Anatomy and Neurophysiology of Cough

Chang, Anne B.; Smith, Jaclyn A.; Adams, Todd M.; Altman, Kenneth W.; Barker, Alan F.; Birring, Surinder S.; Blackhall, F.; Bolser, Donald C.; Boulet, Louis‐Philippe; Braman, Sidney S.; Brightling, Christopher; Callahan-Lyon, Priscilla; Canning, Brendan J.; Chang, Anne B.; Coeytaux, Remy R; Cowley, Terrie; Davenport, Paul; Diekemper, Rebecca L.; Ebihara, Satoru; Solh, Ali A. El; Escalante, Patricio; Feinstein, Anthony; Field, Stephen K.; Fisher, Dina; French, Cynthia T.; Gibson, Peter H.; Gold, Philip M.; Grant, Cameron; Harding, Susan M.; Harnden, Anthony; Hill, Adam T.; Irwin, Richard S.; Kahrilas, Peter J.; Keogh, Karina A.; Lane, Andrew P.; Lewis, Sandra Zelman; Lim, Kaiser G.; Malesker, Mark A.; Mazzone, Peter J.; Mazzone, Stuart B.; McGarvey, Lorcan; Molasiotis, Alex; Murad, Mohammad Hassan; Newcombe, Peter; Nguyen, Huong Q.; Oppenheimer, John; Prezant, David J.; Pringsheim, Tamara; Restrepo, Marcos I.; Rosen, Mark J.; Rubin, Bruce K.; Ryu, Jay H.; Smith, Jennifer A.; Tarlo, Susan M.; Turner, Ronald B.; Vertigan, Anne E.; Wang, Gang; Weir, Kelly A.

doi:10.1378/chest.14-1481

Cited by 233 publications

(84 citation statements)

References 171 publications

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“…TRP ion channels are present in the airways, primary airway sensory neurons, smooth muscle, and epithelial cells [21]. In cough, inflammation in the lungs or esophagus increases the afferent nerve excitation [28] that leads to a referred sensation of irritation in the throat and a reduced cough threshold. The reduced cough threshold in refractory CC is associated with increased expression of TRPV1 receptors on airway nerves [29].…”

Section: Introductionmentioning

confidence: 99%

“…Peripheral sensitization can occur in sensitized areas like the larynx, esophagus, pharynx, and bronchi mediated by the vagus nerve. Inflammatory mediators such as histamine and prostaglandins sensitize cough afferent nerve endings increasing the excitation of afferent nerves [28] and decreasing the threshold for cough. Patients with CC have a fivefold elevation of TRPV1-containing nerves [28] and exposure to low-level tussive stimuli such as smoke results in a hypersensitive cough reflex termed hypertussia [65].…”

Section: Introductionmentioning

confidence: 99%

“…Inflammatory mediators such as histamine and prostaglandins sensitize cough afferent nerve endings increasing the excitation of afferent nerves [28] and decreasing the threshold for cough. Patients with CC have a fivefold elevation of TRPV1-containing nerves [28] and exposure to low-level tussive stimuli such as smoke results in a hypersensitive cough reflex termed hypertussia [65]. In refractory CC, there is a significant increase in cough reflex sensitivity to capsaicin [7] that explains why hypertussia is common in refractory CC.…”

Section: Introductionmentioning

confidence: 99%

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An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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Introduction: Chronic Cough (CC) is common and often associated with significant comorbidity and decreased quality of life. In up to 50% of cases, the cough is refractory despite extensive investigation and treatment trials. It is likely that the key abnormality in refractory CC is dysfunctional, hypersensitive sensory nerves, similar to conditions such as laryngeal hypersensitivity and neuropathic pain.Areas covered: The aim of this systematic review is to assess drug therapies for refractory CC. The authors review the current management of CC and provide discussion of the similarities between neuropathic pain and refractory CC. They review repurposed and new pharmacological treatments. Several meta-analyses were performed to compare the efficacy of treatments where possible.Expert opinion: Repurposed pain medications such as gabapentin and pregabalin reduce the frequency of cough and improve quality of life. Along with speech pathology, they are important and alternate treatments for refractory CC. However, more treatments are needed and the P2X3 ion channel receptor antagonists show the most promise. With a better understanding of neuronal activation and sensitisation and their signal processing in the brain, improved animal models of cough, and the use of validated cough measurement tools, more effective treatments will develop.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An update and systematic review on drug therapies for the treatment of refractory chronic cough

Ryan

Vertigan

Birring

2018

Expert Opinion on Pharmacotherapy

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“…Yet, prominent discoveries of immunochemically distinct receptor end organs, such as the unmistakable guinea pig cough receptor (10) and the murine smooth muscle-associated airway receptor and neuroepithelial body (NEB) innervation (11), have been conspicuously absent in descriptions of human airway innervation to date (12). The sparsity of such vagal afferent mechanoreceptors in comparison with the easily identified vagal and spinal C fiber counterparts and lack of appropriate antibodies might explain this phenomenon.…”

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confidence: 99%

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies

West

Canning²,

Merlo‐Pich

et al. 2015

Am J Respir Crit Care Med

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Rationale: Neuroplasticity of bronchopulmonary afferent neurons that respond to mechanical and chemical stimuli may sensitize the cough reflex. Afferent drive in cough is carried by the vagus nerve, and vagal afferent nerve terminals have been well defined in animals. Yet, both unmyelinated C fibers and particularly the morphologically distinct, myelinated, nodose-derived mechanoreceptors described in animals are poorly characterized in humans. To date there are no distinctive molecular markers or detailed morphologies available for human bronchopulmonary afferent nerves.Objectives: Morphologic and neuromolecular characterization of the afferent nerves that are potentially involved in cough in humans.Methods: A whole-mount immunofluorescence approach, rarely used in human lung tissue, was used with antibodies specific to protein gene product 9.5 (PGP9.5) and, for the first time in human lung tissue, 200-kD neurofilament subunit. Measurements and Main Results:We have developed a robust technique to visualize fibers consistent with autonomic and C fibers and pulmonary neuroendocrine cells. A group of morphologically distinct, 200-kD neurofilament-immunopositive myelinated afferent fibers, a subpopulation of which did not express PGP9.5, was also identified.Conclusions: PGP9.5-immunonegative nerves are strikingly similar to myelinated airway afferents, the cough receptor, and smooth muscle-associated airway receptors described in rodents. These have never been described in humans. Full description of human airway nerves is critical to the translation of animal studies to the clinical setting.

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“…The larynx has the highest density of tussigenic nerve endings followed by the carina, trachea, and the proximal bronchi. 17,18 The diffusion of BtxA into the pharyngeal area and resultant dysphagia may be a factor to be considered in future studies. Behavioral response to the urge to cough is susceptible to suppression and modification by desensitization and distraction.…”

Section: Discussionmentioning

confidence: 99%

Bilateral Thyroarytenoid Botulinum Toxin Type A Injection for the Treatment of Refractory Chronic Cough

Sasieta

Iyer

Orbelo

et al. 2016

JAMA Otolaryngol Head Neck Surg

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IMPORTANCERefractory chronic cough is a debilitating condition with limited therapeutic options. Laryngeal botulinum toxin type A (BtxA) has been anecdotally reported to benefit patients with chronic cough. We report on our experience with the use of BtxA for the treatment of patients with refractory chronic cough. MAIN OUTCOMES AND MEASURESThe primary outcome is a self-reported improvement of 50% or more in cough severity and/or symptoms by a 2-month follow-up telephone call. Adverse events and patient-reported quality measures were also assessed. RESULTS A total of 22 patients (median [interquartile range] age 61 [57.5-85] years; 19 of 22 women) underwent 31 distinct laryngeal BtxA treatment sessions. The primary outcome of self-reported improvement of 50% or more of cough severity and/or symptoms was achieved in 16 of 31 (52%) treatment sessions. Eleven patients (50%) reported greater than 50% improvement after the first BtxA injection. No major complications occurred. Postprocedural liquid dysphagia had a positive predictive value of 84% and negative predictive value of 100% for response to therapy.CONCLUSIONS AND RELEVANCE In this case series, laryngeal BtxA injection was well tolerated in patients with refractory chronic cough with half of participants experiencing at least short-term improvement in their cough. The occurrence of liquid dysphagia after a BtxA injection appeared to be predictive of a beneficial response. The durability of response, patient selection criteria, and optimal BtxA dosage remains to be determined.

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Anatomy and Neurophysiology of Cough

Cited by 233 publications

References 171 publications

An update and systematic review on drug therapies for the treatment of refractory chronic cough

An update and systematic review on drug therapies for the treatment of refractory chronic cough

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies

Bilateral Thyroarytenoid Botulinum Toxin Type A Injection for the Treatment of Refractory Chronic Cough

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