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LIMMUNOTERAPIA (AIT) ATTUALE Giovanni
Passalacqua
Allergy Respiratory Diseases Dept.Internal
Medicine- University of Genoa ITALY
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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 clinica allallergene
stesso. Limmunoterapia allergene specifica è un
vaccino a tutti gli effetti La via tradizionale
di somministrazione è quella iniettiva sottocutane
a (SCIT), ad oggi affiancata anche dalla via
sublinguale (SLIT)
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Immunol Allergy Clin North Am. 2016
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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
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Committee on the safety of medicines (CMS) CMS
Update
Desensitizing vaccines Br Med J 1986 293948
26 fatalities since 1957 certainly due to IT 11
of them since 1980
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Dal 1910 fino agli anni 70 Prescrizione
ingiustificata dellITS Prescrizione non
corretta Pratica non adeguata, senza regole
precauzionali e con estratti scadenti
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Desensitizing vaccines
26 deaths due to SCIT
Committee on the Safety of Medicines
BMJ 1986
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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
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• L'ITS e' mirata all'allergene causale e non
  all'organo principalmente coinvolto.
• LITS non è un trattamento di ultima scelta da
  usare se i farmaci falliscono, ma è complementare
  ad essi.
• LITS è efficace nelle allergie da
• Inalanti (acari, pollini, alcuni funghi,
  epitelio di gatto)
• Veleno di imenotteri

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SCIT - Meta-analysis Symptom score
RINITE SINTOMI
RINITE FARMACI
Calderon M et al 2007
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SYMPTOM SCORE
Cochrane 2010
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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
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WHO pos pap (1998) 4 trials ARIA pos pap (2001)
22 trials EAACI pos pap (2006) 36 trials 1st WAO
pos pap (2009) 60 trials 2nd WAO pos pap (2013)
77 trials After 2013 87 trials
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The optimal maintenance dose has been clearly
identified (by dose-ranging studies) only for
SLIT tablets. The efficacy has been anyway proven
over a wide range of doses, and therfore the
recommendation of the manufacturers should be
followed.
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)
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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
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Indications
Moderate- severe persistent
Not cost- effective?
Mild persistent
RHINITIS
Moderate- severe intermitt.
Mild intermitt.
HIGH RISK?
ASTHMA
Intermitt.
Mild
Moderate
Severe
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I fattori da valutare nella prescrizione dellITS
1 Il disturbo deve essere IgE - mediato (skin
test o RAST positivi) 2 Lallergene 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 lITS? (costi, impegno, stile di
vita) 6 È disponibile un vaccino
standardizzato? 7 Lefficacia del vaccino che si
intende usare é dimostrata?
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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.
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BIRCH
CYPRESS
OLIVE
300
270
240
GRASS
210
180
150
120
90
60
30
jan
feb
mar
apr
may
jun
jul
21
300
MITE
270
240
210
PARIETARIA
180
150
120
GRASS
90
60
RAGWEED
30
oct
mar
apr
may
jun
jul
aug
sep
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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)
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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
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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 lt 1/2.000.000
injections
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SLIT
No fatal event reported since 1986 15 cases of
anaphylaxis in 20 years
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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
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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.
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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

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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
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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
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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.
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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 manufacturers
suggestion and to own experience
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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
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Practical aspects. SCIT BUILD-UP Usually
recommended (4-8 wks) MAINTENANCE usually every
4 wks DURATION 3-5 yrs PROTOCOL continuous or
pre-coseasonal (with the MPL-adjuvanted SCIT,
only 4 preseasonal injections) SLIT PREPARATION
drops, pre-dosed spray, tablets BUILD-UP Very
short (days) or absent MAINTEINANCE Preferably
daily (can vary according to the
manufacturer). DURATION 3-5 yrs PROTOCOL
Preferred pre- coseasonal (continuous for HDM)
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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)
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PREMEDICATION
PROS Preventing reactions Avoiding severe
reactions Diminishing reactionsintensity
?
CONS May mask symptoms onset May delay
appropriate treatment
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JACI 2016
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EFFETTI SPECIALI DELLAIT Efficacia a lungo
termine dopo la sospensione Prevenzione di nuove
sensibilizzazioni Riduzione del rischio di
insorgenza di asma Modificazione della risposta
immunitaria
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AIT carry-over EFFECT
Passalacqua G. Ann Allergy Asthma Immunol.
2011107401 406.
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AUTHOR (ref) ALLERGEN PATIENTS DURATION SIT LONG-LASTING EFFECT
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

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Specific immunotherapy has long-term preventive
effect of seasonal and perennial asthma 10-year
follow-up on the PAT study
Jacobssen, Allergy 2007
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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     1 Pneumology 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 4          Pediatric Allergy Unit, S.
Pertini Hospital, Rome
AAAI 2008, 101 261
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PERSISTENT ASTHMA
70
60

50
40

PATIENTS
30
20
NS
10
baseline
3rd year
CONTROLS
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New approaches for Immunotherapy
Milk Egg Peanut
Food allergy Latex Atopic dermatitis Nickel?
NEW INDICATIONS
Liposomes Intralymphatic (ILIT) Epicutaneous
(EPIT) Biolistic injection Mucoadhesive substances
ADMINISTRATION
Alum-alginates Bacterial wall derived DNA-adjuvant
s
ADJUVANTS
Recombinant purified Hypoallergenic
isoforms Peptides Chimeric proteins (constructs)
RECOMBINANT/ ENGINEERED
c-DNA Plasmids Replicons
GENIC VACCINATION
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Passalacqua G, Canonica GW. WAO J 2015
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SIT
Azione rapida Effetto preventivo Effetti
collaterali Costo Lunga durata
NO
SI
NO
ALTO
SI
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CONCLUSIONI
Farmacoterapia e immunoterapia hanno meccanismi
diversi Il loro effetto è additivo LITS
consente un risparmio di farmaci
sintomatici LITS ha effetti preventivi e a
lungo termine che i farmaci non hanno LITS
agisce contemporaneamente su naso e
bronchi FARMACI E ITS NON SONO MUTUAMENTE
ESCLUSIVI