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L’IMMUNOTERAPIA ALLERGENE SPECIFICA (AIT) ATTUALE Giovanni Passalacqua

L’IMMUNOTERAPIA ALLERGENE SPECIFICA (AIT) ATTUALE Giovanni Passalacqua. Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY. IMMUNOTERAPIA SPECIFICA (AIT). Somministrazione di estratti allergenici purificati (prima

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L’IMMUNOTERAPIA ALLERGENE SPECIFICA (AIT) ATTUALE Giovanni Passalacqua

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  1. L’IMMUNOTERAPIA ALLERGENE SPECIFICA (AIT) ATTUALE Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY

  2. IMMUNOTERAPIA SPECIFICA (AIT) 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. Immunol Allergy Clin North Am. 2016

  4. 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

  5. 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

  6. 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

  7. 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

  8. L'ITS e' mirata 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

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

  10. SYMPTOM SCORE Cochrane 2010

  11. Meta-analysis of the efficacy of sublingual immunotherapy in allergic asthma in pediatric patients, 3 to 18 years of age. M Penagos, G Passalacqua, E Compalati, C Baena-Cagnani, S Orozco, A Pedroza GW Canonica SYMPTOMS MEDICATIONS

  12. WHO pospap (1998): 4 trials ARIA pospap (2001): 22 trials EAACI pospap (2006): 36 trials 1st WAO pospap (2009): 60 trials 2nd WAO pospap (2013): 77 trials After 2013: 87 trials

  13. Sublingual immunotherapy with once-dailygrass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis Durham SR, JACI 2006 > 800 pts

  14. JACI 2013

  15. OPTIMAL DOSES (dose-finding studies) DURHAM 2006: 15 mcg Phl p 5/day DIDIER 2007: 25 mcg Group 5 /day CRETICOS 2013: 12 mcg Amb a 1/day BERGMANN 2014: 28/120 Der p 1/Der f 1/day MOSBECH 2014: 6 SQ/day (70 mcg day) NOLTE 2015: 12 DU/day (equivalent to 6 SQ/day)

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

  17. 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?

  18. 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.

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

  20. 300 MITE 270 240 210 PARIETARIA 180 150 120 GRASS 90 60 RAGWEED 30 oct mar apr may jun jul aug sep

  21. GRASS Phl p 1 Phl p 5 Phl p 6 Phl p 7 (profilin) Phl p 12 (CBP) BIRCH Bet v 1 Bet v 2 (profilin) Bet v 3 (CBP) PARIETARIA Par j 1 Par j 2 Par j 3 (profilin)

  22. 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

  23. 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

  24. NEAR FATAL ASTHMA (respiratory failure) SEVERE ASTHMA (Control) UNCONTROLLED ASTHMA

  25. SLIT No fatal event reported since 1986 15 cases of anaphylaxis in 20 years

  26. Passalacqua G, Nowak-Węgrzyn A, Canonica GW. JACI IP 2016 in press

  27. 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 AIT vengono preparati su scala industriale, come i farmaci e quindi uguali per tutti i pazienti. Due soli prodotti SLIT (graminacee) sono registrati come farmaco Gli estratti sono standardizzati (ossia è nota la quantità di allergene maggiore e la potenza) Con la SCIT Si effettua una fase di induzione graduale (solitamente 1/sett per 2 mesi), seguita da una fase di mantenimento (1/mese). Con la SLIT la fase di induzione può essere omessa Per allergeni pollinici si può effettuare un trattamento pre-costagionale. Per allergeni perenni, il trattamento è continuativo. Durata consigliata 3-5 anni, da sospendere se dopo 2 anni non si ha beneficio.

  28. SCIT: PRACTICAL ASPECTS • Ascertain that the dose and preparation are correct • Assess the clinical condition of the patient • Record date, hour, dose, reactions at previous injection • Use upper outer surface of arm • Ensure sterile technique • Use 1mL syringe • Inject at 45º by deep subcutaneous route • Record any local/systemic reaction • A waiting period of 30 min after injection is recommended

  29. 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

  30. 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

  31. SLIT: PRACTICAL ASPECTS SLIT is self-administered at home by the patient. SLIT can be adminstered as mono-dose vials, drops, pre dosed spray or tablets After prescription, the first dose must be given under direct medical control The preparation (drops, tablets, spray-dose) should be assumed in the morning, being the patient fastened. The dose should be kept under the tongue for 1-2 minutes (until dissolved for tablets), then swallowed. The patient must be instructed on the possible (local) side effects, and on how to manage them.

  32. 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

  33. 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

  34. Practicalaspects. SCIT BUILD-UP: Usuallyrecommended (4-8 wks) MAINTENANCE: usuallyevery 4 wks DURATION: 3-5 yrs PROTOCOL: continuous or pre-coseasonal (with the MPL-adjuvanted SCIT, only 4 preseasonalinjections) SLIT PREPARATION: drops, pre-dosed spray, tablets BUILD-UP: Very short (days) or absent MAINTEINANCE: Preferablydaily (can varyaccording to the manufacturer). DURATION: 3-5 yrs PROTOCOL: Preferredpre- coseasonal (continuous for HDM)

  35. 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)

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

  37. JACI 2016

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

  39. AIT: carry-over EFFECT Passalacqua G. Ann Allergy Asthma Immunol. 2011;107:401– 406.

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