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GLORIA Module 4:Allergen Specific Immunotherapy

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regional and national presentations. GLORIA modules are created from established guidelines

and recommendations to address different aspects of allergy-related patient care.

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The World Allergy Organization is an international coalition of 74 regional and national allergy and clinical immunology

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GLORIA Module 4:Allergen Specific Immunotherapy

Lecture objectives

♦ Following this presentation, you will be able to:♦ Discuss and define indications for specific

allergen immunotherapy (SIT)♦ Describe the safety and benefits of SIT♦ Explain the mechanisms of action of SIT♦ Discuss the current status of alternative methods

of immunotherapy

Source Documents♦ EAACI Immunotherapy Position Paper 1993

♦ Position Paper on Allergen Immunotherapy.Report of BSACI Working Party 1993

♦ WHO Position Paper on Immunotherapy 1998

♦ EAACI Local Immunotherapy 1998

♦ ARIA: Allergic Rhinitis – Its Impact on Asthma 2001

♦ Allergen Immunotherapy: A Practice Parameter ACAAI 2003

WAO Expert Panel

♦ G Walter Canonica, Italy, Chair♦ Carlos Baena-Cagnani, Argentina♦ Stephen R Durham, UK♦ Richard Lockey, USA♦ Daniel Vervloet, France

Invited Contributor♦ Giovanni Passalacqua, Italy

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and

standaridization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts andstandardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Definition

♦ Allergen immunotherapy is the administration of gradually increasing quantities of an allergen vaccine to an allergic subject, reaching a dose which is effective in ameliorating the symptoms associated with subsequent exposure to the causative allergen.

WHO Position Paper 1998

Allergen Specific Immunotherapy♦ Definition

♦ Extracts andstandardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Allergen Extracts - 1

♦ Allergen extracts are a preparation of an allergen obtained by extraction of the active constituents from animal or vegetable substances with a suitable menstruum.

Allergen Extracts - 2

♦ For allergen immunotherapy, products may be either unmodified vaccines or vaccines modified chemically and /or by absorption onto different carriers:

♦ Aqueous vaccines♦ Depot and modified vaccines♦ Mixtures of allergen vaccines

Allergen Extracts- 3

♦ The quality of the allergen vaccine is critical for both diagnosis and treatment. Where possible, standardized vaccines of known potency and shelf-life should be used.

ARIA, JACI, 2001

Allergen Standardization - 1

♦ Standardization allows definition of the “potency” of allergenic extracts and warrants that the batches of vaccine produced from different lots of raw material are consistent and have comparable activities.

Allergen Standardization - 2

♦ The standardization can be made:

Biologically; the potency of the vaccine is compared to the cutaneous response obtained in a reference population;

Immunologically; the potency of the vaccine is based on RAST-inhibition experiments using standard pools of sera.

Allergen Standardization - 3

♦ Many different units are used:♦ Protein nitrogen units (PNU- world wide) ♦ Allergy unit (AU- U.S. FDA) ♦ Bioequivalent allergy unit (BAU)♦ Biologic units (BU- Europe) ♦ International unit (IU- WHO) ♦ Index of reactivity (IR- Europe) ♦ Specific treatment unit (STU) ♦ Activity Units by RAST (AUR- Europe)

Allergen Standardization - 4

♦ The major allergen(s) content in micrograms per ml is provided for most products.

♦ Standardized allergen extracts should be preferred for allergy diagnosis and therapy.

Allergen Immunotherapy Indications

Hymenoptera venom immunotherapy is the only effective preventive treatment for insect sting-induced anaphylaxis.

Inhalant allergen immunotherapy reduces symptoms and/or medication needs for patients with allergic asthma and/or rhinoconjunctivitis.

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Efficacy - 1

♦ Allergen immunotherapy is the only treatment that can modify the immune response to allergens and alter the course of allergic diseases.

♦ In some guidelines the indication for allergen immunotherapy for asthma and rhinitis has been separated. This separation is incorrect - respiratory allergy is a unique immunological disorder of the airways.

ARIA 2001

Efficacy - 2

♦ Allergen immunotherapy should be based on allergen sensitization not on the disease

Allergens of Proven Efficacy in Double Blind Placebo Controlled Studies

PollensCatHouse dust mitesHymenoptera venoms

Few data (though encouraging) are available for dog dander and mould allergens

Solenopsis invicta

Bombus spp.

Apis melifera.

Polistes spp.

Vespa Crabro.

Vespula spp.

Stinging Insects

Clinical Features of Hymenoptera Allergy

Large local reaction Oedema >10cm > 24 hr

I Urticaria

II Stage I + angioedema or rhinoconjunctivitis or abdominal pain

III Stage I + dyspnoea, dysphonia, dysphagia

IV Anaphylaxis

Müller HL. J Asthma Res 1966

Venom Immunotherapy – When to StartSevere systemic reactions stages III - IV

Yes

Mild systemic reactions stages I - II

Adults: only if at risk

Children (age <10 yrs): No

Large local reaction No

Unusual reactions No

Müller Clin. Exp. Allergy 1998

Effects of Immunotherapy

♦ Symptom improvement and/or reduction of the need for symptomatic drugs in allergic rhinitis and asthma.

♦ Long-lasting effect once discontinued.

♦ Prevention of the onset of new skin sensitizations.

♦ Prevention of the onset of asthma (?).

Parameters of Efficacy - Paraclinical

♦ Systemic immunological changes

Immunoglobulins

Cells

Mediators

♦ Local immunological changes

Specific organ reactivity

Nonspecific hyperreactivity

Allergen Immunotherapy for Asthma

♦ 76 trials with 3,188 patients♦ Significant improvement in asthma

symptom scores♦ Significant reduction of allergen

specific bronchial hyperreactivity♦ Some reduction also in non-specific

bronchial hyperreactivity

Abramson, Weiner and Puy

Cochrane Database Systematic Review 2003

Allergen Immunotherapy for Asthma

It would have been necessary to treat 4 (95% CI 3 to 5) patients with immunotherapy to avoid one deterioration in asthma symptoms, and overall to treat 5 (95% CI 4 to 6) patients with immunotherapy to avoid one requiring increased medication.

Abramson, Weiner and Puy Cochrane Database Systematic

Review 2003

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts andstandardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Safety

♦ Millions of subcutaneous immunotherapy injections are administered annually. The risk of a fatal or near-fatal systemic reaction is extremely small, but not completely absent.

♦ Physicians prescribing or administering subcutaneous immunotherapy should be aware of these risks and institute appropriate procedures to minimize them.

Grading of Systemic Reactions - 1

♦ 1. Non-specific reactions (likely non-IgE-mediated), discomfort, nausea, headache, arthralgia.

♦ 2. Mild systemic reactions; mild rhinitis/asthma (PEFR > 60%), responding to β2

agonists/antihistamines.

Grading of systemic reactions - 2

♦ 3. Non-life-threatening systemic reactions; urticaria, angioedema, severe asthma (PEFR < 60%). Responding well to treatment.

♦ 4. Anaphylaxis; itching, urticaria, bronchospasm, with hypotension, requiring intensive care.

Malling and Weeke, Allergy, 1993

Fatalities

Period 1945-198446 FatalitiesLockey RF et al JACI 1987

Period 1985-198917 FatalitiesReid MJ et al, JACI 1993

Estimated risk for fatal reactions less than 1 per 2 million injections

Safety

♦ The safety of immunotherapy; a prospective study

♦ 2,989 patients♦ Period 7 months♦ Systemic reactions

25/2898 (0.8%)♦ No fatalities

Hepner M et al, JACI 1987

Evaluation of Risk Factors for Systemic Reactions 1-year prospective study; nonstandardized

extracts, titrated W/V

Build Up Maintenance

Patients

Visits

Reactions

Rate/pts

Rate/visits

1.887

38.287

36

1/32

1/1063

2.691

113.550

62

1/47

1/1831

Tinkelman, JACI, 1995

Systemic Allergic Reactions to SIT

Correlation with: ♦ a) severity of systemic

reactions; ♦ b) time of onset.

242 patients11.045 injections10 years112 systemic reactions 4 near-fatal

Petalas K et al. Allergy 2000

Risk Factors Based on Fatal and Non-Fatal Reactions

♦ Uncontrolled asthma♦ Severe asthma♦ Use of betablockers♦ Rush immunotherapy♦ Build-up phase♦ Use of new vials♦ Technical errors

Contraindications for Allergen Immunotherapy - 1

♦ Serious immunopathologic diseases and immunodeficiencies.

♦ Malignancies.♦ Severe psychological disorders.♦ Treatment with beta blockers, even when

administered topically.

Contraindications for Allergen Immunotherapy - 2

♦ Poor compliance.♦ Severe asthma, or uncontrolled by

pharmacotherapy (FEV1< 70%).♦ Significant cardiovascular diseases.♦ Children under 5 years (relative

contraindication).

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and

standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Long-Lasting Efficacy of Subcutaneous IT: Controlled Studies

Author

Hedlin, 1995

Ariano, 1999

Durham, 2000

Eng, 2002

Allergen

Cat/dog

Parietaria

Grass

Grass

Duration

3 yrs

4 yrs

5 yrs

3 yrs

IT: Prevention of New SensitizationsNew sensitizations after 3 years:55% SIT group vs 100% control group.

Des Roches et al, JACI 1997

New sensitizations after 3 years: 25% SIT group vs 67% control group.

Pajno et al, Clin Exp Allergy 2001

New sensitizations after 4 years23% SIT group vs 68% control group.Purello D’Ambrosio et al, Clin Exp Allergy 2001

Specific immunotherapy prevents the development of asthma in children with allergic rhinitis (the PAT study) Moller C et al, JACI 2002

205 children with rhinitis

age: 6-14 yrs

grass or birch allergy

3 yrs immunotherapy

SIT CONTROL

%60

19

4032

No asthmaAsthma

0

20

40

60

80

100

0

20

40

60

80

3 17 31 14 28 12 26 9 23 6 2 16 30 13 27 11 25 8 22 5 1 15 29 12 26 10 24 7 21 4

19931995

1994 1995

PollenCount/m

3

Symptoms

IT 7 yr IT 4 yr/Placebo 3 yr (from 1992) IT-naive hay fever control patients

MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST

(108.4)

Durham SR et al New Engl J Med 1999;341:468-75

Grass pollen immunotherapy: longterm efficacy

Duration of benefit

♦ Add slide showing asthma data from Johnson, that patients were still symptom free after 7 years

Allergen Specific Immunotherapy

♦ Definition

Extracts andstandardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Injection Technique

♦ Use upper outer surface of arm

♦ Ensure sterile technique

♦ Use 1ml syringe and orange needle

♦ Inject at 45º by deep subcutaneous

route

♦ Record any local/systemic reaction

Administration of Immunotherapy

Recommendations - 1

♦ Specific allergen immunotherapy must be prescribed by a specialist in the field of allergy and immunology.

♦ (Delete for US:Subcutaneous IT should be administered by physicians and other care professionals who are trained to recognize and treat anaphylaxis.)

♦ Patients sensitive to a single allergen versus those who are polysensitized benefit more from immunotherapy.

Recommendations - 2

♦ Allergen immunotherapy is more effective in children and young adults.

♦ Patients with non-allergic triggers may not benefit from IT.

♦ Allergen immunotherapy preferably should be initiated as early as possible, in the earliest phases of the disease, hopefully to prevent additional sensitization and/or the onset of asthma.

WHO, 1998

Factors to be Considered Before Prescribing Immunotherapy - 1

♦ Presence of an IgE-mediated disease (allergic rhinitis, allergic asthma) hymenoptera hypersensitivity.

♦ Symptoms are caused by specific allergen(s).♦ Exclude other triggers.♦ Severity and duration of symptoms.♦ Response to allergen avoidance and

pharmacotherapy.

Factors to be Considered Before Prescribing Immunotherapy - 2

♦ Contraindications♦ Cost/ benefit ratio♦ Patient compliance♦ Availability of standardized extracts♦ Documented efficacy

Modified from WHO, 1998

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Mechanisms

It has been demonstrated that IT decreases

allergen-induced inflammation in allergic rhinitis

and allergic asthma.

ARIA 2001

The Experimental Evidence

SIT decreases the migration of eosinophils

Nagayata H, 1996

SIT decreases eosinophil numbers and airways BHR

Van Oosterhat AJ, 1988

SIT decreases the number of mast cells

Durham, S R, 1997

SIT decreases the number and activity of eosinophils

Rak 1988, Durham 1996

Mechanisms

♦ Studies have provided insight into the mechanisms of immunotherapy. The efficacy of immunotherapy may be secondary to alteration in the T-cell response to allergen.

♦ Mechanisms are probably heterogeneous, depending on the nature of allergen, the site of allergic disease and the route, dose and duration of immunotherapy.Durham S R, N Eng J Med 1999

APC

IgE

IL-4

IL-5 Allergicresponse

EosinophilsTh2

B-cell

+

+

Tr1

IL-10

TGF-

--

+

IT

Th1

IgG

IFN-B-cell

IT -CD4

CD80/86

T cell

Allergen

TCRHLA

CD28

Th1

Th2

TCD4+IT

IMMUNE DEVIATION?ANERGY?BOTH?

IL-4IL-5IL-9

IL-2INF-

Mechanisms

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Non-Injection or Local Routes - 1

♦ Oral immunotherapy (OIT): allergen immediately swallowed, as drops, tablets or capsules.

♦ Sublingual immunotherapy (SLIT): allergen kept under the tongue for 1-2 minutes, then swallowed (the sublingual- spit mode is no longer in use).

Non-Injection or Local Routes - 2

♦ Local nasal (LNIT): allergen sprayed into the nostrils as aqueous solution or dry powder.

♦ Local bronchial (LBIT): allergen inhaled with a deep inspiration.

Non-Injection or Local Routes

♦ Bronchial and oral route are not recommended for clinical use, due to insufficient demonstration of efficacy and the occurrence of side effects.

♦ Nasal IT (LNIT) and Sublingual IT (SLIT): “Based on the available literature, local nasal immunotherapy and sublingual immunotherapy can be considered as viable alternatives to subcutaneous administration”.

WHO Position Paper 1998

Local Nasal Immunotherapy (LNIT)-1

♦ May be indicated in carefully selected adult patients with rhinitis caused by pollen and possibly by mites.

♦ Potential candidates are patients who:

1. Cannot be properly controlled by standard pharmacotherapy;

2. Have experienced previous systemic reactions induced by subcutaneous allergen immunotherapy;

3. Who refuse injections.ARIA 2001

Local Nasal Immunotherapy (LNIT)-2

♦ LNIT requires a careful administration technique, and premedication with cromolyn is suggested.

♦ It acts only on rhinitis symptoms, and seems not to have a long lasting effect.

♦ For these reasons, its use is progressively declining.

SLIT-Swallow: Efficacy - 1

A meta-analysis of 22 DBPC trials has shown that SLIT is effective in rhinitis caused by pollens and mites.

There are few studies showing additional efficacy on asthma symptoms.

More studies about efficacy in children are required.

SLIT-Swallow: Efficacy - 2

The long-lasting effect has been demonstrated in children with mite-induced asthma.

Di Rienzo et al Clin Exp Allergy 2003

The preventive effect on new skin sensitizations has been demonstrated.

Marogna et al Allergy 2004

Long-lasting effect of sublingual immunotherapyin children with asthma due to house dust mite:

a ten-year prospective studyV.Di Rienzo, F.Marcucci, P.Puccinelli, S.Parmiani, F.Frati, L.Sensi, GW Canonica, G. Passalacqua Clin Exp Allergy, 2003

60

pts

35 SLIT +drugs

25 onlydrugs

0 5 10YEARS

No More SLITNo More SLIT

4

2

32

1

SLIT SLIT CTRLCTRL

BASELINE 10 YEARS

0.001

10

20

30

40

31

17

1

SLIT CTRL

END SLIT

n

0.001

0.0010.001NS

No asthma

Asthma

4

31

2324

3

24

DiRienzo et al Clin.Exp.Allergy. 2003Long-Lasting Efficacy of SLIT: Children with Asthma

SLIT: Safety - 1

♦ In post-marketing studies, the overall rate of side effects (all grades) ranges between 3% and 8% of patients.

♦ The most frequently reported side effects are local (gastrointestinal); oral itching/swelling, nausea, stomach-ache.

♦ The side effects are usually mild and treatment discontinuation is rarely required.

SLIT: Safety - 2

♦ Gastrointestinal side effects are dose-dependent.

♦ No life-threatening side effect or fatality has ever been reported since the introduction of SLIT in 1986.

♦ The occurrence of systemic effects in controlled trials does not differ from the placebo treated patients.

Local Routes: Sublingual-Swallow Immunotherapy

May be indicated in pollen and mite induced rhinitis and asthma in adults and children, using maintenance dosages 5 -100 times higher then injection IT.

SLIT-Swallow in the ARIA Document

♦ “Sublingual immunotherapy can

be administered in adults and children”

ARIA, JACI, 2001

Efficacy of sublingual immunotherapy Efficacy of sublingual immunotherapy

in in allergic rhinitisallergic rhinitis in in pediatric patients 4 to 18 years

Meta-analysis of RCT

Penagos M., Compalati E., Tarantini F.,Baena Penagos M., Compalati E., Tarantini F.,Baena Cagnani R., Huerta Lopez J., Passalacqua G.,Cagnani R., Huerta Lopez J., Passalacqua G.,

&& Canonica G.W. Canonica G.W.

Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

PurposePurpose: To assess the efficacy of : To assess the efficacy of Immunotherapy delivered by the Immunotherapy delivered by the sublingual route, whether or not the sublingual route, whether or not the allergen was subsequently swallowed in allergen was subsequently swallowed in the treatment of allergic rhinitis in the treatment of allergic rhinitis in children.children.

Study SelectionStudy Selection: Randomized, placebo-: Randomized, placebo-controlled and double-blind trials that controlled and double-blind trials that studied SLIT in pediatric patients (4 to studied SLIT in pediatric patients (4 to 18 years) with allergic rhinitis.18 years) with allergic rhinitis.

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Data Sources:

Comprehensive searches of the EMBASE, LILACS, OVID and MEDLINE databases from 1966 to November 2005 and references of identified articles and reviews.

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Outcomes measured in the active treatment and placebo groups were symptom scores and concomitant use of anti-allergic medication.

Review Manager 4.2.7 Program (Cochrane Collaboration) was used for data synthesis.

Outcomes were Outcomes were extracted from original extracted from original articles.articles.

When this information When this information was not available, was not available, authors of each trial authors of each trial were contacted. were contacted.

Some graphics were Some graphics were digitalized.digitalized.

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

ResultsResults: The initial scanning identified : The initial scanning identified 102 102 articles, articles, 6060 of which were of which were potentially relevant trials on SLIT use potentially relevant trials on SLIT use in pediatric patients with allergic in pediatric patients with allergic rhinitis.rhinitis.

1616 studies were randomized. studies were randomized. 10 10 met met inclusion criteria for the meta-analysis.inclusion criteria for the meta-analysis.

All randomized clinical trials included All randomized clinical trials included 491 491 participantsparticipants, 251, 251 allocated to SLIT allocated to SLIT group and group and 240240 to placebo group. to placebo group.

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Interpreting Effect Size ResultsInterpreting Effect Size Results

♦ Cohen’s “Rules-of-Thumb”♦ standardized mean difference effect sizeeffect size

♦ small = 0.20small = 0.20♦ medium = 0.50medium = 0.50♦ large = 0.80large = 0.80

♦ correlation coefficient♦ small = 0.10♦ medium = 0.25♦ large = 0.40

♦ odds-ratio♦ small = 1.50♦ medium = 2.50♦ large = 4.30

Symptom ScoreSymptom Score

Effect SizeEffect Size

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Medication Medication scorescore

Effect SizeEffect Size

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

ConclusionConclusion: :

SLIT reduces both symptom SLIT reduces both symptom and medication scores in and medication scores in pediatric patients withpediatric patients with

allergic rhinitis.allergic rhinitis.

Penagos et alPenagos et al. . Annals of Allergy Asthma and Immunology 2006 Annals of Allergy Asthma and Immunology 2006

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

Novel Approaches

♦ New immunological treatment modalities for allergic diseases are presently under investigation:

♦ Liposome vaccines♦ Adjuvants ♦ Anti-IgE antibodies combined with IT♦ Peptide vaccination♦ Recombinant allergens♦ cDNA vaccines

Allergen Specific Immunotherapy

♦ Definition

♦ Extracts and standardization

♦ Efficacy

♦ Safety

♦ Long-term benefit

♦ Practical aspects of immunotherapy

♦ Mechanisms

♦ Non injection routes

♦ Novel approaches

♦ Summary

allergenavoidance

indicated when possible

allergenavoidance

indicated when possible

pharmacotherapysafety

effectivenesseasy to be administered

pharmacotherapysafety

effectivenesseasy to be administered

immunotherapyeffectiveness

specialist prescription may alter the natural course of the disease

immunotherapyeffectiveness

specialist prescription may alter the natural course of the disease

patient'seducation

always indicated

patient'seducation

always indicated

patient

Modified from

Allergen Immunotherapy Can Modify the Natural History of Allergy - 1

♦ Allergen immunotherapy is the only treatment that can modify the natural history of allergic disease.

♦ SCIT and SLIT- swallow can prevent the onset of new sensitizations.

Allergen Immunotherapy Can Modify the Natural History of Allergy - 2

♦ SCIT and SLIT-swallow administered for several years (3 to 5 years) - efficacy is maintained for up to 3 or more years after discontinuation.

♦ SCIT could prevent the onset of asthma in children with allergic rhinitis.

Allergen Specific Immunotherapy VS Pharmacologic Treatment

♦ Specific immunotherapy does not take the position of being an ultimate treatment principle. It should be part of the global treatment, and should be used in the early phase of disease.

Modified from ARIA JACI 2001

Conclusion

♦ Allergen Specific Immunotherapy is an effective and safe treatment

of allergic rhinitis, allergic asthma and hymenoptera venom allergy

Immunotherapy for Hymenoptera Venom Allergy

In countries with a predominantly temperate climate over half the population receives a sting at least once in their first 20 years of life and virtually the entire adult population has been stung at least once.

Kemp S F et al JACI 2000

Hymenoptera Venom

Epidemiology

♦ Epidemiologic studies of the general population indicate similar data in Australia (17.5%) and England (16%)

Brown AF et al JACI 2001

Stewart AG et al QJ Med 1996

♦ Insect stings cause 29% of anaphylaxis in adults in Italy Cianferoni A et al Ann Allergy Asthma Immunol 2001

♦ 1.36 million to 13.6 million of people in USA are at risk for anaphylaxis from insect stings

Neugut A I et al JAMA 2001

Epidemiology - 2

♦ The incidence of insect sting mortality is low but probably underestimated.

♦ The presence of specific immunoglobulin E to venoms was found in 23% of the post-mortem sera samples obtained from victims between 15 and 65 years of age, who died suddenly and inexplicably between the end of May and the beginning of November 1997.

Schwartz HJ et al Clin Allergy 1988

Apis mellifera Scutellata

Apis mellifera Bombus spp.

Ants

Bees

Solenopsis invicta

Polistes spp.

Vespa crabro

Vespula spp.

Vespids

Stinging Insects by Region

Hymenoptera in USA♦ Yellow jackets♦ Imported fire ants♦ African honey bee♦ Wasps♦ Domestic honey bee♦ Bumblebees

Hymenoptera in Australia

♦ Jack jumper ant♦ Domestic honey bee♦ Yellow jacket wasp

Hymenoptera in Europe♦ Yellow jackets♦ Wasps♦ Bumblebees

The normal reaction of the skin to an Hymenoptera sting consists of a painful, sometimes itchy, local wheal, developing up to 2 cm diameter, surrounded by a swelling of the subcutaneous tissue several centimetres in diameter .

Clinical Features

Clinical Features of Hymenoptera Allergy

Large local reaction Oedema >10cm > 24 hr

I Urticaria

II Stage I + angioedema or rhinoconjunctivitis or abdominal pain

IIIStage I + dyspnoea, dysphonia, dysphagia

IV Anaphylaxis

Müller HL J Asthma Res 1966

Skin Tests in Europe

♦ Skin prick test with venom 100 mcg/mL

↓♦ Intradermal injection of 0.05 mL venom 0.1

mcg/mL; if negative

↓♦ Intradermal injection of 0.05 ml venom 1 mcg/mL

Reisman RE Allergol Int 1998

Skin Tests in Europe - 2

♦ Skin prick test with venom 100 mcg/mL♦ Higher venom concentrations may cause irritant

reactions, which are not immunologically specific♦ Stop skin tests when one intradermal injection is

positive♦ Perform test for all Hymenoptera venoms♦ Systemic reactions following tests: 1.4%♦ Severe systemic reactions following tests:

0.25%

Reisman RE Allergol Int 1998

Skin Tests in USA

♦ Skin prick test with venom 100 mcg/mL

↓♦ Intradermal tests usually start with a

concentration in the range of 0.001 to 0.01 µg/mL

↓♦ If intradermal tests at this concentration are non-

reactive, the test dose is increased by 10-fold increments until a positive skin test response occurs, to a maximum concentration of 1.0 µg/mL

Portnoy et al JACI 1999

Venom Immunotherapy – When to Start EuropeSevere systemic reactions stages III - IV

Yes

Mild systemic reactions stages I - II

Adults: only if at risk

Children (age <10 yrs): No

Large local reaction No

Unusual reactions No

Müller Clin Exp Allergy 1998

Venom Immunotherapy – When to Start USA

Severe systemic reactions stages III - IV

Yes

Mild systemic reactions stages I - II

Adults: only if at risk

Children (age <16 yrs): Yes if stung by fire ants

Large local reaction No

Unusual reactions No

Portnoy et al JACI 1999

Induction Regimens of Hymenoptera Venom Immunotherapy

Sturm G et al JACI 2002

Induction Regimens of Hymenoptera Venom Immunotherapy

♦ Conventional (increasing doses in weekly intervals for outpatients) rush (induction phase over 4-7 days for inpatients)

♦ Ultrarush (the maintenance dose is reached within 1-2 days)

♦ Cluster (a modified rush approach schedule, which involves giving several injections at 15- to 30-minute intervals during the first visits and reaches a maintenance does in about 6 weeks

Induction Regimens of Hymenoptera Venom Immunotherapy - 2♦ In rush protocols patients receive higher doses of

venom in a shorter time period and thus reach the maintenance dose of 100 µg faster than in conventional schedules; this might be of great importance before the onset of the flying season of insects

♦ Rush (induction phase over 4-7 days for inpatients)

Sturm G. et al JACI 2002

Mechanisms of Efficacy of VIT ♦ Induction VIT induces a shift from a Th2 cytokine

response to a Th1 dominant pattern

♦ The immediate drop in IL-4 production in rush VIT suggests profound down-regulation in T-cell responsiveness to allergen

♦ The mechanism might be due to T-cell anergy or activation induced apoptosis

O‘Hehir RE et al J. Immunol 1991

Radvanyi LG et al J Immunol 1996

Mechanisms of efficacy of VIT - 2

♦ Induction of allergen-specific IgG provides a possible mechanism by which immunotherapy might inhibit co-stimulation of allergen-specific T cells

Barcy S et al Int Immunol 1995

♦ T cells producing IL-10 and IFN-gamma play a key role for the inhibition of histamine and sulphidoleukotriene release of effector cells

Pierkes M et al JACI 1999

Bee Venom Immunotherapy (VIT)

♦ Allergic side-effects are a significant problem when honeybee venom is used (up to 20-40% of patients treated)

Müller Clin Exp Allergy1998

♦ VIT has been shown to be protective in approximately 80% of bee and 95% of wasp venom-allergic patients

Müller et al JACI 1992

Hymenoptera Immunotherapy: When to Stop♦ 3 years Müller et al JACI 1991♦ 5 years Golden et al JACI 1996

♦ The risk of systemic sting reactions when immunotherapy is stopped after 5 years reaches 15% in 5 to 10 years after stopping VIT

Golden et al JACI 2000

♦ Most Hymenoptera venom allergic patients can be safely and effectively treated with 8 to 12-weekly injections of 100 mcg venom

Reisman R. Allergol Int 1998

G Passalacqua, C Baena-Cagnani, G W Canonica

World Allergy Organization (WAO)

For more information on the World Allergy Organization (WAO), please visit www.worldallery.org or contact the:

WAO Secretariat

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United States

Tel: +1 414 276 1791

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