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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 clinicaall’allergene stesso.
L’immunoterapia allergene specifica è un vaccinoa tutti gli effetti
La via tradizionale di somministrazione è quella iniettivasottocutanea (SCIT), ed è disponibile in alternativa anche la via sublinguale
Leonard Noon 1877-1913
NOON
1928 1960
Uso empirico
1986 2005
Studi randomizzati
ISHIZAKA
IgE
1986 2005
SLITPeptidi Allergeni
ricombinantiLiposomi,Adiuvanti
DNA-Based
ITS
AllergoidiTh1/Th2
1990
Meccanismi
DURHAM
ROMAGNANI
1998
WHOPos Pap
Rands DA. Anaphylactic reaction to desensitization for allergic rhinitis and astmaBr Med J 1980; 281: 854
Ewan PW. Anaphylactic reaction to desensitization.Br Med J 1980; 281: 1069
Frankland AW. Anaphylactic reaction to desensitization.Br Med J 1980; 281: 1429
Committee on the safety of medicines (CMS)CMS Update
Desensitizing vaccinesBr Med J 1986; 293:948
26 fatalities since 1957 certainly due to IT11 of them since 1980
Dal 1910 fino agli anni ’70:
Prescrizione ingiustificata dell’ITS
Prescrizione non corretta
Pratica non adeguata, senza regole precauzionali e con estratti scadenti
DUBBIA EFFICACIA E SCARSA SICUREZZA
Committee on the Safety of Medicines
Desensitizing vaccinesDesensitizing vaccines
BMJ 198626 deaths due to SCIT
Non-injection routes for immunotherapyNon-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
Standards for practical allergen-specific immunotherapy.
Allergy 2006
Allergen immunotherapy: A practice parameter second updateJACI 2007
WHO Pos Pap. Therapeutical vaccines for allergic diseasesAllergy 1998
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
SCIT - Meta-analysis: Symptom score
Calderon M et al 2007
RINITE SINTOMI
RINITE FARMACI
Passalacqua G, Canonica GW. Clin Exp Allergy 2011
Cochrane 2010
MEDICATIONS
BHR
Cochrane 2010
SCIT SLIT
Clinical efficacy: Rhinitis Ia Ia
Clinical Efficacy: Asthma Ia Ia
Clinical efficacy: Children (rhinitis)Children (asthma)
IbIb
IaIa
Prevention of new sensitizations Ib IIa
Longterm effect Ib IIa
Prevention of asthma IIb IIb
ARIA Update on immunotherapySR Durham and G.PassalacquaJACI 2007
Aspetti pratici.
In Italia è un “patient named product” (preparato dalla dittaper 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.
Mildintermitt.
MildpersistentModerate-
severeintermitt.
Moderate-severe
persistent
Indications
Intermitt.Mild
ModerateSevere
IMMUNOTHERAPY.
RHINITIS
ASTHMA HIGHRISK?
Not cost-effective?
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 sintomi4 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?
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.
Verificare ed annotare la dose, l’ora e il sito di iniezioneVisitare il paziente!!!Iniezione sottocutaneaAspirare per escludere di iniettare in un vasoTempo di osservazione 30 minuti
PROS:Preventing reactionsAvoiding severe reactionsDiminishing reactions’intensity
CONS:May mask symptoms’ onsetMay delay appropriate treatment
PREMEDICATION:
1 2 3 4 5 6 7 8 9 10 11 124 5 6 7 8 9 10 11 12
0.2 0.4 0.6 0.2 0.4 0.6 0.2 0.4 0.6 0.8 0.8
settimane
mesi
Flac 1 Flac 2 Flac 3
INDUZIONE O BUILD-UP MANTENIMENTO
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)
•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
CONTRAINDICATIONS
POSTPONE INJECTION IF:Concurrent ilnessAsthmaExacerbation of allergy
GRADING OF SYSTEMIC REACTIONS1) 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
Lockey RF et al. JACI 1987Period: 1945-1984
46 fatalities
Reid MJ et al. JACI 1993Period 1985-1989
17 fatalities
FATALITIES
FATALITIES: 1/2.000.000 injections
RISK FACTORS
Based on nonfatal reactions
Uncontrolled asthmaSevere asthmaUse of betablockersRush immunotherapyUse of new vialsTechnical errors
Based on fatal reactions
Uncontrolled asthmaSevere asthmaUse of betablockersRush immunotherapyBuild-up phaseUse of new vialsTechnical errors
Estimated incidence of fatalities < 1/2.000.000 injections
COSA OCCORRE:
Adrenalina (iniezione i.m.)Broncodilatatore short actingSteroide orale e i.v.Antistaminico orale e i.v.Set da infusione
OssigenoAmbu
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
Effect of SIT or ICS on asthmaShaikh et al Clin.Exp.Allergy 1997; 27:1279-84
0123456789
ICSIT
Symptom Score Treatment discontinued
months3 6 9 12 15 18 21 24
AUTHOR (ref) ALLERGEN PATIENTS DURATION SIT LONG-LASTINGEFFECT
Mosbech (36) Grass 2.5 years 6 years
Grammer (37) Ragweed 61 adult/children
4 months 2 years
Hedlin (38) Cat/dog 32 adult/chidren
3 years 5 years
Des Roches (39) Mite 40 adult 1-4 years 3 years
Ariano (40) Parietaria 35 adult 4 years 4 years
Durham (41) Grass 52 adult 3-4 years 3 years
Eng (43) Grass 25 children 3 years 12 years
Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study
Jacobssen, Allergy 2007
1970tiesORAL IT
1986, Scadding et al1st DBPC trial
1998, firstTablet SLIT
1993. SLIT is Mentioned in anEAACI pos pap
1998: WHOSLIT is accepted
1997, Tari, 1st pediatric trial
2001: ARIAdocument
2004 1st METAANALYSIS
2005: SLIT in children below the age of 5
2005-2009: Large randomized controlled trialsStudies on the mechanism of action
2004: Preventive effectCompliance
20 y
ears
THE LITERATURE
60 RDBPC TRIALS
8 RANDOMIZED OPEN TRIALS
6 COMPARATIVE (SLIT vs SCIT)
5 TRIALS IN OTHER DISEASES
JACI 2010
SCIT SLIT
Clinical efficacy: Rhinitis Ia Ia
Clinical Efficacy: Asthma Ia Ia
Clinical efficacy: Children (rhinitis)Children (asthma)
IbIb
IaIa
Prevention of new sensitizations Ib IIa
Longterm effect Ib IIa
Prevention of asthma IIb IIb
ARIA Update on immunotherapySR Durham and G.PassalacquaJACI 2007 in press
WAO POSITION PAPER 2009ON SUBLINGUAL IMMUNOTHERAPY
Allergy, Dec 2009 WAO Journal, Nov 2009
CHAIRS: GW Canonica, J Bousquet, RF Lockey, T.Casale
Mildintermitt.
MildpersistentModerate-
severeintermitt.
Moderate-severe
persistent
Indications
Intermitt.Mild
ModerateSevere
IMMUNOTHERAPY.
RHINITIS
ASTHMA HIGHRISK?
Not cost-effective?
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.
NO BUILD UP 7/60 MAINTENANCE DAILY 31/60MAINTENANCE 3/wk 20/60MAINTENANCE 2/wk 7/60MAINTENANCE 1/wk 2/60 POLLEN CONTINUOUS 8/43POLLEN PRESEASONAL 3/43POLLEN COSEASONAL 3/43POLLEN PRECOSEASONAL
29/43
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
Jan Feb Apr JunMar May JulDec
preseasonal
Pre-coseasonal
Pollen count
coseasonal
NO BUILD UP 7/60 MAINTENANCE DAILY 31/60MAINTENANCE 3/wk 20/60MAINTENANCE 2/wk 7/60MAINTENANCE 1/wk 2/60 POLLEN CONTINUOUS 8/43POLLEN PRESEASONAL 3/43POLLEN COSEASONAL 3/43POLLEN PRECOSEASONAL
29/43
No fatal or near-fatal event reported since 1986
6 cases of anaphylaxis
SLIT
SLIT: KNOWN SIDE EFFECTS
Local: oral itching-swelling stomach-ache nausea-vomiting
Systemic: Urticaria/angioedemaRhinitisAsthma
Anaphylaxis
Relatively frequent.Usually self-resolve after the first doses without treatment. If persistreduce the dose.
Rare. Give symptomatictreatment and reduce the dose. If persist, stop SLIT
Exceptional. Treat properly and stop SLIT
CONTRAINDICATIONS
Systemic immunological diseases Immunodeficiecies
Malignancies Cardiovascular diseases
Severe/uncontrolled asthma
Age < 5 years (relative contraindication)
Modified from WHO 1998
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
PROBLEM:
Recommendations differ among guidelines
PROBLEM:
The vast majority of patientsare polysensitized
30
60
90
120
150
180
210
240
270
jan feb mar apr may jun jul
300
BIRCH
GRASS
CYPRESS OLIVE
30
60
90
120
150
180
210
240
270
mar apr may jun jul aug sep
300
GRASS
RAGWEED
oct
PARIETARIA
MITE
Vrtala S
Allergy 2008
CONCLUSIONIFarmacoterapia e immunoterapia hanno meccanismi diversi
Il loro effetto è additivo
L’ITS consente un risparmio di farmaci sintomatici
L’ITS ha effetti preventivi e a lungo termine che i farmaci non hanno
L’ITS agisce contemporaneamente su naso e bronchi
FARMACI E ITS NON SONO MUTUAMENTE ESCLUSIVI
Azione rapida
Effetto preventivo
Effetti collaterali
Costo
Lunga durata
NO
SI
SI
NO
ALTO
SIT
SI
SI
BASSO
NO
NO
FARMACI