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Immunoterapia specifica

Immunoterapia specifica

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Azienda Ospedaliera di Verona

Azienda Ospedaliera di Verona
Ospedale Civile Maggiore
Ospedale Civile Maggiore
Unità Operativa di Allergologia
Unità Operativa di Allergologia

Specific Allergen Immunotherapy
Specific Allergen Immunotherapy
Prophylactic inoculation Prophylactic inoculation
against hay fever against hay fever
Lancet 1911; 1: 1572 Lancet 1911; 1: 1572
Vaccination against hay fever Vaccination against hay fever
-
results during the last 3 years- results during the last 3 years-
Lancet 1914; 1: 1178 Lancet 1914; 1: 1178
Leonard Noon John Freeman Leonard Noon John Freeman

NOON
1911 1966
Uso empirico
1986 2009
RCTs
1986 2009
SLIT
Peptidi
Allergeni
ricombinanti
Liposomi,
Adiuvanti
DNA-
Based
ITS
Allergoidi
Th1/Th2
1990
ISHIZAKA
IgE
Meccanismi-Studi Clinici
DURHAM
ROMAGNANI
Evoluzione dell’immunoterapia
CANONICA
SLIT
SCIT

INDICAZIONI ALL’IMMUNO TERAPIA NELL’ASMA
L’ITS è indicata nei pazienti con asma allergica, da lieve
a
moderata, specialmente quando l’asma è associata a
rinite.
Lo scopo è quello di ridurre i sintomi ed il consumo di
farmaci, nonché di interferire con la storia naturale della
malattia.
L’immunoterapia ed il trattamento farmacologico non
sono mutuamente esclusivi.
L’immunoterapia non deve essere somministrata a
pazienti con asma severa persistente o non
adeguatamente controllata dalla terapia.
Linee-Guida Italiane – Aggiornamento 2006

Attempt to interfere with the natural course of
the disease should be introduced at a time
where the patient has the capacity to respond
positively.
In this way immunotherapy does not take the
position of being an ultimate treatment
principle, but represents a supplement to drug
treatment used in the early phase of the disease
Allergic Rhinitis and its Impact on Asthma - ARIA
Aggiornamento Italia 2005

lieve
intermitt.
lieve
persistente
Moderata-
grave
intermitt.
Moderata-
grave
persistente
INDICAZIONI
Intermitte.
lieve
moderata
grave
IMMUNOTERAPIA
RINITE
ASMA

CATEGORIE DI PROVA SPERIMENTALE
Ia: risultati di meta-analisi di studi randomizzati controllati
Ib: risultati da almeno uno studio randomizzato controllato
IIa: risultati da almeno 1 studio controllato non randomizz.
IIb: risultati di studi sper. non randomizzati né controllati
III: studi comparativi, studi caso-controllo
IV: opinioni di panel di esperti o autorità scientifiche
Shekelle PG et al. BMJ 1999; 318: 593-96



Subcutaneous Immunotherapy
Subcutaneous Immunotherapy
for Allergic Asthma
for Allergic Asthma
Systematic Review and Meta-analysis Systematic Review and Meta-analysis


75 DB PC RC studies were included (1954-2001)

Participants: n=3,506 (adults and children)

Patients with Allergic Asthma due to HDM (36), pollen
(20), animal dander (10), moulds (2), latex (1), mixed (6)

Improvement in asthma symptoms

Reduction in Allergen PC20

Reduction in non-specific bronchial hyperresponsiveness
Abramson M et al. In: The Cochrane Library, Issue 1, 2004

SCIT for Allergic Asthma
SCIT for Allergic Asthma
Systematic Review and

Meta-analysis
SMD (95% CI) p value
Symptom -0.72 (-0.99,-0.44) < 0.0001
Medication -0.80 (-1.13,-0.48) < 0.0001
Abramson M et al. In: The Cochrane Library, Issue 1, 2004

Subcutaneous Immunotherapy
Subcutaneous Immunotherapy
for Allergic Rhinitis
for Allergic Rhinitis
Systematic Review and Meta-analysis Systematic Review and Meta-analysis

51 DB PC RC studies were included (1950-2006)

Patients with Seasonal Allergic Rhinitis due to
grass, tree or weed pollen

Participants: n=2,871 (1,645 active, 1,226 placebo)

Adults (children 1 study)
Calderon M et al 2007 Cochrane Reviews Jan 2007

A wide range of allergens was administered in these studies:
- mixed grass : 16 studies
- ragweed : 12 studies
- parietaria : 6 studies
- timothy : 5 studies
- birch : 4 studies
- orchard : 2 studies
- cedar : 3 studies
- bermuda : 1 study
- juniperus ashei: 1 study
- cocos : 1 study
Calderon M et al 2007 in press Cochrane Reviews Jan 2007
Subcutaneous Immunotherapy
Subcutaneous Immunotherapy
for Allergic Rhinitis
for Allergic Rhinitis
Systematic Review and Meta-analysis Systematic Review and Meta-analysis

Calderon M et al 2007 Cochrane Reviews Jan 2007
Subcutaneous Immunotherapy for Allergic Rhinitis
Subcutaneous Immunotherapy for Allergic Rhinitis

SCIT for Seasonal Allergic Rhinitis
SCIT for Seasonal Allergic Rhinitis
Meta-analysis for nasal, bronchial and ocular symptoms and RQoLQ Meta-analysis for nasal, bronchial and ocular symptoms and RQoLQ
Calderon M et al. Cochrane Collaboration 2007

JACI 2005; 116 : 961 JACI 2005; 116 : 961


Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of SCIT

Long-lasting effect of SCIT
Long-lasting effect of SCIT
Long-term clinical efficacy of grass pollen immunotherapy Long-term clinical efficacy of grass pollen immunotherapy
Durham SR et al. N Engl J Med 1999; 341: 468-75
DB PC RCT, n=32, 3 years IT
*Clinical improvement was accompanied by persistent alteration in immunologic reactivity
Twelve-year follow-up after discontinuation of pre-seasonal Twelve-year follow-up after discontinuation of pre-seasonal
grass pollen immunotherapy in childhood grass pollen immunotherapy in childhood
Eng PA et al. Allergy 2006; 61: 198-201
Non-randomized controlled open study, n=22, 3 years IT
* Reduction in onset of new sensitization was sustained 12 years later



Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of IT

Grembiale RD et al. Am J Respir Crit Care Med 2000
“Effects of specific
immunotherapy in allergic
rhinitic individuals with
bronchial
hyperresponsiveness”
SCIT CONTROL
60
19
40
32
NO ASTHMA
ASTHMA
Prevenzione dello sviluppo di
asma dopo 3 anni
Moller et al. JACI 2002


Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of SCIT

SCIT Reduces New Sensitisations
Des Roches A et al. J Allergy Clin Immunol 1997; 99: 450-3
10
6
4
2
1
0
12
8
6 6
0
2
4
6
8
10
12
14
None Cat Dog Alt Grass
New Sensitivities
N
u
m
b
e
r

o
f

P
a
t
i
e
n
t
s
SCIT
Control
Children under 6 years with asthma
(HDM sensitisation)
3-year follow-up
6

Prevention of new sensitizations
in monosensitized subjects
submitted to SIT or not.
A retrospective study
Prevention of new sensitizations
in asthmatic children
monosensitized to house dust
mite by specific SIT.
A six-year study
20
40
60
80
% newly polysensitized
After 4 years After 7 years
0.001 0.001
20
40
60
80
M
O
N
O
S
E
N
S
I
T
I
Z
E
D
Baseline After 6 years
Purello D’Ambrosio et al. Clin Exp Allergy 2001 Pajno et al. Clin Exp Allergy 2001
Drugs only
SIT

“There is a good evidence from immunotherapy
studies that a maintenance dose of 5-20 µg of
major allergen per injection is associated with
significant improvement in patient symptom score.
J Allergy Clin Immunol 1998; 102: 558-62

Randomised controlled trial
with alum-adsorbed grass
pollen extract for seasonal
allergic rhinoconjunctivitis
UK Immunotherapy Study Group
26 centres, n=410
100,000 SQ, 10,000 SQ and placebo
Frew AJ et al, JACI, 2006
Pollen
Medication
Symptoms
0
20
40
60
80
100
120
140
160
1 2 3 4 5 6 7 8 9 10 11
Week
G
r
a
in
s
/m
3
-
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
1 2 3 4 5 6 7 8 9 10 11
Week
S
c
o
r
e
G
r
a
i
n
s
/
m
3
-
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
1 2 3 4 5 6 7 8 9 10 11
Week
S
c
o
r
e
Alutard 100,000 SQ Alutard 10,000 SQ Placebo
S
c
o
r
e
S
c
o
r
e
100,000 SQ vs. Placebo P<0.001
100,000 SQ vs. Placebo P<0.001
Frew AJ et al,
JACI 2006
Reduction in symptom and medication
score over placebo – whole season
0 10 20 30 40 50 60
Medication
Symptoms
Percent reduction
Alutard 100,000 SQ median Alutard 10,000 SQ median
Frew AJ et al, JACI 2006
p<0.001
p=0.027
p=0.027
Rhinoconjunctivitis QoL score
0
0.5
1
1.5
2
2.5
Baseline Season Baseline/Season
100,000 SQ-U 10,000 SQ-U Placebo
0
0.5
1
1.5
2
3
P=0.027
P=0.027
Frew AJ et al, JACI 2006

Systemic reactions (EAACI)
Grade 0: No symptoms
Grade 1: Non-specific symptoms
(i.e. discomfort, headache, fatigue, etc.)
Grade 2: Mild systemic reactions
(mild rhinitis or asthma responding adequately to
antihistamines or salbutamol 100 µg inhalations)
Grade 3: Non-life-threatening systemic reactions
(generalised urticaria, angioedema or
moderate/severe asthma)
Grade 4: Anaphylactic shock
(rapidly evoked reaction of itching, flushing, erythema,
hypotension and severe bronchial obstruction etc,
requiring intensive treatment).

Rands DA.
Anaphylactic reaction to desensitization for
allergic rhinitis and astma
Br 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


26 fatalities 1957-1986

16/17 in patients with asthma
Committee on the Safety of Medicines
UPDATE: desensitive vaccine
BMJ 1986; 293:948

1 / 2.500.000 17 1990-2001 Bernstein*
(2004)
1 / 2.800.000 15 1985-89 Reid
(1993)
1 / 2.500.000 24 1959-84 Lockey*
(1987)
Fatality rate/
injections
Fatalities Period Author
*1 in a child of 5 years
*4/17 between 10-18 years

SCIT Adverse Events: Systemic Reactions
SCIT Adverse Events: Systemic Reactions
Systematic Review and Meta-Analysis
Calderon M et al. Cochrane Collaboration 2007

Subcutaneous Immunotherapy
Subcutaneous Immunotherapy
for Allergic Rhinitis
for Allergic Rhinitis
Use of Adrenaline Use of Adrenaline
Calderon M et al. Cochrane Collaboration 2007

Evaluation of near-fatal reactions to allergen
immunotherapy injections
Amin et al. JACI 2006; 117 : 169
-
1 NFR / 1.000.000 injections
-
Asthma present in 46% of NFR and 88% of fatal
reactors
-
Hypotension in 80% and respiratory failure in 10% of
NFR and exclusively in asthmatics
-
FR had prior emergency department visits and
hospitalizations for asthma
-
NFR experienced more often cutaneous symptoms
-
Epinephrine was delayed for longer than 20 minutes
or not administered in 30% FRs compared with 6% of
NFRs


Safety of allergen-specific
immunotherapy for inhalant
allergy: a prospective study
Senna G, Bonadonna P, Schiappoli M, Dama A
Abstract EAACI Barcellona 2008
-
248 patients received 9.650 injections
according to a traditional (204 p) and a cluster
(44 p) schedule
-
19 SRs (0.20% of injections) were reported in
18 patients (7.3%)
-
most (17) were mild (I-II°); Epinephrine was
used only in 2 cases
-
Grass gave most problems

Population study
34.1 (7-67) 108
(43.6%)
140
(56.4%)
248
Age (mean yrs) females males Tot. pts
5 14 8 17 Cluster
46 62 23 70 Conventional
51 76 31 87 Total
Mite Parietaria Tree Grass Allergen

Systemic Reactions
18/248 (7,3%)
13/248 (5,2%)
5/248 (2,0%)
SR/Pt
18/9078 (0,20%)
13/582 (2,23%)
5/8496 (0,06%)
SR/Injection
Total SRs
Build up
Maintenance
Le 5 SRs in fase di mantenimento sono tutte con GR Le 5 SRs in fase di mantenimento sono tutte con GR

O
O
O
O
O
O
O
O
O
G
11
1 Allergy Unit, General Hospital, Verona
2 Respiratory Diseases, University of Pavia
3 Allergic & Respiratory Diseases, Regional Hospital, Ancona
4 Allergy Office, S.Carlo Clinic, Paderno Dugnano (MI)
5 Allergy Unit, C. Poma Hospital, Mantova
6 Allergy Office, Basic Health District, Tropea (VV)
7 Allergy Unit, Local Healthcare, Reggio Calabria
8 Allergy and Clinical Immunology, University of Bari
9 Department of Clinical Sciences, University of Parma
10 Allergy Unit, G.da Saliceto Hospital, Piacenza
11 Allergy & Respiratory Diseases, University of Genova
12 Allergy Unit, Occupational Medicin, University of Padova
A PROSPECTIVE ITALIAN SURVEY ON THE SAFETY OF
SUBCUTANEOUS IMMUNOTHERAPY FOR RESPIRATORY ALLERGY
CEA 2009, submitted
12

A PROSPECTIVE ITALIAN SURVEY ON THE SAFETY
OF SUBCUTANEOUS IMMUNOTHERAPY
FOR RESPIRATORY ALLERGY
1.738 patients (847 male, age range 5-71)
2.038 courses SCIT (300 patients received two extracts)
60.785 injections with a mean immunotherapy duration of 3 years
95 reactions in 57/1.738 patients (3.28%) and 57/2.038 SCIT (4.7%)
1,56/1.000 injections.
25 patients experienced more than one adverse event
34 grade 2, 60 grade 3 and 1 grade 4 reactions and no fatality
More frequently in asthma than in rhinitis alone (4,1% vs 1.1%, p= 0.03)
Equally distributed between the build-up and the maintenance phase
Ragweed and grass extracts caused significantly more side effects
CEA 2009, submitted

Table 1. Demography and clinical characteristics of the subjects with or without SRs
Pts with SR
(N= 57)
Pts without SR
(N= 1,681)
P
Age 29.0 ± 15.6 33.3 ± 18.1
NS for all decades
Sex (m/f) 24/33 823/858
% male 42.1 48.9
NS
OR= 0.76 (0.44-1.29)
RR= 0.99 (0.97-1.1)
Asthma (%) 51 (89%) 1,183 (70.3)
Rhinitis alone (%) 6 (11%) 498 (29,7)
0.01
OR= 3.57 (1.5-8.4)
RR= 1.04 (1.01-1.05)



Table 2. Characteristics of the patients with SRs
Asthma No asthma p
51/1234 (4.1 %) 6/504 (1.1 %) 0.03
Female Male
33/1,738 (1.9%) 24/1,738 (1.4%) NS
Build-up - patients Maintenance - patients
28/57 (49.1%) 29/57 (50.9%) NS
Build-up - reactions Maintenance – reactions
43/95 (45%) 52/95 (55%) NS
Immediate onset - patients Late onset - patients
33/57 (57%) 34/57 (43%) NS
Immediate onset - reactions Late onset – reactions
42/95 (44%) 53/95 (56%) NS

Schiappoli M. et al. CEA 2009 in press

Table 3. Characteristics of the SRs

Onset time Phase
Symptom
N.
Pts
N.
SRs
<30’ >30’ Mainte
nance
Build-
up

Actions taken
Urticaria w/w
angioedema
25 48 24 24 23 25
none or antihistamine with/without
oral or i.v. steroid
Rhinitis only 12 16 9 7 11 5
none or antihistamine
Mild asthma° 10 18 6 12 11 7
inhaled albuterol
Asthma and
Urticaria
7 10 6 4 6 4
albuterol+i.v.steroid+antihistamine
(adrenaline in 1 patient)
Severe asthma 2 2 2 0 1 1
albuterol + i.m.adrenaline + i.v.steroid
+ oxygen
Anaphylaxis 1 1 1 0 0 1
albuterol +i.m adrenaline+ i.v steroid+
oxygen+ i.v.saline
TOTAL 57 95 48 47 52 43

° with/without rhinitis (grade 2)

the logistic regression analyses showed that ragweed extracts (OR= 5.032
[2.9-8.6]; RR= 1.08 [1.06-1.10]; p=.01) and grass extracts (OR=1.8 [1.04-3.1];
RR= 1.02 [1-1.04]; p=.04) were significantly associated with SRs

Antihistamine premedication in specific cluster
immuotherapy: a DB PC study
Nielsen L. JACI 1996
Reduction of side effects of specific immunotherapy by
premedication with antihistamines
Jarisch R. 1988
Reduction of side effects from rush-immunotherapy
with honey bee venom by treatment with terfenadine
Berchtold E. Clin Exp Allergy 1992
Omalizumab pretreatment decrease acute reactions
after rush immunotherapy for ragweed-induced
seasonal allergic rhinitis
Casale TB. JACI 2006

Q
stetoscopio e sfigmomanometro
Q
lacci, siringhe ed aghi di diverse misure
Q

Q
ossigeno
Q
set per infusione
di liquidi
Q
cannule orofaringee
Q
pallone Ambu
Q
antistaminici, steroidi
ADRENALINA

Specific immunotherapy among Italian specialists
C. Lombardi, GE Senna, G Passalacqua
Allergy 2006: 61:898-899 - july

Non-injection routes for immunotherapy
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
Committee on the Safety of Medicines
Desensitizing vaccines
Desensitizing vaccines
BMJ 1986; 293:948
26 deaths due to SCIT

…a viable alternative to SCIT in adults…
..safety in children has to be confirmed….
WHO Pos Pap 1998
SLIT can be administered
in adults and children...
ARIA Pos Pap 2001
A promising route….
More data are needed…
Risk of too rapid absorption...
EAACI Pos Pap 1993
NOT CONSIDERED
BSACI Pos Pap 1993
SLIT IN THE OFFICIAL DOCUMENTS

“ “More than 50% of the current population of patients in Central Europe More than 50% of the current population of patients in Central Europe
receiving specific immunotherapy are on SLIT” receiving specific immunotherapy are on SLIT”
Bousquet J & Demoly P. Allergy 2006; 61: 1155 -1158
0
10
20
30
40
50
60
70
80
90
%
2002 2003 2004 2005 2006
Year
FRANCE
SLIT
SCIT
0
10
20
30
40
50
60
70
80
%
2002 2003 2004 2005 2006
Year
ITALY
SLIT
SCIT
Staloral (Stallergènes); SLIT 1, Grazax (ALK-Abello);
TOL (Leti); ALLERSLIT Forte (Allergopharma)
SLIT vs SLIT
SLIT vs SLIT

… I also hope that pro and con sessions will
cease on SLIT as it has now been validated !
( july )

Sublingual Immunotherapy
Sublingual Immunotherapy
for Allergic Rhinitis
for Allergic Rhinitis
Systematic Review and Meta-analysis Systematic Review and Meta-analysis


22 DB PC RC studies were included (1986-2002)

Patients with Seasonal and Perennial Allergic Rhinitis

Participants: n=959 (484 active, 475 placebo)

Adults (16 studies), children (5 studies), mixed (1 study)
Wilson D et al. Allergy 2005; 60: 4-12

SLIT for Allergic Rhinitis
SLIT for Allergic Rhinitis
Meta-analysis: Symptom scores Meta-analysis: Symptom scores
Wilson D et al. Allergy 2005; 60: 4-12
• Subgroup analysis: seasonal allergens better than perennials
• Better > 12 months’ duration

SLIT for Allergic Rhinitis
SLIT for Allergic Rhinitis
Meta-analysis: Medication scores Meta-analysis: Medication scores
• Subgroup analysis: seasonal allergens better than perennials
• Better > 12 months’ duration
Wilson D et al. Allergy 2005; 60: 4-12


SLIT is effective compared to placebo

SLIT is safe with only minor local side
effects

Comparative studies, long-term studies
and more pediatric studies are needed

Sublingual Immunotherapy
Sublingual Immunotherapy
for Allergic Rhinitis
for Allergic Rhinitis
Systematic Review and Meta-analysis
Systematic Review and Meta-analysis

Sublingual Immunotherapy
Sublingual Immunotherapy
in Allergic Asthma
in Allergic Asthma

Systematic Review and Meta-analysis


25 DB PC RC studies were included (1966-2005)

Patients with Allergic Mild-Moderate Asthma

Allergens administered: mites (10), pollen (14), mixture (2) and latex (1)

Participants: n=1,706

Adults and children (10 studies)

Duration: 3 months to 3 years

Extracts given as drops and then swallowed, with the patient fasting
Calamita Z et al. Allergy 2006; 61: 1162-72

SLIT for Allergic Asthma
SLIT for Allergic Asthma
Meta-analysis: Symptom score
Calamita Z et al. Allergy 2006; 61: 1162-72

Allergy, october 2006 ; pp. 1162-72

Sublingual Immunotherapy for
Sublingual Immunotherapy for
Allergic Rhinitis in Children
Allergic Rhinitis in Children
Systematic Review and Meta-analysis Systematic Review and Meta-analysis


10 DB PC RC studies were included (1990-2004)

All patients had allergic rhinitis: 59% asthma and 73% conjunctivits

Participants: n=484 (245 active, 239 placebo)

Age range: 3 to 18 years
Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48

META-ANALYSIS OF THE EFFICACY OF SLIT IN RHINITIS IN PEDIATRIC PATIENTS
SYMPTOMS
MEDICATIONS
Penagos M, Compalati E, Baena-Cagnani R, Passalacqua G, Canonica GW
Ann Allergy Asthma Immunol 2006
10 studies

Sublingual Immunotherapy for
Sublingual Immunotherapy for
Allergic Rhinitis in Children
Allergic Rhinitis in Children
Systematic Review and Meta-analysis Systematic Review and Meta-analysis

SMD (95% CI) p value
Symptom -0.56 (-1.01,-0.10) = 0.02
Medication -0.76 (-1.46,-0.06) = 0.03
Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48
• Subgroup analysis: pollen better than mites
• Better > 18 months’ duration

Efficacy of sublingual allergen vaccination
for respiratory allergy in children.
Conclusion from a meta-analysis
Olaguibel & Alvarez Puebla J Invest Allergol Clin
Immunol 2005; 15 : 9
-
7 dbpc trials enrolling 256 children (129
treatemnts; 127 placebo) were analyzed;
-
decrease in symptoms (SMD : -1.42 for asthma;
- 0.44 for rhinitis and – 1.49 for conjunctivitis) and
medications requirement (SMD : - 1.09) ;
-
Only reductions in asthma (p= 0.01) and drug
dosage (p= 0.06) scores reached statistical
significance;
-
Safety was constant in all the studies


Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of SLIT

Long-lasting effect of sublingual immunotherapy
in children with asthma due to house dust mite:
a ten-year prospective study
V.Di Rienzo, F.Marcucci, P.Puccinelli,
S.Parmiani, F.Frati, L.Sensi, GW Canonica,
G. Passalacqua Clin Exp Allergy, 2003
60
pts
35 SLIT +
drugs
25 only
drugs
0 5 10 YEARS

Long-lasting effect of SLIT
Long-lasting effect of SLIT
Children with asthma due to HDM
10-year open prospective study
0
50
100
150
200
250
300
350
400
450
Baseline End SLIT 10 years
Controls (n=16)
SLIT (n=22)
p<0.01
Di Rienzo V et al. Clin Exp Allergy 2003; 33: 206-10
PEFR
(L/mim)
Mean
• SLIT 4-5 years
• Control: only treatment


Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of SLIT

SLIT Reduces Risk of Developing Asthma
SLIT Reduces Risk of Developing Asthma

Children (5-14 yo) with Allergic Rhinoconjunctivitis
3-year follow-up (n=113)
0%
20%
40%
60%
80%
100%
SLIT Control
%

o
f

p
a
t
i
e
n
t
s
w asthma
w/o asthma
Novembre E et al. J Allergy Clin Immunol 2004; 114: 851-7
Odds ratio 3.80
(1.5-10.0)
80% 60%
n=8
n=37
20% 40%
n=18
n=26
• Open, randomized study
• SLIT for 3 years
• Symptomatic treatment


Long lasting effect

Reduction of development of asthma

Reduction of new sensitizations
Preventive effects of SLIT

SLIT Reduces New Sensitisations
SLIT Reduces New Sensitisations
Randomized controlled open study of SLIT for
Randomized controlled open study of SLIT for
respiratory allergy in real-life:
respiratory allergy in real-life:
clinical efficacy and more
clinical efficacy and more
Marogna M et al. Allergy 2004: 59: 1205-10
n=511 with AR +/- intermittent asthma
Two groups: SLIT+drugs or drugs only for 3 years
New sensitizations appeared in 38% of the controls and
5.9% of the SLIT patient (p=0.01)

SLIT - SIDE EFFECTS
Local: oral itching-swelling
stomach-ache
nausea-vomiting
Systemic: Urticaria/angioedema
Rhinitis
Asthma
Anaphylaxis

SLIT Adverse Events: Systemic Reactions
SLIT Adverse Events: Systemic Reactions
Systematic Review and Meta-Analysis
Systematic Review and Meta-Analysis
All of the studies included reported a complete absence
of systemic effects *
Minor local side effects consisting of itching and swelling
of the oral mucosa were reported almost universally but
were rarely of significance.
Wilson D et al. Allergy 2005; 60: 4-12
* GI, nasal-ocular, asthma, urticaria

* Penagos M et al. Ann Allergy Asthma Immunol 2006; 97: 141-48

0.2/1,000 5. 6% 2 years 3-5 years 128 Di Rienzo
0.07/1,000 5 % 2 years 3-5 years 36 Agostinis
0.15/1,000 6 % 36 months 5-15 years 354 Pajno
0.5/1,000 7.5 % 3 years > 14 years 198 Lombardi
0.1/1,000 3 % 3 years 2-15 years 268 Di Rienzo
AE/1,000
doses
AE % of
patients
Follow-
up
Age range N pats Author
SLIT: POST MARKETING SURVEYS
80% local mild transient

SIDE EFFECT
Conjunctivitis
G.I. complaints
Rhinitis
Urticaria
Oral itching
Angioedema
Asthma
Anaphylaxis
TOTAL
EPISODES
1
3
7
3
3
0
0
0
17
% OF
PATIENTS
0.5
1.5
3.5
1.5
1.5
-
-
-
8.6
GRADE
Moderate
Mild
Mild
2 mild
1 moderate
Mild
-
-
-
15 mild
2 moderate
TIME OF
ONSET
45 min
30-120 min
< 60 min
> 30, <60 min
< 30 min
-
-
-
-
Characteristics of reported systemic side-effects
198 pts, 1 to 3 years of SLIT
Lombardi C et al. Allergy 2001

Andrè C. et al. Int Arch Allergy Immunol 2000
Safety of SLIT in children and adults
No difference between active and placebo in
rhinitis, conjunctivitis, asthma, laryngeal edema
and urticaria occurence.
Gastrointestinal effects:
in adults 67 active and 12 placebo
in children 41 active and 60 placebo
No difference between children and adults for
adverse events occurrence.

The age below 5 years is a relative contraindication for injection
Immunotherapy, mainly for safety reasons….
WHO Position Paper, 1998
WHAT ABOUT SLIT?

Post-marketing survey on the safety of
sublingual immunotherapy in children below
the age of 5 age
Di Rienzo et al. Clin Exp Allergy 2005; 35: 560

34 R, 16 A
76 R+A
79 4,2 (3-5) 67/59 126 Total
1 R
2 R+A
2 4,3 (4-5) 2/1 3
(2)
Alternaria
9 R, 2 A
4 R+A
6 4,6 (3-5) 11/4 15
(12)
Parietaria
1 R
1 R+A
1 4,5 (4-5) 1/1 2
(2)
Olive
10 R,
18 R+A
16 4,14 (3-5) 17/11 28
(22)
Grass
(4 + olive / 1 +
Alternaria)
13 R, 14 A
51 R+A
54 4,16 (3-5) 36/42 78
(62)
House dust mite
(3 + Alternaria)
DISEASE* Mono
sensitized
MEAN AGE
(range)
SEX M/F N
(%)
SLIT
Safety of SLIT in children below the age of 5:
Post-marketing survey
Di Rienzo V, Musarra A, Minelli M, Sambugaro R, Pecora S, Canonica GW, Passalacqua G.
Clin Exp Allergy 2005

Spit 2 hrs moderate Parietaria Diarrhea 5 F 9
Spit 30 min moderate Grass Abdominal
pain-diarrhea
4 M 8
Spit 2 hrs moderate Grass Diarrhea 5 M 7
Spit 1 hrs moderate Mite Diarrhea 4 M 6
Spit 1 hrs moderate Mite Diarrhea 5 F 5
Spit 2 hrs moderate Mite Abdominal
pain-diarrhea
5 F 4
None 30 min moderate Mite Abdominal
pain
4 F 3
None 10 min Mild Mite Oral itching 4 M 2
None 15 min Mild Mite Oral itching 3 M 1
Action taken Onset
time
Grade Allergen Side effect Age Sex Pt
9

S
I
D
E

E
F
F
E
C
T
S
:

7
.
1
%

p
a
t
i
e
n
t
s

a
n
d

0
.
2
/
1
.
0
0
0

d
o
s
e
s

Safety of sublingual immunotherapy with a
monomeric allergoid in very young children
Agostinis F, Tellarini L, Canonica GW
Passalacqua G
Allergy 2005; 60 : 133
-
36 children (mean age 3 yrs 2 months) were
enrolled;
-
mean follow-up was 22.2 months and the number of
doses was 25.200;
-
One episode of abdominal pain occured in two
children (5% of patients – 0.071 per 1.000 doses)

No fatal or near-fatal event
reported since 1986
SLIT

5.81 +/- 4.43 5.57 +/- 4.54 Tryptase
87.0 +/- 12.7 82.6 +/- 9.2 Heart rate
125.45 +/- 8.2 121.91 +/- 125 +/- 13.3
BP (mmHg)
95.73 +/- 11.29 97.09
+/-
10.05 FEV 1
After physical
exercise
Before clinical
exercise
Parameter
Senna G, Bonadonna , Crivellaro MA et al,
Eur Ann Allergy Clin Immunol 2005; 37 : 58
Physical exercise does not favour adverse
reactions to allergen immunotherapy by
sublingual route

SCIT - SLIT
Comparison of
clinical efficacy
The double-blind, double-dummy
design is the gold standard

0
+2
+1
-1
-2
-0.4
+0.3
+1.4
NS
0.002
MEAN CHANGE
DAILY MEDICATION SCORE
0
+2
+1
-1
-2
-0.6
-0.3
+0.2
NS
0.002
MEAN CHANGE
DAILY SYMPTOM SCORE
Khinki et al. Allergy 2004
PLB
SLIT
SCIT



SCIT SLIT
SMD (95% CI) SMD (95% CI)
Symptoms - 0.71 (-1.11,-0.30) - 0.42 (-0.69,-0.15)
z=3.4, p=0.0006 z=3.1, p< 0.002
Medication - 0.84 (-1.31,-0.37) - 0.43 (-0.63,-0.23)
z=3.5, p=0.0005 z=4.2, p<0.0003
Wilson D et al, 2005 Calderon M et al, 2005
Cochrane meta-analyses of
immunotherapy for allergic rhinitis

Grade II
Grade III
Grade IV
23
5
1
33
0
0
36
1
0
SCIT SLIT PLA
SYSTEMIC IMMEDIATE SIDE EFFECTS
Khinki et al. Allergy 04
SLIT showed significantly fewer and milder side effect
compared with SCIT

0
25% >50%
OIT
SLIT
SCIT
S
I
D
E



E
F
F
E
C
T
S
CLINICAL EFFICACY
Malling, 2006
Risk/benefit in IT

Experimental Evidence for Immunotherapy
Experimental Evidence for Immunotherapy
SCIT SCIT SLIT SLIT
Clinical efficacy: Rhinitis Ia Ia
Clinical efficacy: Asthma Ia Ia
Clinical efficacy: Children (AR) Ib Ia
Long-term effect Ib IIa
Prevention of new sensitizations IIb IIb
Prevention of asthma IIb IIb
Safety Ia Ia
Ia Evidence from meta analysis of RCT
Ib Evidence from at least one RCT
IIa Evidence from at least one controlled trial without randomization
IIb Evidence from at least one other type of quasi experimental trial

Specific Allergen Immunotherapy:
Specific Allergen Immunotherapy:
Risk & Benefit
Risk & Benefit
Efficacy ++
Safety +
Efficacy +
Safety ++
SCIT SCIT
SLIT SLIT

Specific Allergen Immunotherapy:
Specific Allergen Immunotherapy:
Risk & Benefit
Risk & Benefit
Efficacy ++
Safety +
Efficacy +
Safety ++
SCIT SCIT
SLIT SLIT
Patient selection !

Experimental Evidence for Immunotherapy
Experimental Evidence for Immunotherapy
Conclusions Conclusions

More PC, DB and RC studies are needed with standardization of
symptom scores

Characterization of participants (disease severity)

Lack of studies in children

Number of patients recruited (sample size and power calculation)

Safety in high-risk groups

Experimental Evidence for Immunotherapy
Experimental Evidence for Immunotherapy
Conclusions
Conclusions

Quality of vaccines: standardization

Duration treatment: pre-season and maintenance

Schedule: up-dosing and maintenance

Dose: units of major allergen protein

Adverse events

Cost

G. Senna
P. Bonadonna
M. Conte
A. Dama
E. Olivieri
M. Schiappoli
Collaborations Collaborations
A. Romano (Roma) A. Romano (Roma)
B. Caruso (Verona) B. Caruso (Verona)
P. Gisondi (Verona) P. Gisondi (Verona)
C. Le Pera (Verona) C. Le Pera (Verona)
R. Zanotti (Verona) R. Zanotti (Verona)
S. Durham (Londra) S. Durham (Londra)
M. Pagani (Mantova) M. Pagani (Mantova)
M. Calderon (Londra) M. Calderon (Londra)
L. Castellani (Trento) L. Castellani (Trento)
C. Lombardi (Brescia) C. Lombardi (Brescia)
M. Crivellaro (Padova) M. Crivellaro (Padova)
L. Antonicelli (Ancona) L. Antonicelli (Ancona)
G.W. Canonica (Genova) G.W. Canonica (Genova)
G. Passalacqua (Genova) G. Passalacqua (Genova)
Centro regionale di riferimento per la prevenzione, Centro regionale di riferimento per la prevenzione,
la diagnosi e la terapia delle malattie allergiche la diagnosi e la terapia delle malattie allergiche
Azienda Ospedaliera di Verona
Azienda Ospedaliera di Verona
Ospedale Civile Maggiore
Ospedale Civile Maggiore
Unità Operativa di Allergologia
Unità Operativa di Allergologia

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