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ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Severe Chronic Upper Respiratory Disease: Phenotyping Inflammation Upper Airways.

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Presentation on theme: "ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Severe Chronic Upper Respiratory Disease: Phenotyping Inflammation Upper Airways."— Presentation transcript:

1 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Severe Chronic Upper Respiratory Disease: Phenotyping Inflammation Upper Airways Research Laboratory Department of Otorhinolaryngology Claus Bachert DGAKI Germany GA 2 LEN Ghent

2 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Prevalence of SCURD in the EU Disease%CURD SCURD Allergic rhinitis15-25113 millions 37 m Non-allergic rhinitis10-1568 millions 17 m Chronic rhinosinusitis6-1870 millions 35 m More than 350 000 surgeries/year In Europe, 1M in the world Aspirin sensitivity0.5-312 millions 10 m Consider socio-economic impact of SCURD ! Total population (2007): 490 millions

3 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD One third suffered from both, CRS and asthma.

4 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Management of Chronic Rhinosinusitis

5 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD The expression of the transcription factors FOXP3, T-bet, GATA-3, the suppressive cytokines TGF-β1, IL-10 and major TH1/ TH2 cytokines (IFN-γ, IL-4, IL-5, IL13) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP and 10 control samples. Additional protein measurements were performed for TGF-β1 and IFN-γ by means of ELISA, and immunohistochemistry was performed for FOXP3 N. Van Bruaene et al, JACI 2008. Lack of T- regulatory cells in nasal polyps

6 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD TGF-beta receptors (mRNA) * * ** * Van Bruaene et al, submitted

7 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Different types of T effector cells orchestrate mucosal inflammation in chronic sinus disease Nan Zhang ; T Van Zele; C Perez- Novo; N Van Bruaene; G Holtappels; N Deruyck; C Bachert. JACI 2008

8 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD South Chinese controls South Chinese nasal polyps Belgian controlsBelgian nasal polyps ANOVA * Fishers Exact test N 29 2126 Age, yr (range) 38·6 (33·2-43·5)36·4 (28·6-46·5)30·3 (21·3-37·9)46·2 (38·4-55·5) Female / Male 10/199/209/1211/15 0.767 Asthma 0/292/292/2114/26<0.0001* Phadiotop positive 11/299/298/2111/26 0.845 Aspirin intolerance 0/29 0/217/26<0.0001* CT score (Lund & Mackay) 0 16 (11-20) 1 (0-2) 13 (11-20) <0.0001 Polyp score (Davos) 0 (0-0) 5 (4-6) 0 (0-0) 4 (4-6) <0.0001 Total symptom score 5 (3-6) 10 (7-11) 5 (3-7) 9 (7-11) <0.0001 Nasal congestion 2 (2-3)3 (2-3)2 (1-3)3 (2-3) 0.033 Rhinorrhea 0 (0-1)2 (1-3)0 (0-2)1 (0-2) 0.008 Sneezing 0 (0-1)1 (0-2)0 (0-2)0 (0-1) 0.093 Loss of smell 0 (0-1)2 (2-3)0 (0-1)3 (2-3) <0.0001 Headache 1 (0-2)2 (1-3)1 (0-2)2 (1-2) 0.006 Different types of T effector cells orchestrate mucosal inflammation in chronic sinus disease Nan Zhang ; T Van Zele; Claudina Perez-Novo; N Van Bruaene; Gabriele Holtappels; Natalie DeRuyck; C Bachert. JACI 2008

9 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Objective and study design To asses the therapeutic potential of two injections of 750 mg IV mepolizumab (28days) endoscopic score symptom scores CT scan Two-arm, randomized, double blind, placebo controlled, trial 30 Subjects Severe nasal polyps 20 Subjects 10 Subjects Weeks 0 1 4 128 * MEPO 750mg IV Placebo Dosing Follow up * Primary endpoint 24 3648

10 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Endoscopic Nasal polyp score and improvement * * intranasal steroids permitted 10/2 0 12/2 0 13/2 0

11 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Multiclonal IgE Chemokines Massive polyclonal lymphocyte activation TB Cytokines Hyper IgE Eosinophils ( apoptosis) Superantigens Epithelial damage (barrier dysfunction) colonisation S. aureus superantigens as disease modifiers Bachert C et al. JACI 2001 Review: Bachert C et al. Clin Allergy Immunol. 2007

12 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD ControlsNP- SAEs (-) NP-SAEs (+) Tissue ECP (µg/ ml) 602.5 (IQR: 309.9- 894.3) 9806.9 (IQR: 1686.5 - 17673.8) 25 583.0 (IQR: 17226.0 - 29870.3) p < 0.0001 (*) IL- 5 (pg/ ml) 20.9 (IQR: 16.9- 25.0) 81.5 (IQR: 38.9- 291.9) 327.9 (IQR: 106.2- 385.5) p < 0.0005 (*) MPO (ng/ ml) 4882.8 (IQR: 3007.1- 7015.0) 8013.9 (IQR: 4912.1- 11476.0) 9705.2 (IQR: 7426.1- 17427.1) Total IgE (kU/ L) 1.93 (IQR: 1.9- 1.9) 323.9 (IQR: 67.2- 387.5) 1 564.0 (IQR: 739.1- 2039.7) p < 0.0005 (*) Specific IgE to SAEs (kU A / L) BDL 8.6 (IQR: 6..3- 17.0) P < 0.0005 (*) Serum ECP (µg/ ml) 9.0 (IQR: 3.8- 14.1)10.9 (IQR: 7.1- 32.7) 22.4 (IQR: 16.4- 36.9) p = 0.0467 (**) MPO (ng/ ml)11.8 (IQR: 8.3- 13.1)7.5 (IQR: 3.7- 16.7)10.3 (IQR: 5.9- 13.4) Total IgE (kU/ L) 21.8 (IQR: 8.9- 56.0)37.2 (IQR: 20.8- 215.2) 211.2 (IQR: 152.5- 431.5) p = 0.0064 (**) Specific IgE to SAEs (kU A / L) BDL 0.4 (IQR: 0.1- 1.3)

13 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD SCURD - Phenotyping Inflammation Unmet needs: Create valid nomenclature Improve clinical diagnostics and markers Define and validate targets per subgroup Understand link to lower airways Advantages: Easy access, SCURD may serve as model Animal and human ex-vivo models available Clinical and epidemiologic studies achievable

14 ENT Department Upper Airways Research Laboratory Claus Bachert, MD PhD Sinusitis cohort study GA 2 LEN 8 centres in Europe (2 co-operative centres in Asia) Inclusion started in March 2007 Clinical phenotyping completed by end of 2008 800 patients and 250 controls included Biobank –1050 blood samples and nasal secretions –450 tissue samples


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