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GLORIA Module 4Allergen Specific Immunotherapy
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Global Resources in Allergy (GLORIA)

• Global Resources In Allergy (GLORIA) is the
  flagship program of the World Allergy
  Organization (WAO). Its curriculum educates
  medical professionals worldwide through 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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World Allergy Organization (WAO)
The World Allergy Organization is an
international coalition of 74 regional and
national allergy and clinical immunology
societies.
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WAOs Mission

• WAOs mission is to be a global resource and
  advocate in the field of allergy, advancing
  excellence in clinical care, education, research
  and training through a world-wide alliance of
  allergy and clinical immunology societies

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GLORIA Module 4Allergen Specific Immunotherapy
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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

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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

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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

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standaridization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

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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

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

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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.

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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

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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

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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.

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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.

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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)

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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.

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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.

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Allergen Specific Immunotherapy

• Definition
• Extracts and standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

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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
25
Efficacy - 2

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

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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
27
Stinging Insects
Apis melifera.
Bombus spp.
Vespula spp.
Polistes spp.
Solenopsis invicta
Vespa Crabro.
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Clinical Features of Hymenoptera Allergy
Müller HL. J Asthma Res 1966
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Venom Immunotherapy When to Start
Müller Clin. Exp. Allergy 1998
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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 (?).

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Parameters of Efficacy - Paraclinical

• Systemic immunological changes
• Immunoglobulins
• Cells
• Mediators
• Local immunological changes
• Specific organ reactivity
• Nonspecific hyperreactivity

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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

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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

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

35
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.

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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 gt 60), responding to ß2 agonists/antihistam
  ines.

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Grading of systemic reactions - 2

• 3. Non-life-threatening systemic reactions
  urticaria, angioedema, severe asthma (PEFR lt
  60). Responding well to treatment.
• 4. Anaphylaxis itching, urticaria,
  bronchospasm, with hypotension, requiring
  intensive care.
• Malling and Weeke, Allergy, 1993

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Fatalities

• Period 1945-1984
• 46 Fatalities
• Lockey RF et al JACI 1987
• Period 1985-1989
• 17 Fatalities
• Reid MJ et al, JACI 1993
• Estimated risk for fatal reactions less than 1
  per 2 million injections

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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

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Evaluation of Risk Factors for Systemic
Reactions

• 1-year prospective study nonstandardized
  extracts, titrated W/V

Tinkelman, JACI, 1995
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Systemic Allergic Reactions to SIT

• Correlation with
• a) severity of systemic reactions
• b) time of onset.
• 242 patients
• 11.045 injections
• 10 years
• 112 systemic reactions
• 4 near-fatal
• Petalas K et al. Allergy 2000

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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

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Contraindications for Allergen Immunotherapy - 1

• Serious immunopathologic diseases and
  immunodeficiencies.
• Malignancies.
• Severe psychological disorders.
• Treatment with beta blockers, even when
  administered topically.

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Contraindications for Allergen Immunotherapy - 2

• Poor compliance.
• Severe asthma, or uncontrolled by pharmacotherapy
  (FEV1lt 70).
• Significant cardiovascular diseases.
• Children under 5 years (relative
  contraindication).

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

46
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
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IT Prevention of New Sensitizations
New 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 years 23 SIT group vs 68 control
group. Purello DAmbrosio et al, Clin Exp Allergy
2001
48
Specific immunotherapy prevents the development
of asthma in children with allergic rhinitis
(the PAT study) Moller C et al, JACI 2002
No asthma

Asthma
60
205 children with rhinitis age 6-14 yrs grass
or birch allergy 3 yrs immunotherapy
40
32
19
SIT
CONTROL
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Grass pollen immunotherapy longterm efficacy
Durham SR et al New Engl J Med 1999341468-75
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Duration of benefit

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

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Allergen Specific Immunotherapy

• Definition
• Extracts and
• standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

52
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

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Administration of Immunotherapy
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Recommendations - 1

• Specific allergen immunotherapy must be
  prescribed by a specialist in the field of
  allergy and immunology.
• (Delete for USSubcutaneous 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.

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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

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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.

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Factors to be Considered Before Prescribing
Immunotherapy - 2

• Contraindications
• Cost/ benefit ratio
• Patient compliance
• Availability of standardized extracts
• Documented efficacy
• Modified from WHO, 1998

58
Allergen Specific Immunotherapy

• Definition
• Extracts and standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

59
Mechanisms

• It has been demonstrated that IT decreases
  allergen-induced inflammation in allergic
  rhinitis and allergic asthma.

ARIA 2001
60
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

61
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

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APC

63
Mechanisms
IL-2 INF-g
Th1
IMMUNE DEVIATION? ANERGY? BOTH?
IT
TCD4
Th2
IL-4 IL-5 IL-9
64
Allergen Specific Immunotherapy

• Definition
• Extracts and standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

65
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).

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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.

67
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

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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
69
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.

70
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.
71
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
72
Long-lasting effect of sublingual
immunotherapy in children with asthma due to
house dust mite a ten-year prospective study
V.Di Rienzo, F.Marcucci, P.Puccinelli,
S.Parmiani, F.Frati, L.Sensi, GW Canonica, G.
Passalacqua
Clin Exp Allergy, 2003
35 SLIT drugs
60
No More SLIT
pts
25 only drugs
0
5
10
YEARS
73
Long-Lasting Efficacy of SLIT Children with
Asthma
DiRienzo et al Clin.Exp.Allergy. 2003
0.001
0.001
n
40
NS
0.001
0.001
4
30
2
1
1
20
32
31
31
24
23
24
10
17

4
3
SLIT
SLIT
CTRL
CTRL
SLIT
CTRL
BASELINE
10 YEARS
END SLIT
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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.

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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.

76
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.

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SLIT-Swallow in the ARIA Document

• Sublingual immunotherapy can
• be administered in adults and children
• ARIA, JACI, 2001

78
Efficacy of sublingual immunotherapy in allergic
rhinitis in pediatric patients 4 to 18
yearsMeta-analysis of RCT
Penagos M., Compalati E., Tarantini F.,Baena
Cagnani R., Huerta Lopez J., Passalacqua G.,
Canonica G.W.
Annals of Allergy Asthma and Immunology 2006
79

• Purpose To assess the efficacy of Immunotherapy
  delivered by the sublingual route, whether or not
  the allergen was subsequently swallowed in the
  treatment of allergic rhinitis in children.
• Study Selection Randomized, placebo-controlled
  and double-blind trials that studied SLIT in
  pediatric patients (4 to 18 years) with allergic
  rhinitis.

Penagos et al. Annals of Allergy Asthma and
Immunology 2006
80
Penagos et al. Annals of Allergy Asthma and
Immunology 2006
81

• 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 al. Annals of Allergy Asthma and
Immunology 2006
82

• 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.

83

• Outcomes were extracted from original articles.
• When this information was not available, authors
  of each trial were contacted.
• Some graphics were digitalized.

Penagos et al. Annals of Allergy Asthma and
Immunology 2006
84

• Results The initial scanning identified 102
  articles, 60 of which were potentially relevant
  trials on SLIT use in pediatric patients with
  allergic rhinitis.
• 16 studies were randomized. 10 met inclusion
  criteria for the meta-analysis.
• All randomized clinical trials included 491
  participants, 251 allocated to SLIT group and 240
  to placebo group.

Penagos et al. Annals of Allergy Asthma and
Immunology 2006
85
Interpreting Effect Size Results

• Cohens Rules-of-Thumb
• standardized mean difference effect size
• small 0.20
• medium 0.50
• large 0.80
• correlation coefficient
• small 0.10
• medium 0.25
• large 0.40
• odds-ratio
• small 1.50
• medium 2.50
• large 4.30

86
Symptom Score
Effect Size
Penagos et al. Annals of Allergy Asthma and
Immunology 2006
87
Medication score
Effect Size
Penagos et al. Annals of Allergy Asthma and
Immunology 2006
88
Penagos et al. Annals of Allergy Asthma and
Immunology 2006

• Conclusion
• SLIT reduces both symptom and medication scores
  in pediatric patients with
• allergic rhinitis.

89
Allergen Specific Immunotherapy

• Definition
• Extracts and standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

90
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

91
Allergen Specific Immunotherapy

• Definition
• Extracts and standardization
• Efficacy
• Safety
• Long-term benefit

• Practical aspects of immunotherapy
• Mechanisms
• Non injection routes
• Novel approaches
• Summary

92
Modified from
allergen avoidance indicated when possible
immunotherapy effectiveness specialist
prescription may alter the natural course of
the disease
pharmacotherapy safety effectiveness easy to be
administered
patient
patient's education always indicated
93
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.

94
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.

95
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
96
Conclusion

• Allergen Specific Immunotherapy is an effective
  and safe treatment
• of allergic rhinitis, allergic asthma and
  hymenoptera venom allergy

97
Immunotherapy for Hymenoptera Venom Allergy
98
Hymenoptera Venom
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
99
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

100
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

101
Bees
Apis mellifera
Bombus spp.
Apis mellifera Scutellata
Ants
Solenopsis invicta
102
Vespids
Polistes spp.
Vespula spp.
Vespa crabro
103
Stinging Insects by Region

• Hymenoptera in Australia
• Jack jumper ant
• Domestic honey bee
• Yellow jacket wasp

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

• Hymenoptera in Europe
• Yellow jackets
• Wasps
• Bumblebees

104
Clinical Features
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 .
105
Clinical Features of Hymenoptera Allergy
Müller HL J Asthma Res 1966
106
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

107
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

108
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

109
Venom Immunotherapy When to Start Europe
Müller Clin Exp Allergy 1998
110
Venom Immunotherapy When to Start USA
Portnoy et al JACI 1999
111
Induction Regimens of Hymenoptera Venom
Immunotherapy
Sturm G et al JACI 2002
112
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

113
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

114
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
• OHehir RE et al J. Immunol 1991
• Radvanyi LG et al J Immunol 1996

115
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

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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

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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

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G Passalacqua, C Baena-Cagnani, G W Canonica
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World Allergy Organization (WAO)

• For more information on the World Allergy
  Organization (WAO), please visit
  www.worldallery.org or contact the
• WAO Secretariat
• 555 East Wells Street, Suite 1100
• Milwaukee, WI 53202
• United States
• Tel [phone]
• Fax [phone]
• Email info_at_worldallergy.org

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