovirta E, Jacobsen L, Ljorring C, Koivikko A, SavolainenJ. Clinical efficacy and safety of sublingual immunotherapywith tree pollen extract in children. Allergy 2006;6:1177–1183.


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43. Bousquet PJ, Demoly P, Passalacqua G, Canonica GW,Bousquet J. Immunotherapy: clinical trials - optimal trial andclinical outcomes. Curr Opin Allergy Clin Immunol2007;7:561–566.

44. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ,Lockey RF, Malling HJ et al. Recommendations for stan-dardization of clinical trials with Allergen Specific Immuno-therapy for respiratory allergy. A statement of a WorldAllergy Organization (WAO) taskforce. Allergy 2007;62:317–324.

45. Committee for medicinal products for human use (CPMP).Guideline on allergen products: production and quality issues.EMEA/CHMP/BWP/304831/2007. London, 20 November2008. 2008.

46. Bousquet P, Delgado L. WAO Methodology of sublingualimmunotherapy trials. Allergy 2009; in press.

47. Alvarez-Cuesta E, Bousquet J, Canonica GW, Durham SR,Malling HJ, Valovirta E. Standards for practical allergen-specific immunotherapy. Allergy 2006;61(Suppl 82):1–20.

48. Alvarez-Cuesta E, Bousquet J, Canonica WG, Durham S,Malling HJ, Passalacqua G et al. Reply to the letter byDr Fleming Madsen (EAACI �Standards for practicalallergen-specific immunotherapy�). Allergy 2008;63:939–940.

49. Blazowski L. Anaphylactic shock because of sublingual immu-notherapy overdose during third year of maintenance dose.Allergy 2008;63:374.


51. Cox L. Safety of sublingual immunotherapy. Allergy 2009; inpress.

52. Caubet JC, Eigenmann PA. Late side-effects during systemicimmunotherapy in children. Allergy 2008;63:1561–1562.

53. Fiocchi A, Pajno G, La Grutta S, Pezzuto F, Incorvaia C, SensiL et al. Safety of sublingual-swallow immunotherapy in childrenaged 3 to 7 years. Ann Allergy Asthma Immunol 2005;95:254–258.

54. Omnes LF, Bousquet J, Scheinmann P, Neukirch F, Jasso-Mosqueda G, Chicoye A et al. Pharmacoeconomic assessmentof specific immunotherapy versus current symptomatic treat-ment for allergic rhinitis and asthma in France. AllergImmunol (Paris) 2007;39:148–156.

55. Bachert C, Vestenbaek U, Christensen J, Griffiths UK, PoulsenPB. Cost-effectiveness of grass allergen tablet (GRAZAX) forthe prevention of seasonal grass pollen induced rhinoconjunc-tivitis - a Northern European perspective. Clin Exp Allergy2007;37:772–779.

56. Canonica GW, Poulsen PB, Vestenbaek U. Cost-effectiveness ofGRAZAX((R)) for prevention of grass pollen induced rhino-conjunctivitis in Southern Europe. Respir Med 2007;101:1885–1894.

57. Nasser S, Vestenbaek U, Beriot-Mathiot A, Poulsen PB.Cost-effectiveness of specific immunotherapy with Grazax inallergic rhinitis co-existing with asthma. Allergy 2008;63:1624–1629.

58. BMJ Publishing Group Ltd. Grazax for hay fever? Drug TherBull 2008;46:9–10.

59. Sculpher M. The use of quality-adjusted life-years in cost-effectiveness studies. Allergy 2006;61:527–530.

60. Bruggenjurgen B, Reinhold T, Brehler R, Laake E, Wiese G,Machate U et al. Cost-effectiveness of specific subcutaneousimmunotherapy in patients with allergic rhinitis andallergic asthma. Ann Allergy Asthma Immunol 2008;101:316–324.

61. Clavel R, Bousquet J, Andre C. Clinical efficacy of sublingual-swallow immunotherapy: a double-blind, placebo-controlledtrial of a standardized five-grass-pollen extract in rhinitis. Al-lergy 1998;53:493–498.

62. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Klimek L,Stephan V et al. Phase III trial with grass allergen tablet forsublingual immunotherapy in children. J Allergy Clin Immunol2008;121:S127.

63. Global strategy for asthma management and prevention.GINA. Update from NHLBI/WHO Workshop Report 1995,Revised 2006. Available at: http://www.ginasthma.com2006.

64. Bacharier LB, Boner A, Carlsen KH, Eigenmann PA, FrischerT, Gotz M et al. Diagnosis and treatment of asthma inchildhood: a PRACTALL consensus report. Allergy 2008;63:5–34.

Chapter 9: Definition of


patient selection

• To be eligible for SLIT, patients should have:- a clinical history of allergy.- documented ALLERGEN SPECIFIC IgE positivetest.

- the allergen used for Immunotherapy must beclinically relevant to their clinical history.

• Age does not appear to be a limitation.• Monosensitized patients are ideal candidates forSLIT, and recently single allergen SLIT has beendemonstrated to be effective in polysensitizedpatients.

• Presently use of SLIT in Latex Allergy, AtopicDermatitis, Food Allergy and Hymenoptera venomis under investigation: more demonstrations areneeded to support clinical use.

• There is no indication whatsoever for treating non-IgE-mediated hypersensitivity (for instance nickelsensitivity) with SLIT.



• SLIT may be considered as initial treatment. Failureof pharmacological treatment Is not an essentialprerequisite for the use of SLIT.

• SLIT may be proposed as an early treatment inrespiratory allergy therapeutic strategy.

• Special SLIT Indications exist in the followingpatients.

- Patients uncontrolled with optimal pharmaco-therapy (SCUAD).

- Patients in whom pharmacotherapy inducesundesirable side effects.

- Patients refusing injections.- Patients who do not want to be on constant orlong-term pharmacotherapy.

Allergen-specific immunotherapy (SIT) is a highly effec-tive treatment in patients with IgE-mediated diseases,asthma, rhinoconjunctivitis, insect venom systemicreactions and probably atopic dermatitis and food allergy.Patients must have IgE sensitization to an allergen

demonstrated either by skin tests or serum IgE antibodiesand a relationship between symptoms and exposure to anallergen to which patient is sensitive. Immune modulationby administration of increasing doses of specific allergensprovides protection against allergy symptoms on naturalexposure to the allergen but only if the allergen is clinicallyrelevant. Many people may have IgE antibodies (apositive skin test or serum specific IgE>0.35 kU/L)though do not develop symptoms.Patient selection is important, and efficacy must always

be balanced against the risk of side effects. The necessity forinitiating SITdepends on thedegree towhich symptoms canbe reduced by medication, the amount and type ofmedication required to control symptoms, and whethereffective allergen avoidance is possible. Therefore, it isessential to consider SIT on the basis of allergen sensitiza-tion rather than on a particular disease manifestation (1, 2).Although the majority of subjects is polysensitized,

monosensitized patients or patients concomitantly sen-sitized to non-cross-reacting allergens are ideal for asingle allergen vaccine study and are more likely todemonstrate the beneficial effects of SIT. Inclusioncriteria should be defined in relation to age, gender,disease, disease severity, comorbid conditions and pre-vious SIT. Concomitant medications for non-allergicdiseases, other illnesses and undesirable daily activitiesare examples of exclusion criteria (3).

Age

There is no specific upper or lower age limitation for SIT.SLIT may be a safe and effective treatment for all ages ifan atopic mechanism is involved in the pathogenesis of

disease, although efficacy in children under 5 years of ageis not documented. A meta-analysis showed that SLIT iseffective in children 3–18 years of age with allergic rhinitis(4).

To evaluate the clinical efficacy of SLIT in respiratoryallergy in children, eight DBPC-RCTs on SLIT wereselected. Five studies were run with house dust mite(HDM), one with olive pollen, one with wall pellitory(Parietaria) pollen, and one with grass pollen. SLIT couldbe currently considered to have low to moderate clinicalefficacy in children of at least 4 years of age, monosen-sitised to house dust mites, and suffering from mild tomoderate persistent asthma (5).

Children with asthma or persistent rhinitis, aged1 year and 11 months to 3 years and 10 months weretreated with a monomeric allergoid. The mean follow-upwas 22.3 months and 30/36 children were highly ormoderately improved. SLIT was safe in these very youngchildren (6).

Asthma

Patients allergic to mites may be candidates for SLIT ifthey have significant symptoms of rhinitis or asthma whenthey are exposed to domestic mite allergens.

A metanalysis of DBPC-RCTs evaluated SLIT effi-cacy in the treatment of allergic asthma in children.Nine studies reported 441 subjects who had concludedtreatment and had received a final clinical assessment.SLIT with standardized extracts (mainly mites) reducedboth symptom scores and rescue medication use inchildren with allergic asthma compared with placebo(7).

An asthma expert panel recommends that allergenimmunotherapy be considered for patients with persistentsymptoms and in patients whose asthma is not wellcontrolled by pharmacotherapy, or in whom multiplemedications are required (8).

Immunotherapy can prevent the development ofasthma in allergic rhinitis patients and new sensitivitiesin monosensitized children and adults. As in the case ofrhinitis, SIT is indicated when there is a significant allergiccontribution to the patient�s symptoms (9).

Although efficacy of SIT has been shown for treatmentof allergic asthma, there is a risk of acute asthma inpatients with severe asthma. Thus, severe or uncontrolledasthma is a contraindication for SIT (8, 10).

Allergic rhinitis

Allergen immunotherapy is an effective treatment forallergic rhinitis and can potentially modify the disease.Clinical benefits may be sustained years after discontin-uation of treatment, may prevent the development ofnew allergen sensitization and reduce the risk for the


G. Walter Canonica

future development of asthma in some patients. As forasthma, SLIT should be considered if: (i) symptoms arepersistent or severe, despite pharmacological and non-pharmacological measures; (ii) medications cause unac-ceptable side effects; (iii) patients or parents unwilling touse intranasal corticosteroid; (vi) asthma is present.Again, allergen immunotherapy should only be consid-ered if there is clear evidence of a relationship betweensymptoms and exposure to an allergen to which thepatient is sensitive (11–13).

Special considerations

Venom

In a proof-of-concept study, honeybee SLIT significantlyreduced the extent of large local reactions to honeybee inmonosensitized adult patients, and its safety profile wasgood. Local reactions are not an indication for venom ITand the efficacy of venom SLIT should be assessed inpatients with systemic reactions (14).

Atopic dermatitis

SLIT with a standardized mite extract showed efficacy inchildren with mild-moderate allergic atopic dermatitis,whereas the benefit was variable in the severe form.Children aged 5 to 16 years with atopic dermatitis(Scoring Atopic Dermatitis [SCORAD] >7) and sensi-tized to dust mites (mean mite specific IgE: 10.6 kU/L)received SLIT for 18 months (15). Further studies inatopic dermatitis are necessary before recommendationcan be made regarding effectiveness.

Food allergy

The efficacy and tolerance of SLIT with a standardizedhazelnut extract were evaluated in 23 patients allergic tohazelnut in a randomised, double-blind, placebo-con-trolled study. Systemic reactions (SRs) were observed inonly 0.2% of the total doses administered. After8–12 weeks treatment, efficacy was assessed by double-blind, placebo-controlled food challenge: almost 50% ofpatients who underwent active treatment, but only 9% inthe placebo group reached the highest food challenge dose(20 g) provoking objective symptoms. IgG4 and IL-10levels after SLIT increased only in the active treatmentgroup (16). None of these last three diseases should bepresently considered indications for clinical use of SLIT.

Latex allergy

Patients with latex-induced urticaria may benefit fromlatex SLIT (17). In an open trial designed to evaluatetolerance, SLIT (4 days) with a standardized NRL extract

was followed by a 9-week maintenance treatment. In 26patients, the glove-use test improved significantly after5 days and 10 weeks of treatment (P = 0.003, P =0.0004 respectively); the rubbing test also improvedsignificantly (18).

Finally, consideration should be given to the possibilityto predict responder patients to SIT; including SLIT;recently the evaluation of serum s-IgE/total IgE ratio hasbeen proposed (19). Further studies are needed to betterpredict SLIT responders.

Summary

SLIT is indicated for treatment of different allergicconditions following the general criteria of selectingpatients for SIT; mild to moderate IgE-mediated disease,clinically relevant allergens, exhausting pharmacologicaland non-pharmacological therapeutic options, andunavoidable side-effects of medication.


1. Bousquet J, Lockey R, Malling H-J. Allergen immunotherapy:therapeutic vaccines for allergic diseases. J Allergy Clin Immu-nol 1998;102:558–562.

2. Cox LS, Larenas-Linnemamm D, Nolte H, Weldon D, FinegoldI, Nelson HS. Sublingual immunotherapy: a comprehensive re-view. J Allergy Clin Immunol 2006;117:1021–1035.

3. Canonica WG, Baena-Cagnani CE, Bousquet J, Bousquet PJ,Lockey RF, Malling H-J et al. Recommendations for stan-dardization of clinical trials with Allergen Specific Immuno-therapy for respiratory allergy. A statement of a World AllergyOrganization (WAO) taskforce the general validity of the re-sults. Allergy 2007;62:317–324.

4. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R,Huerta J, Passalacqua G et al. Efficacy of sublingual immu-notherapy in the treatment of allergic rhinitis in pediatric pa-tients 3 to 18 years of age: a metanalysis of randomized,placebo-controlled, double-blind trials. Ann Allergy AsthmaImmunol 2006;97:141–148.

5. Sopo SM, Macchiaiolo M, Zorzi G, Tripodi S. Sublingualimmunotherapy in asthma and rhinoconjunctivitis; systematicreview of paediatric literature. Arch Dis Child 2004;89:620–624.

6. Agostini F, Tellarini L, Canonica GW, Falagiani P, Passa-lacqua G. Safety of sublingual immunotherapy with amonomeric allergoid in very young children. Allergy 2005;60:133–134.

7. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,Socorro O, Pedroza A et al. Metaanalysis of the efficacy ofsublingual immunotherapy in the treatment of allergic asthmain pediatric patients, 3 to 18 years of age. Chest 2008;133:599–609.

8. Global strategy for asthma management and prevention. WHO/NHLBI workshop report. National Institutes of Health, Na-tional Heart, Lung and Blood Institute; Expert Panel Report 3:Guidelines for the Diagnosis and Management of Asthma. FullReport 2007.



9. DiRienzo V, Marcucci F, Puccinelli P, Parmiani S, Frati F,Sensi L et al. Long-lasting effect of sublingual immunotherapyin children with asthma due to house dust mite: a 10-year pro-spective study. Clin Exp Allergy 2003;33:206–210.

10. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,Togias A et al. Allergic Rhinitis and its Impact on Asthma(ARIA) 2008 update (in collaboration with the World HealthOrganization, GA(2)LEN and AllerGen). Allergy 2008;63(Suppl86):8–160.

11. Wallace D, Dykewicz MS, Bernstein DI, Blessing-Moore J, CoxL, Khan DA et al. The diagnosis and management of rhinitis: anupdated practice parameter. J Allergy Clin Immunol2008;122:s1–s84.

12. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A,Durham S. Allergen injection immunotherapy for seasonalallergic rhinitis. Cochrane Database Syst Rev 2007;1:CD001936.


14. SeverinoMG,CortelliniG, BonadonnaP, FrancescatoE, PanziniI, Macchia D et al. Sublingual immunotherapy for large localreactions caused by honeybee sting: a double-blind, placebo-controlled trial. J Allergy Clin Immunol 2008;122:44–48.

15. Pajno G, Caminiti L, Vita D, Barberio G, Salzano G, Lom-bardo F et al. Sublingual immunotherapy in mite-sensitizedchildren with atopic dermatitis: a randomized double-blindplacebo-controlled study. J Allergy Clin Immunol 2007;120:164–170.

16. Enrique E, Pineda F, Malek T, Bartra J, Basagana M, Tella Ret al. Sublingual immunotherapy for hazelnut food allergy: arandomized, double-blind, placebocontrolled study with astandardized hazelnut extract. J Allergy Clin Immunol2005;116:1073–1079.

17. Nettis E, Colanardi MC, Soccio AL, Marcandrea M, Pinto L,Ferrannini A et al. Double-blind, placebo-controlled study ofsublingual immunotherapy in patients with latex-induced urti-caria: a 12-month study. Br J Dermatol 2007;156:674–681.

18. Bahima AC, Sastre J, Enrique E, Fernandez M, Alonso R,Quirce S et al. Tolerance and effects on skin reactivity to latex ofsublingual rush immunotherapy with a latex extract. J InvestAllergol Clin Immunol 2004;14:17–25.

19. Di Lorenzo G, Mansueto P, Pacor ML, Rizzo M, Castello F,Martinelli N et al. Evaluation of serum s-IgE/total IgE ratio inpredicting clinical response to allergen-specific immunotherapy.J Allergy Clin Immunol 2009;123:1103–1110.

Chapter 10: The Future of

Immunotherapy in the

Community Care Setting

• The significance of Primary Care: Globally, allergicdisease is under-recognised, under- or mis-diagnosedand under- or maltreated, since the symptoms of IgEmediated allergic disease (rhinitis/asthma/eczema/conjunctivitis etc.) overlap with many other condi-tions. The majority of patients who seek medicaladvice are seen in primary care.

• Allergy Education: Allergy teaching needs to becomea core part of under- and post-graduate curricula.Primary care teams in particular require furthertraining in the early detection, diagnosis, manage-ment and treatment of allergic disorders. Pragmaticprogrammes need to be developed for a betterPatient-Physician Partnership.

• Delivery of SLIT in the community setting:

a. Primary Care Physicians/GPs should be armedwith the knowledge of selecting the appropriatetreatment relevant to the patient�s illness andshould be trained to make a comprehensiveassessment, recognise treatment failure (inade-quate therapy, mal-administered therapy, inade-quate control) and exacerbations of illness.

b. They should be trained in all aspects of sublingualimmunotherapy (SLIT), including assessment ofpatients and administration of SLIT. Emphasisshould be placed on detection and managementof untoward side effects, possible local and sys-temic reactions, adverse effects and other unto-ward incidents in detail, and taught how tomanage such incidents.

• Collaboration between primary care team and aller-

gists: Primary Health Care Workers (including phy-sicians, nurses and others) should be able toadminister SLIT under the mentorship of a trainedallergist, and maintain regular liaison with him. Incollaboration, the allergist and the GP willcommence, devise and plan SLIT for the patient, andfollow up as and when needed: they will also jointlydecide when to discontinue therapy. However, thedecision whether or not to initiate SLIT (as forSCIT) should be made by the allergist.

Introduction

Allergic diseases are increasing worldwide. They aremanifest in many different organ systems, often causingdistressing and disabling symptoms for the sufferer andtheir families alike. Allergy is currently managed sub-optimally (1, 2) in the community setting and allergyspecialists are often difficult to access.

It is important that health care professionals (HCPs)working in the community have a clear understanding ofallergy in order to differentiate the problem from non-allergic causes, such as sensitivity or intolerance, for whichallergy medicines have limited effectiveness. NonethelessH1-antihistamines and other agents may benefit thepatient in conditions mimicking allergy (e.g. where phar-macological, hormonal, neurogenic or other stimuli initi-ate direct degranulation of the mast cell). Many patients�problems can be managed with the judicious use of


G. Walter Canonica

medications but for some, particularly where medicationsare not effective, SIT offers the prospect of a cure. Theadvent of SLIT now offers the possibility of once againproviding immunotherapy in the community setting.

Background

Globally, over the last 50 years or so, allergic diseases haveincreased to epidemic proportions, as clearly demonstratedin longitudinal population studies (3), with a concomitantrise in hospital admissions for severe disease (4). Manypeople consult their primary health care teams with wideranging symptoms, whichmay ormay not be due to allergy,the most common manifestations of which are rhinitis,asthma and eczema. Allergy is a set of signs and symptomscaused by mast cell degranulation in response to crosslink-ing of IgE molecules bound to the membrane of these mastcells by an allergen. The term �allergy� is loosely usedbybothpatients andHCPs,with patients ascribingmany symptomsto an allergic cause when a carefully taken history revealsthis is not the case (5). Most patients with allergic diseasesconsult primary care physicians (6).Similarly lax use of the term by HCPs creates further

anxiety and misunderstanding, for example the wateringof eyes while cutting onions; or explaining the diarrhoeacaused by antibiotics as an allergy instead of as analteration in bowel flora. It is clear that we have a duty ofcare to our patients to attempt to make the correctdiagnosis by taking a careful history and performingappropriate examinations and investigations (7). Failureto meet patients� needs leads them to seek help fromalternative practitioners who may do more harm thangood, and often at great expense to the patient.

Educational needs

In many medical schools allergy is not given a highpriority or even included in the medical curriculum. Thisfact is compounded by the paucity of allergy educationgiven to or acquired by those working in the communitysetting (8, 9). A description of those needs is beyond thescope of this statement but has been addressed elsewhere(10). It is imperative that clear educational messages aremade available to the general public concerning what isand is not allergic disease and what treatments are and arenot effective.

Allergy management

This consists of a variety of strategies, foremost of whichis avoidance of the offending allergen. This of course maynot be possible for example with the ubiquitous housedust mite (11) but for other allergens e.g. peanuts, iscurrently the only reasonable course of action. Manyallergies can be managed by the judicious use of medica-tions and for some diseases such as rhinitis and asthma,

there are clear guidelines e.g. ARIA (12), GINA (13), andIPCRG (14).

Rescue medications may be needed to treat some allergicconditions, e.g. use of adrenaline in acute anaphylaxis ororal corticosteroids for an exacerbation of asthma or severeacute intermittent rhinitis. Similarly routine medicationssuch as anti-histamines and intranasal steroidsmay provideadequate control of many allergic problems such asurticaria or intermittent rhinitis.

Immunotherapy

Prior to the mid 1980s many patients received subcuta-neous immunotherapy (SCIT) in the community settingand were assessed, by skin prick testing, prior toadministration of allergen extract solutions. Anecdotallymany of these patients benefitted from this therapy,although it was delivered in a haphazard, random fashionwith no true systematic evaluation, resulting in a numberof deaths, leading to an abandonment of immunotherapyin primary care coupled with a loss of confidence in thistreatment modality, especially in the UK (15). Howeverthe use of allergen immunotherapy in the Primary Caresetting (16–19) and also the use of allergen extracts forthe diagnosis of allergic disease (20), has been welldocumented.

More recently both subcutaneous (SCIT) (21, 22) andsublingual (SLIT) (23–28) immunotherapy have beenfound to be effective treatment for allergies.

For the foreseeable future some forms of immuno-therapy (Hymenoptera venom) will have to continue tobe administered in specialist units, because of the risk ofanaphylaxis. On the other hand SLIT offers an effective(29, 30), safe (31–34) and easy-to-use form of treatmentwhich may be administered by or through primary care(35–38). Fatal anaphylaxis has yet to be encountered,although local side effects are relatively common.Because patients self administer at home, there is littledrain on the time of the primary care team who onlyhave to supervise the first dose: it is also cost effective tothe patient (39–42). There is now a wide range ofallergens available for SLIT, for example, grass (43)andhouse dust mite (44–50) and the evidence for cumulativebenefit is emerging (51, 52).

The current challenge is to identify those patients whoare most likely to benefit from the administration of SLIT,what are the steps necessary to identify likely candidates,what investigations are needed to validate that choiceand what mechanisms need to be made available in orderto ensure efficient, effective, cost effective and safe deliveryof this new technology. One suggestion is the creation of aGP with a special interest who would have a higher levelof allergy training and greater resources to assess andinvestigate patients needs, especially where access tospecialist care is difficult (53). However, for the immediatefuture, it would still be advisable that the decision whether



or not to initiate SLIT (as for SCIT) should be made bythe allergist.The IPCRG and WAO could join together, as organ-

isations which encompass the generalism of primary carewith the specialism of secondary and tertiary care toendorse a course of action which will lead to greateraccessibility and availability of these medications coupledwith an initiative to meet the educational needs of patientsand providers alike.

Unmet needs

• HCPs should learn to differentiate between allergic andnon-allergic rhinitis.

• HCPs should be able to use readily available pharma-ceutical agents to ameliorate the symptoms of allergicrhinitis.

• HCPs need educational initiatives to help them tounderstand immunotherapy.

• It is important to recognise which patients might benefitfrom SLIT.


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7. Ryan D, van Weel C, Bousquet J, Toskala E, Ahlstedt S,Palkonen S et al. Primary care: the cornerstone of diagnosisof allergic rhinitis. Allergy 2008;63:981–989.

8. Shehata Y, Ross M, Sheikh A. Undergraduate allergy teachingin a UK medical school: comparison of the described anddelivered curriculum. Prim Care Respir J 2007;16:16–21.

9. Baptist AP, Baldwin JL. Physician attitudes, opinions, andreferral patterns: comparisons of those who have and have nottaken an allergy/immunology rotation. Ann Allergy AsthmaImmunol 2004;9:227–231.

10. Potter PC, Warner JO, Pawankar R, Kaliner MA, Del Giacco S,Rosenwasser L et al. Recommendations for competency inallergy training for undergraduates qualifying as medical prac-titioners: a position paper of the World Allergy Organization.World Allergy Org J 2009;2:50–154.

11. House dust mite control measures in the management of asth-ma: meta-analysis. BMJ 1998; 317:1105–1110; discussion 1110.

12. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ,Togias A et al. Allergic rhinitis and its impact on asthma(ARIA) 2008 update (in collaboration with the World HealthOrganization, GA(2)LEN and AllerGen). Allergy 2008;63(Suppl86):8–160.

13. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM,FitzGerald M et al. Global strategy for asthma managementand prevention: GINA executive summary. Eur Respir J2008;31:143–178.

14. Price D, Bond C, Bouchard J, Costa R, Keenan J, Levy MLet al. International Primary Care Respiratory Group (IPCRG)Guidelines: management of allergic rhinitis. Prim Care Respir J2006;15:58–70.

15. CSM update: desensitising vaccines. Br Med J (Clin Res Ed)1986;293:948.

16. Kramer J, Crocetti S. JHQ 132 – allergy immunotherapy in theprimary care setting. J Healthc Qual. Available at : http://www.nahq.org/journal/ce/article.html?article_id=162. Accessed 13November 2008.

17. Craig T, Sawyer AM, Fornadley JA. Use of immunotherapy in aprimary care office. Am Fam Physician 15 Apr 1998. Availableat: http://www.aafp.org/afp/980415ap/craig.html. Accessed 13November 2008.

18. Platts-Mills T, Leung DYM, Schatz M. The role of allergens inasthma. Am Fam Physician 2007;76:675–680.

19. James TL, Lockey RF, Bernstein L, Portnoy JM, Nicklas RA.Allergen immunotherapy – a practice parameter. Ann AllergyAsthma Immunol 2003;90:2–28.

20. Niggemann B, Nilsson M, Friedrichs F. Paediatric allergydiagnosis in primary care is improved by in vitroallergen-specific IgE testing. Pediatr Allergy Immunol2008;19:325–331.

21. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A,Durham S. Allergen injection immunotherapy for seasonalallergic rhinitis. Cochrane Database of Systematic Reviews2007, Issue 1. Art. No.: CD001936. DOI: 10.1002/14651858.CD001936.pub2

22. Moreno C, Cuesta-Herranz J, Fernardez-Javora L, Alvarez-Cuesta E, on behalf of the SEAIC. Immunotherapy safety: aprospective multi-centre monitoring study of biologically stan-dardised therapeutic vaccines for allergic disease. Clin Exp Al-lergy 2004;34:527–531.


24. Brit Med J Group. Grazax for hay fever? Drug Ther Bull2008;46:9–10.

25. Markert UR. Local immunotherapy in allergy: prospects for thefuture. Chem Immunol Allergy 2003;82:127–135.

26. Halken S, Lau S, Valovirta E. New visions in specific immuno-therapy in children: an iPAC summary and future trends. PediatrAllergy Immunol 2008;19(Suppl 19):60–70.


28. van Wijk RG. Sublingual immunotherapy in children. ExpertOpin Biol Ther 2008;8:291–298.

29. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy ofsublingual immunotherapy in asthma: systematic review ofrandomized-clinical trials using the Cochrane Collaborationmethod. Allergy 2006;61:1162–1172.


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30. Saporta D, McDaniel AB. Efficacy comparison of multiple-antigen subcutaneous injection immunotherapy and multiple-antigen sublingual immunotherapy. Ear Nose Throat J2007;86:493–497.

31. Passalacqua G, Guerra L, Compalati E, Canonica GW. Thesafety of allergen specific sublingual immunotherapy. Curr DrugSaf 2007;2:117–123.

32. Rodrıguez-Perez N, Ambriz-Moreno Mde J, Canonica GW,Penagos M. Frequency of acute systemic reactions in patientswith allergic rhinitis and asthma treated with sublingualimmunotherapy. Ann Allergy Asthma Immunol 2008;101:304–310.

33. Esch RE, Bush RK, Peden D, Lockey RF. Sublingual-oraladministration of standardized allergenic extracts: phase 1 safetyand dosing results. Ann Allergy Asthma Immunol2008;100:475–481.

34. Esch RE. Sublingual immunotherapy. Curr Opin OtolaryngolHead Neck Surg 2008;16:260–264.

35. de Bot CM, Moed H, Berger MY, Roder E, de Groot H, deJongste JC et al. Randomized double-blind placebo-controlledtrial of sublingual immunotherapy in children with house dustmite allergy in primary care: study design and recruitment. BMCFam Pract 2008;9:59.

36. Stokes JR, Casale TB. Allergy immunotherapy for primary carephysicians. Am J Med 2006;119:820–823.

37. Charron M, Kramer J, Crocetti S. Allergy immunotherapyin the primary care setting: integrating national practicestandards to promote safe delivery. J Nurs Care Qual2006;21:187–193.

38. Kramer J, Crocetti S. Allergy immunotherapy in the primarycare setting. J Health Qual 2003;25:8–13. quiz 13-14.

39. Canonica GW, Poulsen PB, Vestenbaek U. Cost-effectivenessof GRAZAX for prevention of grass pollen induced rhino-conjunctivitis in Southern Europe. Respir Med 2007;101:1885–1894.

40. Bruggenjurgen B, Reinhold T, Brehler R, Laake E, Wiese G,Machate U et al. Cost-effectiveness of specific subcutaneousimmunotherapy in patients with allergic rhinitis and aller-gic asthma. Ann Allergy Asthma Immunol 2008;101:316–324.

41. Weber RW. Allergic rhinitis. Prim Care 2008;35:1–10. v42. Berto P, Frati F, Incorvaia C, Cadario G, Contiguglia R, Di

Gioacchino M et al. Comparison of costs of sublingual immu-notherapy and drug treatment in grass-pollen induced allergy:results from the SIMAP database study. Curr Med Res Opin2008;24:261–266.

43. Mosges R, Bruning H, Hessler HJ, Gotz G, Knaussmann HG.Sublingual immunotherapy in pollen-induced seasonal rhinitisand conjunctivitis: a randomized controlled trial. Acta Derma-tovenerol Alp Panonica Adriat 2007;16:143–148.

44. Antunez C, Mayorga C, Corzo JL, Jurado A, Torres MJ. Twoyear follow-up of immunological response in mite-allergic chil-dren treated with sublingual immunotherapy. Comparison withsubcutaneous administration. Pediatr Allergy Immunol2008;19:210–218.

45. Nuhoglu Y, Ozumut SS, Ozdemir C, Ozdemir M, Nuhoglu C,Erguven M. Sublingual immunotherapy to house dust mite inpediatric patients with allergic rhinitis and asthma: a retro-spective analysis of clinical course over a 3-year follow-upperiod. J Investig Allergol Clin Immunol 2007;17:375–378.

46. Cadario G, Galluccio AG, Pezza M, Appino A, Milani M,Pecora S et al. Sublingual immunotherapy efficacy in patientswith atopic dermatitis and house dust mites sensitivity: aprospective pilot study. Curr Med Res Opin 2007;23:2503–2506.

47. Ozdemir C, Yazi D, Gocmen I, Yesil O, Aydogan M, Semic-Jusufagic A et al. Efficacy of long-term sublingual immuno-therapy as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma. Pediatr Allergy Immunol2007;18:508–515.




51. Marogna M, Spadolini I, Massolo A, Zanon P, Berra D,Chiodini E et al. Effects of sublingual immunotherapy formultiple or single allergens in polysensitized patients. Ann Al-lergy Asthma Immunol 2007;98:274–280.

52. Frew AJ, Smith HE. Sublingual immunotherapy. J Allergy ClinImmunol 2001;107:441–444.

53. Ryan D, Levy M, Morris A, Sheikh A, Walker S. Managementof allergic problems in primary care: time for a rethink? PrimCare Respir J 2005;14:195–203.

Chapter 11: Methodology of

clinical trials in sublingual

immunotherapy

• The methodology of randomised clinical trials isessential to critically assess and register treatmentinterventions.

• Recently, large well-performed randomised clinicaltrials have been published for specific sublingualimmunotherapy.

• Requirements for conducting trials in SLITinclude:– allergen standardization– patient�s inclusion and exclusion criteria– Phase I trials to assess safety– dose-ranging studies– adequate pollen counts in trials on pollen

allergic patients– pivotal trials which should be of randomised,

parallel-group, placebo-controlled design:the number of patients should be adequate.

• Primary and secondary outcome measures areidentified.



• There are needs for specific trials in asthma, foodallergy, disease-modifying efficacy, cost-effective-ness and children.

• In all trials, safety should be carefully monitored.

Introduction

The efficacy and safety of sublingual allergen immuno-therapy (SLIT) were until recently a matter of debate. Themethodology of many SIT trials was insufficient (1).Meta-analyses could not reach a clear conclusion

because they included RCTs of insufficient methodology,which were not always devoid of defects and the newadequately-powered, well-designed DBPC-RCTs werepublished later (2–5). The major issues that can beaddressed to currently available meta-analyses on SLITrelate to the high level of inter-study heterogeneity(clinical, methodological and statistical) and the size ofthe studies included. Trials administering different aller-gens, with different schedules, in different cumulativedoses, to different kinds of patients and for differentdurations were analysed together. Open or single-blindstudies were included. The quality of trials measured byaccepted evaluation scales, detected defects regardingallocation concealment, blinding, randomization andpatient selection in most of the trials, especially in thepaediatric population. Therefore, small studies are poten-tially misleading for the risk of overestimating the sizeeffect of intervention or missing moderate/low effects.Finally, most studies included symptoms as a primaryoutcome without taking into account the concomitantrescue medications inducing misinterpretation.Although there are negative DBPC-RCTs (6), ade-

quately-powered, well-designed DBPC-RCTs have re-cently confirmed the efficacy and safety in adults andchildren with pollen-induced rhinitis (7–13). It is thereforeimportant to propose guidelines for the performance andevaluation of RCTs in SLIT in order to optimize thequality and reporting of RCTs and guidelines (14).A paper under the auspices of the World Allergy

Organization (WAO) (15) on the methodology of RCTshas been used as a basis for the present paper. Moreover,the European Medicines Agency (EMEA) Committee ForMedicinal Products For Human Use (CHMP) Guidelineon the Clinical Development of Products for SpecificImmunotherapy for the Treatment of Allergic Diseasesand other related European regulatory issues were care-fully studied (16, 17).

Diseases and allergens to be investigated

The clinical efficacy of SLIT is well established for grasspollen rhinitis and conjunctivitis but more studies areneeded for other allergens and asthma. For other allergic

diseases such as atopic dermatitis (18), latex (19) or foodallergy (20, 21), SIT is still not recommended and ade-quately-powered, well-designed DBPC-RCTs need to becarried out to critically assess efficacy and safety. Immuno-therapy using venomswill not be considered in this chapter.

Quality and standardization of allergen vaccines

The quality of the allergen vaccine is critical. Wheneverpossible, standardized vaccines of known potency andshelf-life should be used (22, 23).

The potency of allergen vaccines depends on the type ofvaccine (allergen extract, recombinant allergen, allergoids)and should follow recommendations such as the recentCHMP guideline on allergen products (24). In any RCTusing allergen extracts, the characteristics of the vaccineneed to be included, namely the content of representativemajor allergens in mass units (lg/ml) (22, 23). However,comparison between different manufacturer labelling maybe difficult due to differences in assays and methodologiesfor measurement of the major allergens (25, 26). Formixtures, the principle of homologous groups is advised inEurope (27), together with the careful assessment of thestability of the extracts when mixing together differentallergens.

Placebo

Double-blind, placebo-controlled, SLIT studies have foundthat up to 65%of subjects on active treatment with allergenversus under 30% on placebo have had local allergysymptoms allegedly associated with absorption of theallergen. This imbalance of adverse local/regional reactionsin these studies makes the blinding of the study difficult.

Collins English Dictionary defines placebo as �an activesubstance or other form of therapy administered to apatient usually to compare its effects with those of a realdrugor treatment…�. The use of a placebo is essential in anystudy, and appears particularly important in SLIT. Ideally,the placebo should have the same characteristics as theactive allergen in appearance, smell, taste, consistency, andcause local symptoms consistent with an allergen extract.

However, the choice for a placebo in SLIT is unclear.Histamine, under the tongue, does not elicit itching; norare there any other substances that produce similarsymptoms to an allergen extract in a person allergic to agiven allergen. Therefore, it would be difficult to manu-facture a placebo which causes local allergy symptoms. Inaddition, from some studies, the adverse local effects fromSLIT typically remit within a week or two. Because it isnot feasible to devise an active placebo, any analysis ofefficacy should take into account the incidences of sideeffects in assessing efficacy. However, in a study, the levelof local/regional side reactions was not associated withefficacy (9).


G. Walter Canonica

Patient characteristics

a. Selection of patients

Many subjects with positive skin tests and/or serumspecific IgE do not present with symptoms (28). Thus,only patients with an accurate diagnosis of an allergicdisease, and in whom the allergen sensitization is corre-lated with the time of symptoms should be included inRCTs. The diagnosis of allergy should be based on skinprick tests and/or the measurement of allergen-specificIgE in serum. It is not clear whether both tests are needed.Additionally, nasal and/or conjunctival allergen provoca-tion tests can be used to establish the relevance of theallergen. The history of allergic diseases should cover atleast two consecutive years (16).Allergic diseases should be classified in terms of

duration and severity (or control) according to the mostrecent guidelines: ARIA for allergic rhinitis (29) andGINA for asthma (30). Small studies in patients withperennial rhinitis showed usually less efficacy (31) thanthose in persistent rhinitis (32). It is therefore advised tostudy patients with persistent rhinitis.Patients enrolled in SIT studies should have a minimal

level of symptoms (historical for pollen trials or atbaseline). The maximum mean (or median) symptomscore of patients receiving placebo is usually low in SITstudies by comparison to drug trials. These low scores donot reflect the severity of the disease but may be associatedwith low allergen exposure of patients during the season.Because most allergic patients are polysensitized (33), it

is important to characterize the different inhalant aller-gens to which the patients are sensitized, to differentiatemono- and polysensitized subjects, and to consider cross-reactivities between allergens. The exposure to relevantallergens overlapping with the allergen used in a SLITtrial, can cause misleading results. Co-morbidities shouldbe clearly stated and eventually used in multivariateanalyses. Patients should not have had any form ofimmunotherapy within the past 5 years (16).

b. Co-medication and allergen avoidance

The indication of SIT with inhalant allergens is not toreplace pharmacologic treatment, but to improve thecontrol of patients who are insufficiently controlled usingdrugs (22). Concomitant medications are therefore neededin most patients. In most SIT trials, rescue medicationsare proposed, and should be administered in a standardway in order to calculate a medication score (34). In astudy, patients were instructed to use medications in orderto control symptoms as best as possible and the primaryend point was the medication score (35). In patients withhigh morbidity, preventer medication should be consid-ered in accordance to ARIA and GINA guidelines. Acomposite score that includes medication can be consid-ered.

Allergen avoidance is a matter of discussion since singlemeasures to avoid mites are not effective in asthma (36). Ithas however been proposed that patients should have acontrol of mites in SLIT trials (16).

Design of clinical trials

a. Phase I studies

The methodology of Phase I studies should follow strictrecommendations (16). Only allergic patients should beincluded in Phase I trials. Some SLIT trials have beenpublished (37–39).

b. Phase II studies

i. Outcomes to be measured. Many different outcomesmay be examined in Phase II studies in order to supportthe efficacy of SIT. They are detailed in the WAO Paper(Table 11-1) (15).

ii. Dose-finding studies. One important issue is the optimaldose of allergenwhich should be used to obtain themaximalefficacy without side effects. Dose-finding studies aretherefore required. It has been suggested that challengestudies may be used (16) but RCTs may be needed (9).

iii. Pharmacodynamic studies. The first experimental basisfor exploring the in vivo kinetics of allergen administeredthrough non-injectable routes was achieved by radiola-belled allergens, scintigraphic images and chromatogra-phy (41, 42). Pharmacodynamic studies can be performedassessing changes on immunologic markers or allergenchallenge (16).

c. Phase III studies

i. Baseline assessment. In pollen allergy, the inclusion of abaseline period of observation, e.g. one pollen seasonbefore randomization would be optimal. However, due tothe unpredictability and variability of allergenic exposureto pollen allergens this baseline period cannot be used tocompare with treatment years (43, 44). This baselineseason may be used to exclude patients who do notpresent a clear increase in symptoms during the season.During patient selection, attention should be paid to theout of season level of symptoms in active and controlgroups in order to check the correlation between increasein symptoms and in pollen counts.

In house dust mite allergy (HDM), a baseline may beused (45), and the fluctuations in the levels of indoorallergens may be observed throughout the studies (32). Inthe case of corticosteroid-withdrawal studies, a baselineobservation period is needed to stabilize asthma and toassess the baseline level of inhaled corticosteroids.



ii. Randomised clinical trial in rhino-conjunctivitis. Arandomised, parallel group, placebo-controlled and dou-ble-blind design remains the gold standard to determineefficacy and safety of allergen products (15, 46). Superi-ority studies need to be carried out (16). Trials should beregistered.Many SLIT studies have methodological flaws:

• Inclusion of a small number of participants• Studies of unmatched groups with respect to disease

severity• Undefined primary outcome• Non-significant primary outcome and significant

secondary outcomes

1. Assessment of allergen exposureIn pollen RCTs, pollen counts should be measured and

pollen traps should be located in order to match the pollenseason of all patients of the study. However, it is almostimpossible to have a sufficient number of pollen traps inmulti-national trials. Moreover, the local exposure ofpatients is very important and cannot be assessed usingpollen traps. Thus, there is only a poor associationbetween pollen counts and individual patients� symptoms.In mite studies, the association between household mite

allergen levels and symptoms is questionable at best;major allergen content of house dusts in patient�s homesmay be measured serially during the trial. However, thelevels of mite allergens often decrease during the trial (47).

2. Number of patients needed to be treatedPhase III trials for registration will need a large number

of perfectly characterized subjects. From the recent PhaseIII trials in SLIT, it seems that a number of 150–200 patients(36) per group is adequate (7–9). However, an appropriatecalculation is necessary depending on the primary outcomechosen and the magnitude of effect desired (48, 49).

3. Primary outcome parametersThe primary end point should, if possible, be a single

end point giving a global assessment of the patient. In thecase of allergic rhinitis induced by pollens, it is advisableto use the total symptom score including all nasalsymptoms (nasal obstruction, rhinorrhoea, sneezing andpruritus) with one or more ocular symptoms (7–9). Theuse of electronic devices to assess the daily symptom scoreis recommended. There is no universally accepted systemto measure symptoms: ordinal scales, days free of symp-toms, days free of medications, symptom scores correctedfor medications, etc. The most frequently used approachin SIT clinical trials is a four-point rating scale (from0 = absent to 3 = severe) applied to each symptom.The minimal relevant magnitude of efficacy has been

proposed to be at least 20% higher than placebo (14) andthis level appears to be clinically relevant (50).The use of rescue medication has an impact on

symptom severity. Therefore, a primary end point

reflecting both symptom severity and intake of rescuemedications is favoured. Different approaches to com-bine the two scoring systems have been proposed butthere is no standardized method as yet (51). Anyanalysis of such a combined score should be supportedby a responder analysis (16). A consensus to standardizenasal symptoms or combined scores is still needed.

4. Secondary outcome parametersSeveral secondary outcome parameters can be used:

• Rescue medications or score if they are not includedin a global score

• Individual symptoms (52)• Visual analogue scale (VAS)• Quality-of-life (50)• Symptom-free days• Physician and patient rated clinical global improve-

ment (7–9)• There is, however, no objective measurement for

rhinitis or conjunctivitis.

5. Exploratory outcome parametersExploratory outcomes include:

• Evolution of nasal or conjunctival challenges• Chamber studies• Evolution of skin tests to allergens• Allergen-specific antibodies (7–9) and other immu-

nologic parameters (53–55).

6. Methodological aspects (56)Some characteristics of the trials need to be defined

before starting the trial and considered until the end of thestudy:

• Allocation needs to be guaranteed very strictly andverified. At best, a centralized randomization usingpermutation blocs, generated by computer with aspecific list (different random order and/or bloc size)has to be carried out for each centre (allocation withinsite). Any stratification, justification and methodshould be explained.

• The double-blind method has to be described, espe-cially for placebo, which has to be strictly similar toactive vaccine (same composition, aspect, colour,taste…) except for allergens (57). However, for SLIT,there are no defined placebo local side effects similarto allergen. Finally, usually in RCTs, double-blindmethodology should be maintained and confirmedduring administration of intervention, data collectionand analysis of results. This has to be discussed,especially for long term RCTs.

• Drop-outs are difficult to avoid due to the usuallength of the trials (months or even years). Attemptsto reduce drop-outs are essential in order to reduce apotential attrition bias. Drop-out rates should be


G. Walter Canonica

under 20% (58). If the drop-out rate is over this level,a sensitivity analysis is needed to evaluate the reli-ability of the results (59).

• The analysis has to be conducted as intent-to-treat (59).This approach is often inadequately described andinadequately applied. Deviations from allocation andmissing responseshas tobedescribedand theirpotentialeffect discussed in the final report and publications.

• RCTs are conducted to respond to one objective.Post-hoc analyses are commonly performed. How-ever, these analyses must be declared before startingpatient inclusion.

7. SafetySafety is a key factor for any SLIT trial and may differ

depending on the sensitization of the patient (60). Adversedrug reactions (ADR) should be codified using MedDRA(Medical Dictionary for Regulatory Activities) (61). Atleast during the first month of use, safety should berecorded every day.It is recommended that anaphylactic ADRs should be

defined according to the definition of anaphylaxis (62),and the ADR severity needs to be reported using theproposals of EAACI (25).

8. Study durationFor pollen allergy, the pollen count is important and

the clinical effects of SLIT should be recorded duringthe entire pollen season. However, the primary outcomeanalysis can be made for the peak of the pollen season,represented for instance by the weeks including 50% ofthe total pollen load. House dust mites and animaldander can induce both intermittent and persistentsymptoms, thus, patients with persistent rhinitis and/orasthma should be carefully selected.The duration of the treatment needs to be carefully

defined (64–66).

9. Compliance to immunotherapyCompliance to treatment, amajor problemof allergy and

asthma management, is far better in RCTs than in real life.Thus, �real life� or pragmatic trials are needed (67) but are

rarely available for allergic diseases (68). If initiated, suchtrials should include pharmacoeconomic analyses.

Very few studies have assessed the compliance toimmunotherapy. It was found that compliance to SCITand SLIT is adequate (68–72) although some studies werebased on low numbers of patients. On the other hand, in afew patients, compliance to intranasal immunotherapywas found to be low (69). In a �real life� situation, theFlorida Medicaid database, it was found that among the3048 children who were prescribed SCIT, only 16% werestill on treatment after 3 years of treatment (73). The realcompliance with SLIT is therefore unknown and �real life�studies should be carried out for assessment.

10. Publication of the resultsThe publication of the RCTs should follow the CON-

SORT statement whenever possible (74, 75). Funding ofthe trial should be clearly stated (76). In order to improvetransparency, the results should be reported both numer-ically and with graphs.

iii. Randomised clinical trials in asthma. For a claim ofefficacy in asthma, specific trials should be performed(Table 11-2).

Bronchial symptoms (wheezing, shortness of breath,cough) may be used as a primary outcome, but they shouldbe associated as a co-primary end point with FEV1 or PEF,which can be measured serially using electronic diaries. Assecondary outcomes, the control of the disease and quality-of-life appear to be the most important parameters.Exploratory outcomes, e.g. non-specific bronchial hyper-responsiveness may complement the study. Moreover,patients should have sufficient symptoms to demonstratea significant difference between placebo and SLIT (77).

Most guidelines propose to avoid SIT in moderate tosevere asthmatics because of the increased rate of severeasthmatic reactions. However, a recent SCIT study sug-gested that patients with moderate asthma may be safelytreated by SCIT (78). If new studies are carried out, it will beof great importance to carefully scrutinize the safety.

In asthma, many studies have attempted to find a spar-ring effect of treatments, on asthma control or symptoms.However, many of these studies were inconclusive withmedications because the placebo effect is significant (43, 79).

d. Studies in children

Despite limitations due to the limited number of patientsstudied in many reports, recent reviews and meta-analyses(3, 4) usually, but not always (5) showed positive effects ofSLIT in children. Moreover, recent large RCTs providedfinal evidence of effectiveness of SLIT in children (11–13).The European Medicinal Agency (EMEA Directive 2001/20/EC) and FDA state clearly that �children are not smalladults� and that specific trials should be conducted in thisage group. Allergy is difficult to demonstrate in preschoolchildren and SLIT trials may be very difficult to carry out.

Table 11-1 Surrogate or paraclinical parameters

Target organ allergen specificreactivity

- Skin: end point skin test,late cutaneous response

- Nose, eye and bronchi:allergen specific provocation test

- Allergen chambers

Immunological parameters- Total and allergen specific IgE

and IgG subclasses- Mucosal IgA- Lymphocyte subsets and cytokines

(e.g. IL-12, IFNc, IL-5, IL-10)- Local and systemic inflammatory

markers (e.g. adhesion molecules,urinary leukotrienes, sECP, tryptase)

Non specific organ reactivity- Bronchial challenge with

methacholine, carbachol, histamine,AMP

AMP, Adenosine Monophosphate; sECP, serum Eosinophil Cationic Protein: From (40)




Table 11-2 Points to consider for RCTs in SLIT

Allergen vaccine• Composition (24) • Single allergen

• Mixtures

• If mixture (27) • Homologous allergens

• Standardization (24) • Defined• Differ depending on vaccine

• Daily dose (22, 23) • lg of major allergen

• Cumulative dose (22, 23) • lg of major allergen

• Weekly dose (22, 23) • lg of major allergen

Patient selection• Demographic characteristics (16, 17)• Assess all sensitizations (mono or polysensitization): for EU (76) • Panel of allergens

• Skin prick tests

Prove concordance of sensitization and symptoms as not all sensitizations areclinically relevant (16, 17)

• Skin prick tests• And serum specific IgE

• Optional: allergen challenge

• Assess severity of symptoms (16, 17) • Historical or run-in

• Report co-morbidities (16, 17) • May be used in the analysis

• Exclude patients who received SIT within 5 years (16, 17)

RCT (16, 17)• Randomised• Double-blind• Placebo-controlled• Superiority trial• Intent-to-treat analysis

Objective of the study (16, 17) • Treatment of allergic symptoms: short term trial• Sustained clinical effect: 2–3 years trial• Disease modifying effect:

3 year trial and efficacy after discontinuation

Protocol of the trial • Maximum daily dose(if possible lg allergen)

• Protocol to reach maintenance• Number of doses per week• Duration of the study• Co-seasonal administration

Rescue medication • Standardized list• Weighted medication score

Primary outcome • Total symptom score• Combined symptom-medication score• For asthma: co-primary: FEV1 or PEF

Secondary outcomes • Rescue medications• Individual symptoms• Visual analogue scale (VAS)• Quality-of-life (QOL)• Asthma control• Symptom-free days• Physician and patient rated clinical global improvement

Exploratory analyses • Evolution of nasal or conjunctival challenges• Evolution of skin tests to allergens• Specific immunoglobulins• Other immunologic parameters• Non-specific BHR (asthma)• Inflammatory biomarkers:

induced sputum, FeNO (asthma)

G. Walter Canonica

Special ethics should be considered since children cannotusually give their informed consent.Immunotherapy is not recommended in children under

5 years of age due to the possible severity of side-effects. Apost-marketing surveillance safety study on 126 3–5 year-old children (73% with asthma) demonstrated the safetyof SLIT prescribed mostly for mite allergy (80).

Preventative studies

Studies assessing long-term efficacy with sustainedclinical effect after immunotherapy is stopped (disease-modifying effect) should be specifically designed. Specifictrials for this claim need to be carried out (16). Somestudies suggest that this effect may be observed duringSLIT (81), but more data in sufficiently poweredplacebo-controlled RCTs are needed.

Cost-effectiveness studies

New studies will need to incorporate cost-effectivenessparameters in their design (40, 82–84) and comparisonwith other forms of SIT (85).


1. Malling HJ. Sublingual immunotherapy: efficacy – methodologyand outcome of clinical trials. Allergy 2006;61(Suppl. 81):24–28.

2. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapyfor allergic rhinitis: systematic review and meta-analysis. Allergy2005;60:4–12.

3. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Hu-erta J, Passalacqua G et al. Efficacy of sublingual immuno-therapy in the treatment of allergic rhinitis in pediatric patients 3to 18 years of age: a meta-analysis of randomized, placebo-controlled, double-blind trials. Ann Allergy Asthma Immunol2006;97:141–148.

4. Penagos M, Passalacqua G, Compalati E, Baena-Cagnani CE,Orozco S, Pedroza A et al. Metaanalysis of the efficacy of sub-lingual immunotherapy in the treatment of allergic asthma inpediatric patients, 3 to 18 years of age. Chest 2008;133:599–609.



7. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emm-inger W et al. Efficacy and safety of sublingual immunotherapywith grass allergen tablets for seasonal allergic rhinoconjuncti-vitis. J Allergy Clin Immunol 2006;118:434–440.

8. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S.Sublingual immunotherapy with once-daily grass allergentablets: a randomized controlled trial in seasonal allergicrhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802–809.



11. Valovirta E, Jacobsen L, Ljorring C, Koivikko A, Savolainen J.Clinical efficacy and safety of sublingual immunotherapy withtree pollen extract in children. Allergy 2006;61:1177–1183.



14. Brozek JL, Baena-Cagnani CE, Bonini S, Canonica GW, RasiG, van Wijk RG et al. Methodology for development of theallergic rhinitis and its impact on asthma guideline 2008 up-date. Allergy 2008;63:38–46.

15. Canonica GW, Baena-Cagnani CE, Bousquet J, Bousquet PJ,Lockey RF, Malling HJ et al. Recommendations forstandardization of clinical trials with Allergen SpecificImmunotherapy for respiratory allergy. A statement of a WorldAllergy Organization (WAO) taskforce. Allergy 2007;62:317–324.

16. Committee for medicinal products for human use. Guideline onthe clinical development of products for specific immunotherapyfor the treatment of allergic diseases. CHMP/EWP/18504/2006.London, European Medicines Agency. Pre-authorisationevaluation of medicines for human use. 20 November 2008.

17. Lorenz AR, Luttkopf D, Seitz R, Vieths S. The regulatorysystem in europe with special emphasis on allergen products. IntArch Allergy Immunol 2008;147:263–275.


Table 11-2 (Continued)

Assess exposure to allergen • Pollen counts• Mite allergen content in individual homes

Safety MedDRA (61)Anaphylactic reactions (62)Severity of reactions (25)

Number of patients needed to be treated (48, 49)

Statistical analysis • Depends on study objectives

Publication of results • CONSORT statement (73, 74)


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