Module 4:
Immunotherapy
Updated: June 2011
Sponsored by an unrestricted educational grant from
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.
World Allergy Organization (WAO)
The World Allergy Organization is an
international coalition of 89 regional and
national allergy and clinical immunology
societies.
WAO’s Mission
WAO’s 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
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
• Definition
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• 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.
Vespa Crabro.
Solenopsis invicta
Clinical Features of
Hymenoptera Allergy
Large local reaction
Oedema >10cm > 24 hr
I
Urticaria
II
Stage I + angioedema or
rhinoconjunctivitis or abdominal
pain
Stage I + dyspnoea, dysphonia,
dysphagia
Anaphylaxis
III
IV
Müller HL. J Asthma Res 1966
Venom Immunotherapy –
When to Start
Severe systemic reactions
stages III - IV
Mild systemic reactions
stages I - II
Yes
Large local reaction
No
Unusual reactions
No
Müller Clin. Exp. Allergy 1998
Adults: only if at risk
Children (age <10 yrs): No
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
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• 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 1945-1984
46 Fatalities
Period 1985-1989
17 Fatalities
Estimated risk for fatal
reactions less than 1 per
2 million injections
Lockey RF et al JACI 1987
Reid MJ et al, JACI 1993
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
Patients
Visits
Reactions
Rate/pts
Rate/visits
Tinkelman, JACI, 1995
Build Up
1.887
38.287
36
1/32
1/1063
Maintenance
2.691
113.550
62
1/47
1/1831
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
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
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• Summary
Long-Lasting Efficacy of
Subcutaneous IT: Controlled Studies
Author
Allergen
Duration
Hedlin, 1995
Cat/dog
3 yrs
Ariano, 1999
Parietaria
4 yrs
Durham, 2000
Grass
5 yrs
Eng, 2002
Grass
3 yrs
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 D’Ambrosio et al, Clin Exp Allergy 2001
Specific immunotherapy prevents the development
of asthma in children with allergic rhinitis
(the PAT study)
%
No asthma
Asthma
60
40
32
19
SIT
Moller C et al, JACI 2002
CONTROL
205 children with rhinitis
age: 6-14 yrs
grass or birch allergy
3 yrs immunotherapy
Grass pollen immunotherapy: long-term efficacy
1
0
0
8
0
6
0
4
0
2
0
1993
1994
1
1995
(
1
0
8
.
4
)
Pol l e n
3
Cou n t / m
0
8
0
6
0
4
0
2
0
Sy m
pt o m
s
0
3 1
M
I T
3 7 11 24 1 8 22 96 2
A
Y
7 I Ty r 4
Durham SR et al New Engl J Med 1999;341:468-75
63
2 1
M
3 6 10 23 1 7 21 85 2
A
Y
J
52
U
1 1
N
E
M
25 19 2 2 16 2 0 74 2
A
Y
J
41
U
N
E
J
U
L
y r / P l a c e Ib To - n3 a iy vr e ( hf ar yo m f e v1 e9 r
Duration of benefit
• Add slide showing asthma data from Johnson,
that patients were still symptom free after 7
years
Allergen Specific Immunotherapy
• Definition
Extracts and
standardization
• Practical aspects of
immunotherapy
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• 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
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• 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
IgE
IL-4
B-cell
Allergen
APC
CD80/86
CD28
HLA
TCR
CD4
-
IT
T cell
IT
+
Eosinophils
Th2
IL-5
-
Allergic
+ response
-
TGF- b
Tr1
IL-10
Th1
IFNg
+
B-cell
IgG
Mechanisms
Th1
TCD4+
IT
Th2
IL-2
INF-g
IMMUNE DEVIATION?
ANERGY?
BOTH?
IL-4
IL-5
IL-9
Allergen Specific Immunotherapy
• Definition
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• 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 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
YEARS
10
Long-Lasting Efficacy of SLIT: Children with Asthma
DiRienzo et al Clin.Exp.Allergy. 2003
40
0.001
No asthma
0.001
n
Asthma
NS
0.001
0.001
4
30
1
2
20
31
1
32
31
23
10
24
24
17
CTRL
4
SLIT CTRL
3
SLIT
BASELINE
END SLIT
10 YEARS
SLIT
CTRL
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 in
allergic rhinitis
in pediatric patients 4 to 18 years
Meta-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
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, placebocontrolled 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
Penagos et al. 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 al. 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
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
 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
Interpreting Effect Size Results
• Cohen’s “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
Symptom Score
Effect Size
Penagos et al. Annals of Allergy Asthma and Immunology 2006
Medication score
Effect Size
Penagos et al. Annals of Allergy Asthma and Immunology 2006
Conclusion:
SLIT reduces both symptom and
medication scores in pediatric
patients with
allergic rhinitis.
Penagos et al. Annals of Allergy Asthma and Immunology 2006
Allergen Specific Immunotherapy
• Definition
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• 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
• Practical aspects of
immunotherapy
• Extracts and
standardization
• Mechanisms
• Efficacy
• Non injection routes
• Safety
• Novel approaches
• Long-term benefit
• Summary
Modified from
allergen
avoidance
indicated
when possible
pharmacotherapy
safety
effectiveness
easy to be administered
patient
patient's
education
always indicated
immunotherapy
effectiveness
specialist prescription
may alter the natural
course of the disease
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
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
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
Bees
Apis mellifera
Bombus spp.
Apis mellifera Scutellata
Ants
Solenopsis invicta
Vespids
Polistes spp.
Vespula spp.
Vespa crabro
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
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 .
Clinical Features of Hymenoptera
Allergy
Large local reaction
Oedema >10cm > 24 hr
I
Urticaria
II
Stage I + angioedema or
rhinoconjunctivitis or
abdominal pain
Stage I + dyspnoea,
dysphonia, dysphagia
Anaphylaxis
III
IV
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 nonreactive, 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
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
Large local reaction
Adults: only if at risk
Children (age <16 yrs): Yes
if stung by fire ants
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 costimulation 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
• 5 years
Müller et al JACI 1991
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
555 East Wells Street, Suite 1100
Milwaukee, WI 53202
United States
Tel: +1 414 276 1791
Fax: +1 414 276 3349
Email: info@worldallergy.org