CHRONIC COUGH

MÜNEVVER ERDİNÇDepartment of Chest Diseases

Ege University Faculty of Medicine

Differential Diagnosis And Treatment In Adults

Acute Cough lasting less than 3 weeks

Subacute Cough lasting 3 to 8 weeks

Chronic Cough

Lasting more than 8 weeks

Morice AH.Eur Respir J 2004 :24:481-492

Fontana GA.Thorax 2003;58:1092-1095

Irwin RS.NEJM 343(23): 1715-1721,2000

Irwin RS. Chest 1998; 114(suppl1) :133S-181S

Differantial Diagnosis of Chronic Cough in Adults

Differantial Diagnosis of Chronic Cough in Adults

• PNDS– Allergic rhinitis– Chronic sinusitis

• GERD• Cough variant asthma• ACEI induced cough• Pertusis• Neurogenic

– Traumatic – Postinfectious cough

• Phychogenic cough• Chronic aspiration• Zenker diverticulosis

• Foreign body

• Chronic bronchitis

• Bronchiectasis

• Lung cancer

• Subglottic stenosis

• Tracheomalasie

• Tracheoesophageal fistul

• Tuerculosis

• Sarcoidosis

• Congestive heart failure

Simpson CB. Otolaryngology–Head Neck Surg 2006; 134: 693-700

In prospective studies in adults, In prospective studies in adults, chronic cough is most commonly chronic cough is most commonly

due to 6 disorders :due to 6 disorders :

Upper Airway Cough Syndrome (Upper Airway Cough Syndrome (UACSUACS))

AstAsthmahma

GGERDERD

Chronic BronchitisChronic Bronchitis

BronBronchiectasischiectasis

Non-astNon-asthhmatimaticc EEoosinophilic Bronchitissinophilic Bronchitis

In prospective studies in adults, In prospective studies in adults, chronic cough is most commonly chronic cough is most commonly

due to 6 disorders :due to 6 disorders :

Upper Airway Cough Syndrome (Upper Airway Cough Syndrome (UACSUACS))

AstAsthmahma

GGERDERD

Chronic BronchitisChronic Bronchitis

BronBronchiectasischiectasis

Non-astNon-asthhmatimaticc EEoosinophilic Bronchitissinophilic Bronchitis

Guidelines Writing Committee. Chest 2006; 129 (Suppl. 1): 1S-292S

New New ConsiderationsConsiderations

Eosinophilic bronchitis

Atopic cough

Non acid(volume)/ weakly acid reflux

Idiopathic (unexplained) öksürük

Diagnosis and Management of Cough Diagnosis and Management of Cough ACCP Evidence-Based CPG 2006ACCP Evidence-Based CPG 2006

Guidelines Writing Committee. Guidelines Writing Committee. ChestChest 2006; 129 (Suppl. 1): 1S-292S 2006; 129 (Suppl. 1): 1S-292SPlevkova, et al. Plevkova, et al. Respir Physiol NeurobiolRespir Physiol Neurobiol 2004; 142: 225-235 2004; 142: 225-235

Postnasal drip syndrome (PNDS) renamed upper airway cough syndrome (UACS)Upper airway afferents may reflexly enhance coughing

Nonasthmatic eosinophilic bronchitis recognized as a common cause of chronic cough

Idiopathic cough renamed unexplained coughThe term acid reflux disease, unless it can be definitively shown to

apply, replaced by reflux diseaseUpdate of current diagnostic and therapeutic approaches

Common diseases, Uncommon diseasesNew algorithms for the management of cough in adults and

childrenAn empiric integrative approach is recommended

Postnasal drip syndrome (PNDS) renamed upper airway cough syndrome (UACS)Upper airway afferents may reflexly enhance coughing

Nonasthmatic eosinophilic bronchitis recognized as a common cause of chronic cough

Idiopathic cough renamed unexplained coughThe term acid reflux disease, unless it can be definitively shown to

apply, replaced by reflux diseaseUpdate of current diagnostic and therapeutic approaches

Common diseases, Uncommon diseasesNew algorithms for the management of cough in adults and

childrenAn empiric integrative approach is recommended

10

12

1312

16

64

ASTHMA

PNDS

GERD

Chest 1999;116:279-284

1. Gastroesophageal reflux disease (21-41%)

2. Cough variant asthma (24-59%)

3. Postnasal drip syndrome (41-58%)

38,5%

35,9%

16,7%

8,9%

Chest 1999;116:279-281

Percentage of Cases Presenting 1,2,3, and 4 Causative Factors

1

2

3

4

İmmunocompetent patients Not exposed to enviromental

irritants Chest radiograph is normal Not taking an ACE inhibitor Not a current smoker

Asthma and/or GERD, PNDS

responsible for 93.6% of the casesof chronic cough

Harding SM .Chest 2003;123:659-660

Changing Trends in Changing Trends in DiagnosisDiagnosis

0

10

20

30

40

50

60

70

80

90

1998 1999 2000 2001 2002 2003

Perc

en

tag

e o

f D

iag

no

ses

REFLUX ASTHMA RHINITIS

Perc

en

tag

e o

f D

iag

nosis

(%

)

GERD ASTHMA RHINITIS

Impaired esophageal clearanceFunctional

defect in LES syphincter Hiatal hernia

Delayed gastric emptying İncreased intra-abdominal

pressure

GERD ?

Decreased saliva

Heartburn (pyrosis) and regurgitationAt least weekly symptoms

extraesophageal reflux symptoms and/or esophageal mucosal damage /

Katzka & DiMarino 1995

FLR Signs

•Edema and hyperemia of larynxEdema and hyperemia of larynx•Vocal cord erythema, polyps, granulomas, ulcersVocal cord erythema, polyps, granulomas, ulcers•Hyperemia and lymphoid hyperplasiaHyperemia and lymphoid hyperplasia

of posterior pharynx of posterior pharynx •Interarytenoid changesInterarytenoid changes•Subglottic stenosisSubglottic stenosis

GERD-related cough incidence GERD-related cough incidence 5 - 55% 5 - 55%

May be the sole presenting symptom(1/3)May be the sole presenting symptom(1/3)

Thorax 2003:58;1092-1095)

(Chest 1997; 111: 1389-1402)

Irwin RS. Chest 2006;129:80S-94S

Association between cough and reflux is important

Esophageal-tracheal-bronchial reflex Esophageal-tracheal-bronchial reflex MicroaspirationMicroaspiration

ARRD 1981;123:413-417 Arch Intern Med 1996;156:997Chest 1993;104:1511-1517 El Hennawi, 2004 OHNS

Nonacidic factors?Esophageal dismotility?

.. Mediator Mediator ReleaseRelease.. I Inflammationnflammation.. Edema Edema.. Mucus Mucus .. Smooth Smooth MuscleMuscle

MicroaspirationMicroaspirationREFLUXREFLUX

EsophagealEsophagealVagalVagal

AfferentsAfferents

Bronchial HyperreactivityBronchial Hyperreactivity

Airway VagalAirway VagalAfferentsAfferents

CNSCNS

Stein MR.Am J Med 2003Chest 1997;111: 1389-1402Chest 1997;111: 1389-1402

Airway

Airway VagalAirway VagalEfferentsEfferents

EsophagusEsophagus Tracheobronchial Tracheobronchial TreeTree

Stomach

Oesophagus

Pharyngeal pHmetryPharyngeal pHmetry

+-Not GERD

Clinical GERD symptoms ?Nonacid, weakly acid reflux?

Increase dose PPI + alginate

İmproved Not improved

ContinuepHmetry

under treatment

Consider

Simultaneously dual probes

24 hours pHmonitoringand

intraesophageal impedance Irwin RS.AJRCCM 165:1469-74,2002McGarvey LPA.Thorax 59:342-346,2004

3 cm

5 cm

7 cm

9 cm

15 cm

17 cm

pH - 5 cm

6 impedance channels

1 pH electrode

+

Adult Standard

Model ZAN-S61C01E

Multichannel intraluminal impedance-pH catheter

NonNon acid acid refluxreflux

On going reflux of ‘non-acid’ material may be

responsible for continuing symptoms while on

acid-suppressing medications

Therapy in Esophageal-pulmonary refluxTherapy in Esophageal-pulmonary reflux

Conservative and lifestyle measuresConservative and lifestyle measures Ampirical therapyAmpirical therapy: Acid suppression: Acid suppression

Proton pump inhibitorsProton pump inhibitors

PPI x 2 / 3 monthsPPI x 2 / 3 months Therapy failure Therapy failure 24 hour intraesophageal pHmetry 24 hour intraesophageal pHmetry

( pharyngeal( pharyngeal pHmetry pHmetry ) )

GERD (+)GERD (+)

High dose PPI High dose PPI

+ H+ H22 blocker agent blocker agent

Surgery(Fundoplication) Pulmonary and Crit Care Update 1994;

Vol 9

Morice AH. ERJ 2004;24:481-492

Weeks of antireflux therapy Patients responded

No No (%)

2 16 (41)

4 38 (86)

6 42 (95)

8 43 (99)

12 weeks 44 (100)

Poe RH.Chest 2003;123:679-684

Cumulative Response to GERD Therapy

Preop

pH <4: %23.6

De Meester: 85

Postop

pH <4: %2.4

De Meester: 9.9

1. Chronic cough for at least 2 months

2. Immunocompetent patients

3. Chest radiograph is normal

4. Not exposed to enviromental irritants nor a present smoker

5. Not taking an ACE inhibitor

6. Symptomatic asthma has been ruled out

7. Rhinosinus diseases has been ruled out:

8. ‘Silent sinusitis’ has been ruled out

9. Nonasthmatic eosinophilic bronchitis

has been ruled out:

BPT is negativeCough has not improved

with asthma therapy

First generation H1 antagonists has been used

Eo 3%in induced sputum

Cough has not improved with steroids

Irwin RS. Chest 2006;129:80S-94Sİrwin RS. AJRCCM Vol 165; 1469-1474, 2002

Clinical Profile That ChronicCough İs Likely Due To ‘Silent GERD’

PostPostnasal Drip Syndrome nasal Drip Syndrome (PNDS)(PNDS)

• Prevalence : 8 – 87%• Pathogenesis : The sensation of drainage of secretions

from the nose or paranasal sinuses into the pharynx• Clinical Presentation:

Dripping sensation Tickle in the throatNasal congestionMucus in oropharynx

Cobblestone appearence of oropharynx

ACCP consensus. CHEST 1998; 114: 133-181ERS Task Force. ERS Journal ; 24: 553-566

Pathogenic Triad in Chronic Cough. CHEST 1999; 116: 279-284Evaluation of chronic cough. UPTODATE 2005

Chest 2006;129:63S-71S

In patient with chronic cough that isrelated to upper airway abnormalities

Upper Airway Cough SyndromeUpper Airway Cough Syndrome

UACSUACS Treatment Treatment

Antihistamines / decongestant combinations

- “Older” sedating antihistamines more effective

- Treatment effect should be observed in 1 week

Additional / Alternative treatments :

Ipratropium nasal spray : 2-7 days

Nasal steroids (such as BDP, FP,BUD) :

2-3 days - 2 week

3 months prescribed

EosinophilicEronchitis

Airway obstruction

Bro

nch

ial

hyp

erre

acti

vity

NO YES

Y

ES

NO

Asthmatic CoughsAsthmatic Coughs

Cough Variant Asthma

Asthma

Cough Variant Asthma Cough Variant Asthma

Prevalence : 24 – 59% Clinical Diagnosis

Gold standard History- Episodic symptoms, Family history

Reversibility testingPEF monitoringBronchoprovocation test

Differential Diagnosis:

Decreased of cough with

classical asthma therapy ACCP consensus. CHEST 1998; 114: 133-181ERS Task Force. ERS Journal ; 24: 553-566

The Journal of Respiratory Disease; 25; 310-315THORAX 59; 342-346

Middle age patients Smoking is unusual, occupational ?Prevalence of atopy similar population Good respond to inhaled steroids

Gibson et al. Lancet 1989 Chest 2006;129:116S-121S

Eosinophilic BronchitisEosinophilic Bronchitis

• Isolated chronic cough, productive of sputum • Normal lung function without variable airflow limitation• Airway hyperresponsiveness absent • Eosinophilia in sputum and BAL • Cough reflex to capsaicin increased • Normal daily variability in peak expiratory flow (<20%)

10% Australia30 patients, 20004

15% Korea92 patients, 20023

14% USA37patients 20031

33% Turkey36 patients, 20036

13% UK91patients, 19992

20% China86 patients 20035

1)Kim et al AJRCCM 2003; 2) Brightling et al AJRCCM 1999;160:406-10, 3) Joo Korean JIM 2002;17:31-7, 4) Carney et al AJRCCM 1997; 156:211-6,

5) Ma et al Zhongua 2003;26:362-5, 6) Ayik, Erdinc et al Respir Med 2003;97:695-701

Eosinophilic BronchitisEosinophilic Bronchitis A Worldwide DiseaseA Worldwide Disease

Causes of chronic cough

Primary cause of cough No. of patients (%)*

Eosinophilic bronchitis 12 (33.3%)

Postnasal drip syndrome 8 (22.2%)

Gastroesophageal reflux 8 (22.2%)

Idiopathic chronic cough 8 (22.2%)

Postinfectious cough 2 (5.6%)

Cough-variant asthma 1 (2.8%)

Ayık SÖ, Başoğlu ÖK, Erdinç M. Respir Med Vol. 97 (2003) 695-701

Causes of Isolated Chronic Causes of Isolated Chronic CoughCough

Primary cause of chronic cough Patients (%)

Rhinitis/PND 24

Asthma 17.6

Post-viral 13.2

Eosinophilic bronchitis 13.2

GERD 7.7

Unexplained (Idiopathic) 6.6

COPD 6.6

Bronchiectasis 5.5

ACE inhibitor-induced cough 4.4

Lung cancer 2.2

Cryptogenic fibrosing alveolitis 1.1

Brightling CE et al. AJRCCM 1999

Positive Cough Cough Variant AsthmaVariant Asthma

İnhaled steroidβ2-agonist

Negative

Induced sputum(3% eosinophilia

Eosinophilic Eosinophilic BronchitisBronchitis

İnhaled steroid

Asthmatic CoughAsthmatic CoughAirway obstructionReversibilityPEF değişkenliği

AsthmaAsthmaİnhaled steroid

β2-agonist

Yes

Bronchial provocation test

No

Increased NO all of them

PEF monitoring

• Prevalence: 0-50%

• More agressive diagnosis and treatments

UACS, GERD and postinfectious cough leads

to lower incidence ‘unexplained’.

• Airway inflammation

Mast cell, histamin, cysteinil LTs, PD2, PE2

Irwin RS,et al. Chest 2006;130:362-370

Chronic Unexplained Chronic Unexplained (Idiopathic)(Idiopathic) CoughCough

Important missed history (smoking,ACEI,enviromental,drugs,allergy)

Failure to do correct diagnostic tests Failure to use ‘empiric’ treatment Failure to use effective therapy Unknown disease process

Potential Reasons Potential Reasons

Chronic Unexplained Chronic Unexplained (Idiopathic) (Idiopathic) CoughCough

« Truly idiopathic cough is rare and misdiagnosis very common, especially if cough is provoked by sites outside the airways »

Eur Respir J 24: 481-492 2004

Idiopathic coughIdiopathic cough%% ? ?

0

10

20

30

40

Asthma GERD PNAS I diopathic

I rwin 1981

Poe 1982

Poe 1989

Studies in the 1980’s

% p

ati

en

ts

0

10

20

30

40

50

Asthma PNAS

I rwin 1990

Hoff stein 1994

O Connel 1994

Smyrinos 1995

1990-1995


% p

ati

ents


1996-1999

% p

ati

en

ts

0

10

20

30

40

50

60

ASTHMA OESOPH NOSE IDIO

Mello 1996

Marchesani 1998

Mc Garvey 1998

Palombani 1999

Brightling 1999

Simpson 1999


2000

0

10

20

30

40

50

ASTHMA NOSE

Birring 2003

Hague 2005

Kastelik 2005

Matsumoto 2007% p

ati

en

ts

Haque et al Chest 2005Haque et al Chest 2005;127:1710-1713;127:1710-1713

Chronic Idiopathic Chronic Idiopathic CoughCough

Predominantly female and

associated with BAL lymphocytosis

Raising the possibility of a link between

autoimmune diseases

Surinder S. Et al. Respir Med 98:242-246;2004

Chronic Idiopathic Cough (n=22)

Control (n=65)

p

Autoimmune disease 13/22 (59%) 8/65 (12%) p<0.001*

Positive autoantibody 6/15 (40%) 3/24 (13%) p<0.05


*OR: 8.8

InflammationInflammationChronic Idiopathic Chronic Idiopathic CoughCough

Birring et al AJRCM 2004Birring et al AJRCM 2004

+ BAL lymphocytosis

• Sarcoidosis• Hypersensitivity pneumonitis• Rheumatoid Arthritis• Sjögren’s syndrome• Lung tx• Inflammatory bowel disease• Hypothyroidism• Autoimmune disorders (SLE, RA)• Pernisious anemia• DM

Thorax 2003;58:1066-1070


Irwin RS,et al. Chest 2006;130:362-370

It is not correct to state that “a typical

lymphocytic airways inflammation is seen in

idiopathic cough” because lymphocytic or

lymphoplasmacytic inflammation a non-specific

finding related to trauma of coughing


Psychogenic CoughPsychogenic Cough

• Cough is often triggered by a common cold

• Usually dissapears during sleep

• Like a dog barking

• The diagnosis of psychogenic cough is one of exclusion, after ruling out an organic or functional cause of cough.

• Specific or empiric treatment

• Antitussives are usually ineffective.

Respirology 2006;Suppl 4 ;S160-S174

Irwin RS et al. Chest 1998, 114:2 supplERS Task Force: Eur Respir J 2004, 24:481-492

• Prevalence: 11-25 %• History: After a respiratory tract infection• Diagnosis:

Spasmodic coughNormal chest radiograph, with/without ronchiiRespiratory viruses, m.pneumoniae,

c.pneumoniae, B.pertussis Serum acute IgA antibody ELISA

Rarely lymphocytosis

Airway inflammation +/- Airway hyperresponsivenes

Irwin RS et al. Chest 1998, 114:2 supplACCP consensus. CHEST 1998; 114: 133-181ERS Task Force. ERS Journal ; 24: 553-566

Postinfectious CoughPostinfectious Cough

– Oral and/or inhaled steroid (2-3 weeks)

– Antibiyotic : Macrolides (Chlamydia, mycoplasma)

TMP/SMX : Pertusis (3-6 weeks)

– Ipatropium bromid

decrease efferent limb of the cough reflex

decrease stimulation of cough receptors

– Antitussive therapy Irwin RS et al. Chest 1998,114:2 suppl

Miyashita N. J Med Microbiol 2003, 52:3,265-269

Postinfectious CoughPostinfectious Cough

ACEI Induced Chronic ACEI Induced Chronic Cough Cough • Frequency: 0.2-33%

• Predominantly female

• Not dose related

• Appears within hours, weeks, months

• Pathogenesis: Neurokinin, Substance P, Prostoglandins,

stimulates afferent C-fibers in the airway

increased cough reflex sensitivity

• Prefer Angiotensin II receptör antagonists

TreatmenTreatmentt

NONSPECIFIC SPECIFIC

Antitussive Protussive Causative

treatmentCodein

Dextromethorphan

Difenhidramin

Pseudoephedrine

Dekstrobromfeniramin

Ipatropium Bromide

Naproksen

Hypertonic saline

Erdostein

Amilorid

N asetilsistein

Terbutalin

Physiotherapy

Postural drainage

Irwin RS et al. Chest 1998, 114:2

– Capsaicin type I Vanilloid receptor antagonists

– Selective opioid receptor agonists

– Opioid-like receptor agonists

– Tachykinin receptor antagonists

– Endogenous cannabinoids

– 5-HT receptor agonists

– Large-conductance calcium-activated potassium channel openers

Dicpinigaitis PV.Chest 2006 ;129:284S-286S

Future TherapiesFuture Therapies

Chronic cough

History,Examination, Chest X-Ray, PFT

Normal

Abnormal Sputum, bronchoscopy,CT,

Cardiac tests

Smoking, ACEI , Irritants ?Specific

diagnosis - treatment

Stop 4 weeks

yes

Chronic Cough AlgoritmChronic Cough Algoritm For the Management of AdultsFor the Management of Adults

Chronic cough


Normal

Abnormal

Sputum, bronchoscopy,CT,

Cardiac tests

Smoking, ACEI, Irritants ?

Specific diagnosis - Treatment

Cough?Yes

NoUACS,GERD,

Asthma, NAEB ?

No

Yes

Stop 4 weeks İmproved?

Chronic Cough AlgoritmChronic Cough Algoritm For the Management of AdultsFor the Management of Adults

Chronic cough

Normal

Abnormal

Cough?Yes

Yok

No

Yes

Improved

Cough? NoYes

Empiric/ Specific

Therapy


Sputum, Bronchoscopy,CT,

Cardiac tests

Specific diagnosis - treatment

Smoking, ACEI ?, Irritants?

UACS,GERD, Asthma, NAEB

Stop 4 weeks

Chronic Cough AlgoritmChronic Cough Algoritm

Chronic cough


Normal

Abnormal

Sputum, Bronchoscopy,CT,

Cardiac tests

Smoking, ACEI ?, Irritants? Cough?

Yes

NoUACS,GERD,

Asthma, NAEB

No

Yes

Stop 4 weeksImproved

Empiric Therapy

ENT, Sinus CT BPT,PEF monit., NOEsophageal tests

No response

Specific diagnosis - treatment

Specific

Diagnosis - Treatment

Chronic Cough AlgoritmChronic Cough Algoritm


Empiric or Specific Diagnosis and Treatment

Cough ?No

Sputum, HRCT, Bronchoscopy

ImprovedYes Post infectious?

Yes

Consider uncommon causes

Cough ?No Yes Physcogenic

cough?



Empiric or Specific Diagnosis and Treatment

Cough ?No

Sputum, HRCT, Bronchoscopy

ImprovedYes Post infectious?

Yes

Consider uncommon causes

Cough ?No Yes

Physcogenic cough?


Specific diagnosis - TreatmentImproved

Chronic idiopathic cough

No

THANK YOU…THANK YOU…

Documents

CHRONIC COUGH