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
Leonard
Noon 1877-1913
ISHIZAKA
NOON
1986
Uso empirico
Studi randomizzati
IgE
1928
2005
1960
ROMAGNANI
Allergoidi
SLIT
1986
Peptidi
Meccanismi
Th1/Th2
WHO
Pos Pap
Liposomi,
Adiuvanti
Allergeni
ricombinanti
1990
1998
DURHAM
DNABased
ITS
2005
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
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
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
Desensitizing vaccines
26 deaths due to SCIT
Committee on the Safety of Medicines BMJ 1986
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
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
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
RINITE SINTOMI
SCIT - Meta-analysis: Symptom score
RINITE FARMACI
Calderon M et al 2007
Passalacqua G, Canonica GW. Clin Exp Allergy 2011
Cochrane 2010
MEDICATIONS
BHR
Cochrane 2010
ARIA Update on immunotherapy
SR Durham and G.Passalacqua
JACI 2007
SCIT
SLIT
Clinical efficacy: Rhinitis
Ia
Ia
Clinical Efficacy: Asthma
Ia
Ia
Clinical efficacy:
Children (rhinitis)
Children (asthma)
Ib
Ib
Ia
Ia
Prevention of new sensitizations
Ib
IIa
Longterm effect
Ib
IIa
Prevention of asthma
IIb
IIb
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 prestagionale. Per allergeni perenni, il trattamento è
continuativo. Durata consigliata 3-5 anni, da sospendere se
dopo 2 anni non si ha beneficio.
Indications
Not costeffective?
Mild
intermitt.
Mild
Moderate- persistent
severe
intermitt.
Moderatesevere
persistent
RHINITIS
IMMUNOTHERAPY.
ASTHMA
HIGH
RISK?
Intermitt.
Mild
Moderate
Severe
I fattori da valutare nella prescrizione dell’ITS
1
2
3
4
5
6
7
Il disturbo deve essere IgE - mediato
(skin test o RAST positivi)
L’allergene responsabile deve essere individuato
con sicurezza
Valutare la gravità e la durata dei sintomi
l trattamento farmacologico é sufficientemente
ben tollerato?
Il paziente é in grado di affrontare l’ITS?
(costi, impegno, stile di vita)
È disponibile un vaccino standardizzato?
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 iniezione
Visitare il paziente!!!
Iniezione sottocutanea
Aspirare per escludere di iniettare in un vaso
Tempo di osservazione 30 minuti
PREMEDICATION:
PROS:
Preventing reactions
Avoiding severe reactions
Diminishing reactions’intensity
CONS:
May mask symptoms’ onset
May delay appropriate treatment
INDUZIONE O BUILD-UP
Flac 1
0.2 0.4 0.6
Flac 2
Flac 3
0.2 0.4 0.6
0.2 0.4 0.6
MANTENIMENTO
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
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)
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
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
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
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
COSA OCCORRE:
Adrenalina (iniezione i.m.)
Broncodilatatore short acting
Steroide orale e i.v.
Antistaminico orale e i.v.
Set da infusione
Ossigeno
Ambu
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 asthma
Shaikh et al Clin.Exp.Allergy 1997; 27:1279-84
Symptom Score
Treatment discontinued
9
8
7
6
5
ICS
IT
4
3
2
1
0
3
6
9
12
15
18
21 24 months
AUTHOR (ref)
ALLERGEN
Mosbech (36)
Grass
Grammer (37)
Ragweed
Hedlin (38)
PATIENTS
DURATION SIT
LONG-LASTING
EFFECT
2.5 years
6 years
61
adult/children
4 months
2 years
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
1986, Scadding et al
1st DBPC trial
1998: WHO
SLIT is accepted
2001: ARIA
document
1998, first
Tablet SLIT
20 years
1970ties
ORAL IT
2004 1st
META
ANALYSIS
2005-2009: Large randomized controlled trials
Studies on the mechanism of action
1993. SLIT is
Mentioned in an
EAACI pos pap
1997, Tari,
1st pediatric trial
2004: Preventive effect
Compliance
2005: SLIT in children
below the age of 5
THE LITERATURE
60 RDBPC TRIALS
8 RANDOMIZED OPEN TRIALS
6 COMPARATIVE (SLIT vs SCIT)
5 TRIALS IN OTHER DISEASES
JACI 2010
ARIA Update on immunotherapy
SR Durham and G.Passalacqua
JACI 2007 in press
SCIT
SLIT
Clinical efficacy: Rhinitis
Ia
Ia
Clinical Efficacy: Asthma
Ia
Ia
Clinical efficacy:
Children (rhinitis)
Children (asthma)
Ib
Ib
Ia
Ia
Prevention of new sensitizations
Ib
IIa
Longterm effect
Ib
IIa
Prevention of asthma
IIb
IIb
WAO POSITION PAPER 2009
ON SUBLINGUAL
IMMUNOTHERAPY
CHAIRS: GW Canonica, J Bousquet, RF Lockey, T.Casale
Allergy, Dec 2009
WAO Journal, Nov 2009
Indications
Not costeffective?
Mild
intermitt.
Mild
Moderate- persistent
severe
intermitt.
Moderatesevere
persistent
RHINITIS
IMMUNOTHERAPY.
ASTHMA
HIGH
RISK?
Intermitt.
Mild
Moderate
Severe
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
31/60
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
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
Pre-coseasonal
preseasonal
Pollen count
coseasonal
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
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
SLIT
No fatal or near-fatal event
reported since 1986
6 cases of anaphylaxis
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
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 patients
are polysensitized
BIRCH
CYPRESS
OLIVE
300
270
240
GRASS
210
180
150
120
90
60
30
jan
feb
mar
apr
may
jun
jul
300
MITE
270
240
210
PARIETARIA
180
150
120
GRASS
90
60
RAGWEED
30
mar
apr
may
jun
jul
aug
sep
oct
Vrtala S
Allergy 2008
CONCLUSIONI
Farmacoterapia 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
FARMACI
Azione rapida
Effetto preventivo
NO
SI
NO
SI
Effetti collaterali
SI
Costo
BASSO
Lunga durata
SIT
NO
NO
ALTO
SI