1

MÜNEVVER ERDİNÇDepartment of Chest Diseases

Ege University Faculty of Medicine

2

Acute Cough lasting less than 3 weeks

Subacute Cough lasting 3 to 8 weeks

Chronic CoughLasting 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

3

10

12

1312

16

64

ASTHMAPNDS

GERD

Chest 1999;116:279-284

1. Gastroesophageal reflux disease (21-41%) 2. Cough variant asthma (24-59%) 3. Postnasal drip syndrome (41-58%)

4

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

5

İmmunocompetent patients Not exposed to enviromental irritants Chest radiograph is normal Not taking an ACE inhibitor Nonsmoker

Asthma and/or GERD, PNDS

responsible for 93.6% of the casesof chronic cough

Harding SM .Chest 2003;123:659-660

6

Coughthe most common complaint for

seeking medical care

In the USA Ist (1993)

GERD GERD the most common chronic

disease ın the USA!

R. C. Orlando

7Journal of the best Sabah. January 2004: 7

8

GASTROESOPHAGEAL REFLUX The backflow of stomach contents into the esophagus

(gastric acid, pepsin, bile, pancreatic enzymes)

Heartburn (pyrosis) and regurgitationAt least weekly symptoms

manifested by either by extraesophageal reflux symptoms

and/or esophageal mucosal damage

Irwin SR. Chest 2006:129:80S-94S

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

9

What happens during nonpathologic reflux?

Kahrilas PJ.CCJM 70(5):S4-19,2003

10

ANTIREFLUX BARRIERS

Intraabdominal

+5 mmHg

Expiration Inspiration

LES +25mmHg

Intrathoracic

-5 mmHg

Diaphragma

11

Impaired esophageal clearance

Functional defect in

LES syphincter Hiatal hernia

Delayed gastric emptying İncreased intra-abdominal

pressure

Katzka & DiMarino 1995

GERD ? Decreased

saliva

12

Causative Factors in GERD1.Gastroesophageal barrier function impairment

Hiatal herniaİmpaired diyaphragmatic crus Transient LES relaxations

2.Delayed esophageal clearanceLow amplitude or simultaneous contractionsReduced salivation

3.Exogen factors Alcohol, smoking, drugs, hot drinks , hypertonic foods, aging

4.Gastric factorsAcid hypersecretion ?Delayed gastric emptyingAbnormal antropyloroduodenal motility (Alkalen reflux)

5.Impaired mucosal resistance

13

Gastroesophageal Reflux Diseases İzmir - Olmsted Prevalance

02

46

8101214

1618

20

Heartburn Regurgitation

Wee

kly

sym

ptom

s %

Izmir, Türkiye (630) S.Bor et al. DDW 2000Olmsted, USA (2073) Locke et al. Gastroenterology,1997

20 19.8

10

15.6

6.3

17.8

Pyrozis/ Regurgitation

14

Menderes (Ege ÜTF) Olmsted (Mayo)Symptom GERD (+)

%GERD (-)

%GERD (+)

%GERD (-)

%

Dysphagia 35,7 7,9 * 29,4 13,5 *

NCCP 44,4 18,7 * 37 23,1 *

Odynophagia 10,3 2,4 *    

Globus 23,8 8,1 * 14,2 10,6 *

Regurgitation 24,6 13,8 *    

Hiccup 9,5 2,4 *    

Cough 19,8 10,3 *    

Hoarseness 28,6 13,1 *    

Asthma 0,8 2,2 11,6 9,3

GERD Related Symptoms

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Physiologic

GERD SPECTRUM

ComplicationsExtraesophageal

Typical

AtypicalNERDChronic coughHoarsenessAsthmaLaryngitisAspiration pneumoniaDental erosionsSnoringNoncardiac chest pain

StrictureBleedingBarrett Adenocarcinoma

Chest painHiccupDyspepsiaNight sweatsGlobusSleep disturbances

Esophagitis

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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

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GERD-related cough incidence GERD-related cough incidence 5 - 41% 5 - 41%

ARRD 1981;123:413-417 ARRD 1981;123:413-417 Arch Intern Med 1996;156:997Arch Intern Med 1996;156:997

Chest 1993;104:1511-1517Chest 1993;104:1511-1517 Irwin RS. Chest 2006;129:80S-94SIrwin RS. Chest 2006;129:80S-94S

May be the sole presenting symptomMay be the sole presenting symptom

Thorax 2003:58;1092-1095)Thorax 2003:58;1092-1095)Chest 1997; 111: 1389-1402Chest 1997; 111: 1389-1402Irwin RS. Chest 2006;129:80S-94S

Association between cough and reflux is importantEsophageal-tracheal-bronchial Esophageal-tracheal-bronchial

reflex reflex MicroaspirationMicroaspiration

Nonacid factors?Esophageal dysmotility?

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.. 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 Central Central Nervous Nervous SystemSystem

Tracheobronchial Tracheobronchial TreeTree

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Diagnostic Tests

inGERD

HistoryPPI test

Impedans

Endoscopy

Bernstein test

Bilier scintigraphy

Esophagography

Aspiration methods

Bilier scintigraphy

Reflux scintigraphy

Esophageal biopsy

Esophageal manometry

Standardized acid reflux test

High magnificated endoscopy

24-h intraesophageal impedance and pH

Telemetric esophageal pH monitorization

24-h intraesophageal pH monitoring

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Stomach

Oesophagus

21

DeMeester scoreDeMeester score-Total time below pH 4

- Fractional of total time 4.2% - Fractional time of upright position 6.3% - Fractional time of supine position 1.2%

-Total reflux events 50 - Length of time 9.2 min.

Richter JE, DeMeester TR.Gastroenterology 1990;98:122

ProximalProximal

DistalDistalDeMeester score >14.7

-Total time below pH 4- Fractional of total time 1.1% - Fractional time of upright position 1.7% - Fractional time of supine position 0.6%

-Total reflux events 5- Length of time 3 min.

The most sensitive and specific test for GERD is

24-h esophageal pH monitoring

22

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

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Reflux symptoms in chronic cough patients are associated Reflux symptoms in chronic cough patients are associated with pathologic reflux in proximal esophaguswith pathologic reflux in proximal esophagus

Ayık SÖ,Erdinç M,Bor SAyık SÖ,Erdinç M,Bor S

Pathologic reflux in proximal (+)

Pathologic reflux in proximal (-) p

Sex 2 E-10 K 1 E-16K 0.18

Age 44.081±13.95 45.59 ±12.71 0.38

Duration of chronic cough

17.25 ±23.21 40.71 ±61.41 0.11

Reflux at distal probe 5 3 0.083

GERD symptoms 8 3 0.003

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Esophageal-pulmonary Reflux Lipid-laden macrophages in BAL Adding indicators to feedings Glucose oksidase test Scintigraphic monitoring Exhaled breath condensate (EBC) Esophageal pH monitoring Symptoms Empiric PPI therapy

Effros RM.Am J Med 2003;115:137S-143S

25

90

75

85

70

80

GER (-)Grade 1

Severei GERGrade 3

İntermittent GER Grade 2

FEV

1/FVC

%

GER severity

Schachter LM.Chest 2003;123:1932-38

DLCO decrease in severe GER

30

DLC

O

ml/m

in/m

mH

g

28

18

20

22

24

26

GER severity

GER (-)Grade 1

Severei GERGrade 3

İntermittent GER Grade 2

26

The empiric trial of medical therapyis appropiate when pHmonitoring cannot

be done or is not available

American College of Chest Physicians Chest 1998; 114(suppl1) :133S-181S

The empiric trial of medical therapyshould be considered even in cases

pHmonitoring can be done

Thorax 2003 ;58:901-907Poe RH.Chest 2003;123:679-684Chest 2003 ;123:650-660

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1. GERD the most common cause of chronic cough2. Empiric PPI therapy is not only practical but is also ‘cost-effective’3. Consensus should be reconsidered4. pHmetry should be done in nonresponsive to empiric therapy

24 hour pHmetry Empiric PPI therapy

Harding SM. Chest 2003 ;123:650-660

28

pHmetry,High sensitive in typical symptoms

however diagnostic value in extraesophageal symptoms

50 - 80%

Symptom / reflux associationis more important in atypical symptoms

Empiric PPI therapy sensitivity 62.5 - 81%-Patients presented with laryngeal symptoms and cough-

29Roka R.Digest.2005:92-96

Respiratory symptoms prevalance

with GERD symptoms

30

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

31Kastelik JA. Thorax 2003;58:699-702

Results of oesophageal manometry and 24 hour ambulatory pH monitoring in patients with chronic cough with (n=34)

and without (n=9) symptoms of gastro-oesophageal reflux

Normalinvestigations

AbnormalManometry

alone

Abnormal24-h pHalone

Abnormalmanometry

and 24-h pH

10

20

30

40

50

0

SymptomsNo symptoms

Per

cent

age

of

subj

ects

Oesophageal Oesophageal dysmotility ?dysmotility ?

32Sifrim D.Gut 2005;54:449-54Weakly acidic reflux with chronic cough

33

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

In patients with chronic cough who had failedto respond very intensive medical therapy,the improvement or elimination of cough in

all subjects 12 months following surgery

Irwin RS.Chest 2002;121:1132-1140

The term acid reflux disease when appliedto chronic cough due to GERD, can be misnomer

34

PPIs H2RB

Life-styles

Prokinetic agents

Antacids/ alginates

Fundoplication

Hatlebakk & Berstad, Clin Pharmacokinet 1996; 31: 386–406.

GERD

Therapetic Options

Endoscopic

35

1) Acid inhibition / neutralizationAntascides

H2 receptor blockersRanitidinFamotidinNizatidin

Proton pump inhibitorsOmeprazolLansoprazolPantoprazolRabeprazol Esomeprazol

Pharmacological Therapy in GERD

2) Barrier Alginic acid

3) Cytoprotectives Sucralfat Mizoprostol

4) Prokinetics Cisapride Domperidon? Metoclopramid?

36

Risk ratio.012003 1 83.3135

Study % Weight Risk ratio (95% CI)

0.26 (0.15,0.46) Bardhan 1995 5.0 0.33 (0.16,0.69) Klinkenberg-Knol 1987 3.3 0.42 (0.28,0.62) Havelund 1988* 7.1 0.48 (0.33,0.69) Sandmark 1988 7.8 0.59 (0.48,0.73) Bate 1990 11.1 0.60 (0.37,0.98) Dehn 1990* 5.9 0.63 (0.42,0.94) Bianchi Porro 1992 7.1 0.72 (0.54,0.95) Koop 1995 9.5 0.61 (0.38,0.99) IROSG 1991 5.9 0.37 (0.24,0.57) Robinson 1995 6.6 0.26 (0.10,0.67) Vantrappen 1988* 2.2 0.64 (0.52,0.79) Farley 2000 11.0 0.35 (0.21,0.59) Jansen 1999 5.5 0.59 (0.29,1.20) Armbrecht 1997 3.5 0.52 (0.36,0.76) Van Zyl 2000 7.6 0.09 (0.01,0.62) Soga 1999 0.6

0.50 (0.43,0.58) Overall (95% CI)

Moayyedi. Health Care Needs Assessment, 2002

Comparison of H2B with PPI Metaanalysis

PPI H2RA

37

Therapy in Esophageal-pulmonary Therapy in Esophageal-pulmonary refluxreflux

Conservative and lifestyle measuresConservative and lifestyle measures Pharmacological therapyPharmacological therapy: Proton pump inhibitors: Proton 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 Surgery, Surgery,

+ H + H22 blocker agent blocker agentPulmonary and Crit Care Update 1994;Pulmonary and Crit Care Update 1994;

Vol 9Vol 9 Morice AH. ERJ 2004;24:481-492Morice AH. ERJ 2004;24:481-492

38

J. A.Koufman. ENT-Ear, Nose & Throat Journal, Sep 2002 SuppMorice AH.ERJ 24:481-492,2004

Reflux /Symptom/ Therapy GERD FLR Esophagopulmonary

Nocturnal reflux (supine) ++++ + +Upright reflux (daytime) + ++++ +++Pyrosis and/or regurgitation

++++ + +Cough, dysphonia, globus +/- ++++ ++++Respond to H2 antagonists

85% 65% 70%

Respond to PPI (once a day) +++ + +Respond to PPI (twice a day) ++++ +++ ++++

39

Stomach

Esophagus

PPI PPI

40Poe RH.Chest 2003;123:679-684

Specific therapyfor diagnosis and treatment

Results of therapy in treating cough due to GERD

41

Weeks of antireflux therapy Patients responded

No No (%)

2 16 (41) 4 38 (86) 6 42 (95) 8 43 (99) 12 44 (100)

Poe RH.Chest 2003;123:679-684

Cumulative Response to GERD Therapy

42Ciccaglione AF.Gut 2003;52:464-470

Effect of the GABAEffect of the GABABB agonist baclofen agonist baclofen on symptoms in patients with GERDon symptoms in patients with GERD

43

Approximate Diaphragmatic

crurae

Reduce Hiatal Hernia

Anti-Reflux SurgeryRestore

Intraabdominal esophagus

Perform Fundoplication

44

PreoppH <4: %23.6De Meester:

85

PostoppH <4: %2.4De Meester:

9.9

45

PreoppH <4: %14.5De Meester:

52.9

PostoppH <4: %3.8De Meester:

14.2

46

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

1st 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 Chronic Cough İs Likely Due To ‘Silent GERD’

47

abnormalabnormalnormalnormal

History and Physical

Asthma, PNDSSpirometry (BPT)ENT evaluation

pHmetry ( surgery?)Psychogenic cough(?)

Spesific diagnosis and treatment

Avoid irritantsDiscontinue ACE ihibitors

Smoking cessation

GERD symptoms (-) (+)

Chest radiograph

Ampiric PPI Three months b.i.d.

Sputum cytology,HRCT scanBronchoscopyEsophagographyCardiac evaluation

Cough persists

Chronic CoughChronic Cough

Cough persistsCough persists

Spesific diagnosis and treatment

48

Pharyngeal pHmetryPharyngeal pHmetry

+-Not GERD

Clinical GERD symptoms ?Nonacid, weakly acid reflux?

Increase dose PPI + alginate

İmproved Not improved

Continue pHmetry under treatment

Consider

Simultaneously dual probes

24 hours pHmonitoringand

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

49

GastroenterolojiErişkin-Çocuk

Göğüs, Pulmoner reflü

KBB Faringolaringeal

reflü

KardiyolojiNCCP

CerrahiErişkin, Çocuk

PatolojiDiş Hek.

Psikiyatri, Halk sağlığı

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