11

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

22

Spontaneous or induced sputum Spontaneous or induced sputum eosinophils ratio > 2.5 %eosinophils ratio > 2.5 %

Eosinophilic Bronchitis

Gibson PG et al, Thorax 2002

33

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)

44

Eosinophilic BronchitisEosinophilic Bronchitis PrevalancePrevalance

Healthy Rhinitis Cough ERS CVA Asthma

Gibson PG et al, Thorax 2002

20

40

60

80

100

%

55

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

66

Eosinophilic BronchitisEosinophilic BronchitisChronic CoughChronic Cough

Cough variant asthmaCough variant asthma Nonasthmatic eosinophilic bronchitisNonasthmatic eosinophilic bronchitis Atopic coughAtopic cough

77

Chronic Cough & Eosinophilic BronchitisChronic Cough & Eosinophilic Bronchitis

CE

G

A B

88

Eosinophilic bronchitis with chronic cough

Airflow obstruction

Remodelling

ASTHMA? COPD?

99

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

1010

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

1111

Cough Variant AsthmaCough Variant Asthma

Is a subgroup of asthma ?Is a subgroup of asthma ?

1212

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

1313

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

1414

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

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

)

1616

De Diego et al, Allergy 2005

IL5 IL8 TNFά

Cough variant asthma and asthma share a similar airway inflammatory marker profile

1717

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

1818

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

1919

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

2020

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

2121

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

2222

Cough Cough VariantVariant asthma asthma

Small degree contractions of airway Small degree contractions of airway smooth muscle trigger cough.smooth muscle trigger cough.

2323

Cough Variant AsthmaCough Variant Asthma

Pre-asthmatic statePre-asthmatic state

Early stage of mild persistant asthmaEarly stage of mild persistant asthma

2424

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

25250

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 (%)

2626

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

2727

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

?

2828

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

2929

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

3030

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

3131

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,

3232

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

3333

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.

3434

Why is NAEB not asthma ? Why is NAEB not asthma ?

3535

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

3636

Mast cell infiltration of airway smooth muscle in asthma

Brightling CE et al , NEJM 2002

3737Brightling CE et al, NEJM 2002 p<0.001

There is no mast cell infiltration of airway smooth muscle in nonasthmatic eosinophilic bronchitis

3838

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

3939

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

4040

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

4141

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.

4242

NAEB is generally benign andNAEB is generally benign and self-limiting disease (?)self-limiting disease (?)

Hancox RJ et al, Lancet 2001

4343

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

4444

Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic BronchitisTreatmentTreatment

Inhale corticosteroids (200-400 Inhale corticosteroids (200-400 mcg)mcg)Oral corticosteroidsOral corticosteroidsAvoidance strategiesAvoidance strategies

Brightling CE, Chest 2006

4545

Nonasthmatic Eosinophilic BronchitisNonasthmatic Eosinophilic Bronchitis

Persistent eosinophilic inflammationPersistent eosinophilic inflammation

Airway Airway remodellingremodelling

Progressive irreversible airflow obstructionProgressive irreversible airflow obstruction

4646

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.