ENT Department Upper Airways Research Laboratory New insights in the pathophysiology of chronic...

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


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?


EG2, X 100H, X 100

CRS without and with NPRemodelling


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


** *

**

TGF-beta 1 and 2 proteinin CRSs/wNP

Van Bruaene et al, JACI 2009


** *

** *

Immunostaining Phospho-smad 2 Picrosirus red staining for collagen

Van Bruaene et al, JACI 2009


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


EG2, X 100H, X 100

CRS without and with NP

TGFß1 highFIBROSIS

TGFß1 lowOEDEMA


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


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


Treg and TH17: major revisions in the TH1/TH2 hypothesis of T cell differentiation

Steinman, Nat Med, 2007


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


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


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 ?


EG2, X 100H, X 100

CRS without and with NP

Th1 Th2– Th17 Treg deficit

Zhang N, Bachert C et al. JACI 2008


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


Nasal polyp tissue stained for

S. aureus with PNA-FISH

M-N. Corriveau, Zhang NAm J Rhinol, 2009


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


120

100

80

60

40

20

0R

PMI

SEB 0

.5µg

/ml

RPM

ISE

B 0.5

µg/m

l

CO NP


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


Follicle-like structures and lymphocyte accumulations in NP CD3

CD20

CD38

IgE

SEAGevaert P et al, Allergy 2005


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.


Management of Nasal Polyposis


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)


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


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


Local anti-inflammatory effects of doxycyclin

* p<0,05 (Mann-Whitney)

p<0,05 (paired Wilcoxon)


Anti-MMPs IL-5

ECP

IgE



Anti-IgE

Anti-CCR3 ?

Antibiotics


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)


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


Endoscopic nasal polyp score improvement

**

intranasal steroids permitted

10/20

12/20

13/20


Anti-MMPs IL-5

ECP

IgE



Anti-IgE

Anti-CCR3 ?

Antibiotics


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


Inclusion criteria


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)


Improvement in symptomsOmalizumab (n=15) versus placebo (n=8)


CT-scans before and after Anti-IgE


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) ?


Case reportMale, 46 years: nasal polyps, asthma, AERDNasal polyp score after 4 injections Omalizumab


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


ENT Department Upper Airways Research Laboratory New insights in the pathophysiology of chronic...

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