Transcript IMMUNOTHERAPY IN ALLERGIC DISEASES

IMMUNOTHERAPY IN
ALLERGIC DISEASES
Dr Narayan Pradeep
Pulmonologist
kasaragod
IMMUNOTHERAPY IN
ALLERGIC DISEASES
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History
Definition
Is it useful?
Is it harmful?
Mechanisms of action
Indications
Contraindications
IMMUNOTHERAPY IN
ALLERGIC DISEASES
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Guidelines for immunotherapy
Precautions
Types of Immunotherapy
Effects of withdrawal
Case studies
History
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1565 –
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1819 –
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1872 –
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1873 –
Leonardo Botello
Seasonal Allergy
Bostock
Classical Case of Hay Fever
Morrill Wyman
Autumnal Catarrh
Blackley
Grass Pollen Counts
History
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1900 -
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1910 –
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1913 –
Curtis
Aqueous extracts for immunization
Leonard Noon
Subcutaneous injections of pollen
extracts
Standardisation by wt
Clowes
Demonstrated a 1000 fold increase
in resistance by conjunctival testing
History
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1914 - Robert Cooke
Basics of Immunotherapy as
practiced today
PNU – Kjeldahl method
Mechanisms of Immunotherapy
Blocking antibodies
Dosage and testing techniques
History
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1968 – Norman
Immunotherapy replace
Desensitization
1980’s – Newer routes of drug delivery
Sublingual Immunotherapy
1990’s – Oral microencapsulated
Local Nasal, Bronchial
History
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1998 – 60 million patients annually
treated in the world
33 million injections every year
in USA alone
2002 - 50% of Immunotherapy in
Europe is Sublingual
Definition
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Allergy
An exaggerated response on exposure
to allergen following prior exposure,
mediated by an immune reaction
involving IgE
Definition
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Atopy
Increased tendency to IgE based
sensitivity to common environmental
allergens in genetically predisposed
patients
Definition
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Immunotherapy
The technique of treating IgE mediated
disease with increasing doses of an
allergen in order to decrease sensitivity
to that allergen
IS IT USEFUL?
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Large Volume of data in favour
Van Metre ( 1980)
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Decrease in symptoms
Decrease in medication use
Improvement limited to antigens used
IS IT USEFUL?
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Horak (1993)
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Immunotherapy is an integral component
in treatment strategy
Standardized extracts improve treatment
safety and efficacy
IS IT USEFUL?
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British Society Position Paper – 1993
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Immunotherapy reduces inflammation and
bronchial hyper responsiveness
European Academy of Allergy &
Immunology – 1993
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Immunotherapy influences favourably the
progression of clinical disease
IS IT USEFUL?
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Canadian Guidelines (1995)
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Immunotherapy is effective in patients with
allergy to insect stings, allergic rhino
conjunctivitis and in some patients with
asthma who have been correctly diagnosed
through a cautious history and
corroborated with positive skin test results
IS IT USEFUL?
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Donovan (1996)
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Schoen wetter (1996)
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Nasal symptoms significantly less
Correct allergen, adequate dose,
appropriate patient, safe and effective
Creticos ( 1996)
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Decreases hay fever symptoms, skin
sensitivity & sensitivity to bronchial
challenge
IS IT USEFUL?
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New Zealand, Australia and Australasian
Society on Allergy – 1997
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Immunotherapy should not be regarded as
an alternative to established forms of
preventive therapy
Safe and Effective
IS IT USEFUL?
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Adkinson (1997)
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Children with moderate to severe perennial
asthma
Not much benefit
Small number of patients
Too many aeroallergens
Timothy Craig(1998)
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Data to support use is less concrete
IS IT USEFUL?
META ANALYSIS
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ABRAMSON – 1995 – Adults
ROSS – 2000 - Adults
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20 Randomized Placebo Controlled Double
Blind trials between 1966-80
Concluded that Immunotherapy is effective
TO OVERTURN THESE RESULTS 33
NEGATIVE STUDIES ARE REQUIRED
IS IT USEFUL?
META ANALYSIS
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ABRAMSON – 1995 – Adults
ROSS – 2000 - Adults
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Reductions in symptoms
Decreased need for asthma medications
Improved lung functions
Decreased bronchial hyper reactivity
IS IT USEFUL?
META ANALYSIS
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Arnaldo (1998) Children
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27/29 studies of controlled pediatric
studies with 1443 children aged 2-14
Beneficial effects on Natural History
Some had total remissions
Needed to complete immunotherapy
CONCLUDED ONLY CURATIVE
TREATMENT FOR ASTHMA, SAFE
IS IT USEFUL?
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PREVENTION OF ASTHMA
PREVENTING DISEASE PROGRESSION
Preventive immunotherapy – Jacobsen
2001
Prevention of Asthma Treatment – PAT
study - 2002
IS IT HARMFUL?
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Side Effects
Usually minor
Timothy Craig 1998
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Local Swelling, redness in 15%
British Society of Adverse events 1993
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1/500 injections
IS IT HARMFUL?
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Hejjaoui 1992, Wells 1996
Risk increases with
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Rush Desensitization
Use of high doses
Uncontrolled asthma
Strongly positive skin tests
Change of vials
Prior Anaphylaxis
IS IT HARMFUL?
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Systemic Reactions
Portnoy 1994 – Rush Therapy – 27%
Nielsen 1996 - Rush Therapy – 33%
Greinder 1996 - Rush Therapy – 36%
Greinder 1996 - Conventional <1%
IS IT HARMFUL?
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Committee on safety of medicines – BMJ
1986
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1/ 27,854 injections
In 29 years, 14,59,273 courses of treatment – 29
deaths
Lockey and Reid 1993
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24 deaths from 1959-1984
17 deaths from 1985 –1989
ERRORS OF TREATMENT
IS IT HARMFUL?
RISK FACTORS IN NONFATAL REACTIONS
 Uncontrolled asthma
 FEV1 < 70%
 Beta blockers
 High dose therapy
 Rush immunotherapy
 Incorrect technique
 Errors in dosage
IS IT HARMFUL?
RISK FACTORS IN FATAL REACTIONS
 Symptomatic asthma
 High degree of allergen sensitivity
 Injections during seasonal exacerbation
 Injections from new vials
 Errors in dosage
 Beta blockers
MECHANISMS OF ACTION
IMMUNOGLOBULINS
 Creticos(1984), Arnoldo (1998), Lu Fm
(1998), Patterson ( 1998)
 IgE - Levels initially rise, then falls
 IgG - Increases many folds, 8.8 fold rise
 IgG4 - Specific to the antigen increases
MECHANISMS OF ACTION
BIOCHEMISTRY
 Creticos(1989)
 Decreased Histamine
 Decreased tosyl - L - arginine - methyl
esterase(TAME) - activates kinin system
 Decreased Prostaglandins
MECHANISMS OF ACTION
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MAST CELLS
Creticos(1989) Obrein (1997)
Decreased release of mast cell
mediators
MECHANISMS OF ACTION
EOSINOPHILS
 Van Bever (1990) Ohasi(1997)
 Decreased Eosinophil recruitment and
influx
 Decreased Eosinophil activation
 Decreased Eosinophil Cationic protein
MECHANISMS OF ACTION
T LYMPHOCYTES & CYTOKINES
 Roy Patterson (1998) Obrein (1997)
Lu Fi(1998)
 Change of CD4 cells from Th2 to Th1
phenotype (2002)
 Down regulation of IL- 4 production
from T cells
MECHANISMS OF ACTION
SUMMARY
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Stephen Durham (1998)
Reduces early phase reaction
Reduces late phase reaction
Reduces concentration of inflammatory
mediators
Reduces nasal mast cells
Reduces eosinophils, eosinophil cationic
protein
MECHANISMS OF ACTION
SUMMARY
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Modify T Lymphocyte response
Increases gamma interferon, IL 12, IL2
Not known whether immune deviation
due to anergy of Th2/ Th0 or increase
of Th1
Amplification of CD8 cells downregulatory
INDICATIONS
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IgE mediated disease
Skin test or RAST positive for a specific
antigen
Correlation between allergic symptoms
and test results
No relief of symptoms with
environmental changes or not possible
to avoid exposure
INDICATIONS
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Failure to obtain relief with medications
Failure to tolerate medications
Unwillingness to take long term
medications
Significant allergic upper airway or
ocular disease strengthens indication
INDICATIONS
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IN PREGNANT PATIENTS
Immunotherapy should not be initiated
during pregnancy
Immunotherapy can be continued in
pregnancy if she has been tolerating it
well
No teratogenesis observed
IMMUNOTHERAPY IN ASTHMA
GINA I
Asthma
GINA II
Asthma
GINA III
Asthma
Pharmacotherapy
Immunotherapy
GINA IV
Asthma
IMMUNOTHERAPY IN RHINITIS
Mild
Rhintis &
Conj
Severe
Rhintis &
Conj
Moderate
Rhinitis &
Conj
Pharmacotherapy
IMMUNOTHERAPY
CONTRAINDICATIONS
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ABSOLUTE
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Concomitant use of Beta Blockers
Risk of Anaphylaxis
Responds poorly to Resuscitation
Previous Anaphylactic reaction to
Immunotherapy
Lack of adequate resuscitation facilities
Clinicians without training
CONTRAINDICATIONS
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RELATIVE
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If FEV1/PEFR < 70% predicted
Unstable Asthma
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Nocturnal Asthma
Use of bronchodilator more than thrice a week
Diurnal variation >20%
Bronchodilator reversibility >20%
CONTRAINDICATIONS
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RELATIVE
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Autoimmune disease or Malignancy
Pregnancy – do not initiate
Bronchospasm to previous injection
Children <5 years of age
Eczema – may flare up
Beta Blocker eye drops
Unstable coronary artery disease
GUIDELINES FOR IMMUNOTHERAPY
AAAAI & CSAI
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Should not be self administered
Physician’s office, emergency
equipment available
Subcutaneous
High potency extracts needed
Appropriate dose reductions made in
delays, vial change, reactions
GUIDELINES FOR IMMUNOTHERAPY
AAAAI & CSAI
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Informed consent
Universal Precautions
Individual dosage schedule
Store extracts at 4 degree centigrade
Clinical & Peak flow before & after Inj
Stays at clinic for at least 30 minutes
Strenuous exercise, hot baths after 6 hr
GUIDELINES FOR IMMUNOTHERAPY
AAAAI & CSAI
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Local swelling > 50mm requires dosage
reduction
No relief for 2 years- discontinue
High dose therapy usually for 5 years
PRECAUTIONS
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Administer cautiously in all asthmatics
PFT/ Peak flow >70%
PFT/ Peak flow before patient leaves
clinic
Stick to dosage schedule
Irregular patients at risk of reactions
If schedule needs to change - Allergist
PRECAUTIONS
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All vials to be properly labelled
Check patients name and number and
vial and dosage at each visit
Even after reaching maintenance –
decrease dose when new vial is started
Fever, acute asthma skip the injection
TYPES OF IMMUNOTHERAPY
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SUBCUTANEOUS INJECTIONS – 90 YRS
Conventional
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Months to maintenance
Rush
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Days/ weeks for maintenance
Rapid relief & good compliance
Hospital admission
High systemic reactions
TYPES OF IMMUNOTHERAPY
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Short term
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Seven preseasonal injections
Zenner
EXTRACTS
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Specific Monotherapy
Specific Mixture
Nonspecific Mixture
TYPES OF IMMUNOTHERAPY
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NEW METHODS
Sublingual - 25 years
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Intranasal aqueous
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Nelson(1993) Chando(1995)
Andri(1995)
Intranasal powder
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Andri (1996)
TYPES OF IMMUNOTHERAPY
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Oral
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Oral encapsulated
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Bordignon ( 1994)
Litwin (1997)
Van Densen(1997)
Local bronchial
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Bjorksten (1994)
EFFECTS OF WITHDRAWAL
Medin G (1995)
 Beneficial effects persists for years after
full course of IT
 Studies demonstrated both long term
and short term benefits
 Trial of discontinuation attempted after
5 years
EFFECTS OF WITHDRAWAL
Donovan (1997)
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Initial IT significantly reduced
symptoms
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On stopping IT partial return of
mediators, decline in IgG noted
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Seasonal increase in IgE did not occur
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Symptom improvement persisted
Sublingual immunotherapy
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RCT have now demonstrated the
efficacy of sublingual immunotherapy
WHO approved this modality
After nearly 10 years of starting the
procedure in Europe the procedure
picked up in USA and UK in few centres
Sublingual Immunotherapy
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Indications initially were
Patients who cannot tolerate injections
Children who are very apprehensive
about injections
Absorption and mechanism
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Sublingual immunotherapy uses the
principle of oral absorption
Easily reaches submandibular lymph
channels
Faster than subcutaneous route
(absorption)
Advantages
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> 50% Allergologist switched over to
sublingual immunotherapy
Rarely produces any reactions
More compliant to therapy
Children can also take
Disadvantages
Side effects are extremely rare
 Mouth itching and soreness of throat
 Sneezing
 Increase in asthma symptoms initially
( yet to report, only theoritical )
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Duration
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Higher the dose earlier the effect
2 to 3 years on an average
Can be continued upto 5 years
In Nearly 70 to 80 % the treatment can
be stopped much earlier
CASE STUDY - 1
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Mrs. JH 40 years is suffering from
asthma for the past 20 years and needs
medicine daily for her asthma(GINA III)
Her daily requirement to be symptom
free - inhaled corticosteroids 1000
microgram of Fluticasone with LABA.
She has recently developed joint pains
and swellings and has early morning
stiffness.
CASE STUDY - 1
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What are the investigations planned for
her allergy?
Is GINA III Asthma an indication for
immunotherapy?
Will you give her immunotherapy?
CASE STUDY - 1
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What are the investigations planned for
her allergy? – Allergy Test or Specific
IgE
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Is GINA III Asthma an indication for
immunotherapy? - Yes
Will you give her immunotherapy?
Investigate for Rheumatoid arthritis –
Collagen Vascular disease is a
Contraindication
Thank u
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For patient hearing