Module 4:
Immunotherapy
Updated: June 2011
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(GLORIA™)
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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 • Practical aspects of
immunotherapy
• Extracts and
standardization • Mechanisms
• Efficacy • Non injection routes
• Safety • Novel approaches
• Long-term benefit
• Summary
Allergen Specific Immunotherapy
• Definition • Practical aspects of
immunotherapy
• Extracts and
standardization • Mechanisms
• Efficacy • Non injection routes
• Safety • Novel approaches
• Long-term benefit
• 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
• Practical aspects of
• Definition immunotherapy
• Extracts and
• Mechanisms
standardization
• Efficacy • Non injection routes
• Safety • Novel approaches
• Long-term benefit • 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 • Practical aspects of
immunotherapy
• Extracts and
standardization • Mechanisms
• Efficacy • Non injection routes
• Safety • Novel approaches
• Long-term benefit • 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
Pollens
Cat
House dust mites
Hymenoptera
venoms
Few data (though
encouraging) are available
for dog dander and mould
allergens
Apis melifera.
Stinging Insects
Bombus spp.
Vespula spp.
Polistes spp.
Solenopsis invicta
Vespa Crabro.
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 Start
Severe systemic reactions Yes
stages III - IV
Mild systemic reactions Adults: only if at risk
stages I - II Children (age 60%), responding to β2 agonists/antihistamines.
Grading of systemic reactions - 2
• 3. Non-life-threatening systemic reactions; urticaria,
angioedema, severe asthma (PEFR 10cm > 24 hr
I Urticaria
II Stage I + angioedema or
rhinoconjunctivitis or
abdominal pain
Stage I + dyspnoea,
III 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 Europe
Severe systemic reactions Yes
stages III - IV
Mild systemic reactions Adults: only if at risk
stages I - II 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 Yes
stages III - IV
Mild systemic reactions Adults: only if at risk
stages I - II 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
• T cells producing IL-10 and IFN-gamma play a key role
for the inhibition of histamine and sulphidoleukotriene
release of effector cells
Barcy S et al Int Immunol 1995
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)
• VIT has been shown to be protective in approximately
80% of bee and 95% of wasp venom-allergic patients
Müller Clin Exp Allergy1998
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
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