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  1. IMMUNOTERAPIA SPECIFICA (ITS) Somministrazione di estratti allergenici purificati (prima a dosi crescenti e poi a dose di mantenimento), al fine di ottenere la riduzione della risposta clinica all’allergene stesso. L’immunoterapia allergene specifica è un vaccino a tutti gli effetti La via tradizionale di somministrazione è quella iniettiva sottocutanea (SCIT), ed è disponibile in alternativa anche la via sublinguale

  2. Leonard Noon 1877-1913

  3. ISHIZAKA IgE ROMAGNANI WHO Pos Pap Meccanismi Allergoidi DNA- Based ITS Th1/Th2 SLIT Liposomi, Adiuvanti Allergeni ricombinanti Peptidi 1986 1990 1998 2005 DURHAM NOON 1986 2005 Studi randomizzati Uso empirico 1928 1960

  4. Rands DA. Anaphylactic reaction to desensitization for allergic rhinitis and astma Br Med J 1980; 281: 854 Frankland AW. Anaphylactic reaction to desensitization. Br Med J 1980; 281: 1429 Ewan PW. Anaphylactic reaction to desensitization. Br Med J 1980; 281: 1069

  5. Committee on the safety of medicines (CMS) CMS Update Desensitizing vaccines Br Med J 1986; 293:948 26 fatalities since 1957 certainly due to IT 11 of them since 1980

  6. DUBBIA EFFICACIA E SCARSA SICUREZZA Dal 1910 fino agli anni ’70: Prescrizione ingiustificata dell’ITS Prescrizione non corretta Pratica non adeguata, senza regole precauzionali e con estratti scadenti

  7. Non-injection routes for immunotherapy ... the overall aim of improving safety of immunotherapy and making it more convenient for the patients... EAACI IT Position Paper 1993 Desensitizing vaccines 26 deaths due to SCIT Committee on the Safety of Medicines BMJ 1986

  8. WHO Pos Pap. Therapeutical vaccines for allergic diseases Allergy 1998 Standards for practical allergen-specific immunotherapy. Allergy 2006 Allergen immunotherapy: A practice parameter second update JACI 2007

  9. L'ITS e' mirata invece all'allergene causale e non all'organo principalmente coinvolto.” • L’ITS non è un trattamento di ultima scelta da usare se i farmaci falliscono, ma è complementare ad essi. • L’ITS è efficace nelle allergie da • Inalanti (acari, pollini, alcuni funghi, epitelio di gatto) • Veleno di imenotteri

  10. RINITE SINTOMI SCIT - Meta-analysis: Symptom score RINITE FARMACI Calderon M et al 2007

  11. Passalacqua G, Canonica GW. Clin Exp Allergy 2011

  12. Cochrane 2010

  13. MEDICATIONS

  14. BHR Cochrane 2010

  15. ARIA Update on immunotherapy SR Durham and G.Passalacqua JACI 2007

  16. Aspetti pratici. In Italia è un “patient named product” (preparato dalla ditta per ciascun paziente dietro indicazione specialistica. Gli estratti sono standardizzati (ossia è nota la quantità di allergene maggiore e la potenza) Si effettua una fase di graduale incremento del dosaggio (solitamente 1/sett per 2 mesi), seguita da una fase di mantenimento (1/mese). Per allergeni pollinici si può effettuare un trattamento pre-stagionale. Per allergeni perenni, il trattamento è continuativo. Durata consigliata 3-5 anni, da sospendere se dopo 2 anni non si ha beneficio.

  17. IMMUNOTHERAPY. Indications Moderate- severe persistent Not cost- effective? RHINITIS Mild persistent Moderate- severe intermitt. Mild intermitt. HIGH RISK? ASTHMA Intermitt. Mild Moderate Severe

  18. I fattori da valutare nella prescrizione dell’ITS 1 Il disturbo deve essere IgE - mediato (skin test o RAST positivi) 2 L’allergene responsabile deve essere individuato con sicurezza 3 Valutare la gravità e la durata dei sintomi 4 l trattamento farmacologico é sufficientemente ben tollerato? 5 Il paziente é in grado di affrontare l’ITS? (costi, impegno, stile di vita) 6 È disponibile un vaccino standardizzato? 7 L’efficacia del vaccino che si intende usare é dimostrata?

  19. CAUSAL ROLE OF THE ALLERGEN(S): Clinical history and exposure SKIN TESTING RAST ASSAY NASAL (CONJUNCTIVAL) CHALLENGE SLIT (IT in general) for the clinically relevant allergen(s) Preferably one, but in selected cases 2 or 3 extracts.

  20. Verificare ed annotare la dose, l’ora e il sito di iniezione Visitare il paziente!!! Iniezione sottocutanea Aspirare per escludere di iniettare in un vaso Tempo di osservazione 30 minuti

  21. PREMEDICATION: PROS: Preventing reactions Avoiding severe reactions Diminishing reactions’intensity CONS: May mask symptoms’ onset May delay appropriate treatment

  22. 0.2 0.2 0.2 0.4 0.4 0.4 0.6 0.6 0.6 INDUZIONE O BUILD-UP MANTENIMENTO Flac 1 Flac 2 Flac 3 0.8 0.8 1 2 3 4 5 6 7 8 9 10 11 12 settimane 4 5 6 7 8 9 10 11 12 mesi

  23. INIZIO: Prima della stagione di pollinazione (2 mesi) In qualsiasi momento per i perenni SCHEMA: Tradizionale, cluster, rush MANTENIMENTO: Prestagionale, precostagionale, continuo DURATA: Almeno 3-5 anni, poi se beneficio sospendere Se non beneficio dopo 2 anni sospendere VALUTAZIONE: Clinica (riduzione dei sintomi e dei farmaci)

  24. CONTRAINDICATIONS • Co-existent uncontrolled asthma (within the UK, presence of asthma is considered a relative contraindication). • Patients taking beta blockers • Patients with other medical/immunological disease • Small children (less than 5 years) • Pregnancy (maintenance injections may be continued during pregnancy) • Patients unable to comply with the immunotherapy protocol POSTPONE INJECTION IF: Concurrent ilness Asthma Exacerbation of allergy

  25. GRADING OF SYSTEMIC REACTIONS 1) Nonspecific reactions (likely non IgE-mediated) disomfort, nausea, headache, arthralgia 2) Mild systemic reactions mild rhinitis/asthma (PEF>60%) responding to b2 agonists/antihistamines 3) Non life-threatening systemic reactions Urticaria, angioedema, severe asthma (PEF<60%) Responding well to treatment 4) Anaphylaxis itching, urticaria, bronchospasm, with HYPOTENSION requiring intensive care Malling & Weeke, Allergy 1993

  26. FATALITIES Lockey RF et al. JACI 1987 Period: 1945-1984 46 fatalities Reid MJ et al. JACI 1993 Period 1985-1989 17 fatalities FATALITIES: 1/2.000.000 injections

  27. RISK FACTORS Based on nonfatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Use of new vials Technical errors Based on fatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Build-up phase Use of new vials Technical errors Estimated incidence of fatalities < 1/2.000.000 injections

  28. COSA OCCORRE: Adrenalina (iniezione i.m.) Broncodilatatore short acting Steroide orale e i.v. Antistaminico orale e i.v. Set da infusione Ossigeno Ambu

  29. EFFETTI “SPECIALI” DELL’ITS Efficacia a lungo termine dopo la sospensione Prevenzione di nuove sensibilizzazioni Riduzione del rischio di insorgenza di asma Modificazione della risposta immunitaria

  30. Effect of SIT or ICS on asthmaShaikh et al Clin.Exp.Allergy 1997; 27:1279-84 Symptom Score Treatment discontinued 3 6 9 12 15 18 21 24 months

  31. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study Jacobssen, Allergy 2007

  32. 1993. SLIT is Mentioned in an EAACI pos pap 1986, Scadding et al 1st DBPC trial 1970ties ORAL IT 1997, Tari, 1st pediatric trial 1998, first Tablet SLIT 1998: WHO SLIT is accepted 20 years 2004 1st META ANALYSIS 2004: Preventive effect Compliance 2001: ARIA document 2005: SLIT in children below the age of 5 2005-2009: Large randomized controlled trials Studies on the mechanism of action

  33. THE LITERATURE 60 RDBPC TRIALS 8 RANDOMIZED OPEN TRIALS 6 COMPARATIVE (SLIT vs SCIT) 5 TRIALS IN OTHER DISEASES

  34. JACI 2010

  35. ARIA Update on immunotherapy SR Durham and G.Passalacqua JACI 2007 in press

  36. WAO POSITION PAPER 2009 ON SUBLINGUAL IMMUNOTHERAPY CHAIRS: GW Canonica, J Bousquet, RF Lockey, T.Casale WAO Journal, Nov 2009 Allergy, Dec 2009

  37. IMMUNOTHERAPY. Indications Moderate- severe persistent Not cost- effective? RHINITIS Mild persistent Moderate- severe intermitt. Mild intermitt. HIGH RISK? ASTHMA Intermitt. Mild Moderate Severe

  38. The optimal maintenance dose has been clearly identified (by dose-ranging studies) only for grass tablets. It is 15-25 mcg major allergen per day (30 times an equivalent SCIT course) Dose ranging studies are lacking for the remaining alllergens The efficacy has been anyway proven over a wide range of doses, and therfore the recommendation of the manufacturers should be followed.

  39. NO BUILD UP 7/60 MAINTENANCE DAILY 31/60 MAINTENANCE 3/wk 20/60 MAINTENANCE 2/wk 7/60 MAINTENANCE 1/wk 2/60 POLLEN CONTINUOUS 8/43 POLLEN PRESEASONAL 3/43 POLLEN COSEASONAL 3/43 POLLEN PRECOSEASONAL 29/43

  40. The omission of the build-up phase seems not to increase the risk of adverse events. Build up is usually not done with the more recent tablet preparations Short build-up courses (1-5 days) can be applied, according to the manufacturer’s suggestion and to own experience

  41. Pre-coseasonal preseasonal Pollen count coseasonal Dec Jan Feb Mar Apr May Jun Jul

  42. NO BUILD UP 7/60 MAINTENANCE DAILY 31/60 MAINTENANCE 3/wk 20/60 MAINTENANCE 2/wk 7/60 MAINTENANCE 1/wk 2/60 POLLEN CONTINUOUS 8/43 POLLEN PRESEASONAL 3/43 POLLEN COSEASONAL 3/43 POLLEN PRECOSEASONAL 29/43

  43. SLIT No fatal or near-fatal event reported since 1986 6 cases of anaphylaxis

  44. SLIT: KNOWN SIDE EFFECTS Local: oral itching-swelling stomach-ache nausea-vomiting Systemic: Urticaria/angioedema Rhinitis Asthma Anaphylaxis Relatively frequent. Usually self-resolve after the first doses without treatment. If persist reduce the dose. Rare. Give symptomatic treatment and reduce the dose. If persist, stop SLIT Exceptional. Treat properly and stop SLIT

  45. CONTRAINDICATIONS Systemic immunological diseases Immunodeficiecies Malignancies Cardiovascular diseases Severe/uncontrolled asthma Age < 5 years (relative contraindication) Modified from WHO 1998

  46. Explain to patients the possible side effects Explain that side effects tend to disappear after few doses Suggest medications (e.g. oral antihistamines) to control local side effects if any Administer the first dose under medical supervision

  47. PROBLEM: Recommendations differ among guidelines PROBLEM: The vast majority of patients are polysensitized

  48. BIRCH CYPRESS OLIVE 300 270 240 GRASS 210 180 150 120 90 60 30 jan feb mar apr may jun jul