Evaluation of airway

remodelling & angiogenesis

in

Cough Variant Asthma

Evaluation of airway

remodelling & angiogenesis

in

Cough Variant Asthma

İ.Kıvılcım Oğuzülgen, Nalan Akyürek*, Nurdan Köktürk ve Haluk Türktaş

Gazi University School of Medicine

Dept. Of Pulmonary Medicine and Pathology*, Ankara

İ.Kıvılcım Oğuzülgen, Nalan Akyürek*, Nurdan Köktürk ve Haluk Türktaş

Gazi University School of Medicine

Dept. Of Pulmonary Medicine and Pathology*, Ankara

In a subgroup of asthmatic patients, cough is

the predominant or sole symptom. This

condition has been termed cough variant

asthma (CVA) in 1979.

Cough Variant Asthma (CVA)Cough Variant Asthma (CVA)

Dicpinigaitis PV. CHEST 2006; 129:75S–79S.

Corrao WM et al. N Engl J Med 1979; 300: 633-7.2

CVA comprise a distinct subgroup of individuals

with asthma, rather than simply being asthmatic

patients who cough. Subjects with the typical form

of asthma do not differ from healthy volunteers in

terms of experimentally measured cough reflex

sensitivity, whereas those with CVA have a

significantly more sensitive cough reflex.

Cough Variant Asthma (CVA)Cough Variant Asthma (CVA)

3

In a patient suspected of having CVA but in whom

physical examination and spirometry findings are

nondiagnostic, MIC testing should be performed to

confirm the presence of asthma. However, a diagnosis of

CVA is established only after the resolution of cough with

specific antiasthmatic therapy.

Dicpinigaitis PV. CHEST 2006; 129:75S–79S.

Diagnosis of CVADiagnosis of CVA

4

5Nature Reviews Immunology 2008; 8:218-230

Airway remodelling in asthmaAirway remodelling in asthma

5

...

..........

Vasodilatation

Inflamation

Edema

Epithelial desquamation

Smooth muscle hypertrophia

Subepithelial fibrosis with tickening of basement membrane

Mucous gland hyperplasia

Angiogenesis

Airway remodelling in asthmaAirway remodelling in asthma

6

The aim of this study was to evaluate airway

remodeling and bronchial mucosal agiogenesis in

CVA patients and compare the findings with classic

asthma and control subjects with other causes of

cough.

Aim:Aim:

7

Patients with duration of cough over 8 weeks

Who has never smoked

Who has not experienced any upper or lower airway

infection within 3 months

Who do not have any chronic lung disease

With normal oscultation findings, normal PFT, normal

chest x-ray

Patients with cough:

Methods:Methods:

8

Steroid naive mild-moderate asthmaics:

Classic asthmaClassic asthmaClassic asthmaClassic asthma

Methods-II:Methods-II:

Classic asthmatics:

9

PFT

Methacoline challenge test

Fiberoptic bronchoscopy with bronchial biopsies

(+) İnhaled CS

CVACVACVACVA

(-)

Non-asthmatic Non-asthmatic

coughcough

Non-asthmatic Non-asthmatic

coughcough

Methods-III:Methods-III:

Patients with chronic cough (≥ 8 weeks)

(Inclusion /exclusion criteria)

Classic Classic

asthmaticsasthmatics

Classic Classic

asthmaticsasthmatics

10

Methods-IV:Methods-IV:

Bronchial biopsy samples were stained with hematoxilen

eosin and asseses for the typical morphological cahnges

of asthma.

Immunoperoxidase staining was performed to retrieve

antigen expression for Collagen type 4 and CD31

antibodies in vessels. By the computerized image

analysis system; the total number of vessels was divided

by the biopsy area examined to determine the number of

vessels per square millimeter of lamina propria to a depth

of 150 m below the basement

11

3 patients: GER

.. patients: Post nasal drip syndrome

.. patents: Cough associated with ACE inhibitors

... Patients: Miscalenous

Non-asthmatic cough patients:Non-asthmatic cough patients:

12

# of patients# of patients

Asthmatics CVA Non-asthmatic cough

Planned 15 15

Undervent investigations 10 12 13

Immunohystochemistry 6 8 10

Study subjectsStudy subjects

13

AsthmaticsAsthmatics

(n:10)(n:10)

CVACVA

(n:12)(n:12)

Non-asthmatic Non-asthmatic cough (n:13)cough (n:13)

Age 40.8 ± 8.4 43.8 ± 10.3 44.0 ± 11.5

Gender (F/M) 7/3 12/0 9/4

Symptom duration (months-median)

36*

(12-300)

9

(2-120)

24

(2-120)

FEV1 (%) 84.0 ± 13.6** 102.8 ± 14.1 111.4 ± 13.2

Presence of atopy (+/-) 5/5 4/8 0/13

*p=0.004

**p=0.007

Patients characteristicsPatients characteristics

14

Bronchial biopsy findinsBronchial biopsy findins

Hematoxilen eosin (x200)

Non-asthmatic

cough

CVAClassic asthma

15

Hematoxilen eosin (x400)

Classic asthma Non-asthmatic

cough

Bronchial biopsy findinsBronchial biopsy findins

16

Bronchial biopsy findings Bronchial biopsy findings

17

Presence of inflamation AsthmaticsAsthmatics

(n:10)(n:10)

CVACVA

(n:12)(n:12)

Non-asthmatic Non-asthmatic cough (n:13)cough (n:13)

None 0 0 %58.3 (7)

+ %60 (6) %66.7 (8) %33.3 (4)

++ %30 (3) %16.7 (2) %8.3 (1)

+++ %10 (1) %16.7 (2) 0

Missing data - - %8.3 (1)

Presence of airway inflammationPresence of airway inflammation

18

Non-asthmatic

cough

CVA Classic asthma

Bas

al m

emb

ran

e (µ

m)

p=0.025

p= 0.000

p=0.000

Basal membrane Basal membrane

19

Bronchial biopsy findings (angiogenesis)Bronchial biopsy findings (angiogenesis)

Anti-human collagen 4

Non-asthmatic

cough(x400)

CVA

(x200)

Classic asthma

(x200)

20

Ves

sel

den

sity

/ m

m2

p= NS

p=0.003

p=0.001

Angiogenesis (Collagen 4)Angiogenesis (Collagen 4)

21

Anti-CD 31

Bronchial biopsy findings (angiogenesis)Bronchial biopsy findings (angiogenesis)

Non-asthmatic

cough(x400)

CVA

(x200)

Classic asthma

(x200)

22

Ves

sel

den

sity

/ m

m2

Angiogenesis (CD 31)Angiogenesis (CD 31)

23

Li X et al. Am J Tespir Crit Care Med 1997; 156:229-33Doherty T et al Curr Opin Immunol 2007;19:676-680.

Walters EH et al. Curr Opin Allergy Immunol 2008;8:39-43.

Angiogenesis as a part of airway remodelling in

asthma has been accepted in the last 10 years.

Angiogenesis is present even in mild-moderate

asthmatics.

The main cause of angiogensis is the secretion

of angiogenic growth factors (VEGF) secondary

to inflammation.

DiscussionDiscussion

24

Author Findings

Niimi A et al

Eur Respir J 1998; 11:1064-9CVA (n:14) vs classic asthma (n:21) vs control (n:7)

FOB (eosinophils in BAL and bronchial biopsy) and

serum ECP

Eosinophilic inflammation is present in both CVA

and classic asthma

Lancet 2000; 356:564-5

J Allergy Clin Immunol 2005;116:565-70CVA (n:14) vs non-asthmatic cough (n: 33) vs

control (n:15)

Submucosal eosinophils and neutrophils are

increased in CVA

Remodelling is linked to chronic cough

Inflammation & pathological studies on CVAInflammation & pathological studies on CVA

25

Author Findings

De Diego A et al.

Allergy 2005; 60:1407-11CVA (n:12) vs classic asthma (n:15)

eNO & sputum induction (ECP, IL-8, IL-5, TNFα)

Two groups had similar findings.

Kanazawa H et al.

Ann Allegy Asthma Immunol 2005; 95: 266-71

CVA (n:16) vs Classic asthma (n:16) vs Control

(n:12)

eNO & sputum induction (cell count, ECP,

VEGF, alb concentration)

Classic asthma have higher VEGF levels, but

other inflammation markers were similar in CVA

and classic asthma but different from controls.

Inflammation & pathological studies on CVAInflammation & pathological studies on CVA

26

These finding suggest that remodelling

and partly angiogenesis is present in CVA

but findings are moderate when compared

to classic asthma.

ConclusionConclusion

27