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IMMUNOTHERAPY IN ALLERGIC DISEASES

IMMUNOTHERAPY IN ALLERGIC DISEASES. Dr Narayan Pradeep Pulmonologist kasaragod. IMMUNOTHERAPY IN ALLERGIC DISEASES. History Definition Is it useful? Is it harmful? Mechanisms of action Indications Contraindications. IMMUNOTHERAPY IN ALLERGIC DISEASES. Guidelines for immunotherapy

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IMMUNOTHERAPY IN ALLERGIC DISEASES

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  1. IMMUNOTHERAPY IN ALLERGIC DISEASES Dr Narayan Pradeep Pulmonologist kasaragod

  2. IMMUNOTHERAPY IN ALLERGIC DISEASES • History • Definition • Is it useful? • Is it harmful? • Mechanisms of action • Indications • Contraindications

  3. IMMUNOTHERAPY IN ALLERGIC DISEASES • Guidelines for immunotherapy • Precautions • Types of Immunotherapy • Effects of withdrawal • Case studies

  4. History • 1565 – Leonardo Botello Seasonal Allergy • 1819 – Bostock Classical Case of Hay Fever • 1872 – Morrill Wyman Autumnal Catarrh • 1873 – Blackley Grass Pollen Counts

  5. History • 1900 - Curtis Aqueous extracts for immunization • 1910 – Leonard Noon Subcutaneous injections of pollen extracts Standardisation by wt • 1913 – Clowes Demonstrated a 1000 fold increase in resistance by conjunctival testing

  6. History • 1914 - Robert Cooke Basics of Immunotherapy as practiced today PNU – Kjeldahl method Mechanisms of Immunotherapy Blocking antibodies Dosage and testing techniques

  7. History • 1968 – Norman Immunotherapy replace Desensitization • 1980’s – Newer routes of drug delivery Sublingual Immunotherapy • 1990’s – Oral microencapsulated Local Nasal, Bronchial

  8. History • 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

  9. Definition • Allergy An exaggerated response on exposure to allergen following prior exposure, mediated by an immune reaction involving IgE

  10. Definition • Atopy Increased tendency to IgE based sensitivity to common environmental allergens in genetically predisposed patients

  11. Definition • Immunotherapy The technique of treating IgE mediated disease with increasing doses of an allergen in order to decrease sensitivity to that allergen

  12. IS IT USEFUL? • Large Volume of data in favour • Van Metre ( 1980) • Decrease in symptoms • Decrease in medication use • Improvement limited to antigens used

  13. IS IT USEFUL? • Horak (1993) • Immunotherapy is an integral component in treatment strategy • Standardized extracts improve treatment safety and efficacy

  14. IS IT USEFUL? • British Society Position Paper – 1993 • Immunotherapy reduces inflammation and bronchial hyper responsiveness • European Academy of Allergy & Immunology – 1993 • Immunotherapy influences favourably the progression of clinical disease

  15. IS IT USEFUL? • Canadian Guidelines (1995) • 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

  16. IS IT USEFUL? • Donovan (1996) • Nasal symptoms significantly less • Schoen wetter (1996) • Correct allergen, adequate dose, appropriate patient, safe and effective • Creticos ( 1996) • Decreases hay fever symptoms, skin sensitivity & sensitivity to bronchial challenge

  17. IS IT USEFUL? • New Zealand, Australia and Australasian Society on Allergy – 1997 • Immunotherapy should not be regarded as an alternative to established forms of preventive therapy • Safe and Effective

  18. IS IT USEFUL? • Adkinson (1997) • Children with moderate to severe perennial asthma • Not much benefit • Small number of patients • Too many aeroallergens • Timothy Craig(1998) • Data to support use is less concrete

  19. IS IT USEFUL? META ANALYSIS • ABRAMSON – 1995 – Adults • ROSS – 2000 - Adults • 20 Randomized Placebo Controlled Double Blind trials between 1966-80 • Concluded that Immunotherapy is effective • TO OVERTURN THESE RESULTS 33 NEGATIVE STUDIES ARE REQUIRED

  20. IS IT USEFUL? META ANALYSIS • ABRAMSON – 1995 – Adults • ROSS – 2000 - Adults • Reductions in symptoms • Decreased need for asthma medications • Improved lung functions • Decreased bronchial hyper reactivity

  21. IS IT USEFUL? META ANALYSIS • Arnaldo (1998) Children • 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

  22. IS IT USEFUL? • PREVENTION OF ASTHMA • PREVENTING DISEASE PROGRESSION • Preventive immunotherapy – Jacobsen 2001 • Prevention of Asthma Treatment – PAT study - 2002

  23. IS IT HARMFUL? • Side Effects • Usually minor • Timothy Craig 1998 • Local Swelling, redness in 15% • British Society of Adverse events 1993 • 1/500 injections

  24. IS IT HARMFUL? • Hejjaoui 1992, Wells 1996 • Risk increases with • Rush Desensitization • Use of high doses • Uncontrolled asthma • Strongly positive skin tests • Change of vials • Prior Anaphylaxis

  25. IS IT HARMFUL? • Systemic Reactions • Portnoy 1994 – Rush Therapy – 27% • Nielsen 1996 - Rush Therapy – 33% • Greinder 1996 - Rush Therapy – 36% • Greinder 1996 - Conventional <1%

  26. IS IT HARMFUL? • Committee on safety of medicines – BMJ 1986 • 1/ 27,854 injections • In 29 years, 14,59,273 courses of treatment – 29 deaths • Lockey and Reid 1993 • 24 deaths from 1959-1984 • 17 deaths from 1985 –1989 • ERRORS OF TREATMENT

  27. IS IT HARMFUL? RISK FACTORS IN NONFATAL REACTIONS • Uncontrolled asthma • FEV1 < 70% • Beta blockers • High dose therapy • Rush immunotherapy • Incorrect technique • Errors in dosage

  28. 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

  29. 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

  30. MECHANISMS OF ACTION BIOCHEMISTRY • Creticos(1989) • Decreased Histamine • Decreased tosyl - L - arginine - methyl esterase(TAME) - activates kinin system • Decreased Prostaglandins

  31. MECHANISMS OF ACTION • MAST CELLS • Creticos(1989) Obrein (1997) • Decreased release of mast cell mediators

  32. MECHANISMS OF ACTION EOSINOPHILS • Van Bever (1990) Ohasi(1997) • Decreased Eosinophil recruitment and influx • Decreased Eosinophil activation • Decreased Eosinophil Cationic protein

  33. 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

  34. MECHANISMS OF ACTIONSUMMARY • 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

  35. MECHANISMS OF ACTIONSUMMARY • 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

  36. INDICATIONS • 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

  37. INDICATIONS • 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

  38. INDICATIONS • 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

  39. IMMUNOTHERAPY IN ASTHMA GINA IV Asthma GINA III Asthma GINA II Asthma GINA I Asthma Pharmacotherapy Immunotherapy

  40. IMMUNOTHERAPY IN RHINITIS Severe Rhintis & Conj Moderate Rhinitis & Conj Mild Rhintis & Conj Pharmacotherapy IMMUNOTHERAPY

  41. CONTRAINDICATIONS • ABSOLUTE • 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

  42. CONTRAINDICATIONS • RELATIVE • If FEV1/PEFR < 70% predicted • Unstable Asthma • Nocturnal Asthma • Use of bronchodilator more than thrice a week • Diurnal variation >20% • Bronchodilator reversibility >20%

  43. CONTRAINDICATIONS • RELATIVE • 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

  44. GUIDELINES FOR IMMUNOTHERAPYAAAAI & CSAI • 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

  45. GUIDELINES FOR IMMUNOTHERAPYAAAAI & CSAI • 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

  46. GUIDELINES FOR IMMUNOTHERAPYAAAAI & CSAI • Local swelling > 50mm requires dosage reduction • No relief for 2 years- discontinue • High dose therapy usually for 5 years

  47. PRECAUTIONS • 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

  48. PRECAUTIONS • 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

  49. TYPES OF IMMUNOTHERAPY • SUBCUTANEOUS INJECTIONS – 90 YRS • Conventional • Months to maintenance • Rush • Days/ weeks for maintenance • Rapid relief & good compliance • Hospital admission • High systemic reactions

  50. TYPES OF IMMUNOTHERAPY • Short term • Seven preseasonal injections • Zenner • EXTRACTS • Specific Monotherapy • Specific Mixture • Nonspecific Mixture

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