1. Severe Chronic Upper Respiratory Disease: Phenotyping Inflammation
Claus Bachert
DGAKI Germany
GA2LEN Ghent
Upper Airways Research Laboratory
Department of Otorhinolaryngology

2. Prevalence of SCURD in the EU
Total population (2007): 490 millions
Disease %
CURD SCURD
Allergic rhinitis
15-25
113 millions m
Non-allergic rhinitis
10-15
68 millions m
Chronic rhinosinusitis
6-18
70 millions m
More than surgeries/year
In Europe, 1M in the world
Aspirin sensitivity
0.5-3
12 millions m
Consider socio-economic impact of SCURD !

3. One third suffered from both, CRS and asthma.

4. Management of Chronic Rhinosinusitis

5. Lack of T-regulatory cells
in nasal polyps
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.

6. TGF-beta receptors (mRNA)* * *
Van Bruaene et al, submitted

7. 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. Different types of T effector cells orchestrate mucosal inflammation
South Chinese controls
South Chinese nasal polyps
Belgian controls
Belgian nasal polyps
ANOVA
* Fisher’s Exact test N 29 21 26
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
10/19
9/20
9/12
11/15
0.767
Asthma
0/29
2/29
2/21
14/26
<0.0001*
Phadiotop positive
11/29
9/29
8/21
11/26
0.845
Aspirin intolerance
0/21
7/26
CT score (Lund & Mackay)
16 (11-20)
1 (0-2)
13 (11-20)
<0.0001
Polyp score (Davos)
0 (0-0)
5 (4-6)
4 (4-6)
Total symptom score
5 (3-6)
10 (7-11)
5 (3-7)
9 (7-11)
Nasal congestion
2 (2-3)
3 (2-3)
2 (1-3)
0.033
Rhinorrhea
0 (0-1)
0 (0-2)
0.008
Sneezing
0.093
Loss of smell
Headache
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. 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
20 Subjects
30 Subjects
Severe nasal polyps
MEPO 750mg IV
Placebo
Dosing
Follow up *
Primary endpoint
10 Subjects
The design of this study was a two-arm, randomized, double-blind, placebo-controlled study.
30 patients with severe nasal polyposis were randomized in a double blinded way. 20 patients received 2 single IV injections with mepolizumab with a 4 week interval, and 10 patients received placebo injections.
Follow up visits are scheduled 1 week after first dosing and 1, 3, 6, 9 months post last dose.
Weeks 1 4 8 12 24 36 48 *

10. Endoscopic Nasal polyp score and improvement
13/20
12/20
10/20
intranasal steroids permitted
When we look at our primary endpoint, the endoscopic NP score, we see that after two injections of mepolizumab, wet get a strong significant decrease in NP score at week 8, which was maintained until 6 months after treatment . Of importance, After w8 rescue medication was permitted. In the placebo group, none of the patients had a change in the NP score. When we then look at the number of patients that had an improvement in NP score
Eventually, we could even speculate that if we could give even more than 2 injections, we could expect an even further decrease of the nasal polyp score.
When we look then at the number of patients that showed an improvement on the endoscopic score, we found 10/20 patients that were better, which was significantly higher compared to placebo with 1/10 better. a significant higher number of better patients that were better in the treated group compared to placebo 1 month after the first dosing. This number increased after the second dosingThe percentage of patients that showed an improvement in endoscopic score was significantly better after treatment compared to placebo after week 4, week 8 till week 12. * *

11. S. aureus superantigens as disease modifiers
Massive polyclonal lymphocyte activation
Epithelial damage (barrier dysfunction) B T
Hyper IgE 
Cytokines 
colonisation
Multiclonal IgE
Superantigens
Eosinophils 
( apoptosis)
Chemokines
Bachert C et al. JACI 2001
Review: Bachert C et al. Clin Allergy Immunol. 2007

12. Tissue Serum ECP (µg/ ml) 602.5 (IQR: 309.9- 894.3)
Controls
NP- SAEs (-)
NP-SAEs (+)
Tissue
ECP (µg/ ml)
602.5 (IQR: )
(IQR: )
(IQR: )
p < (*)
IL- 5 (pg/ ml)
20.9 (IQR: )
81.5 (IQR: )
327.9 (IQR: )
p < (*)
MPO (ng/ ml)
(IQR: )
(IQR: )
(IQR: )
Total IgE (kU/ L)
1.93 (IQR: )
323.9 (IQR: )
(IQR: )
Specific IgE to SAEs (kUA/ L)
BDL
8.6 (IQR: )
P < (*)
Serum
9.0 (IQR: )
10.9 (IQR: )
22.4 (IQR: )
p = (**)
11.8 (IQR: )
7.5 (IQR: )
10.3 (IQR: )
21.8 (IQR: )
37.2 (IQR: )
211.2 (IQR: )
p = (**)
0.4 (IQR: )

13. 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. Sinusitis cohort study GA2LEN
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