Role of Allergen Immunotherapy in Allergic Asthma | Jindal Chest Clinic Chandigarh

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Role of Allergen Immunotherapy in Allergic Asthma
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Presentation objectives

• Discuss and define role of allergen
  immunotherapy in allergic asthma including
• Definition
• Mechanism
• Inclusion in 10 world asthma guidelines
• Efficacy studies
• Safety

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Definition
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Definition

• Allergen immunotherapy is the administration of
  gradually increasing quantities of an allergen
  vaccine to an allergic subject, reaching a dose
  which is effective in ameliorating the symptoms
  associated with subsequent exposure to the
  causative allergen.

WHO Position Paper 1998
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History
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History of Allergen Immunotherapy
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Major contributors to development of Allergen
Immunotherapy
Leonard Noon 1877-1913
ROMAGNANI
DURHAM
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Mechanism of action
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Allergen-Specific Immunotherapy Mode of Action
GM-CSF IL-3
MZ,Ba
Mediators
Cytokines
Allergen Immunotherapy shifts the T helper cell
stimulation from TH2 to TH1
A. Nandy, 2010
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Guideline recommendation for Allergen
Immunotherapy
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Allergen Immunotherapy and Asthma
Guideline Statement of Recommendation for Allergen Immunotherapy
Expert Panel Report 3 U.S. Guidelines Allergen immunotherapy be considered for patients who have persistent asthma if there is clear evidence of a relationship between symptoms and exposure to an allergen to which the patient is sensitive
GINA Guideline Specific immunotherapy has long term clinical effects and the potential of preventing development of asthma in children with rhino-conjunctivitis up to 7 years after treatment termination
European Academy of Allergy and Immunology (EAACI) Global Allergy and Asthma European Network (GA2LEN) SIT can be used in mild allergic asthma proven to be caused by a well-defined allergen, if asthma is mild, under control and FEV1 is above 70. Performance of SIT should be based on the allergen sensitization rather than on the disease itself.
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Allergen Immunotherapy and Asthma
Guideline Statement of Recommendation for Allergen Immunotherapy
WHO Position Paper There is good evidence that immunotherapy with inhalant allergens used to treat seasonal or perennial allergic rhinitis and asthma is clinically effective
American Academy of Allergy, Asthma Immunology (AAAAI)American College of Allergy, Asthma Immunology (ACAAI) Joint Council of Allergy, Asthma Immunology (JCAAI) Patients with allergic rhinitis/conjunctivitis or allergic asthma whose symptoms are not well controlled by medications or avoidance measures or require high medication doses, multiple medications, or both to maintain control of their allergic disease might be good candidates for immunotherapy
World Allergy OrganizationWhite Book of Allergy Effects of allergen specific immunotherapy, that are lacking with pharmacological treatment, are the long-lasting clinical effects and the alteration of the natural course of the disease.
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Allergen Immunotherapy and Asthma
Guideline Statement of Recommendation for Allergen Immunotherapy
DGAKI, ÄDA, GPA, ÖGAI, SGAI Advised in patients with controlled asthma (acc. to GINA 2008), with intermittent and mild persistent IgE-mediated allergic asthma.
Allergic Rhinitis and its Impact on Asthma (ARIA) Management of atopic diseases like allergic asthma is based on allergen avoidance, pharmacotherapy and immunotherapy in selected patients. Performance of SIT should be based on the allergen sensitization rather than on the disease itself.
British Society for Allergy and Clinical Immunology (BSACI) Guidelines Immunotherapy for allergic rhinitis has been shown to have a carry-over effect after therapy has stopped. Chronic asthma is a contraindication.
Allergen immunotherapy has been included in 10
world wide asthma guidelines
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Level of Evidence for Allergen Immunotherapy
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Subcutaneous IT evidence for efficacy
GA2LEN/ EAACI SCIT is effective in allergic rhinitis. Long-term benefits were shown. There seems to be a preventive effect on new sensitizations
ARIA Conditional recommendation, moderate-quality evidence SCIT pollen AR adults SCIT AR asthma Conditional recommendation, low-quality evidence SCIT mites AR adults SCIT AR children
DGAKI, ÄDA, GPA, ÖGAI, SGAI Rhinoconjunctivitis A,1a for grass pollen A,1b for birch pollen, HDM B,2b for cat, Alternaria, Cladosporium Asthma GINA I/II A,1a A,1b for asthma prevention B,2c for prevention of new sensitizations
BSACI A,1 for pollen induced rhinitis and/or conjunctivitis 1 for potential for long-term disease remission
EAACI 1a for asthma, 1b for rhinitis, 1b long-term efficacy and preventive capacity
WHO No evidence level
For the treatment of asthma not of rhinitis!
Conclusion Efficacy confirmed for various
allergens!
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Cochrane meta-analysis
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Excerpts from Cochrane database

• 76 trials with 3,188 patients
• Significant improvement in asthma symptom scores
• Significant reduction of allergen specific
  bronchial hyperreactivity
• Some reduction also in non-specific bronchial
  hyperreactivity

Abramson, Weiner and Puy, Cochrane Database
Systematic Review 2003
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Excerpts from Cochrane database

• It would have been necessary to treat 4 (95 CI 3
  to 5) patients with immunotherapy to avoid one
  deterioration in asthma symptoms, and overall to
  treat 5 (95 CI 4 to 6) patients with
  immunotherapy to avoid one requiring increased
  medication.

Abramson, Weiner and Puy, Cochrane Database
Systematic Review 2003
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Meta-analysis SCIT in asthma
The effect of mite SCIT on allergen-specific
bronchial hyperreactivitiy is even strong with
SMD gt0.8.
Data from Abramson MJ, Puy RM, Weiner JM.
Cochrane Database Syst Rev 20108CD001186.
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Cochrane Meta analyses SCIT asthma
SMD 95 CI
SCIT1
Asthma Symptoms (pollen) -0.61 -0.87, -0.35
Asthma Medication (pollen) -0.52 -0.91, -0.13
Bronchial Hyperreagibility, unspecific (metacholine) -0.25 -0.51, -0.00
Bronchial Hyperreagibility, specific (pollen) -0.55 -0.84, -0.27
Bronchial Hyperreagibility, specific (house dust mites) -0.98 -1.39,-0.58
Abramson MJ et al., Cochrane Database Syst Rev
20108CD001186 88 Studies 3792 Patients
Large effect in controlling bronchial
hyper-reactivity seen with house dust mite
immunotherapy
J.C. Cohen, Statistical Power Analysis for the
Behavioral Sciences, 1988
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• Whilst inhaled corticosteroid therapy remains the
  mainstay of asthma management, any reduction in
  this type of treatment while maintaining good
  asthma control would be welcome.

New primary end point in asthma studies
Reduction of ICS while maintaing asthma control
Abramson MJ et al., Cochrane Database Syst Rev
20108CD001186.
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Meta-analysis on Immunotherapy for Asthma
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Meta-Analysis of Immunotherapy for Asthma
(Abramson et al. AARD 1995151)

• Mites
• Smith (n22)
• Maunsell (n34)
• Werner (n51)
• DSouza (n91)
• Pauli (n18)
• Newton (n14)
• BTA (n56)
• Other Allergens
• Frankland (n57)
• Ohman (n17)
• Sundin (n39)
• Valovirta (n27)
• Mites Combined (n286)
• Other Allergens (n140)
• All Studies (n426)

A meta-analysis of all 20 published prospective,
randomized, placebo controlled trials of
immunotherapy showed highly statistical
significance for efficacy of SIT in asthma
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Effect of specific immunotherapy added to
pharmacologic treatment and allergen avoidance in
asthmatic patients allergic to house dust mite  
Maestrelli et al, JACI 2004
Significant improvement over 3 years in morning
PEF and asthma symptom score
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Meta-analysis of the efficacy of immunotherapy in
allergic asthma in pediatric patients, 3 to 18
years of age. M Penagos, G Passalacqua, E
Compalati, C Baena-Cagnani, S Orozco, A Pedroza
GW Canonica
SYMPTOMS
Highly significant improvement in symptom score
and medication score
MEDICATIONS
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Efficacy in prevention of new allergen
sensitization
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Specific immunotherapy has long-term preventive
effect of seasonal and perennial asthma 10-year
follow-up on the PAT study
Statistically significant long term preventive
benefits of asthma after specific immunotherapy
Jacobssen, Allergy 2007
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Immunotherapy Prevents the Development of New
Allergen Sensitizations
10/22 (45) monosensitized children who received
immunotherapy did not develop new sensitivities
whereas the entire control group acquired new
sensitivities (became polysensitized) during this
period of time.
A. Des Roches et al. JACI 199899450-453
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Prevention of Asthma by Immunotherapy
5-Year Follow-Up
Statistically significant increase in development
of asthma in the control group only (58 of
controls vs. 23 of IT group)
Jacobsen L Ann Allergy Asthma Immunol 2001 87
43-46
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Preventative Therapy in Children
Atopic children who were treated with pollen
immunotherapy were twice as likely not to develop
asthma during corresponding pollen season
compared to children not on immunotherapy
Patients
Moller C et al J Allergy Clin Immunol 2002 109
251-256
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Coseasonal SLIT reduces the development of
asthma in children with allergic rhinitis.
Novembre E. et al, JACI 2004
NO ASTHMA
ASTHMA
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Randomized, open, controlled 79
children Allergic rhinitis only Follow-up 3 yrs
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SLIT
NO SLIT
Significantly less children developed asthma when
on immunotherapy
PRESENCE OF ASTHMA AFTER 3 YEARS
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Prevention of New Sensitizations by AIT
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
Evidence suggests that allergen immunotherapy
prevents the development of new sensitisations
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Evidence for early intervention in Allergic
Rhinitis for prevention of Asthma
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The nose-lung interaction in allergic rhinitis
and asthma united airways disease G.Passalacqua,
G.Ciprandi G.W.Canonica 2004
Asthma and rhinitis as different Aspects of a
single disorder
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Allergic rhinitis as a predictor for wheezing
onset in school-aged children. Rochat et al, JACI
2010
Cohort of 1,314 children followed from birth to
13 yrs
Patients with allergic rhinitis have less chances
of remaining free of wheezing symptoms
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MARTINEZ,PEDERSEN
Long-Term Inhaled Corticosteroids in Preschool
Children at High Risk for Asthma Guilbert T, NEJM
2006
Long term inhaled steroids do not have lasting
effects
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Bousquet, Clin Exp Allergy 2005
Untreated rhinitis increases the risk of asthma
attacks.
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Bronchial biopsioes after Specific provocation
in patients with rhinitis or asthma

Crimi E et al, JAP 2001

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Long term Benefits of Allergen Immunotherapy
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Grass pollen immunotherapy long-term efficacy
Seasonal immunotherapy for 4 years and 7 years
showed long term efficacy
Durham SR et al New Engl J Med 1999341468-75
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Long-Lasting Efficacy of Subcutaneous IT
Controlled Studies
Author Allergen Duration (yrs)
Hedlin, 1995 Cat/dog 3
Ariano, 1999 Parietaria 4
Durham, 2000 Grass 5
Eng, 2002 Grass 3
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AUTHOR ALLERGEN PATIENTS DURATION SIT LONG-LASTING EFFECT
Mosbech Grass 2.5 years 6 years
Grammer Ragweed 61 adult/children 4 months 2 years
Hedlin Cat/dog 32 adult/chidren 3 years 5 years
Des Roches Mite 40 adult 1-4 years 3 years
Ariano Parietaria 35 adult 4 years 4 years
Durham Grass 52 adult 3-4 years 3 years
Eng Grass 25 children 3 years 12 years
Long lasting effects of specific immunotherapy
has been evaluated in many randomised double
bling placebo controlled trials
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Dust Mite Immunotherapy Trials for Asthma
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Highlights

• Significant decrease in asthma symptoms
• Decrease in asthma medications
• Decrease in mite-specific immediate and late
  phase reactions

References Aas K. Acta Paediatr Scand 1971 60
264-268 Bousquet J, Calvayrac P, Guerin B, et
al. Allergy Clin Immunol 1985 76 734-744
Bousquet J, Hejjaoui A, Clauzel AM, et al. J
Allergy Clin Immunol 1988 82 971-977 Pichler
CE, Marquardsen A, Sparholt S, et al. Allergy
1997 52 274-283
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High-dose hypoallergenic SCIT in mite asthma
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House dust mite SCIT in asthma
Daily fluticasone dose reduction after 2 years of
SCIT
plt0.05
53 stronger daily fluticasone dose reduction
with Acaroid vs. control group
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House dust mite SCIT in asthma
Early onset efficacy after 9 months of SCIT
Children adults Improvement rate of Improvement rate of
at least 1 step at least 2 steps
SCIT-group (n60) 55.0 30.0
SCIT-group (n60) 32.8 14.8
Children Improvement rate of Improvement rate of
at least 1 step at least 2 steps
SCIT-group (n33) 69.7 36.4
Control-group (n32) 31.3 6.3
69.7 children with asthma saw a 1 step GINA
grades asthma improvement with SIT
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House dust mite SCIT in asthma
Children without need of inhaled steroids
60.6 of house-dust mite allergic asthmatic
children dont need any ICS after 3 years of
high-dose hypoallergenic SCIT
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House dust mite SCIT in asthma
Daily need of fluticasone to retain asthma
control during 3 years of SCIT
plt0.05
plt0.05
plt0.05
330.3
Threshold level, that might reduce growth
Fluticasone dose (µg/day, mean)
190.9
151.5
124.2

• mod. acc. to Rudert M et al., EAACI, Genf,
  16.-20. Juni 2012Poster 1400 and Bacharier LB et
  al., Allergy 2008 635-34

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Increase of the morning lung function
Significant increase in morning lung function
with add on therapy with Acaroid
Median PEF increase after 2 years of SCIT
p lt 0.05
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Safety
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Allergen Immunotherapy Safety

• There is an inherent risk of local allergic
  reactions (wheal flare) at the injection site,
  as well as, systemic anaphylaxis.
• A prospective study has reported the frequency of
  systemic reactions to be 0.3 of immunotherapy
  doses, representing 3.7 of patients. Severe
  systemic reactions to allergy immunotherapy can
  be life threatening and fatal reactions do occur.
• Anaphylactic related fatalities are rare (1 in
  2.5 million injections)

Bernstein DI, Wanner M, Borish L, Liss GM
Immunotherapy Committee, AAAAI. Twelve-year
survey of fatal reactions to allergen injections
and skin testing 1990-2001.J Allergy Clin
Immunol. 2004 Jun1131129-36.
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Allergen Immunotherapy Safety

• Allergy immunotherapy should be administered only
  in a setting where procedures that can reduce the
  risk of anaphylaxis are in place and where the
  prompt recognition and treatment of anaphylaxis
  is ensured
• The preferred location for administration of
  allergy immunotherapy is in the office of the
  physician who prepared the patients allergen
  immunotherapy extract
• Because most systemic reactions resulting from
  SCIT occur within 30 minutes of an injection, the
  allergen immunotherapy practice parameter
  recommends that patients should remain in the
  physicians office for at least 30 minutes after
  an injection

Joint Task Force on Practice Parameters AAAAI
ACAAI JCAAI. Allergen immunotherapy a practice
parameter second update. J Allergy Clin Immunol.
2007120S25-85.
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Conclusion
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Conclusion

• There is sufficient evidence to support the
  overall effectiveness and safety of Allergen
  Immunotherapy for treating both allergic
  rhino-conjunctivitis and asthma.
• It can benefit selected allergic asthma patients
  by improving symptoms, reducing requirement of
  medications, improving quality of life, and has
  long-term benefits.
• Allergen Immunotherapy has been practiced
  worldwide for over 100 years
• Allergen Immunotherapy has been included in over
  10 world asthma guidelines

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