Asthmatic Cough (Cough variant asthma) & Nonasthmatic Eosinophilic Bronchitis
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Transcript of Asthmatic Cough (Cough variant asthma) & Nonasthmatic Eosinophilic Bronchitis
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Asthmatic Cough Asthmatic Cough (Cough variant asthma) & (Cough variant asthma) &
Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic Bronchitis
Necla Songür, MDNecla Songür, MD
Süleyman Demirel University School of MedicineSüleyman Demirel University School of MedicineDepartment of Chest DiseasesDepartment of Chest Diseases
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Spontaneous or induced sputum Spontaneous or induced sputum eosinophils ratio > 2.5 %eosinophils ratio > 2.5 %
Eosinophilic Bronchitis
Gibson PG et al, Thorax 2002
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Eosinophilic BronchitisEosinophilic BronchitisClinical PresentationClinical Presentation
AsthmaAsthma Cough variant asthmaCough variant asthma
Nonasthmatic eosinophilic bronchitisNonasthmatic eosinophilic bronchitis Atopic coughAtopic cough Allergic rhinitisAllergic rhinitis Gastro-esophageal reflux disease (GERD)Gastro-esophageal reflux disease (GERD) Chronic obstructive pulmonary disease (COPD)Chronic obstructive pulmonary disease (COPD)
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Eosinophilic BronchitisEosinophilic Bronchitis PrevalancePrevalance
Healthy Rhinitis Cough ERS CVA Asthma
Gibson PG et al, Thorax 2002
20
40
60
80
100
%
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Eosinophilic BronchitisEosinophilic BronchitisPathogenesisPathogenesis
AsthmaAsthma
Chronic cough Chronic cough ILIL55 COPD COPD
Allergic rhinitis?Allergic rhinitis?GERD?GERD?
Gibson PG et al, J Allergy Clin Immunol 1998Brightling CE et al, Am J Respir Crit Care Med 2000 Saette et al, Clin Exp Allergy 1996
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Eosinophilic BronchitisEosinophilic BronchitisChronic CoughChronic Cough
Cough variant asthmaCough variant asthma Nonasthmatic eosinophilic bronchitisNonasthmatic eosinophilic bronchitis Atopic coughAtopic cough
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Chronic Cough & Eosinophilic BronchitisChronic Cough & Eosinophilic Bronchitis
CE
G
A B
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Eosinophilic bronchitis with chronic cough
Airflow obstruction
Remodelling
ASTHMA? COPD?
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Cough Variant AsthmaCough Variant Asthma DiagnosisDiagnosis
Chronic cough lasting more than 8 weeks Chronic cough lasting more than 8 weeks Absence of a history of wheezing or Absence of a history of wheezing or dyspneadyspneaAbsence of post-nasal drip Absence of post-nasal drip Physical examination of lungs is normalPhysical examination of lungs is normalChest roentgenography is normalChest roentgenography is normal
Corrao et al, N EJM 1979
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Cough Variant AsthmaCough Variant Asthma DiagnosisDiagnosis
FEVFEV11> 80% (pred), FVC>80%(pred)> 80% (pred), FVC>80%(pred)
FEVFEV1 1 / FVC / FVC ≥ ≥ 70 %(pred)70 %(pred)
PCPC2020-FEV-FEV11< 10 mg/ml< 10 mg/ml
Relief of cough after bronchodilator Relief of cough after bronchodilator theraphytheraphy
Corrao et al, NEJM 1979
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Cough Variant AsthmaCough Variant Asthma
Is a subgroup of asthma ?Is a subgroup of asthma ?
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Subject profileSubject profile BABA CVACVA ACAC ControlControl
NumberNumber 3131 1717 2020 2525
Male: FemaleMale: Female 13:1813:18 10:710:7 13.1713.17 11:1411:14
AgeAge 70-1670-16 71-2271-22 72-3672-36 48-2148-21
FVC (pred%)FVC (pred%) 102±12102±12 104±17104±17 92±1692±16 112±13112±13
FEV1(pred%)FEV1(pred%) 74±2374±23 94±1694±16 85±1485±14 91±1191±11
FEV1/FVC %FEV1/FVC % 70±1070±10 79±979±9 85±1185±11 88±1488±14
PC20-FEVPC20-FEV11 0.79(1.69)**0.79(1.69)** 3.60(1.42)3.60(1.42) 24.7(1.79)24.7(1.79) 30.6(1.33)30.6(1.33)
BronchialBronchialReversibilityReversibility
25±17**25±17** 8.2±4.7*8.2±4.7* 3.0±2.33.0±2.3 --
Capsaicin coughCapsaicin coughthresholdthreshold
18.2(1.45)**18.2(1.45)** 9.14(1.54)9.14(1.54) 1.72(0.54)1.72(0.54) --
Songür N et al, J Asthma 1997
Detection of Eosinophils in Hypertonic Saline-Induced Sputum in Patients with Chronic Nonproductive Cough
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GroupGroup nn varvar %%
yokyok %%
no.no.%%
no.no.%%
no.no.%%
BronchialBronchialasthmaasthma
2525 25 25 (100 %)(100 %)
0 0 ( 0 %)( 0 %)
15 15 (60.9%)(60.9%)
10 10 (40%)(40%)
00
CoughCoughvariant variant asthmaasthma
1212 8 8 (66%)(66%)
4 4 (33.3%)(33.3%)
3 3 (37.5%)(37.5%)
5 5 (62.5%)(62.5%)
00
Atopic Atopic coughcough
1717 1515( 88 %)( 88 %)
22(11.8%)(11.8%)
1212( 80 %)( 80 %)
33(20%)(20%)
00
ControlControl 2323 22( 8.6 %)( 8.6 %)
2121( 91.3%)( 91.3%)
00( 0 %)( 0 %)
22(100%)(100%)
00
Presence of Eosinophils in Induced sputum in Each Patients Group
Eosinophils 1-25 % 26-75 % 76-100 %
Songür N et al, J Asthma 1997
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Percentage of Eosinophils in BAL and Percentage of Eosinophils in BAL and Number of Eosinophils in Bronchial TissueNumber of Eosinophils in Bronchial Tissue
Niimi A et al, Eur Res J 1998
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1515Niimi A et al, Lancet 2001
Eosinophilic inflammation in patients with CVA may cause remodelling of the airway.
Control CVA Asthma
Sub
epith
elia
l lay
er th
ickn
ess
(µm
)
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De Diego et al, Allergy 2005
IL5 IL8 TNFά
Cough variant asthma and asthma share a similar airway inflammatory marker profile
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Cough variant asthma comprises a Cough variant asthma comprises a subgroup of asthmasubgroup of asthma
Eosinophilic airway inflammation in asthma Eosinophilic airway inflammation in asthma and cough variant asthma is similar.and cough variant asthma is similar.
The ratio of eosinophilic inflammation is not The ratio of eosinophilic inflammation is not related to differences between symptoms of related to differences between symptoms of cough variant asthma and classic asthmacough variant asthma and classic asthma
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CoughCough
Heightened airway cough receptor Heightened airway cough receptor sensitivitysensitivity ( ( CC55≤ 3.9≤ 3.9uuMM ))
BronchoconstructionBronchoconstruction
Songür N et al, Respirology, 2000Songür N et al, Respirology, 2000 Fujimura M et al, Thorax 1992Fujimura M et al, Thorax 1992
Fujimura M et al, Eur Res J 1992Fujimura M et al, Eur Res J 1992
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Cough receptor sensitivity is within normal limits in patients with cough variant asthma and inhale corticosteroids does not affect the sensitivity
Fujimura M et al, Cough 2005 Songür N et al, J Asthma 1997
Patients with ICSPatients without ICS
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Cough Variant AsthmaCough Variant Asthma““Cough Reflex Sensitivity”Cough Reflex Sensitivity”
within normal limits (Cwithin normal limits (C55>3.9>3.9µµMM) )
not a feature of diseasenot a feature of disease
Fujimura M et al, Eur Res J 1992
Fujimura M et al, J Asthma 1994 Songür N et al, J Asthma 1997 Fujimura M et al, Cough 2005
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Cough Variant AsthmaCough Variant Asthma
Cough in the middle of the night and early Cough in the middle of the night and early in the morningin the morningPEFR monitoring PEFR monitoring →→ morning dip morning dipIncrease in FEV1 after therapyIncrease in FEV1 after therapyRelief of cough with bronchodilator Relief of cough with bronchodilator
therapytherapyShirata et al, Respirology 2005Sano T et al, Lung 2004Fujimura M et al, Clin Exp Allergy 2003Kim CK et al, Clin Exp Allergy 2003
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Cough Cough VariantVariant asthma asthma
Small degree contractions of airway Small degree contractions of airway smooth muscle trigger cough.smooth muscle trigger cough.
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Cough Variant AsthmaCough Variant Asthma
Pre-asthmatic statePre-asthmatic state
Early stage of mild persistant asthmaEarly stage of mild persistant asthma
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Study/Year CVA (n) Median fallow up (year) AsthmaStudy/Year CVA (n) Median fallow up (year) Asthma (%) (%)
Corrao et al 1979Corrao et al 1979 6 1 2 (33) 6 1 2 (33) Braman et al 1985Braman et al 1985 16 3-5 6 (37)16 3-5 6 (37) Kim et al 2003Kim et al 2003 51 4 24 (47)51 4 24 (47)
Fujimura et al 2003Fujimura et al 2003 55 4 8 (14) 55 4 8 (14)
Fujimura et al 2005Fujimura et al 2005 20 3 3 (15) 20 3 3 (15)
Fujimura et al 2005Fujimura et al 2005 27 4 7 (29) 27 4 7 (29)
Nearly 30% of cough variant asthma develop typical asthma within several years
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10
20
30
40
50
60
70
80
D
evel
opm
ent o
f Cla
ssic
Ast
hma
% Cough Variant Asthma
Predictor of Subsequent Development of Classic Asthma
An increased ratio of
eosinophil in induced
sputum can predict the subsequent
development of classic asthma
Kim CK et al, Clin Exp Allergy 2003
0-2.4 2.5-4.7 4.8-8.2 8.3-17.3
Sputum eosinophil (%)
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CoughCough Variant AsthmaVariant Asthma Predictors of Subsequent Development of Predictors of Subsequent Development of
Classic AsthmaClassic Asthma
Univariate analysisUnivariate analysis
Bronchial Bronchial hyperresponsivenesshyperresponsivenessBlood eosinophils (%) Blood eosinophils (%) No use of inhaled No use of inhaled corticosteroidscorticosteroids
Multivariate analysisMultivariate analysisBronchial Bronchial hyperresponsivenesshyperresponsiveness
Fujimura M et al, J Asthma 2005
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Cough Variant AsthmaCough Variant AsthmaTreatmentTreatment
Inhaled bronchodilators (Inhaled bronchodilators (ββ agonist) agonist) Inhaled corticosteroids (mean: 400mcg, 200-800 mcg)Inhaled corticosteroids (mean: 400mcg, 200-800 mcg) Leukotriene receptor antogonists Leukotriene receptor antogonists
Oral corticosteroids (30 or 40mg prednizone/daily / for one Oral corticosteroids (30 or 40mg prednizone/daily / for one week)week)
Suplatast tosilateSuplatast tosilate Dicpinigaitis PV, Thorax 2004
Dicpinigaitis PV, Chest 2006
?
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Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic Bronchitis DiagnosisDiagnosis
Isolated chronic cough lasting more than 8 Isolated chronic cough lasting more than 8 weeks weeks Absence of a history of wheezing and Absence of a history of wheezing and dyspneadyspneaAbsence of post-nasal drip Absence of post-nasal drip Physical examination of lungs is normalPhysical examination of lungs is normalChest roentgenography is normalChest roentgenography is normal
Gibson PG et al, Lancet 1989
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Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic BronchitisDiagnosisDiagnosis
FEVFEV11> 80% (pred), FVC> 80% (pred)> 80% (pred), FVC> 80% (pred)
FEVFEV11/FVC /FVC ≥≥70% (pred)70% (pred)
PCPC2020-FEV-FEV11> 16 mg/ml> 16 mg/ml
Sputum eosinophil > 3% (11% - 85%)Sputum eosinophil > 3% (11% - 85%)Relief of cough treatment with inhaled Relief of cough treatment with inhaled corticosteroids or oral corticosteroidscorticosteroids or oral corticosteroids
Gibson PG et al, Lancet 1989
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EosinophilicEosinophilicbronchitis (n=16)bronchitis (n=16)
AsthmaAsthma(n=15)(n=15)
NormalNormal(n=14) (n=14)
Mean (SE)ageMean (SE)age 48 (3)48 (3) 46 (4)46 (4) 37 (5) 37 (5)
Male Male 10 10 8 8 8 8
AtopyAtopy 90 (17)90 (17) 106 (29)106 (29) 36 (10) 36 (10)
PCPC2020FEVFEV11 (mg/ml) (mg/ml) 94 (18–128)94 (18–128) 0.8 (0.16–4.60.8 (0.16–4.6) ) 128 (16–128) 128 (16–128)
Mean (SE) FEV1 Mean (SE) FEV1 (% pred) (% pred)
100 (2.6)) 100 (2.6)) 99 (3.2)99 (3.2) 100 (3.7) 100 (3.7)
Mean (SE) Mean (SE) FEV1/FVC (%) FEV1/FVC (%)
80 (1.4)80 (1.4) 72 (1.9)72 (1.9) 79 (1.8) 79 (1.8)
Nitric oxide (ppb)Nitric oxide (ppb) 12 (5–30)*12 (5–30)* 8.5 (2-32)*8.5 (2-32)* 2 (1–9)2 (1–9)
Brightling CE et al, Thorax 2003
Nonasthmatic Eosinophilic BronchitisClinical Features
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NAEB Asthma NormalNAEB Asthma Normal
Induced sputumInduced sputum
EosinophilEosinophil 9.75 9.75 ((3.3–683.3–68)** )** 3.43.4 ( (0–33.50–33.5)** )** 0.350.35 ( (0–2.750–2.75))
Bronchial washBronchial wash
EozinophilEozinophil 2.42.4 ( (0.5–250.5–25)** )** 1.41.4 ( (0–40.50–40.5)** )** 00 ( (0–10–1) )
BAL BAL
EosinophilEosinophil 1.61.6 ( (0–130–13)* )* 1.51.5 ( (0–40–4)* )* 0.50.5 ( (0–20–2) )
Eosinophil counts in induced sputum, bronşial wash and BAL fluid in patients with nonasthmatic
eosinophilic bronchitis
Brightling CE et al, Thorax 2003*p<0.05,**p<0.01,
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NAEB Asthma NormalNAEB Asthma Normal
SubepitheliumSubepithelium
MBPMBP 32 32 (12–430)**(12–430)** 20 20 (4–114)**(4–114)** 8 8 (0–24)(0–24)
EpitheliumEpitheliumMBPMBP 11.6 11.6 (0–288)**(0–288)** 16.7 16.7 (0–33.3)**(0–33.3)** 0 0 (0–5.2)(0–5.2)
Basement Basement membrane widhtmembrane widht
9 9 (0.7) µm(0.7) µm 10.7 10.7 (1.1) µm(1.1) µm 7.2 7.2 (0.4) µm(0.4) µm
Epithelial integrityEpithelial integrity 70 %70 % 79 %79 % 86 %86 %
**p<0.01
Nonasthmatic Eosinophilic Bronchitis Pathogenesis
Brightling CE et al, Thorax 2003
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ConclusionConclusion
Airway inflammation is similar in both Airway inflammation is similar in both
conditions and the site of inflammation is conditions and the site of inflammation is mainly in the lower airway.mainly in the lower airway.
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Why is NAEB not asthma ? Why is NAEB not asthma ?
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Induced sputumInduced sputum EosinophilicEosinophilic
BronchitisBronchitisAsthmaAsthma PP
ECP, ng/mlECP, ng/ml 604 (2.2604 (2.2 735 (2.8)735 (2.8) NSNS
LTCLTC44DD44EE4,4,ng/mlng/ml 9.27 (0.08)9.27 (0.08) 11.1 (0.08)11.1 (0.08) NSNS
HA, ng/mlHA, ng/ml 168 (0.19)*168 (0.19)* 25.1 (0.2)25.1 (0.2) <0.01<0.01
PGDPGD2,2,ng/mlng/ml 0.79 (0.11)*0.79 (0.11)* 0.32 (0.06)0.32 (0.06) <0.01<0.01
PGEPGE22, ng/ml, ng/ml 1.95 (0.07)1.95 (0.07) 1.36 (0.06)1.36 (0.06) NSNS
PGFPGF22αα,ng/ml,ng/ml 0.60 (0.11)0.60 (0.11) 0.53 (0.06)0.53 (0.06) NSNS
TXBTXB22, ng/ml, ng/ml 1.58 (0.07)1.58 (0.07) 0.94 (0.10)0.94 (0.10) NSNS
Brightling CE et al, AJCCM 2000
The difference in symptoms of NAEB is not due to the differences in mediator production
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Mast cell infiltration of airway smooth muscle in asthma
Brightling CE et al , NEJM 2002
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3737Brightling CE et al, NEJM 2002 p<0.001
There is no mast cell infiltration of airway smooth muscle in nonasthmatic eosinophilic bronchitis
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AsthmaAsthma Eosinophilic Eosinophilic bronchitisbronchitis
Bronşial wash Bronşial wash and BAL fluid:and BAL fluid: “ “mast cell count” mast cell count” /mm/mm22
↑↑ ↑ ↑↑ ↑ Gibson PG, J Gibson PG, J Allergy Clin Allergy Clin Immunol 1998Immunol 1998
Induced sputum:Induced sputum:HA, PGDHA, PGD22“(ng/ml)“(ng/ml)
↑ ↑ ↑ ↑ ↑ ↑ Brightling CE, Brightling CE, AJCCM 2000AJCCM 2000
Smooth muscle: Smooth muscle: “mast cell “mast cell count” /count” /mmmm22
↑↑ →→ Brightling CE, Brightling CE, NEJM 2002NEJM 2002
Submucosa: Submucosa: IL13IL13++ cell cell /mm/mm22
↑ ↑↑ ↑ ↑↑ Berry MA, J Berry MA, J Allergy Allergy Clin Immunol Clin Immunol 20042004
Why is Eosinophilic Bronchitis not Asthma
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AsthmaAsthma Eosinophilic Eosinophilic Bronchitis Bronchitis
Sputum;Sputum;IL 5 (pg/g)IL 5 (pg/g)
↑ ↑↑ ↑ ↑ ↑↑ ↑ Park SW, Chest Park SW, Chest 20052005
Sputum; Sputum; IL13 (pg/g)IL13 (pg/g)
↑ ↑↑ ↑ ↑↑ Park SW, Chest Park SW, Chest 20052005
Sputum; Sputum; VEGF VEGF ((pg/ml)pg/ml)
↑ ↑↑ ↑ ↑↑ Kanazawa H Kanazawa H ACCM 2004ACCM 2004
HRCT “airwall HRCT “airwall areaarea%”%”
↑ ↑↑ ↑ →→ Park SW, Park SW, Thorax 2006Thorax 2006
Why is Eosinophilic Bronchitis not AsthmaWhy is Eosinophilic Bronchitis not Asthma
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Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic Bronchitis““Cough Reflex SensitivityCough Reflex Sensitivity””
The cause of cough is the hightened The cause of cough is the hightened cough reflex sensitivity cough reflex sensitivity (C5< 3.9(C5< 3.9uuM ). M ). The therapy of inhaled or oral The therapy of inhaled or oral corticosteroid suppresse of coughing, corticosteroid suppresse of coughing, sputum eosinophilia, and cough reflex sputum eosinophilia, and cough reflex sensitivity to inhaled capsaicinsensitivity to inhaled capsaicin..
Gibson PG et al, Clin Exp Allergy 1998Brightling CE et al, Eur Respir J 2000
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The specific role of mast cells in the bronchial epithelium of patients with nonasthmatic eosinophilic bronchitis and its interactions with cough sensory afferents needs further study.
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NAEB is generally benign andNAEB is generally benign and self-limiting disease (?)self-limiting disease (?)
Hancox RJ et al, Lancet 2001
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NAEBNAEB may be forerunner the subsequent may be forerunner the subsequent development of classic asthma and COPDdevelopment of classic asthma and COPD
52 patients with NAEB (1996-2003)52 patients with NAEB (1996-2003) 32 patients (follow up >1year)32 patients (follow up >1year)
3 (9%) patients developed3 (9%) patients developed classic asthmaclassic asthma 5 (16%) patients developed5 (16%) patients developed fixed airflow fixed airflow obstructionobstruction
Berry MA et al, Clin Exp Allegy 2005
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Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic BronchitisTreatmentTreatment
Inhale corticosteroids (200-400 Inhale corticosteroids (200-400 mcg)mcg)Oral corticosteroidsOral corticosteroidsAvoidance strategiesAvoidance strategies
Brightling CE, Chest 2006
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Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic Bronchitis
Persistent eosinophilic inflammationPersistent eosinophilic inflammation
Airway Airway remodellingremodelling
Progressive irreversible airflow obstructionProgressive irreversible airflow obstruction
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The early diagnosis and The early diagnosis and suscessful treatment is very suscessful treatment is very important in patients with NAEB. important in patients with NAEB.