Cough&Pathophysiology:&Upper&Airway& Perspecve ......Association of nasopharyngeal and...
Transcript of Cough&Pathophysiology:&Upper&Airway& Perspecve ......Association of nasopharyngeal and...
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Cough Pathophysiology: Upper Airway Perspec6ve (Including Idiopathic Cough):
Is it Laryngeal Hypersensi6vity?
Ron Balkissoon MD MSC FRCP C Na2onal Jewish Health
Denver
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Conflict of Interest Company Nature of
Relationship Topics Payment
Astra Zeneca Speaker’s Bureau Advisory Board Manuscript Review
COPD/ Asthma
Honoraria Honoraria None
Glaxo Smith Kline
Speaker’s Bureau Advisory Board
COPD/ Asthma
Honoraria Honoraria
Boehringer Ingelheim
Speaker’s Bureau COPD Honoraria
Novartis Speaker’s Bureau Asthma/COPD
Honoraria
Genentech Speaker’s Bureau Asthma Honoraria Forest Speaker’s Bureau COPD Honoraria
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Authors year # Pa6ents
PND/BA/GERD (%)
EB (%) PI (%) CB (%) Misc or No Dx (%)
Irwin et al 1981 49 82 0 0 12 6
Poe et al 1982 109 44 0 25 12 19
Puolijoki et al 1989 198 34 0 15 4 47
Irwin et al 1990 102 86 0 0 5 9
PraHer et al 1993 45 96 0 0 0 4
O’Connell et al 1994 87 40 0 10 0 49
Mello eta ak et al 1996 88 92 0 0 0 8
McGarvey et al 1998 43 81 0 0 0 19
Brightling et al 1999 91 47 13 13 7 20
Palombini et al 1999 78 94 0 0 0 6
Ayik et al 2003 39 44 31 5 0 20
Major Causes of Cough
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Upper Airway Causes of Cough Upper Airway Cough Syndrome: Formerly known as Post Nasal Drip Sinonasal disease
– Hyperplastic nasal polyps – Samter triad – Stubborn bacterial overgrowth – Fungal disease – Distorted anatomy – Post-surgical phenomena
• Retained uncinate process • Caldwell-Luc antrostomies and mucus recirculation • Surgical failure to reopen natural sinus ostia
Courtesy Dr Ed Hepworth: Colorado Sinus Institute
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Upper Airway Causes of Cough
• Regional neurologic reflex/pathology – Arnold’s nerve/reflex from External Auditory Canal
Foreign Body
• Direct contact irritation – Sinonasal mucus – Inhalant or ingestion allergens – Chronic laryngitis
• Infectious • Inflammatory • Neoplastic
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Surgical Failure
Courtesy Dr Ed Hepworth: Colorado Sinus Institute
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Sensory nerve receptors
Superior laryngeal n.
±Cor2cal processing
Nucleus Ambigus (Medulla)
Recurrent laryngeal n.
Afferent
Efferent
Cough Reflex
(Courtesy of Boyd Jacobson)
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Upper Airway Defined
Nasal Passages and Sinuses and Ear canals
Oropharynx
Larynx
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Pathophysiology of Cough
• Cough is a protec2ve reflex to minimize lung injury from poten2ally noxious material(s)
• The larynx is the gateway/gate keeper to the lungs
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The Nose is the Lungs HVAC System
• Hea2ng: • Ven2la2on: Air conduc2on • Air Condi2oning:
– Humidifica2on – Filtra2on
• Warning System (Olfac2on)
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Afferent Cough Receptors Rapidly Adap2ng Receptors in Mucosal Lining
trachea and large central bronchi
nose
oropharynx Larynx
Ear
stomach
pericardium
esophagus diaphragm
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“Laryngeal” Sensory Receptors Cough Receptors: • Myelinated rapidly adapting irritant
receptors • Non myelinated slowly adapting C fibers
Afferent Nerves- trigeminal, glossopharyngeal, superior laryngeal or vagus n.
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Laryngeal Sensory Receptors
, isotonic sugars Chemoreceptors: – Water – Ammonia – CO2, SO2 – CigareHe smoke – milk, gastric content
Mechanoreceptors: – Pressure (touch) – Flow (flow, cooling) – Propriocep2on – Drive (laryngeal muscle contrac2on)
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Laryngeal Sensory Receptors
• Irritant receptors – Nociceptive C fibers – G-Protein coupled receptors (GPCR) – Transient receptor potential vanilloid (TRPV-1) – Transient receptor potential ankyrin 1 (TRPA-1)
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Upper Airway Cough Syndrome
• TRPV-‐1 ac2va2on burning sensa2on • TRPA-‐1 ac2va2on burning cold sensa2on • Other C-‐fiber neurons have H-‐1 receptors that lead to sensa2on of itch.
Baraniuk JN. Proc Am Thorac Soc. Vol 8 pp62-‐69 2011
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Activation of Nociceptors in Trachea
Undem B J , Carr M J. Chest 2010;137:177-184 ©2010 by American College of Chest Physicians
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Hypersensi2vity of Laryngeal C-‐Fibers Induced by Vola2le Anesthe2cs in Young Guinea Pigs
(Mutoh et al AJRCCM 2003)
Background: • Children develop laryngospasm, cough, upper airway obstruc2on following halothane anesthesia.
• Due to s2mula2on of laryngeal C-‐ fibers? • C fibers play important role in triggering airway reflexes
• 50% afferents in SLN are non-‐myelinated C fibers
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Hypersensi2vity of Laryngeal C-‐Fibers Induced by Vola2le Anesthe2cs in Young Guinea Pigs
(Mutoh et al AJRCCM 2003)
Design: 1. Expose Guinea Pigs to inhaled Halothane 2. Dissect out laryngeal mucosal C-‐fiber neurons to test
sensi2vity to chemical (capsaicin) challenge and Mechanical (laryngeal hyperinfla2on) s2muli
Results: • Halothane increased isolated C-‐fiber sensi2vity to chemical (capsaicin) and mechanical (laryngeal hyperinfla2on) s2muli
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Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease.
Doherty MJ, Mister R, Pearson MG, Calverley PM. Thorax 2000;55:643e9.
C5: concentration of aerosolized capsaicin solution that caused five coughs
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Extrathoracic and Intrathoracic Responsiveness in Sinusi2s and VCD (C. Bucca et al. JACI 1995)
• 106 pa2ents with chronic rhinosinusi2s treated with an2bio2cs and inhaled nasal steroids X 2 weeks
• Pre and post treatment histamine challenges
– PC20FEV1 -‐ bronchial hyperresponsiveness B-‐HR – PC25MIF50 -‐ extrathoracic hyperresponsiveness EA-‐HR
• Nasal swabs and lavage • Serum IgE/Rast
Bucca JACI 1995
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Bucca JACI 1995
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Extrathoracic and Intrathoracic Responsiveness in Sinusi2s and VCD (C. Bucca et al. JACI 1995)
88 Pa6ents Completed Study: • EA-‐HR 76/88 (86%) • (EA + B)-‐HR 46/88 (52%) • Nasal Lavage and smears
• neutrophilia 88 (100%) • eosinophilia 36 (41%) • both decreased amer treatment
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Effect of treatment on pre-‐challenge lung func2on, bronchial and EA responsiveness, and neutrophil score in nasal lavage
Variable Before treatment (mean ± SEM)
After treatment (mean ± SEM)
FEV1 (L) 3.25 ± 0.09 3.26 ± 0.09 MEF50 (L/sec) 4.36 ± 0.14 4.54 ± 0.15 MIF50 (L/sec) 5.14 ± 0.15 5.60 ± 0.16 PC20 (mg/ml)* 7.94 ± 1.12 15.8 ± 1.10† B-HR (n) 46 (52%) 17 (19%)† PC25MIF50 (mg/ml)* 3.24 ± 1.12 16.2 ± 1.10†
EA-HR (n) 76 (86%) 18 (20%)† Neutrophil score (n) 3.08 ± 0.17 0.68 ± 0.84†
*Geometric mean. †p < 0.001.
Bucca JACI 1995
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Extrathoracic airway (EA) and Intrathoracic Responsiveness in Sinusi6s and VCD
Conclusions: • Sinusi2s leads to increased responsiveness in EA • mediators from infected sinuses may seed inflammatory process to pharynx/larynx via PND
• may trigger a “pharyngo-‐bronchial” reflex • mechanism of “pharyngo-‐bronchial” reflex remains unknown
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Laryngopharyngeal Reflux (LPR)
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GERD vs. LPR à Cough
• Distal (LES) vagus afferents may stimulate cough – Irwin et al demonstrate stronger
correlation with distal pH probe sensor • Supraglottic sensation more directly
stimulates cough
Irwin RS, Zawacki JK, Curley FJ, et al. Chronic cough as the sole presen2ng manifesta2on of astroesophageal reflux. Am Rev Respir Dis 1989;140:1294 –1300.
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Laryngopharyngeal findings & reflux • Posterior-predominant supraglottic
edema/erythema • Glottic abnormalities • Epiglottic malformations • Posterior pharyngeal wall effects • Lingual tonsillar hypertrophy
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Laryngo-Pharyngeal Reflux (LPR)
Aryepiglorc fold edema and erythema
Posterior Commissure Thickening (pachyderma)
Posterior Cobblestoning
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Laryngoscopic Features of LPR
Posterior Cobblestoning
Posterior Commissure Thickening
Aryepiglorc Fold Thickening
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Laryngeal Biopsy (Patient)
(Marionian N et al Am J Med 2003 115(3A) 105S-108S)
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Nasopharyngeal Reflux
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Posterior Cobblestoning
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Association of nasopharyngeal and laryngopharyngeal reflux with
postnasal drip symptomatology in patients with and without rhinosinusitis. Wise et al: Am J Rhinol. 2006 May-Jun;20(3):283-9.
METHODS: Sixty-eight participants underwent 24-hour pH testing, - chronic rhinosinusitis (CRS) patients symptomatic after endoscopic sinus surgery - CRS patients successfully treated by endoscopic sinus surgery - volunteers without a CRS history.
Assessment: 1. pH probes: nasopharyngeal (NP), laryngopharyngeal (LP), and distal esophagealsensors. 2. SNOT questionnaire 3. MRSI PND questionnaire
RESULTS: - Positive correlation of r = 0.87 between SNOT-20 and MRSI PND items. NPR < pH 4
- no significant difference existed between participants with and without reflux on the SNOT-20 or MRSI (p > 0.05).
NPR < pH 5, - reflux-positive participants exhibited significantly more PND symptoms on the SNOT-20
(p = 0.030) and the MRSI (p = 0.018) compared with participants without reflux. - Participants with LPR had significantly more PND symptomatology on the SNOT-20 (p = 0.010) versus those without LPR. CONCLUSION: Objective evidence of NPR and LPR exists in patients reporting PND. Reflux treatment may reduce PND complaints.
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Direct nasopharyngeal reflux of gastric acid is a contribu2ng factor in refractory chronic
Rhinosinusi2s.
• 38 pa2ents with previous endoscopic sinus surgery
• 76 vs 24% of CRS group had NPR (p=.00003) • pH < 5 greater number of events than pH<4
DelGaudio JM. Laryngoscope. 2005 Jun;115(6):946-‐57.
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Linking laryngopharyngeal reflux to otitis media with effusion: pepsinogen study of adenoid tissue and middle ear fluid.
Al-Saab et al J Otolaryngol Head Neck Surg. 2008 Aug;37(4):565-71 METHODS: Middle ear effusions (MEEs) and adenoidal 2ssue biopsies from: 1. -‐ pa2ents undergoing tympanostomy tube placement and adenoidectomy 2. -‐adenoid specimens were taken during adenoidectomy (+/-‐ tonsillectomy) from children
with no history of OME.
-‐ adenoid 2ssues were analyzed immunohistochemically to confirm the presence of pepsinogen. -‐ MEE total pepsinogen levels were measured with enzyme-‐linked immunosorbent assay. RESULTS: -‐ Adenoid 2ssue of the OME group (n = 25)
-‐ demonstrated significantly higher pepsinogen immunoreac2vity when compared with the adenoid 2ssue of the control group (n = 29),
-‐ pepsinogen was detected in 84% of MEEs from the OME group, -‐concentra2ons 1.86 to 12.5 2mes higher than that of serum
CONCLUSION: LPR plays an important role in the pathogenesis of OME as gastric reflux reaches the middle ear through the nasopharynx and eustachian tube to cause OME.
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ACE inhibitor Induced Cough
• Subjects with ACE inhibitor induced cough typically report a 2ckle or scratching sensa2on in throat
• Mechanism unknown however: – Bradykinin, substance P normally broken down by ACE therefore accumulate in upper airway and or lung in pa2ents on ACE inhibitors
– Bradykinin causes increase prostaglandin produc2on – Bradykinin may induce increased sensi2vity of laryngeal airways
– Studies show increased sensi2vity to Capsaicin challenge Peter V. Dicpinigai/s, MD, FCCP
ACCP guidelines Chest 2006
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Irritant Associated (Occupa2onal) VCD
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Irritant Associated VCD (IVCD) (Perkner et al JOEM 1998)
• Case Defini2on • irritant exposure • onset symptoms within 24 hours • no history of VCD or other laryngeal disease • Laryngoscopy confirmed VCD
• Compared 11 cases with 33 age matched control VCD cases
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Most Common Exposure
NJC Experience • Chlorine gas • Ammonia • Smoke from fires
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Irritant Associated VCD (IVCD) Perkner et al (JOEM 1998)
No significant difference found between IVCD and VCD • Health care worker • Psychiatric history • Signs and symptoms:
• *Chest pain more common in IVCD group • wheeze, cough, dyspnea, choking, stridor, voice changes
• Pulmonary func2on tests • FEV1/FVC, FEF50/FIF50, Flow volume loop
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Reac2ve Airways Dysfunc2on Syndrome (RADS) vs Vocal Cord Dysfunc2on (VCD): Na2onal Jewish Experience
• Review series of pa2ents referred to Department of Environmental and Occupa2onal Health Sciences at Na2onal Jewish Medical Research Center for evalua2on of difficult to treat or atypical “RADS”
• 77 pa2ents reviewed
(Balkissoon R, Abstract, AJRCCM April Supplement 2000)
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Reac6ve Airways Dysfunc6on Syndrome (RADS) vs Vocal Cord Dysfunc6on (VCD): Na6onal Jewish Experience
GERD PND
VCD alone n = 12
11 (91%)
8 (66%)
RADS and VCD N =65
37 (56%)
42 (64%)
(Balkissoon R, Abstract, AJRCCM April Supplement 2000)
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Hypothesized “Vicious Cycle” Upper Respiratory Tract Infection/
(Non)/Allergic rhinitis
Cough
GERD
Laryngopharyngeal Reflux
Nasopharyngeal
Reflux
Chronic Cough
Habituated/ Neuropathic Cough
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Cough Habitua6on or Neuropathic cough: Neural Plas6c Response to Repe66ve Nocis6mula6on
S2mulus depolariza2on NeurotransmiHer
Second messeng
er mRNA fos
fos protein C-‐fos
C-‐jun DNA binding
FOS JUN
fos jun Transcrip2on of IE Genes
(Morrison et al Journal of Voice vol 13:1998)
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Summary • Cough is a protec2ve reflex • Neurologic Pathways for upper airway cough syndrome are complex
• Common causes of chronic cough all lead to laryngeal irrita2on
• Unified airway suggests lower airway disease may cause reflex sensa2ons in throat that induce cough
• Neural plas2city may lead to lower threshold for cough reflex with chronic nocicep2ve input