Module 4:

Immunotherapy

Updated: June

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Global Resources in Allergy

(GLORIA)
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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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(WAO)
The World Allergy Organization
is an international coalition of
89 regional and national
allergy and clinical
immunology societies.

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

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
standardization
Efficacy

Practical aspects
of immunotherapy
Mechanisms

Safety

Non injection
routes

Long-term benefit

Novel approaches
Summary

Allergen Specific
Immunotherapy

Definition

Extracts and
standardization
Efficacy

Practical aspects
of immunotherapy
Mechanisms

Safety

Non injection
routes

Long-term benefit

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

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
Safety
Long-term benefit

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
Pollens
Cat
House dust mites
Hymenoptera
venoms

Few data (though

encouraging) are
available for dog
dander and mould
allergens

Apis melifera.

Stinging Insects
Vespula spp.

Bombus
spp.

Polistes spp.

Vespa Crabro.

Solenopsis
invicta

Clinical Features of
Hymenoptera Allergy
Large local reaction

Oedema >10cm > 24 hr

Urticaria

II

Stage I + angioedema or
rhinoconjunctivitis or
abdominal pain

III

Stage I + dyspnoea,
dysphonia, dysphagia

IV

Anaphylaxis

Mller HL. J Asthma Res 1966

Venom Immunotherapy
When to Start
Severe systemic
reactions stages III IV

Yes

Mild systemic
Adults: only if at risk
reactions stages I - II Children (age <10
yrs): No
Large local reaction

No

Unusual reactions

No

Mller 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 and
standardization
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-IgEmediated), discomfort, nausea, headache,
arthralgia.
2. Mild systemic reactions; mild rhinitis/asthma
(PEFR > 60%), responding to 2
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 19851989
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

Build Up
Patients
Visits
Reactions
Rate/pts
Rate/visits
Tinkelman, JACI, 1995

1.887
38.287
36
1/32
1/1063

Maintenan
ce
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
ubcutaneous 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 DAmbrosio et al, Clin Exp Allergy 2001

Specific immunotherapy prevents the de

of asthma in children with allergic rhini
(the PAT study)
%

No asthma
Asthma
205 children with
40
rhinitis

60

32

19

SIT
Moller C et al, JACI 2002

CONTROL

age: 6-14 yrs

grass or birch
allergy
3 yrs
immunotherapy

Grass pollen immunotherapy: longterm efficacy

1993

100

1994

1995

80
60
40

(108.4)

Pollen
3
Count/m

20
0

80
60
40

Symptoms

20
0
3 17 31 14 28 12 26 9 23 6
MAY

IT 7 yr

JUNE

JULY

AUGUST

2 16 30 13 27 11 25 8 22 5
MAY

JUNE

IT 4 yr/Placebo 3 yr (from 1992)

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

JULY

AUGUST

1 15 29 12 26 10 24 7 21 4
MAY

JUNE

JULY

AUGUST

IT-naive hay fever control patients

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 45 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

Ig
E

IL4

Allergen

B-cell

APC
Th2
CD80/86
CD28

HLA
TCR

T cell

CD4

IT

IT

Eosinophils

IL-5

Allergic
+ response

TGF-b

Tr1

IL-10

Th1

IFNg

B-cell

Ig
G

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 sublingualspit 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

ong-lasting effect of sublingual immunotherap

n 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.
Clin Exp Allergy,
2003
Passalacqua

35 SLIT +
drugs

60
pts

No More SLIT

25 only
drugs
0

YEARS

10

Long-Lasting Efficacy of SLIT: Children

DiRienzo
al Clin.Exp.Allergy. 2003
withetAsthma
0.001
40

No asthma

0.001

Asthma

NS

0.001

0.001

30
1

20

31

32

31

10

23

24

24

17

SLIT CTRL

4
SLIT CTRL

3
SLIT CTRL

BASELINE

END SLIT

10 YEARS

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

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 doubleblind 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 metaanalysis.

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

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

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
Extracts and
standardization
Efficacy
Safety
Long-term benefit

Practical aspects
of immunotherapy
Mechanisms
Non injection
routes
Novel
approaches

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
allergen
avoidance
avoidance

indicated
indicated
when
when possible
possible

pharmacotherapy
pharmacotherapy
safety
safety
effectiveness
effectiveness
easy
easy to
to be
be administered
administered

immunotherapy
immunotherapy

effectiveness
effectiveness
patient specialist
specialist prescription
prescription
may
may alter
alter the
the natural
natural
course
course of
of the
the disease
disease

patient's
patient's
education
education

always
always indicated
indicated

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 postmortem 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 2cm diameter, surrounded by a
swelling of the subcutaneous tissue several
centimetres in diameter .

Clinical Features of
Hymenoptera Allergy
Large local reaction
I
II

III
IV
Mller HL J Asthma Res 1966

Oedema >10cm > 24

hr
Urticaria
Stage I +
angioedema or
rhinoconjunctivitis or
abdominal pain
Stage I + dyspnoea,
dysphonia, dysphagia
Anaphylaxis

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
g/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 g/mL
Portnoy et al JACI 1999

Venom Immunotherapy
When to Start Europe
Severe systemic
reactions stages III IV

Yes

Mild systemic
Adults: only if at risk
reactions stages I - II Children (age <10
yrs): No
Large local reaction

No

Unusual reactions

No

Mller 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

Portnoy et al JACI 1999
Unusual reactions

No
No

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 g 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 downregulation 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

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

Mller Clin Exp Allergy1998

Mller et al JACI 1992

Hymenoptera
Immunotherapy: When to
Stop
3 years
5 years

Mller 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

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Organization (WAO), please visit
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