Neurophenotypes in Airway Diseases. Insights from Translational Cough Studies.

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 E2 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 E2 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).

Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: a double-blind randomized controlled trial.

BACKGROUND: Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents. OBJECTIVE: We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough. METHODS: Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected. RESULTS: Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498. CONCLUSION: This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.

Association Between Low Serum Creatinine and Mortality in Patients With Severe Chronic Obstructive Pulmonary Disease.

INTRODUCTION:  Muscle mass may be a better predictor of mortality than BMI in chronic obstructive pulmonary disease (COPD). Serum creatinine depends on muscle mass and renal function; low values may predict higher mortality. OBJECTIVE:  To determine whether there is an association between low serum creatinine and mortality in severe COPD. METHODS: This is a retrospective study of serum creatinine values at admission and within the last year before admission. Outcomes measured were mortality at 30 days and one year after admission in patients with acute type 2 respiratory failure secondary to COPD, who were admitted over a one-year period to a respiratory ward (N = 130). The statistics were calculated using the chi-squared test. RESULTS:  There appears to be a significant relationship between the one-year pre-admission creatinine values and mortality at one year (p = 0.0003). CONCLUSIONS:  The relationship with mortality appears to be stronger with pre-admission creatinine values rather than the admission values and appears to predict the patients at the highest risk of mortality one year after admission.

A Randomized Controlled Trial to Assess the Effect of Lidocaine Administered via Throat Spray and Nebulization in Patients with Refractory Chronic Cough.

BACKGROUND: Refractory chronic cough (RCC) is a debilitating condition for which there are no licensed treatments. Lidocaine is a nonselective inhibitor of voltage-gated sodium channels with potential antitussive effects, but randomized placebo-controlled studies evaluating its efficacy in RCC are lacking. OBJECTIVE: To investigate the efficacy of nebulized lidocaine and lidocaine throat spray versus matched placebos in RCC. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, 3-way crossover study, comparing the effect of single doses of nebulized lidocaine with lidocaine delivered by a throat spray and matched placebo. The primary end point was cough frequency over the 10 hours following treatment. Secondary end points were visual analog scale scores for urge-to-cough and cough severity; an exploratory analysis evaluated hourly cough rates up to 5 hours after treatment. RESULTS: Twenty-six subjects with RCC were recruited (22 females; mean age, 53.5 ± 12.1 years; FEV1 %predicted, 105.2 ± 16.8 L; forced vital capacity %predicted, 112.4 ± 18 L). Lidocaine throat spray, but not nebulized lidocaine, significantly reduced 10-hour cough frequency as compared with placebo (throat spray, 22.6 coughs/h; nebulization, 26.9 coughs/h; and placebos, 27.6 coughs/h; P = .04,). Lidocaine throat spray showed the greatest effect on cough compared with placebo in the first hour after administration (31.7 coughs/h vs 74.2 coughs/h; P = .004). Both nebulizer and spray treatments significantly alleviated urge-to-cough and cough severity visual analog scale scores compared with placebo (P < .05). There were no serious adverse events associated with lidocaine therapy. CONCLUSIONS: Lidocaine throat spray was effective in reducing cough frequency in patients with RCC. Voltage-gated sodium channel inhibitors applied to pharynx have potential as therapies for RCC.