New Insights in the pathogenesis of nasal polyps

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Severe Chronic Upper Respiratory
Disease Phenotyping Inflammation
Claus Bachert DGAKI Germany GA2LEN Ghent
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Prevalence of SCURD in the EU
Total population (2007) 490 millions
Disease CURD SCURD
Allergic rhinitis 15-25 113 millions 37 m
Non-allergic rhinitis 10-15 68 millions 17 m
Chronic rhinosinusitis 6-18 70 millions 35 m More than 350 000 surgeries/year In Europe, 1M in the world
Aspirin sensitivity 0.5-3 12 millions 10 m
Consider socio-economic impact of SCURD !
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One third suffered from both, CRS and asthma.
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Management of Chronic Rhinosinusitis
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Lack of T-regulatory cells in nasal polyps
The expression of the transcription factors
FOXP3, T-bet, GATA-3, the suppressive cytokines
TGF-ß1, IL-10 and major TH1/ TH2 cytokines (IFN-?
, 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-ß1 and IFN-? by means of ELISA,
and immunohistochemistry was performed for FOXP3
N. Van Bruaene et al, JACI 2008.
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TGF-beta receptors (mRNA)


Van Bruaene et al, submitted
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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
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South Chinese controls South Chinese nasal polyps Belgian controls Belgian nasal polyps ANOVA Fishers Exact test
N 29 29 21 26
Age, yr (range) 386 (332-435) 364 (286-465) 303 (213-379) 462 (384-555)
Female / Male 10/19 9/20 9/12 11/15 0.767
Asthma 0/29 2/29 2/21 14/26 lt0.0001
Phadiotop positive 11/29 9/29 8/21 11/26 0.845
Aspirin intolerance 0/29 0/29 0/21 7/26 lt0.0001
CT score (Lund Mackay) 0 16 (11-20) 1 (0-2) 13 (11-20) lt0.0001
Polyp score (Davos) 0 (0-0) 5 (4-6) 0 (0-0) 4 (4-6) lt0.0001
Total symptom score 5 (3-6) 10 (7-11) 5 (3-7) 9 (7-11) lt0.0001
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) lt0.0001
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
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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
10 Subjects
Weeks
1
12
8
0
4
24
36
48

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Endoscopic Nasal polyp score and improvement
13/20
12/20
10/20
?intranasal steroids permitted


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

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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