1. Immunotherapy: Evidence in atopy Carla Irani, M.D Allergy/Clinical Immunology

2. Epidemiology Epidemiologic studies of temporal and geographic variation in asthma morbidity have identified asthma as an important public health concern. There is tremendous increase in the incidence of asthma and allergic rhinitis Most recently, the NIH joined forces with the World Health Organization to find ways to lessen the global impact of asthma. (GARD)

3. Allergic Rhinitis and Comorbid Airway Diseases Spector SL. J Allergy Clin Immunol. 1997;99:S773-S780

4. Trends in estimated average annual rate of self-reported asthma during preceding 12 months by age group, United States, 1980 to 1993 and 1994. (J Allergy Clin Immunol 1999;104:S1-9.)

5. Allergic Rhinitis Epidemiologic Links between Allergic Rhinitis and Asthma Allergic Rhinitis and Asthma Have Similar Prevalence Patterns Study of worldwide prevalence of atopic diseases in 463,801 children 13–14 years of age. Children self-reported symptoms over 12 months using questionnaires. Adapted from the International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee Lancet 1998;351:1225–1232. UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia 0510152025303540 % prevalence UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia 0510152025303540 % prevalence Asthma

6. General Principles of Allergy Management

7. History of Allergen Immunotherapy

9. The Science of Allergen Immunotherapy To paraphrase William Osler, the father of American medicine: The practice of allergen immunotherapy is an art based on science. Thirty years ago there was little science and today there is considerable science as to how allergen immunotherapy should be prescribed and administered

10. Most common allergens in Lebanon 1. Dust mites: farinae and pteronyssinus 2. Grass: Phleum,Dactylis and Lolium 3. Olive (cross-reactive with ash) 4. Pine, not very allergenic 5. Parietaria 6. Molds: Aspergillus and Altenaria 7. Weeds: Ambrosia 8. Coackroaches: Blatella germanica

11. Allergen Immunotherapy Introduced by Leonard Noon in 1911, then Freeman Historically: Weekly injections given before the season 1920: Perennial treatment

12. Indications Presence of a demonstrated IgE-mediated disease (ST, RAST) Documentation that specific sensitivity is involved in symptoms Severity, duration of symptoms and incomplete response to pharmacotherapy Venom immunotherapy: Hx of severe systemic allergic reaction

13. Contra-indications Inability of patients to comply Auto-Immune diseases & immune deficiencies Age: Chidren < 5 years Uncontrolled severe asthma (FEV1 < 70 % predictive value) Presence of other immunologic diseases Treatment with  -blockers Malignancy Chronic mouth lesions (sublingual immunotherapy)

14. Immunotherapy and pregnancy Risk for a systemic reaction leading to abortion: one case report No increase in prematurity, toxemia, abortion, neonatal death or congenital malformations Fewer immediate skin tests in children whose mothers received IT while in utero (significant for grass pollen)

15. Dosage schedules There is a dose-response relationship Historically: coseasonal and preseasonal, not recommended Injections are started at 1:10,000W/V, or 1:100,000 for more sensitive patients Injections are given weekly until patient reaches the maintenance dose of 0.6 to 0.8ml of 1:100, then interval of 4 to 6 weeks for 3 years Sublingual immunotherapy is administered following a protocol for 3 years

16. Dosage schedule Reduce volume administered (eg: 0.5 to 0.35) when a new vial of extract is given Identify carefully at each time: patient ’ s dose schedule and patient ’ s vial Observe for 20-30 min after injections for evidence of reactions in the case of subcutaneous immunotherapy Sublingual immunotherapy is administered at home

17. Mechanisms Complex, depends on the allergen and route of immunization Diminution of TH2 response and enhancement of TH1 Decreased specific proliferation response to allergen Increase of CD8+ lymphocytes

18. Mechanisms Effect on specific IgE:  Early rise in specific IgE  Suppression of seasonal rise of specific IgE  Later lowers specific IgE levels  Decreased expression on Fc  RII on B cells  Effect an specific IgG:  Initial rise in specific IgG1 and IgG4  Specific IgG1 predominates early, IgG4 by end of year 2

19. Mechanisms Nonspecific loss of basophil histamine release following allergen challenge Decreased cytokine release: IL4, PAF, HRF, TNF, MIF Increased production of IFN-  increased mRNA for IL-2 with a good correlation clinically J Allergy Clin Immunol 97:1356-1365.1996

20. JACI 2005

21. WHO position paper:Allergen immunotherapy Bousquet J, Lockey RF, Malling HJ et al. Allergy 1998;53:suppl 44:1-42 Effective in IgE-mediated disease with a limited spectrum (1 or 2) of allergies Effective in allergic rhinitis/conjunctivitis allergic asthma and systemic reactions to wasp/bee venom Should be combined with allergen avoidance, pharmacotherapy and patient education

22. Grass pollen immunotherapy for hayfever Varney va et al BMJ 1991;302:265-9

23. Immunotherapy for rhinitis (43 studies) Malling HJ. Allergy 1998;53:461-472

24. Grass pollen immunotherapy for seasonal rhinitis/asthma Walker SM et al., J Allergy Clin immunol 2001;107:87-93

25. Randomized placebo controlled studies with SLIT

26. Preventive Effects of immunotherapy: Novel sensitization

27. Immunotherapy and Asthma N Engl J Med 1997;336:324-31 Adkinson et al:  No benefit in children sensitized to many allergens, but decrease in use of inhaled steroids  N Engl J Med 1999;341:468-475 Durham et al:  Immunotherapy for grass-pollen allergy for 3 to 4 years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity

28. Immunotherapy and Asthma Cochrane collaboration:  Fifty-four randomized controlled trials were analyzed:  25 for house mite allergy  13 pollen  8 animal dander  2 Cladosporium  6 with multiple allergens

29. Immunotherapy and Asthma Allergy 1999 Abramson et al: The Cochrane collaboration:  Immunotherapy may reduce asthma symptoms and use of medications  But the size of the benefit compared to other therapies is not known  The possibility of adverse effects (anaphylaxis) must be considered

30. Immunotherapy and Asthma NHLBI recommendations: 1. If avoidance is not possible 2. Appropriate treatment fails to control allergic asthma 3. Greater efficacy in children and young adults 4. Greater likelihood of success if single sensitivity 5. FEV1 at least 70% of predicted

31. The Origins and Prevention of Atopy and Asthma. Immunotherapy as a preventative asthma therapy: The PAT trial In a large multicenter trial 205 children aged 6 to 14 years with grass and/or birch pollen allergy but without any other allergy, were randomized either to receive specific immunotherapy for 3 years or to an open controlled group Möller et al, Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis 8the PAT-Study. J Allergy Clin Immunol 2002; 109:251-6

32. PAT Trial Subjects had moderate to severe hay fever symptoms At inclusion none reported asthma with need of daily treatment. Symptomatic treatment was limited to loratadine, levocabastine, sodium cromoglycate, and nasal budesonide. Asthma was evaluated clinically and by peak flow. Methacholine bronchial provocation tests were carried out during the season(s) and during the winter. Before the start of immunotherapy, 20% of the children had mild asthma symptoms during the pollen season(s).

34. Allergen immunotherapy : the future Conventional subcutaneous immunotherapy Alternative routes: mainly sublingual Recombinant allergens Modified allergens Peptides DNA vaccines Adjuvants (ISS, IL-12, mycobacteria) Anti-IgE

35. Immunotherapy for the 21 st century T cell strategies of allergy vaccination Overlapping peptides of Fel d 1 : Allervax Cat Genetic immunization CpG motifs or immunostimulatory sequence

36. T cell strategies B Kay (AAAAI 2001): multiple, short, overlapping peptides containing T cell epitopes can induce both peptide and whole allergen-specific hyporesponsiveness Norman et al Am J Resp Crit Care Med 1996 Allervax: 2 reactive peptide for chain 1, safe and efficacious Pene et al JACI 1997 Significant decrease in IL4 secretion after 6 wks of high dose Allervax Cat

37. DNA-based immunotherapeutics of allergic disease Immunization with plasmid gene vaccines: Induction of Th1-biased immune response and prevention of development of Th2 Allergen mixed with immunostimulatory aligodeoxynucleotide (ISS-ODN or CpG motifs): Cryptic immunostimulatory DNA sequences which provide Th1 adjuvant activity for the immune responses

38. DNA-based immunotherapeutics of allergic disease Physical allergen-ISS-ODN conjugates (AIC): More immunogenic than native antigens and antigens/ISS-ODN cocktails, and more effective in the prevention of allergic hypersensitivity responses Immunomodulation with ISS-ODN alone: Effective allergen-independent immunomodulator, in early and late phase(short lived, proven in mice only)

39. Specific immunotherapy in perennial rhinitis Mild rhinitisModerate rhinitis+/- conjunctivitis Severe rhinitis+/- conjunctivitis Allergen avoidance (when possible) Pharmacotherapy Consider immunotherapy WHO Position Paper 1997

40. Specific Immunotherapy and Asthma Intermittent asthma Mild persistent asthma Moderate Persistent asthma Severe persistent asthma Pharmacotherapy Consider immunotherapy WHO Position Paper 1997

41. Immunotherapy in Atopic Dermatitis (AD) No evidence in large studies May be useful when done for allergic rhinitis in a patient suffering as well from atopic dermatitis Atopic dermatitis is an atopic state not always caused by allergens But!! Dust mites have been shown to exacerbate AD

42. Toward Allergy and Asthma Prevention There is justifiable hope that some chronic and debilitating diseases, such as asthma and allergic rhinitis, that markedly affect the lives of the young and the old equally can be prevented before they start or can be stopped before resulting in irreversible harm.