Idiopathic Cough

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					Differential Diagnosis And Treatment
                              In Adults


                  MÜNEVVER ERDİNÇ
                Department of Chest Diseases
              Ege University Faculty of Medicine
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

• PNDS                                  •   Foreign body
   – Allergic rhinitis
   – Chronic sinusitis                  •   Chronic bronchitis
• GERD                                  •   Bronchiectasis
• Cough variant asthma                  •   Lung cancer
• ACEI induced cough                    •   Subglottic stenosis
• Pertusis
• Neurogenic                            •   Tracheomalasie
   – Traumatic                          •   Tracheoesophageal fistul
   – Postinfectious cough               •   Tuerculosis
• Phychogenic cough                     •   Sarcoidosis
• Chronic aspiration                    •   Congestive heart failure
• Zenker diverticulosis

                            Simpson CB. Otolaryngology–Head Neck Surg 2006; 134: 693-700
In prospective studies in adults,
chronic cough is most commonly
                 due to 6 disorders :


  Upper Airway Cough Syndrome (UACS)
  Asthma
  GERD
  Chronic Bronchitis
  Bronchiectasis
  Non-asthmatic Eosinophilic Bronchitis
                Guidelines Writing Committee. Chest 2006; 129 (Suppl. 1): 1S-292S
New Considerations

 Eosinophilic bronchitis

 Atopic cough

 Non acid(volume)/ weakly acid reflux

 Idiopathic (unexplained) öksürük
 Diagnosis and Management of Cough
                                 ACCP Evidence-Based CPG 2006
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 cough
The term acid reflux disease, unless it can be definitively shown to
   apply, replaced by reflux disease
Update of current diagnostic and therapeutic approaches
   Common diseases, Uncommon diseases
New algorithms for the management of cough in adults and
  children
   An empiric integrative approach is recommended

                        Guidelines Writing Committee. Chest 2006; 129 (Suppl. 1): 1S-292S
                               Plevkova, et al. Respir Physiol Neurobiol 2004; 142: 225-235
                                                             PNDS
                ASTHMA        12
                                               16

                                                        13
                                           12
                                      6
                                                    4
                                          10
                          GERD
1. Gastroesophageal reflux disease (21-41%)
2. Cough variant asthma (24-59%)
3. Postnasal drip syndrome (41-58%)                      Chest 1999;116:279-284
 Percentage of Cases Presenting 1,2,3 and 4 Causative factors



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


                  8,9%
                            38,5%
                                                                1
 16,7%
                                                     38,5%
                                                                2   1
                                                                    2
                                                                3   3
                                                                    4
                                                                4
              35,9%


                                              Chest 1999;116:279-281
Asthma and/or GERD, PNDS

    responsible for 93.6% of the cases
          of chronic cough


   İmmunocompetent patients
   Not exposed to enviromental irritants
   Chest radiograph is normal
   Not taking an ACE inhibitor
   Not a current smoker



                       Harding SM .Chest 2003;123:659-660
Changing Trends in Diagnosis

                                                         GERD       ASTHMA      RHINITIS
Percentage of Diagnosis (%)



                                                         REFLUX      ASTHMA      RHINITIS

                                             90
                                             80
                   Percentage of Diagnoses




                                             70
                                             60
                                             50
                                             40
                                             30
                                             20
                                             10
                                             0
                                                  1998    1999    2000   2001   2002   2003
                                        GERD ?
Heartburn (pyrosis) and regurgitation
At least weekly symptoms                          Decreased
extraesophageal reflux symptoms                     saliva
and/or esophageal mucosal damage /
                                                  Impaired
                                                 esophageal
                  Functional                      clearance
                 defect in LES
                  syphincter                     Hiatal hernia




                 Delayed gastric
                    emptying              İncreased intra-abdominal
                                                  pressure Katzka & DiMarino 1995
 FLR
        •Edema and hyperemia of larynx
        •Vocal cord erythema, polyps, granulomas, ulcers


Signs
        •Hyperemia and lymphoid hyperplasia
                                 of posterior pharynx
        •Interarytenoid changes
        •Subglottic stenosis
      GERD-related cough incidence
                     5 - 55%              ARRD 1981;123:413-417
                                          Arch Intern Med 1996;156:997
                                          Chest 1993;104:1511-1517
                                          El Hennawi, 2004 OHNS




    May be the sole presenting symptom(1/3)
Association between cough and reflux is important


     Esophageal-tracheal-bronchial reflex
     Microaspiration
                Nonacidic factors?
                                                  Thorax 2003:58;1092-1095)
                Esophageal dismotility?
                                                (Chest 1997; 111: 1389-1402)
                                          Irwin RS. Chest 2006;129:80S-94S
Esophagus            Tracheobronchial      Airway
                           Tree


REFLUX              Microaspiration


                                          . Mediator
                     Airway Vagal               Release
                     Afferents
Esophageal                                . Inflammation
  Vagal      CNS                          . Edema
 Afferents                                . Mucus
                     Airway Vagal         . Smooth
                     Efferents                 Muscle



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




Stomach
              Pharyngeal pHmetry

              -                         +
          Not GERD             Increase dose PPI
 Clinical GERD symptoms ?           + alginate
Nonacid, weakly acid reflux?

                               İmproved           Not
             Consider                           improved
                 
          Simultaneously        Continue
            dual probes                       pHmetry
      24 hours pHmonitoring                under treatment
               and
   intraesophageal impedance     Irwin RS.AJRCCM 165:1469-74,2002
                                 McGarvey LPA.Thorax 59:342-346,2004
 Multichannel intraluminal   17 cm
 impedance-pH catheter
                             15 cm




  6 impedance channels
                             9 cm
                   +         7 cm
        1 pH electrode       5 cm    pH - 5 cm

                             3 cm




  Adult Standard
Model ZAN-S61C01E
Non acid reflux

On going reflux of ‘non-acid’ material may be
  responsible for continuing symptoms while on
  acid-suppressing medications
Therapy in Esophageal-pulmonary reflux

   Conservative and lifestyle measures
   Ampirical therapy: Acid suppression
                Proton pump inhibitors
                 PPI x 2 / 3 months
   Therapy failure  24 hour intraesophageal pHmetry
                      ( pharyngeal pHmetry )
                    GERD (+)
                     High dose PPI
                      + H2 blocker agent
                      Surgery(Fundoplication)
                                      Pulmonary and Crit Care Update 1994; Vol 9
                                                  Morice AH. ERJ 2004;24:481-492
Cumulative Response to GERD Therapy


 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
   Preop
pH <4: %23.6
De Meester:
    85




  Postop
pH <4: %2.4
De Meester:
    9.9
Clinical Profile That Chronic
Cough İs Likely Due To ‘Silent GERD’

   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                             BPT is negative
                                                          Cough has not improved
   6. Symptomatic asthma has been ruled out                 with asthma therapy

   7. Rhinosinus diseases has been ruled out:                   First generation
                                                          H1 antagonists has been used
   8. ‘Silent sinusitis’ has been ruled out
   9. Nonasthmatic eosinophilic bronchitis                        Eo 3%
                                                            in induced sputum
                           has been ruled out:            Cough has not improved
                                                               with steroids


                                                    Irwin RS. Chest 2006;129:80S-94S
                                          İrwin RS. AJRCCM Vol 165; 1469-1474, 2002
Postnasal Drip Syndrome (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 throat
            Nasal congestion
            Mucus in oropharynx
            Cobblestone appearence of oropharynx

                                           ACCP consensus. CHEST 1998; 114: 133-181
                                            ERS Task Force. ERS Journal ; 24: 553-566
                         Pathogenic Triad in Chronic Cough. CHEST 1999; 116: 279-284
                                        Evaluation of chronic cough. UPTODATE 2005
In patient with chronic cough that is
related to upper airway abnormalities

    Upper Airway Cough Syndrome




                                    Chest 2006;129:63S-71S
      UACS 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
Asthmatic Coughs
    Bronchial hyperreactivity

                                        Eosinophilic
                                NO


                                         Eronchitis




                                          Cough           Asthma
                                YES




                                      Variant Asthma



                                          NO               YES
                                          Airway obstruction
    Cough Variant Asthma
   Prevalence : 24 – 59%
   Clinical Diagnosis
     Gold standard  History
       - Episodic symptoms, Family history
     Reversibility testing
     PEF monitoring
     Bronchoprovocation test
   Differential Diagnosis:
         Decreased of cough with
         classical asthma therapy      ACCP consensus. CHEST 1998; 114: 133-181
                                         ERS Task Force. ERS Journal ; 24: 553-566
                                    The Journal of Respiratory Disease; 25; 310-315
                                                               THORAX 59; 342-346
     Eosinophilic 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%)

        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 Bronchitis
                                 A Worldwide Disease
                                                    13% UK
                                                    91patients, 19992




14% USA                                                                        15% Korea
37patients 20031                                                               92 patients, 20023




            33% Turkey                      20% China                         10% Australia
            36 patients, 20036              86 patients 20035                 30 patients, 20004


                         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
    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 Cough
  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
Asthmatic Cough
                    Airway obstruction            Yes        Asthma
                    Reversibility                         İnhaled steroid
                                                            β2-agonist
                    PEF değişkenliği

                                 No

                   Bronchial provocation test
 Eosinophilic
  Bronchitis         Negative         Positive              Cough
                                                        Variant Asthma
 İnhaled steroid              PEF                        İnhaled steroid
                            monitoring                     β2-agonist
           Induced sputum
          (3%  eosinophilia

                       Increased NO all of them
 Chronic Unexplained
            (Idiopathic) Cough


• 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
             (Idiopathic) Cough
      Potential Reasons
     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

« 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 cough
                             %?
Studies in the 1980’s
              40
 % patients




              30

                                                       Irwin 1981
              20
                                                       Poe 1982
                                                       Poe 1989
              10


               0
                   Asthma   GERD   PNAS   Idiopathic
                     Idiopathic cough
                            %?
  1990-1995
             50

             40
% patients




                                   Irwin 1990
             30
                                   Hoffstein 1994
             20                    O Connel 1994
                                   Smyrinos 1995
             10

              0
                  Asthma   PNAS
                     Idiopathic cough
                            %?
      1996-1999
             60

             50
% patients




                                                Mello 1996
             40
                                                Marchesani 1998

             30                                 Mc Garvey 1998
                                                Palombani 1999
             20                                 Brightling 1999
                                                Simpson 1999
             10

              0
                  ASTHMA OESOPH   NOSE   IDIO
                      Idiopathic cough
                             %?
             2000 
              50

              40
% patients




                                   Birring 2003
              30
                                   Hague 2005
              20                   Kastelik 2005
                                   Matsumoto 2007
              10

               0
                   ASTHMA   NOSE
Chronic Idiopathic Cough




                     Haque et al Chest 2005;127:1710-1713
Chronic Idiopathic Cough

Predominantly female and
        associated with BAL lymphocytosis
 Raising the possibility of a link between
                   autoimmune diseases

                        Chronic Idiopathic      Control                   p
                        Cough (n=22)            (n=65)
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
                                      Surinder S. Et al. Respir Med 98:242-246;2004
Chronic Idiopathic Cough   Inflammation




                             Birring et al AJRCM 2004
Chronic Idiopathic Cough
      + 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
Chronic Idiopathic Cough


 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




                            Irwin RS,et al. Chest 2006;130:362-370
Psychogenic 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 suppl
                            ERS Task Force: Eur Respir J 2004, 24:481-492
Postinfectious Cough

• Prevalence: 11-25 %
• History: After a respiratory tract infection
• Diagnosis:
       Spasmodic cough
       Normal chest radiograph, with/without ronchii
       Respiratory 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 suppl
                                       ACCP consensus. CHEST 1998; 114: 133-181
                                       ERS Task Force. ERS Journal ; 24: 553-566
Postinfectious 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
ACEI Induced Chronic 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
  Treatment
                NONSPECIFIC                             SPECIFIC

    Antitussive           Protussive                      Causative
                                                          treatment
Codein                    Hypertonic saline
Dextromethorphan          Erdostein
Difenhidramin             Amilorid
Pseudoephedrine           N asetilsistein
Dekstrobromfeniramin      Terbutalin
Ipatropium Bromide        Physiotherapy
Naproksen                 Postural drainage


                                       Irwin RS et al. Chest 1998, 114:2
Future Therapies
– 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
Chronic Cough Algoritm
  For the Management of Adults



    Chronic cough

    History,Examination,          Abnormal         Sputum,
    Chest X-Ray, PFT                           bronchoscopy,CT,
                                                 Cardiac tests
        Normal
    Smoking, ACEI , Irritants ?
                                                   Specific
                             yes             diagnosis - treatment

                    Stop 4 weeks
Chronic Cough Algoritm
    For the Management of Adults


              Chronic cough
                                                        Sputum,
           History,Examination,         Abnormal    bronchoscopy,CT,
           Chest X-Ray, PFT                           Cardiac tests

               Normal                        Specific diagnosis - Treatment
      No
           Smoking, ACEI, Irritants ?       Yes
                                                        Cough?
                                  Yes                           No
 UACS,GERD,
Asthma, NAEB ?            Stop 4 weeks               İmproved?
Chronic Cough Algoritm

                 Chronic cough
                                                               Sputum,
                                                           Bronchoscopy,CT,
              History,Examination,         Abnormal          Cardiac tests
              Chest X-Ray, PFT
                                           Specific diagnosis - treatment
                    Normal
         No         Smoking, ACEI ?,            Yes
                       Irritants?                             Cough?
                                           Yes
 UACS,GERD,                                                         Yok
                                Stop 4 weeks
Asthma, NAEB
                                                              Improved
                        Yes                           No
Empiric/ Specific                      Cough?
    Therapy
Chronic Cough Algoritm
              Chronic cough
                                                       Sputum,
           History,Examination,                    Bronchoscopy,CT,
                                     Abnormal
                                                     Cardiac tests
           Chest X-Ray, PFT
               Normal                     Specific diagnosis - treatment
      No        Smoking, ACEI ?,             Yes
                   Irritants?                          Cough?
                                          Yes
                                                              No
 UACS,GERD,                Stop 4 weeks
Asthma, NAEB                                           Improved

                        ENT, Sinus CT                      Specific
Empiric                 BPT,PEF monit., NO
                                                     Diagnosis - Treatment
Therapy                 Esophageal tests
          No response
           UACS,GERD, Asthma, NAEB


      Empiric or Specific Diagnosis and Treatment

            No                      Yes     Post infectious?
Improved             Cough ?
                           Yes
           Consider uncommon causes


           Sputum, HRCT, Bronchoscopy

           Specific diagnosis - Treatment
      No                                    Yes    Physcogenic
                     Cough ?                         cough?
                UACS,GERD, Asthma, NAEB


           Empiric or Specific Diagnosis and Treatment

                 No                         Yes    Post infectious?
  Improved                 Cough ?
                                 Yes
                Consider uncommon causes


                Sputum, HRCT, Bronchoscopy

                Specific diagnosis - Treatment
           No                                      Yes
                           Cough ?                        Physcogenic
                                                            cough?
Improved          Specific diagnosis - Treatment
                                 No
                  Chronic idiopathic cough
THANK YOU…

				
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