evaluation of airway remode l ling & angiogenesis in c ough v ariant a sthma
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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
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