ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

Severe Chronic Upper

Respiratory Disease:

Phenotyping Inflammation

Upper Airways Research LaboratoryDepartment of Otorhinolaryngology

Claus Bachert DGAKI GermanyGA2LEN Ghent

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

Prevalence of SCURD in the EUPrevalence of SCURD in the EU

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 mMore than 350 000 surgeries/yearIn Europe, 1M in the world

Aspirin sensitivity 0.5-3 12 millions 10 m

Consider socio-economic impact of SCURD !

Total population (2007): 490 millions

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

Prevalence of "cases" in GA2LEN survey by Centre

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

20.00

45.R

AMS

1.G

hent

32.K

atow

ice

19.L

odz

15.A

mst

erda

m

10.T

UM M

unich

13.P

alerm

o

31.L

ondo

n

8.Cha

rite

6.Hels

inki

CENTRE

Pre

vale

nce

(%

)

Asthma

'Sinusitis'

Both

One third suffered from both, CRS and asthma.

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

Management of Chronic Rhinosinusitis

ENT DepartmentUpper 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

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

TGF-beta receptors (mRNA)

*

** *

*

Van Bruaene et al, submitted

ENT DepartmentUpper 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

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

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

Claus Bachert, MD PhD

Objective and study design

30 SubjectsSevere nasal polyps

20 Subjects

10 Subjects

Weeks 0 1 4 128

*

MEPO 750mg IVPlacebo

Dosing

Follow up

* Primary endpoint

24 36 48

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

Endoscopic Nasal polyp score and improvement

**

intranasal steroids permitted

10/20

12/20

13/20

ENT DepartmentUpper 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 2001Review: Bachert C et al. Clin Allergy Immunol. 2007

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

  Controls NP- 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 (kUA/ L)

BDL 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 (kUA/ L)

BDL BDL 0.4 (IQR: 0.1- 1.3)

ENT DepartmentUpper 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

ENT DepartmentUpper Airways Research Laboratory

Claus Bachert, MD PhD

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