Slide 2 Module 4: Immunotherapy Updated: June 2011 Slide 3 Slide
4 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. Slide 5 World
Allergy Organization (WAO) The World Allergy Organization is an
international coalition of 89 regional and national allergy and
clinical immunology societies. Slide 6 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 Slide 7 GLORIA Module 4: Allergen Specific
Immunotherapy Slide 8 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 Slide 9
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 Slide 10 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 Slide 11
Allergen Specific Immunotherapy Definition Extracts and
standardization Efficacy Safety Long-term benefit Practical aspects
of immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 12 Allergen Specific Immunotherapy Definition
Extracts and standardization Efficacy Safety Long-term benefit
Practical aspects of immunotherapy Mechanisms Non injection routes
Novel approaches Summary Slide 13 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 Slide
14 Allergen Specific Immunotherapy Definition Extracts and
standardization Efficacy Safety Long-term benefit Practical aspects
of immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 15 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. Slide 16 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 Slide 17 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 Slide 18 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. Slide 19 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. Slide 20 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) Slide 21 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. Slide 22 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. Slide 23 Allergen
Specific Immunotherapy Definition Extracts and standardization
Efficacy Safety Long-term benefit Practical aspects of
immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 24 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 Slide
25 Efficacy - 2 Allergen immunotherapy should be based on allergen
sensitization not on the disease Slide 26 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 Slide 27
Solenopsis invicta Bombus spp. Apis melifera. Polistes spp. Vespa
Crabro. Vespula spp. Stinging Insects Slide 28 Clinical Features of
Hymenoptera Allergy Large local reactionOedema >10cm > 24 hr
IUrticaria IIStage I + angioedema or rhinoconjunctivitis or
abdominal pain IIIStage I + dyspnoea, dysphonia, dysphagia
IVAnaphylaxis Mller HL. J Asthma Res 1966 Slide 29 Venom
Immunotherapy When to Start Severe systemic reactions stages III -
IV Yes Mild systemic reactions stages I - II Adults: only if at
risk Children (age 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 2
agonists/antihistamines. Slide 37 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 Slide 38
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 Slide 39 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 Slide 40 Evaluation
of Risk Factors for Systemic Reactions 1-year prospective study;
nonstandardized extracts, titrated W/V Build UpMaintenance Patients
Visits Reactions Rate/pts Rate/visits 1.887 38.287 36 1/32 1/1063
2.691 113.550 62 1/47 1/1831 Tinkelman, JACI, 1995 Slide 41
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 Slide 42 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 Slide 43 Contraindications for Allergen
Immunotherapy - 1 Serious immunopathologic diseases and
immunodeficiencies. Malignancies. Severe psychological disorders.
Treatment with beta blockers, even when administered topically.
Slide 44 Contraindications for Allergen Immunotherapy - 2 Poor
compliance. Severe asthma, or uncontrolled by pharmacotherapy
(FEV1< 70%). Significant cardiovascular diseases. Children under
5 years (relative contraindication). Slide 45 Allergen Specific
Immunotherapy Definition Extracts and standardization Efficacy
Safety Long-term benefit Practical aspects of immunotherapy
Mechanisms Non injection routes Novel approaches Summary Slide 46
Long-Lasting Efficacy of Subcutaneous IT: Controlled Studies Author
Hedlin, 1995 Ariano, 1999 Durham, 2000 Eng, 2002 Allergen Cat/dog
Parietaria Grass Duration 3 yrs 4 yrs 5 yrs 3 yrs Slide 47 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 Slide 48 Specific immunotherapy prevents
the development of asthma in children with allergic rhinitis (the
PAT study) 205 children with rhinitis age: 6-14 yrs grass or birch
allergy 3 yrs immunotherapy SITCONTROL % 60 19 40 32 No asthma
Asthma Moller C et al, JACI 2002 Slide 49 Durham SR et al New Engl
J Med 1999;341:468-75 Grass pollen immunotherapy: long-term
efficacy Slide 50 Duration of benefit Add slide showing asthma data
from Johnson, that patients were still symptom free after 7 years
Slide 51 Allergen Specific Immunotherapy Definition Extracts and
standardization Efficacy Safety Long-term benefit Practical aspects
of immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 52 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
Slide 53 Administration of Immunotherapy Slide 54 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. Slide 55
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 Slide 56 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. Slide 57 Factors to be Considered
Before Prescribing Immunotherapy - 2 Contraindications Cost/
benefit ratio Patient compliance Availability of standardized
extracts Documented efficacy Modified from WHO, 1998 Slide 58
Allergen Specific Immunotherapy Definition Extracts and
standardization Efficacy Safety Long-term benefit Practical aspects
of immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 59 Mechanisms It has been demonstrated that IT
decreases allergen-induced inflammation in allergic rhinitis and
allergic asthma. ARIA 2001 Slide 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 Slide 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 Slide 62
APC IgE IL-4 IL-5 Allergic response Eosinophils Th2 B-cell + + Tr1
IL-10 TGF - b - - + IT Th1 IgG IFN- g B-cell IT - CD4 CD80/86 T
cell Allergen TCR HLA CD28 Slide 63 Th1 Th2 TCD4+ IT IMMUNE
DEVIATION? ANERGY? BOTH? IL-4 IL-5 IL-9 IL-2 INF-g Mechanisms Slide
64 Allergen Specific Immunotherapy Definition Extracts and
standardization Efficacy Safety Long-term benefit Practical aspects
of immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 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). Slide 66 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. Slide 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 Slide 68 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 Slide 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. Slide 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. Slide 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 Slide 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 60 pts 35 SLIT + drugs 25 only
drugs 0510YEARS No More SLIT Slide 73 4 2 32 1 SLIT CTRL BASELINE
10 YEARS 0.001 10 20 30 40 31 17 1 SLITCTRL END SLIT n 0.001 NS No
asthma Asthma 4 31 23 24 3 DiRienzo et al Clin.Exp.Allergy. 2003
Long-Lasting Efficacy of SLIT: Children with Asthma Slide 74 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.
Slide 75 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. Slide 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. Slide 77
SLIT-Swallow in the ARIA Document Sublingual immunotherapy can be
administered in adults and children ARIA, JACI, 2001 Slide 78
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 Slide 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 Slide 80 Slide 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 Slide 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. Slide 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 Slide 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 Slide
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
Slide 86 Symptom Score Effect Size Penagos et al. Annals of Allergy
Asthma and Immunology 2006 Slide 87 Medication score Effect Size
Penagos et al. Annals of Allergy Asthma and Immunology 2006 Slide
88 Conclusion: SLIT reduces both symptom and medication scores in
pediatric patients with allergic rhinitis. Penagos et al. Annals of
Allergy Asthma and Immunology 2006 Slide 89 Allergen Specific
Immunotherapy Definition Extracts and standardization Efficacy
Safety Long-term benefit Practical aspects of immunotherapy
Mechanisms Non injection routes Novel approaches Summary Slide 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 Slide 91 Allergen
Specific Immunotherapy Definition Extracts and standardization
Efficacy Safety Long-term benefit Practical aspects of
immunotherapy Mechanisms Non injection routes Novel approaches
Summary Slide 92 allergen avoidance indicated when possible
allergen avoidance indicated when possible pharmacotherapy safety
effectiveness easy to be administered pharmacotherapy safety
effectiveness easy to be administered immunotherapy effectiveness
specialist prescription may alter the natural course of the disease
immunotherapy effectiveness specialist prescription may alter the
natural course of the disease patient's education always indicated
patient's education always indicated patient Modified from Slide 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. Slide 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. Slide 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 Slide 96 Conclusion
Allergen Specific Immunotherapy is an effective and safe treatment
of allergic rhinitis, allergic asthma and hymenoptera venom allergy
Slide 97 Immunotherapy for Hymenoptera Venom Allergy Slide 98 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. Hymenoptera Venom Kemp S F et al JACI 2000 Slide 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 Slide 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 Slide 101 Apis mellifera Scutellata Apis mellifera
Bombus spp. Ants Bees Solenopsis invicta Slide 102 Polistes spp.
Vespa crabro Vespula spp. Vespids Slide 103 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 Slide 104 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 Slide 105
Clinical Features of Hymenoptera Allergy Large local reactionOedema
>10cm > 24 hr IUrticaria IIStage I + angioedema or
rhinoconjunctivitis or abdominal pain III Stage I + dyspnoea,
dysphonia, dysphagia IVAnaphylaxis Mller HL J Asthma Res 1966 Slide
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 Slide 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 Slide 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 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 Slide 109
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
