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Rationale: Most airway diseases, including chronic obstructive pulmonary disease (COPD), are associated with excessive coughing. The extent to which this may be a consequence of increased activation of vagal afferents by pathology in the airways (e.g., inflammatory mediators, excessive mucus) or an altered neuronal phenotype is unknown. Understanding whether respiratory diseases are associated with dysfunction of airway sensory nerves has the potential to identify novel therapeutic targets.Objectives: To assess the changes in cough responses to a range of inhaled irritants in COPD and model these in animals to investigate the underlying mechanisms.Methods: Cough responses to inhaled stimuli in patients with COPD, healthy smokers, refractory chronic cough, asthma, and healthy volunteers were assessed and compared with vagus/airway nerve and cough responses in a cigarette smoke (CS) exposure guinea pig model. Measurements and Main Results:Patients with COPD had heightened cough responses to capsaicin but reduced responses to prostaglandin E 2 compared with healthy volunteers. Furthermore, the different patient groups all exhibited different patterns of modulation of cough responses. Consistent with these findings, capsaicin caused a greater number of coughs in CS-exposed guinea pigs than in control animals; similar increased responses were observed in ex vivo vagus nerve and neuron cell bodies in the vagal ganglia. However, responses to prostaglandin E 2 were decreased by CS exposure.Conclusions: CS exposure is capable of inducing responses consistent with phenotypic switching in airway sensory nerves comparable with the cough responses observed in patients with COPD. Moreover, the differing profiles of cough responses support the concept of disease-specific neurophenotypes in airway disease.Clinical trial registered with www.clinicaltrials.gov (NCT 01297790).

Rationale: Cough is one of the principal symptoms of chronic obstructive pulmonary disease (COPD) but the potential drivers of cough are likely to be multifactorial and poorly understood. Objectives: To quantify cough frequency in an unselected group of subjects with COPD and investigate the relationships between cough, reported sputum production, smoking, pulmonary function, and cellular airway inflammation. Methods: We studied 68 subjects with COPD (mean age, 65.6 6 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 6 8.9 yr; 37.5% male; 12 smokers; 12 nonsmokers). Subjects reported cough severity, cough-specific quality of life, and sputum expectoration and performed spirometry, sputum induction, cough reflex sensitivity to capsaicin, and 24-hour ambulatory cough monitoring. Measurements and Main Results: COPD current smokers had the highest cough rates (median, 9 coughs/h [interquartile range, 4.3-15.6 coughs/h]), almost double that of COPD ex-smokers (4.9 [2. 3-8.7] coughs/h; P ¼ 0.018) and healthy smokers (5.3 [1.2-8.3] coughs/h; P ¼ 0.03), whereas healthy volunteers coughed the least (0.7 [0.2-1.4] coughs/h). Cough frequency was not influenced by age or sex and only weakly correlated with cough reflex sensitivity to capsaicin (log C5 r ¼ 20.36; P ¼ 0.004). Reported sputum production, smoking history, and current cigarette consumption strongly predicted cough frequency, explaining 45.1% variance in a general linear model (P , 0.001). In subjects producing a sputum sample, cough frequency was related to current cigarette consumption and percentage of sputum neutrophils (P ¼ 0.002). Conclusions: Ambulatory objective monitoring provides novel insights into the determinants of cough in COPD, suggesting sputum production, smoking, and airway inflammation may be more important than sensitivity of the cough reflex.Keywords: cough; smoking; sputum; neutrophils; capsaicin Chronic obstructive pulmonary disease (COPD) is a major public health problem, with a lifetime risk in smokers of 35-50% (1). By 2020, it is estimated that more than 200 million people will have COPD, and it will be the third leading cause of death worldwide. Cough (either with or without sputum) is one of the principle symptoms of COPD, along with breathlessness. Epidemiologic studies have found that the reported presence of chronic cough and mucus hypersecretion in established COPD may be linked to accelerated decline in lung function (2), more frequent exacerbations (3), and hospitalizations (4), yet little is known about the mechanisms underlying coughing (5).The potential drivers for cough in patients with COPD are multifactorial. Excessive airway mucus may provide a mechanical stimulus to coughing, especially in the presence of ciliary dysfunction, airflow obstruction, and airway collapse (caused by destruction of the supporting parenchyma), all of which impair clearance. In addition the inflammation, infection, and in some continuing exposure to cigarette smoke provide chemical stimuli capable of provok...