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L’IMMUNOTERAPIA: ATTUALE Giovanni Passalacqua

L’IMMUNOTERAPIA: ATTUALE Giovanni Passalacqua. Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY. IMMUNOTERAPIA SPECIFICA (ITS). Somministrazione di estratti allergenici purificati (prima a dosi crescenti e poi a dose di mantenimento),

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L’IMMUNOTERAPIA: ATTUALE Giovanni Passalacqua

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  1. L’IMMUNOTERAPIA: ATTUALE Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY

  2. 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), ad oggi affiancata anche dalla via sublinguale (SLIT)

  3. Leonard Noon 1877-1913

  4. ISHIZAKA IgE NOON UK CSM 1986 2012 Randomized trials EMPIRICAL USE 1928 1960 ROMAGNANI WHO Pos Pap DNA- ITS Mechanisms Allergoids Th1/Th2 SLIT ILIT EPIT Recombinants Liposomes Adjuvants Peptides 1986 1990 1998 2012 DURHAM

  5. 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

  6. 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

  7. 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

  8. 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

  9. WHO Pos Pap. Therapeutical vaccines for allergic diseases Allergy 1998 Standards for practical allergen-specific immunotherapy. Allergy 2006 Allergen immunotherapy: A practice parameter third update JACI 2011

  10. 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

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

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

  13. Cochrane 2010

  14. MEDICATIONS

  15. BHR Cochrane 2010

  16. SLIT: THE LITERATURE 75 RDBPC TRIALS 8 RANDOMIZED OPEN TRIALS 6 COMPARATIVE (SLIT vs SCIT) 5 TRIALS IN OTHER DISEASES

  17. 1st WAO pos pap (2009): 60 trials 2nd WAO pos pap (2013): 77 trials After 2013: 82 trials 9/22 big trials conducted in the USA

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

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

  20. Aspetti pratici. In Italia è formalmente un “named patient product” (preparato dalla ditta per ciascun paziente dietro indicazione), anche se ad oggi i vaccini per ITS vengono preparati su scala industriale, come i farmaci 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.

  21. 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?

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

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

  24. 300 MITE 270 240 210 PARIETARIA 180 150 120 GRASS 90 60 RAGWEED 30 oct mar apr may jun jul aug sep

  25. Vrtala S Allergy 2008

  26. 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

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

  28. 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

  29. 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

  30. 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)

  31. 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.

  32. 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

  33. 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

  34. 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

  35. 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

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

  37. 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

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

  39. 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

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

  41. 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

  42. 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

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

  44. PREVENTIVE EFFECTS OF SUBLINGUAL IMMUNOTHERAPY IN CHILDHOOD. AN OPEN RANDOMIZED CONTROLLED STUDY MAURIZIO MAROGNA MD1 , D.TOMASSETTI1, A. BERNASCONI1, F.COLOMBO1, ALESSANDRO MASSOLO BS2, A. DI RIENZO BUSINCO4, GIORGIO W CANONICA MD3, GIOVANNI PASSALACQUA MD3 AND SALVATORE TRIPODI MD4 1Pneumology Unit, Cuasso al Monte, Macchi Hospital Foundation, Varese 2 Department of Animal Biology, University of Pavia, Pavia 3 Allergy & Respiratory Diseases,Department of Internal Medicine, Genoa University 4Pediatric Allergy Unit, S. Pertini Hospital, Rome AAAI 2008, 101: 261

  45. MONOSENSITIZED PATIENTS 70 *** 60 *** 50 40 % PATIENTS 30 20 10 baseline 3rd year SLIT PERSISTENT ASTHMA 70 60 *** 50 40 *** % PATIENTS 30 20 NS 10 baseline 3rd year CONTROLS

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