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					                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
                      • Practical aspects of
• Definition            immunotherapy

• Extracts and
                      • Mechanisms
  standardization

• Efficacy            • Non injection routes


• Safety              • Novel approaches

• Long-term benefit   • Summary
          Allergen Extracts - 1

• Allergen extracts are a preparation of an allergen
  obtained by extraction of the active constituents
  from animal or vegetable substances with a
  suitable menstruum.
         Allergen Extracts - 2
• For allergen immunotherapy, products may be
  either unmodified vaccines or vaccines modified
  chemically and /or by absorption onto different
  carriers:

           » Aqueous vaccines
           » Depot and modified vaccines
           » Mixtures of allergen vaccines
                   Allergen Extracts- 3

     • The quality of the allergen vaccine is critical for
       both diagnosis and treatment. Where possible,
       standardized vaccines of known potency and
       shelf-life should be used.




ARIA, JACI, 2001
    Allergen Standardization - 1


• Standardization allows definition of the
  “potency” of allergenic extracts and warrants
  that the batches of vaccine produced from
  different lots of raw material are consistent and
  have comparable activities.
     Allergen Standardization - 2
• The standardization can be made:

  Biologically; the potency of the vaccine is compared to
  the cutaneous response obtained in a reference
  population;

  Immunologically; the potency of the vaccine is based
  on RAST-inhibition experiments using standard pools
  of sera.
    Allergen Standardization - 3
• Many different units are used:
        – Protein nitrogen units (PNU- world wide)
        – Allergy unit (AU- U.S. FDA)
        – Bioequivalent allergy unit (BAU)
        – Biologic units (BU- Europe)
        – International unit (IU- WHO)
        – Index of reactivity (IR- Europe)
        – Specific treatment unit (STU)
        – Activity Units by RAST (AUR- Europe)
  Allergen Standardization - 4

• The major allergen(s) content in micrograms per
  ml is provided for most products.

• Standardized allergen extracts should be
  preferred for allergy diagnosis and therapy.
Allergen Immunotherapy Indications

   Hymenoptera venom immunotherapy is the only
    effective preventive treatment for insect sting-induced
    anaphylaxis.

   Inhalant allergen immunotherapy reduces symptoms
    and/or medication needs for patients with allergic
    asthma and/or rhinoconjunctivitis.
Allergen Specific Immunotherapy
• Definition          • Practical aspects of
                        immunotherapy
• Extracts and
  standardization     • Mechanisms

• Efficacy            • Non injection routes

• Safety              • Novel approaches

• Long-term benefit   • Summary
                           Efficacy - 1
     • Allergen immunotherapy is the only treatment that can modify
       the immune response to allergens and alter the course of allergic
       diseases.

     • In some guidelines the indication for allergen immunotherapy
       for asthma and rhinitis has been separated. This separation is
       incorrect - respiratory allergy is a unique immunological disorder
       of the airways.




ARIA 2001
               Efficacy - 2



• Allergen immunotherapy should be based on
  allergen sensitization not on the disease
Allergens of Proven Efficacy in
Double Blind Placebo Controlled
            Studies
       Pollens
       Cat
       House dust mites
       Hymenoptera
       venoms

       Few data (though
       encouraging) are available
       for dog dander and mould
       allergens
Apis melifera.
                        Stinging Insects

                                            Bombus spp.
                           Vespula spp.
 Polistes spp.




                                          Solenopsis invicta
                 Vespa Crabro.
                           Clinical Features of
                          Hymenoptera Allergy
      Large local reaction          Oedema >10cm > 24 hr

      I                             Urticaria

      II                            Stage I + angioedema or
                                    rhinoconjunctivitis or abdominal
                                    pain
      III                           Stage I + dyspnoea, dysphonia,
                                    dysphagia
      IV                            Anaphylaxis

Müller HL. J Asthma Res 1966
                    Venom Immunotherapy –
                        When to Start
      Severe systemic reactions   Yes
      stages III - IV
      Mild systemic reactions     Adults: only if at risk
      stages I - II               Children (age <10 yrs): No
      Large local reaction        No

      Unusual reactions           No



Müller 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          • 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
                               Build Up        Maintenance
         Patients              1.887           2.691
         Visits                38.287          113.550
         Reactions             36              62
         Rate/pts              1/32            1/47
         Rate/visits           1/1063          1/1831

Tinkelman, JACI, 1995
            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
    %
                       60           Asthma
                                                205 children with rhinitis
                                    40
                                         32     age: 6-14 yrs
                                                grass or birch allergy
                              19
                                                3 yrs immunotherapy


                            SIT    CONTROL
Moller C et al, JACI 2002
    Grass pollen immunotherapy: long-term efficacy
        1       0   0
                                      1 9 9 3                                     1 9 9 4                                      1 9 9 5
         8      0                                                                                                                   (       1   0   8    .       4   )


         6      0
                    P o l l e n
                           3
         4      0   C o u n t / m
         2      0

            0



         8      0


         6      0


         4      0
                    S y m       p t o m                     s
         2      0


            0
                                3 1   3 7 1 1 2 4 1 8 2 2 96 2    63   2 1     3 6 1 0 2 3 1 7 2 1 85 2   52       1 1   2 5 1 9 2 2 1 6 2 0 74 2   41
                                 M          A     Y                        M         A     Y                   J    MU     N   AE       Y                    J   U   N   E




                        I   T   I
                                7      T y r4                    y r   /       P l       a c e b o a 3
                                                                                            I T - n  i                                 e
                                                                                                                                    v y r           h (a fy r             f
                                                                                                                                                                         o m

Durham SR et al New Engl J Med 1999;341:468-75
          Duration of benefit
• Add slide showing asthma data from Johnson,
  that patients were still symptom free after 7
  years
Allergen Specific Immunotherapy
• Definition          • Practical aspects of
                        immunotherapy
  Extracts and
  standardization     • 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
                               Th2                      Eosinophils           +
  CD80/86
    CD28
               HLA
               TCR
                                             IL-5                         Allergic
                          IT         -                                  + response
            T cell
                     IT                  -     TGF- b
                                                                           -
   CD4
                               Tr1
                                                     IL-10
                                                              +         IgG
                                              IFN-             B-cell
                               Th1
                                                g
Mechanisms
                   IL-2
             Th1   INF-g



                   IMMUNE DEVIATION?
 TCD4+
              IT   ANERGY?
                   BOTH?


                    IL-4
             Th2    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
                                                     0.001                                   No asthma
                                             0.001
          n                                                                                  Asthma
   40                          NS                            0.001               0.001

                          4
   30
                                        2                            1                   1


   20                                                  31                  32
                         31
                                                                     24
                                        23                                           24
   10
                                                                     17
                                                       4                    3
                      SLIT        CTRL                SLIT CTRL           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 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, 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
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                                immunotherapy
             safety
         effectiveness
                             patient                  effectiveness
                                                specialist prescription
  easy to be administered                       may alter the natural
                                                course of the disease


                             patient's
                            education
                            always 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 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       Hymenoptera in
•   Yellow jackets        Australia
•   Imported fire ants   • Jack jumper ant
•   African honey bee    • Domestic honey bee
•   Wasps                • Yellow jacket wasp
•   Domestic honey bee   Hymenoptera in
•   Bumblebees            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,
    III                       dysphonia, dysphagia
    IV                        Anaphylaxis

Müller HL J Asthma Res 1966
                           Skin Tests in Europe
      • Skin prick test with venom 100 mcg/mL
                                   ↓
      • Intradermal injection of 0.05 mL venom 0.1 mcg/mL;
        if negative
                                   ↓
      • Intradermal injection of 0.05 ml venom 1 mcg/mL




Reisman RE Allergol Int 1998
                       Skin Tests in Europe - 2
      • Skin prick test with venom 100 mcg/mL
      • Higher venom concentrations may cause irritant
        reactions, which are not immunologically specific
      • Stop skin tests when one intradermal injection is
        positive
      • Perform test for all Hymenoptera venoms
      • Systemic reactions following tests: 1.4%
      • Severe systemic reactions following tests: 0.25%


Reisman RE Allergol Int 1998
                          Skin Tests in USA
      Skin prick test with venom 100 mcg/mL
                                      ↓
      • Intradermal tests usually start with a concentration in the
        range of 0.001 to 0.01 µg/mL
                                      ↓
      • If intradermal tests at this concentration are non-
        reactive, the test dose is increased by 10-fold increments
        until a positive skin test response occurs, to a maximum
        concentration of 1.0 µg/mL



Portnoy et al JACI 1999
                    Venom Immunotherapy –
                     When to Start Europe
      Severe systemic reactions   Yes
      stages III - IV

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

      Large local reaction        No

      Unusual reactions           No


Müller Clin Exp Allergy 1998
                  Venom Immunotherapy –
                     When to Start USA
      Severe systemic reactions   Yes
      stages III - IV

      Mild systemic reactions     Adults: only if at risk
      stages I - II               Children (age <16 yrs): Yes
                                  if stung by fire ants
      Large local reaction        No
      Unusual reactions           No

Portnoy et al JACI 1999
Induction Regimens of Hymenoptera
      Venom Immunotherapy




Sturm G et al JACI 2002
Induction Regimens of Hymenoptera
      Venom Immunotherapy

• Conventional (increasing doses in weekly intervals for
  outpatients) rush (induction phase over 4-7 days for inpatients)

• Ultrarush (the maintenance dose is reached within 1-2 days)

• Cluster (a modified rush approach schedule, which involves
  giving several injections at 15- to 30-minute intervals during the
  first visits and reaches a maintenance does in about 6 weeks
      Induction Regimens of Hymenoptera
          Venom Immunotherapy - 2
      In rush protocols patients receive higher doses of venom
        in a shorter time period and thus reach the maintenance
        dose of 100 µg faster than in conventional schedules;
        this might be of great importance before the onset of
        the flying season of insects

      • Rush (induction phase over 4-7 days for inpatients)



Sturm G. et al JACI 2002
           Mechanisms of Efficacy of VIT
      • Induction VIT induces a shift from a Th2 cytokine
        response to a Th1 dominant pattern

      • The immediate drop in IL-4 production in rush VIT
        suggests profound down-regulation in T-cell
        responsiveness to allergen

      • The mechanism might be due to T-cell anergy or
        activation induced apoptosis


O‘Hehir RE et al J. Immunol 1991
Radvanyi LG et al J Immunol 1996
       Mechanisms of efficacy of VIT - 2
       • Induction of allergen-specific IgG provides a possible
         mechanism by which immunotherapy might inhibit co-
         stimulation of allergen-specific T cells



       • T cells producing IL-10 and IFN-gamma play a key role
         for the inhibition of histamine and sulphidoleukotriene
         release of effector cells



Barcy S et al Int Immunol 1995
Pierkes M et al JACI 1999
        Bee Venom Immunotherapy (VIT)
      • Allergic side-effects are a significant problem when
        honeybee venom is used (up to 20-40% of patients
        treated)



      • VIT has been shown to be protective in approximately
        80% of bee and 95% of wasp venom-allergic patients




Müller Clin Exp Allergy1998
Müller et al JACI 1992
     Hymenoptera Immunotherapy:
           When to Stop
     • 3 years                                    Müller et al JACI 1991
      • 5 years                                  Golden et al JACI 1996


• The risk of systemic sting reactions when immunotherapy is
  stopped after 5 years reaches 15% in 5 to 10 years after stopping
  VIT
                                                 Golden et al JACI 2000

• Most Hymenoptera venom allergic patients can be safely and
  effectively treated with 8 to 12-weekly injections of 100 mcg
  venom
                                             Reisman R. Allergol Int 1998
G Passalacqua, C Baena-Cagnani, G W Canonica
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

				
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