Immunotherapy Evidence in atopy Carla Irani M D

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

Epidemiology n n n 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)

Allergic Rhinitis and Comorbid Airway Diseases Spector SL. J Allergy Clin Immunol. 1997; 99: S 773 -S 780

(J Allergy Clin Immunol 1999; 104: S 1 -9. ) Trends in estimated average annual rate of self-reported asthma during preceding 12 months by age group, United States, 1980 to 1993 and 1994.

Epidemiologic Links between Allergic Rhinitis and Asthma Have Similar Prevalence Patterns Allergic Rhinitis Asthma UK Australia Canada Brazil USA South Africa Germany France Argentina Algeria China Russia 0 5 10 15 20 25 30 35 40 % prevalence 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.

General Principles of Allergy Management

History of Allergen Immunotherapy

History of Allergen Immunotherapy

The Science of Allergen Immunotherapy n n 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

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

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

Indications n n Presence of a demonstrated Ig. E-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

Contra-indications n Inability of patients to comply n Auto-Immune diseases & immune deficiencies n Age: Chidren < 5 years n Uncontrolled severe asthma (FEV 1 < 70 % predictive value) n Presence of other immunologic diseases n Treatment with b-blockers n Malignancy n Chronic mouth lesions (sublingual immunotherapy)

Immunotherapy and pregnancy n n n 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)

Dosage schedules n n n There is a dose-response relationship Historically: coseasonal and preseasonal, not recommended Injections are started at 1: 10, 000 W/V, or 1: 100, 000 for more sensitive patients Injections are given weekly until patient reaches the maintenance dose of 0. 6 to 0. 8 ml of 1: 100, then interval of 4 to 6 weeks for 3 years Sublingual immunotherapy is administered following a protocol for 3 years

Dosage schedule n n 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

Mechanisms n n Complex, depends on the allergen and route of immunization Diminution of TH 2 response and enhancement of TH 1 Decreased specific proliferation response to allergen Increase of CD 8+ lymphocytes

Mechanisms Effect on specific Ig. E: Ø Early rise in specific Ig. E Ø Suppression of seasonal rise of specific Ig. E Ø Later lowers specific Ig. E levels Ø Decreased expression on Fce. RII on B cells § Effect an specific Ig. G: Ø Initial rise in specific Ig. G 1 and Ig. G 4 Ø Specific Ig. G 1 predominates early, Ig. G 4 by end of year 2 n

Mechanisms n Nonspecific loss of basophil histamine release following allergen challenge n Decreased cytokine release: IL 4, PAF, HRF, TNF, MIF n Increased production of IFN-g, increased m. RNA for IL-2 with a good correlation clinically J Allergy Clin Immunol 97: 1356 -1365. 1996

JACI 2005

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

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

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

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

Randomized placebo controlled studies with SLIT

Preventive Effects of immunotherapy: Novel sensitization

Immunotherapy and Asthma n N Engl J Med 1997; 336: 324 -31 Adkinson et al: Ø 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: Ø Immunotherapy for grass-pollen allergy for 3 to 4 years induces prolonged clinical remission accompanied by a persistent alteration in immunologic reactivity

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

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

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

The Origins and Prevention of Atopy and Asthma. Immunotherapy as a preventative asthma therapy: The PAT trial n 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 8 the PAT-Study. J Allergy Clin Immunol 2002; 109: 251 -6

PAT Trial n n n 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).

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

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

T cell strategies n B Kay (AAAAI 2001): multiple, short, overlapping peptides containing T cell epitopes can induce both peptide and whole allergen-specific hyporesponsiveness n Norman et al Am J Resp Crit Care Med 1996 n Allervax: 2 reactive peptide for chain 1, safe and efficacious Pene et al JACI 1997 Significant decrease in IL 4 secretion after 6 wks of high dose Allervax Cat

DNA-based immunotherapeutics of allergic disease n Immunization with plasmid gene vaccines: Induction of Th 1 -biased immune response and prevention of development of Th 2 n Allergen mixed with immunostimulatory aligodeoxynucleotide (ISS-ODN or Cp. G motifs): Cryptic immunostimulatory DNA sequences which provide Th 1 adjuvant activity for the immune responses

DNA-based immunotherapeutics of allergic disease n 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 n Immunomodulation with ISS-ODN alone: Effective allergen-independent immunomodulator, in early and late phase(short lived, proven in mice only)

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

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

Immunotherapy in Atopic Dermatitis (AD) n n 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

Toward Allergy and Asthma Prevention n 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.