ENT DepartmentUpper Airways Research Laboratory
New insights in the
pathophysiology of chronic
rhinosinusitis
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
PAUL VAN CAUWENBERGE,THIBAUT VAN ZELE, CLAUS BACHERT
Ghent University, Belgium
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Case reportMale, 46 yearsENT: nasal polyps since 12 years, 3 FESS surgeries, continuous use of topical GCSNo smell, nasal obstruction and PNDPneumo: moderate-severe asthma, AERD, inhalant and oral steroid use
Your therapy?
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
EG2, X 100H, X 100
CRS without and with NPRemodelling
ENT DepartmentUpper Airways Research Laboratory
TGF-beta in chronic sinus disease• Dual role: inflammation and remodelling
– Immunmodulatory properties– Master switch in the induction of fibrosis
• Three isoforms and three receptors described in humans
TGF-β1, TGF-β2, TGF-β3, TGF-β4, TGF-β5
prevalent form, until nowmost studied
humansThree receptors:
TGFβrec1TGFβrec2
TGFβrec3 or betaglycan
ENT DepartmentUpper Airways Research Laboratory
** *
**
TGF-beta 1 and 2 proteinin CRSs/wNP
Van Bruaene et al, JACI 2009
ENT DepartmentUpper Airways Research Laboratory
** *
** *
Immunostaining Phospho-smad 2 Picrosirus red staining for collagen
Van Bruaene et al, JACI 2009
ENT DepartmentUpper Airways Research Laboratory
A B C
D E F
CON CRSsNP CRSwNP
Picrosirius red polarized light 400×
Picrosirius red 400×
CONTROL CRSsNP CRSwNP
perc
en
tage
of a
rea
0
20
40
60
80
100
P=0.000
P=0.000 P=0.000
Total collagen content
CONTROL CRSsNP CRSwNP
TG
F-b
eta1
(pg/
ml)
0
10000
20000
30000
40000
50000
P=0.036 P=0.049
TGF-beta1 in tissue homogenates
Li X. et al, JACI 2010
ENT DepartmentUpper Airways Research Laboratory
EG2, X 100H, X 100
CRS without and with NP
TGFß1 highFIBROSIS
TGFß1 lowOEDEMA
ENT DepartmentUpper Airways Research Laboratory
Lack of T-regulatory cells in nasal polyps
FOXP3 mRNA(Normalized relative expression units/ 30ng cDNA)
1,8
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
CON CRS NP
P=0.0324
P=0.0011
FOXP3 mRNA(Normalized relative expression units/ 30ng cDNA)
1,8
1,6
1,4
1,2
1,0
0,8
0,6
0,4
0,2
0,0
CON CRS NP
P=0.0324
P=0.0011
N. Van Bruaene, et al JACI, 2008
ENT DepartmentUpper Airways Research Laboratory
0
5000
10.000
15.000
20.000
25.000
30.000
35.000
0
200
400
600
800
1000
1200
1400
Inflammation in nasal polyposis: increased levels of inflammatory mediators
Bachert et al. J Allergy Clin Immunol. 2001;107:607.
P<0.001
P=0.016
IL-5
P<0.001
P=0.086
ECP
IL-5
(p
g/m
L)
EC
P (
µg
/mL)
Non-polyp NP I NP II NP III Non-polyp NP I NP II NP III
ENT DepartmentUpper Airways Research Laboratory
Treg and TH17: major revisions in the TH1/TH2 hypothesis of T cell differentiation
Steinman, Nat Med, 2007
ENT DepartmentUpper Airways Research Laboratory
South Chinese
controls
South Chinese
nasal polypsBelgian controls Belgian nasal polyps
ANOVA
* Fisher’s Exact
test
N 29 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
positive11/29 9/29 8/21 11/26 0.845
Aspirin
intolerance0/29 0/29 0/21 7/26 <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
score5 (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
ENT DepartmentUpper Airways Research Laboratory
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
ENT DepartmentUpper Airways Research Laboratory
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
ENT DepartmentUpper Airways Research Laboratory
70 nasal polyp tissue homogenates (Belgian patients)
IL-5+ (58; 83%) IL-5- (12; 17%)
93 nasal polyp tissue homogenates (Chinese patients)
IL-5+ (15; 16%) IL-5- (78; 84%)
EOSINOPHILIC ? NEUTROPHILIC ?
ENT DepartmentUpper Airways Research Laboratory
EG2, X 100H, X 100
CRS without and with NP
Th1 Th2– Th17 Treg deficit
Zhang N, Bachert C et al. JACI 2008
ENT DepartmentUpper Airways Research Laboratory
Zhang Nan, URL Ghent
SEC
SEB
SElU
SEG
SElR
SElQSElM
SElVSEI
SElK
SElL
SElO
SEH
SElNSED
SEJ SElP SEA
SEE TSST-1
Staphylococcus aureus superantigens
3327
64 67
88
146
28
54
80
0
10
20
30
40
50
60
70
80
90
100
Controls(n=9)
CRS(n=22)
NP(n=53)
NP +asthma
NP +ASS
S. aureuscolonization
SAE-IgE+
*
*
*
*
**
S. aureus colonization and IgE antibodies to S. aureus enterotoxin mix in mucosal tissue
ENT DepartmentUpper Airways Research Laboratory
Nasal polyp tissue stained for
S. aureus with PNA-FISH
M-N. Corriveau, Zhang NAm J Rhinol, 2009
ENT DepartmentUpper Airways Research Laboratory
IL4 (pg/ml) Medians (error bars: 25-75 percentiles)35
30
25
20
15
10
5
0
RPM
ISE
B 0.5
µg/m
lR
PMI
SEB 0
.5µg
/ml
CO NP
IL5 (pg/ml) Medians (error bars: 25-75 percentiles)140
120
100
80
60
40
20
0R
PMI
SEB 0
.5µg
/ml
RPM
ISE
B 0.5
µg/m
l
CO NP
IL13 (pg/ml) Medians (error bars: 25-75 percentiles)300
250
200
150
100
50
0
RPM
ISE
B 0.5
µg/m
l
RPM
ISE
B 0.5
µg/m
l
CO NP
24 hours stimulation
**
**
**
****
***
****
** p<0.01 * p<0.05 (paired samples; Wilcoxon test/ Intergroup variability; Mann-Whitney U test) CO n=13 NP n=12
Patou J et al, JACI 2008
ENT DepartmentUpper Airways Research Laboratory
ENT DepartmentUpper Airways Research Laboratory
Follicle-like structures and lymphocyte accumulations in NP CD3
CD20
CD38
IgE
SEAGevaert P et al, Allergy 2005
ENT DepartmentUpper Airways Research Laboratory
Multiclonal IgE
Chemokines
Massive polyclonal lymphocyte activation
TB
Cytokines Hyper IgE
Eosinophil
survival
Superantigens
Epithelial damage (barrier dysfunction)
colonisation
S. aureus superantigens as disease modifiers
Review: Bachert C et al. Clin Allergy Immunol. 2007
Mast cell degranulation
FibroblastPGE2 prod.
ENT DepartmentUpper Airways Research Laboratory
Management of Nasal Polyposis
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
24Thibaut Van Zele, Philippe Gevaert, Gabriele Holtappels, Achim Beule, Peter John Wormald, Susanne Mayr, Greet Hens, Peter Hellings, Fenna A Ebbens, Paul Van Cauwenberge, Claus Bachert
Oral steroids in nasal polyps: a 3-month double blind, randomized, placebo-controlled trialDBPC in 32 patient with nasal polyps, 20days methylprednisolon(Day 1-5 32 mg, day 6-10 16 mg, day 11-20 8 mg)
ENT DepartmentUpper Airways Research Laboratory
Anti-MMPs IL-5
ECP
IgE
Anti-IL-5IKK2, SYK, iCRAC, PDE4
The future of treating persistent inflammation in polyp disease
Anti-IgE
Anti-CCR3 ?
Antibiotics
ENT DepartmentUpper Airways Research Laboratory
Doxycycline reduces nasal polyp size in a DBRPC multicenter trial.
* *
P Gevaert, T Van Zele, G Holtappels, A Beule, PJ Wormald, S Mayr, G Hens, P Hellings, FA Ebbens, P Van Cauwenberge, C Bachert
20 days doxycycline (100mg/d)
Area under the curve
Placebo: -145,4
Methylprednisolon: 530,6
ENT DepartmentUpper Airways Research Laboratory
Local anti-inflammatory effects of doxycyclin
* p<0,05 (Mann-Whitney)
p<0,05 (paired Wilcoxon)
ENT DepartmentUpper Airways Research Laboratory
Anti-MMPs IL-5
ECP
IgE
Anti-IL-5IKK2, SYK, iCRAC, PDE4
The future of treating persistent inflammation in polyp disease
Anti-IgE
Anti-CCR3 ?
Antibiotics
ENT DepartmentUpper Airways Research Laboratory
Study design Anti-IL-5 studyMepolizumab 2 x 750mg IV
30 SubjectsSevere nasal polyps
20 Subjects
10 Subjects
Weeks 0 1 4 128
*
MEPO 750mg IVPlacebo
Dosing
Follow up
* Primary endpoints: polyp score, CT scan
24 36 48
• Mepolizumab = a humanized anti-human IL-5 monoclonal antibody
• 30 NP patients with recurrent bilateral nasal polyps after surgery or
massive bilateral nasal polyps (Grade 3 or 4)
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
EndpointsPrimary endpoint
• Endoscopic Nasal polyp score 8 weeks post 1st dosing
Secondary endpoints• CT scan assessment (blinded)• Symptom score• Peak nasal inspiratory flow• Local (nasal secretions) and
systemic Inflammatory mediators• UPSIT smell test
0 1 2 3 4Score
0
1
4
3
2
ENT DepartmentUpper Airways Research Laboratory
Endoscopic nasal polyp score improvement
**
intranasal steroids permitted
10/20
12/20
13/20
ENT DepartmentUpper Airways Research Laboratory
Anti-MMPs IL-5
ECP
IgE
Anti-IL-5IKK2, SYK, iCRAC, PDE4
The future of treating persistent inflammation in polyp disease
Anti-IgE
Anti-CCR3 ?
Antibiotics
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Objective and study design
24 SubjectsSevere nasal polyps
With asthma
8 Subjects
16 Subjects
Weeks 0 2 4 6 8 10 12 16 20
*
SC OMALIZUMABPLACEBO
Dosing
Follow up
* Primary endpoint
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Inclusion criteria
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Dosage and administrationXolair 75 to 375mg is administered SC every 2 to 4 weeks (3 months)
following official drug leaflet
Doses (mg) and dosing frequency are determined by total serum IgE level (IU/ml) measured at the start of treatment and body weight (kg)
Doses of more than 150mg are divided among more than 1 injection site
Injection every 4 weeks (4 injections) or 2 weeks (8 injections)
ENT DepartmentUpper Airways Research Laboratory
ENT DepartmentUpper Airways Research Laboratory
Improvement in symptomsOmalizumab (n=15) versus placebo (n=8)
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
CT-scans before and after Anti-IgE
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Practical management of Nasal Polyposis
Nasal corticosteroids• GCS sprays: 2x/d, symptoms↓• GCS drops: symptoms↓, surgery↓
• Oral corticoids: effective but fast recurrence• Antibiotics:
• Antibiotic ointment• Long-term antibiotics: macrolides 500mg/d for 2m
doxycycline 100 mg/d for 2m
• Future: • Omalizumab (antiIgE; xolair) ?• Mepolizumab (anti-IL5) ?
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
Case reportMale, 46 years: nasal polyps, asthma, AERDNasal polyp score after 4 injections Omalizumab
ENT DepartmentUpper Airways Research Laboratory
Claus Bachert, MD, PhD
Paul van Cauwenberge, MD PhDPhilippe Gevaert, MD, PhDNan Zhang, MD, PhDThibaut Van Zele, MD, PhDSofie Claeys, MD, PhDClaudina Novo-Perez, PhDKoen Van Crombruggen, PhDOlga Krysko, PhDLara Derycke, PhDJoke Patou, MDNicholas Van Bruaene, MDWouter Huvenne, MDPeter Tomassen, MDLien Devuyst, MDTakajuki Sejima, MDMarie-Noelle Corriveau, MDGabi HoltappelsNathalie DeruyckKatrien Blomme
Upper Airways Research LaboratoryDepartment of Otorhinolaryngology
ENT DepartmentUpper Airways Research Laboratory
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