SUBLINGUAL IMMUNOTHERAPY

Giovanni Passalacqua

Allergy & Respiratory DiseasesAllergy & Respiratory DiseasesDept.Internal Medicine-Dept.Internal Medicine-

University of Genoa ITALYUniversity of Genoa ITALY

THE LITERATURE

66 RDBPC TRIALS

8 RANDOMIZED OPEN TRIALS

6 COMPARATIVE (SLIT vs SCIT)

6 TRIALS IN OTHER DISEASES

10

20

grass

HDM

parietaria

cypress

cat ragweed

birch

other

67%

Less or equal 6 months: 23 studies

Less or equal 12 months: 15 studies

More than 12 months: 20 studies

TREATMENT DURATION

< 20 : 4 studies

< 50 : 21 studies

< 100 : 16 studies

PATIENTS ENROLLED

< 150 : 11 studies

> 150 : 8 studies

10 STUDIES WITH SAMPLE SIZE CALCULATION

Durham 2006 De Blay, 2007Dahl 2006 Pfaar 2008Pham Ti 2007 Wahn 2009Roder 2006 Ott 2009Didier 2007 Bufe 2009Skoner 2010 Cortellini 2010

Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitisDurham SR, JACI 2006

Prolonged preseasonal treatment with Grazax improves the clinical efficacy

Calderon M et al, Allergy 2007

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis.Dahl et al, JACI 2006

VERSUS PLACEBO:

SYMPTOM REDUCTION

- 30%MEDICATION REDUCTION

- 38%

634 PATIENTS !!!

VS PLACEBOSymptoms-28% (-39%)Medications- 24% (-48%)

Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis

Wahn 2009

VS PLACEBOSymptoms-34% to –44%

VS PLACEBOSymptoms -24% Medications - 34%

Sublingual immunotherapy for allergic rhinitis.Allergy, 2005. Wilson D., Torres Lima I, Durham S.

21 trials

Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients: Meta-analysis of randomized controlled trials.

Martin Penagos, Enrico Compalati, Francesco Tarantini, Rodrigo Baena Cagnani, Jose Huerta Lopez, Giovanni Passalacqua and Giorgio Walter Canonica

2006

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

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

Abramson 2003

Asthma A-C p< 0.01

Calamita 2006

Asthma A-C P= 0.07

Penagos 2008

Asthma C P= 0.02

Olaguibel 2005

Asthma/Rhinitis

C P= 0.01

Calderon 2007

Rhinitis A p< 0.01

Penagos 2006

Rhinitis C p= 0.02

Wilson 2005

Rhinitis A-C p= 0.002

A = adults C = children

Specific immunotherapy for respiratory allergy: state of the art according to current meta-analyses. Compalati E et al, Ann Allergy Asthma Immunol 2009

Meta analisi: sintomiSCIT

SCIT

SLIT

SLIT

SLIT

SLIT

SLIT

49 (OUT OF 60) RDBPC TRIALS SUITABLE FOR POOLING:2333 SLIT2256 PLACEBO

SYMPTOM SCORE

MEDICATION SCORE

SymptomScoreRhintis

JACI 2010

No fatal event reported since 1986

SLIT

Author, year

Sex (age)

Allergen (producer)

Phase Onset Description Epinephrine

De Groot, 2009

M (13) Grass (Grazax, ALK-Abellò)

First dose 15 min Generalized urticaria, swelling of tongue

NO

De Groot, 2009

F (27) Grass (Grazax, ALK-Abellò)

First dose 5 min Abdominal cramps, asthma, generalized itching, hypotension

YES

Blazowski, 2008

F (16) HDM (Staloral, Stallergenes)

Maintenanceoverdose (60 drops)

10 min Hypotension-collapse, flushing, urticaria

YES

Eifan, 2008 F (11) dust mite + grass pollen mix (Stallergenes)

Maintenance. 

3 min Abdominal pain, chest pain, fever, nausea

Not specified

Dunski, 2006

F (31) Alternaria, cat, doggrass, ragweed, (Greer)

2nd day of updosing 

5 min Angioedema, dizziness, dyspnea, generalized itching

NO

Antico, 2006

F (36) Latex End of rush buildup

10 min Asthma, generalized urticaria

Not specified

Anaphylaxis with SLIT

Cox L, Linneman D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: A comprehensive review. J Allergy Clin Immunol 2006; 117: 1021-35

In 41 studies with information on the total number of AEs, 1047 adverse reactions in a total of 386,149 doses were identified (2.7 reactions/1,000 doses).

In 49 studies with information on the number of patients, the AEs were 529 per 4378 patients (12%).

In the trials that specified the severity of reaction, the occurrence of severe AE was 0.56 per 1,000 doses.

Overall, 14 serious AEs probably related to the treatment were found.

Author N pats Age range Follow-up

AE % ofpatients

AE/1,000 doses

Di Rienzo 268 2-15 years 3 years 3 % 0.1/1,000

Lombardi 198 > 14 years 3 years 7.5 % 0.5/1,000

Pajno 354 5-15 years 36 months 6 % 0.15/1,000

Agostinis 36 3-5 years 2 years 5 % 0.07/1,000

Di Rienzo 128 3-5 years 2 years 5. 6% 0.2/1,000

SLIT: POST MARKETING SURVEYS

THE SAFETY OF SUBLINGUAL IMMUNOTHERAPY WITH ONE OR MORE ALLERGENS IN CHILDREN

Fabio Agostinis, Marcello Cottini, Carlo Lombardi, Giorgio Walter Canonica, Giovanni Passalacqua ,Allergy 2008 in press

SINGLE ALLERGEN n (%) MULTI ALLERGENS n (%)

Grass 140 (82) Grass + pariet 6 (2)

Parietaria 4 (3) Grass+ olive 18 (7)

Birch 14 (9) Grass + birch+alder+hazelnut

220 (87)

Ragweed 4 (3) Grass + ragweed 9 (4)

Olive - Grass + mugwort

    Birch+hazelnut+alder

TOTAL 172 (100)   253 (100)

415 children, 3-18 years, 272 male

Coseasonal SLIT reduces the development of asthma in children with allergic rhinitis.Novembre E. et al, JACI 2004

SLIT NO SLIT

37

8

26

18

NO ASTHMA

ASTHMA

79 childrenAllergic rhinitis onlyFollow-up: 3 yrs

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, Pavia3 Allergy & Respiratory Diseases,Department of Internal Medicine, Genoa University

4          Pediatric Allergy Unit, S. Pertini Hospital, Rome

AAAI 2008, 101: 261

Diary card

Visit

Skin test

MCh challenge

144 SLIT

72 CONTROLS

14 dropout

6 dropout

1 yearBASELINE

RANDOMIZED PHASE

Year 1

PATIENTS216

Year 2 Year 3

* * * ** * * ** ** *

130 SLIT

66 CONT

CONTROLS

NS

***

***

baseline 3rd year

PERSISTENTASTHMA

10

20

30

40

50

60

70

% P

AT

IEN

TS

SLIT

***

***

baseline 3rd year

MONOSENSITIZEDPATIENTS

10

20

30

40

50

60

70

% P

AT

IEN

TS