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.

The Effect of Pain Conditioning on Experimentally Evoked Cough: Evidence of Impaired Endogenous Inhibitory Control Mechanisms in Refractory Chronic Cough.

The pathophysiology of refractory chronic cough (RCC) is unclear. We hypothesised that endogenous inhibitory control mechanisms, such as those activated by noxiousstimuli inducing pain (conditioned pain modulation (CPM)), may be capable of inhibiting coughing and urge to cough evoked by inhaled capsaicin. Furthermore, these mechanisms may be impaired in patients with RCC.The objective was to investigate the effects of pain on cough and urge to cough (UTC) in healthy volunteers (HV) and RCC. HV and RCC patients underwent a randomised, controlled, 4-way cross-over study comparing the effect of 4 interventions on capsaicin evoked coughing and UTC. The interventions comprised immersing a hand in i) noxious cold-water, ii) warm water, iii) warm water but instructed to voluntarily supress coughing and iv) no intervention. The co-primary outcomes were numbers of evoked coughs and UTC scores.Twenty HV (mean age 50.1(±SD14.2), M:F 10:10) and 20 RCC (age 60.1(±7.9), M:F 9:11) participated. Overall, noxious cold water reduced capsaicin evoked UTC scores and cough numbers compared with warm water (1.6 (95% C.I. 1.3-2.0) versus 2.2 (1.8-2.6) p<0.001; 4.8 coughs (3.7-6.2) versus 7.9 coughs (6.7-9.5) p<0.001, respectively). HV and RCC demonstrated similar reductions in the UTC during noxious cold-water immersion, but noxious cold water and voluntary suppression interventions were less effective in RCC than HV in reducing capsaicin evoked cough (p=0.041).Endogenous inhibitory control mechanisms, specifically those activated by pain, can reduce both coughing and the UTC. Impairment of endogenous inhibitory control mechanisms may contribute to excessive coughing in RCC.

Towards understanding and managing chronic cough.

Chronic cough is a common and troublesome condition affecting approximately 12% of the general population. It is associated with poor quality of life with psychological, social and physical consequences. Patients typically complain of a dry irritating cough, driven by a strong urge to cough associated with a sensation or irritation located in the throat. Treatment of potential 'causes', ie asthma, gastro-oesophageal reflux disease and rhino-sinusitis, may produce a complete or partial response, but the response of some patients to opiates and alpha-2-delta ligand antagonists (gabapentin and pregabalin) supports the concept that this is primarily a neurological disorder, characterised by hyper-responsiveness of the nerves. Novel and highly effective neuronal treatments are in development and offer hope of better symptom control with fewer side effects within a few years. This review focuses on understanding the mechanism of chronic cough, current management approaches and research that may lead to novel therapies.

Morphologic Characterization of Nerves in Whole-Mount Airway Biopsies.

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.

PCR based bronchoscopic detection of common respiratory pathogens in chronic cough: a case control study.

BACKGROUND: Viral respiratory tract infection is the most frequent cause of acute cough and is reported at onset in about one third of patients with chronic cough. Persistent infection is therefore one possible explanation for the cough reflex hypersensitivity and pulmonary inflammation reported in chronic cough patients. METHODS: Bronchoscopic endobronchial biopsies and bronchoalveolar lavage cell counts were obtained from ten healthy volunteers and twenty treatment resistant chronic cough patients (10 selected for lavage lymphocytosis). A screen for known respiratory pathogens was performed on biopsy tissue. Chronic cough patients also underwent cough reflex sensitivity testing using citric acid. RESULTS: There was no significant difference in incidence of infection between healthy volunteers and chronic cough patients (p = 0.115) or non-lymphocytic and lymphocytic groups (p = 0.404). BAL cell percentages were not significantly different between healthy volunteers and chronic cough patients without lymphocytosis. Lymphocytic patients however had a significantly raised percentage of lymphocytes (p < 0.01), neutrophils (p < 0.05), eosinophils (p < 0.05) and decreased macrophages (p < 0.001) verses healthy volunteers. There was no significant difference in the cough reflex sensitivity between non-lymphocytic and lymphocytic patients (p = 0.536). CONCLUSIONS: This study indicates latent infection in the lung is unlikely to play an important role in chronic cough, but a role for undetected or undetectable pathogens in either the lung or a distal site could not be ruled out. TRIALS REGISTRATION: Current Controlled Trials ISRCTN62337037 & ISRCTN40147207.

A comparison of objective and subjective measures of cough in asthma.

BACKGROUND: Cough is widely recognized as a key symptom in the diagnosis and the monitoring of asthma, but little is known about how best to assess cough in asthma. OBJECTIVE: To determine how objective cough rates correlate with subjective measures of cough in asthma. METHODS: We studied 56 subjects, median age 42.0 years (range, 28.5-71), 34 (60.7%) female, with asthma. Subjects performed cough reflex sensitivity testing (concentration of citric acid causing 2 and 5 coughs [C2 and C5]), 24-hour fully ambulatory cough recordings, subjectively scored the severity of their cough (visual analog scales and 0-5 score) and completed a cough-related quality of life questionnaire (Leicester Cough Questionnaire). Ambulatory cough recordings were manually counted and reported in cough seconds per hour (cs/h). RESULTS: The median time spent coughing was 2.6 cs/h (range, 0.0-14.2), with subjects spending more time coughing by day (median, 3.9 cs/h [0.0-18.5]) than by night (median, 0.3 cs/h [0.0-8.7]; P < .001). A weak inverse relationship was seen between day cough rates and log(10)C2 (r = -0.39; P = .03) but not log(10)C5 (r = -0.08; P = .65). Objective time spent coughing was also weak-moderately associated with subjective cough scores and visual analog scales, and most strongly correlated with cough-related quality of life (r = -0.54; P < .001). CONCLUSION: Subjective measures of cough and cough reflex sensitivity are poor surrogates for objective cough frequency in asthma. When designing studies to assess interventions for cough in asthma, we advocate a combination of both objective measures of cough and cough-related quality of life.

Non-invasive biomarkers and pulmonary function in smokers.

Limited information exists regarding measurement, reproducibility and interrelationships of non-invasive biomarkers in smokers. We compared exhaled breath condensate (EBC) leukotriene B4 (LTB4) and 8-isoprostane, exhaled nitric oxide, induced sputum, spirometry, plethysmography, impulse oscillometry and methacholine reactivity in 18 smokers and 10 non-smokers. We assessed the relationships between these measurements and within-subject reproducibility of EBC biomarkers in smokers. Compared to non-smokers, smokers had significantly lower MMEF % predicted (mean 64.1 vs 77.7, p = 0.003), FEV1/FVC (mean 76.2 vs 79.8 p = 0.05), specific conductance (geometric mean 1.2 vs 1.6, p = 0.02), higher resonant frequency (mean 15.5 vs 9.9, p = 0.01) and higher EBC 8-isoprostane (geometric mean 49.9 vs 8.9 pg/ml p = 0.001). Median EBC pH values were similar, but a subgroup of smokers had airway acidification (pH < 7.2) not observed in non-smokers. Smokers had predominant sputum neutrophilia (mean 68.5%). Repeated EBC measurements showed no significant differences between group means, but Bland Altman analysis showed large individual variability. EBC 8-isoprostane correlated with EBC LTB4 (r = 0.78, p = 0.0001). Sputum supernatant IL-8 correlated with total neutrophil count per gram of sputum (r = 0.52, p = 0.04) and with EBC pH (r = -0.59, p = 0.02). In conclusion, smokers had evidence of small airway dysfunction, increased airway resistance, reduced lung compliance, airway neutrophilia and oxidative stress.

Improvement in asthma endpoints when aiming for total control: salmeterol/fluticasone propionate versus fluticasone propionate alone.

AIMS: To investigate the magnitude of change in morning peak expiratory flow (PEF), asthma symptoms, and rescue beta2-agonist use, when the aim of treatment is to achieve guideline-defined control. METHODS: This was a protocol-defined analysis of data from the previously-reported one-year, stratified, randomised, double-blind, parallel-group GOAL study comparing the use of salmeterol/fluticasone propionate with fluticasone propionate alone in achieving guideline-defined control; this analysis assessed the magnitude of change in single specific endpoints which were amalgamated into the composite measure of control used in the primary GOAL analysis. RESULTS: Across all strata, improvements were seen for each outcome at 52 weeks as compared to baseline: mean morning PEF, 58.2 l/min (salmeterol/fluticasone propionate) versus 33.9 l/min (fluticasone propionate alone); symptom scores, -1.0 versus -0.8; symptom-free days, 72.5% versus 54.5%; mean of zero night awakenings, 31% versus 22%; rescue-free days, 87.3 versus 74.7; annualised rate of severe exacerbations, 0.02 versus 0.03; p<0.001 for all treatment differences. CONCLUSIONS: Aiming for guideline-defined control resulted in sustained, clinically relevant improvements in a range of individual asthma outcomes. Improvements were greatest with salmeterol/fluticasone propionate versus fluticasone propionate alone.

Establishing a gold standard for manual cough counting: video versus digital audio recordings.

BACKGROUND: Manual cough counting is time-consuming and laborious; however it is the standard to which automated cough monitoring devices must be compared. We have compared manual cough counting from video recordings with manual cough counting from digital audio recordings. METHODS: We studied 8 patients with chronic cough, overnight in laboratory conditions (diagnoses were 5 asthma, 1 rhinitis, 1 gastro-oesophageal reflux disease and 1 idiopathic cough). Coughs were recorded simultaneously using a video camera with infrared lighting and digital sound recording. The numbers of coughs in each 8 hour recording were counted manually, by a trained observer, in real time from the video recordings and using audio-editing software from the digital sound recordings. RESULTS: The median cough frequency was 17.8 (IQR 5.9-28.7) cough sounds per hour in the video recordings and 17.7 (6.0-29.4) coughs per hour in the digital sound recordings. There was excellent agreement between the video and digital audio cough rates; mean difference of -0.3 coughs per hour (SD +/- 0.6), 95% limits of agreement -1.5 to +0.9 coughs per hour. Video recordings had poorer sound quality even in controlled conditions and can only be analysed in real time (8 hours per recording). Digital sound recordings required 2-4 hours of analysis per recording. CONCLUSION: Manual counting of cough sounds from digital audio recordings has excellent agreement with simultaneous video recordings in laboratory conditions. We suggest that ambulatory digital audio recording is therefore ideal for validating future cough monitoring devices, as this as this can be performed in the patients own environment.

The description of cough sounds by healthcare professionals.

BACKGROUND: Little is known of the language healthcare professionals use to describe cough sounds. We aimed to examine how they describe cough sounds and to assess whether these descriptions suggested they appreciate the basic sound qualities (as assessed by acoustic analysis) and the underlying diagnosis of the patient coughing. METHODS: 53 health professionals from two large respiratory tertiary referral centres were recruited; 22 doctors and 31 staff from professions allied to medicine. Participants listened to 9 sequences of spontaneous cough sounds from common respiratory diseases. For each cough they selected patient gender, the most appropriate descriptors and a diagnosis. Cluster analysis was performed to assess which cough sounds attracted similar descriptions. RESULTS: Gender was correctly identified in 93% of cases. The presence or absence of mucus was correct in 76.1% and wheeze in 39.3% of cases. However, identifying clinical diagnosis from cough was poor at 34.0%. Cluster analysis showed coughs with the same acoustics properties rather than the same diagnoses attracted the same descriptions. CONCLUSION: These results suggest that healthcare professionals can recognise some of the qualities of cough sounds but are poor at making diagnoses from them. It remains to be seen whether in the future cough sound acoustics will provide useful clinical information and whether their study will lead to the development of useful new outcome measures in cough monitoring.

A comparison of lung function methods for assessing dose-response effects of salbutamol.

Pulmonary function methods which are able to detect small pharmacological effects may be useful for assessing the full dose-response curve of bronchodilatators. We compared the ability of impulse oscillometry (R5, R20, X5, RF), plethysmography (sGaw) and spirometry [forced expiratory volume in 1 s (FEV(1)), maximal mid expiratory flow rate (MMEF)] to measure the dose-response effects of salbutamol in 12 healthy subjects, 12 mild asthmatics (mean FEV(1) 96% predicted) and 12 moderate asthmatics (mean FEV(1) 63% predicted). The techniques were performed twice to assess variability. Then salbutamol 10, 20, 100, 200 and 800 microg was administered. The sensitivity of the methods were compared by determining the lowest dose that caused changes greater than variability. In healthy subjects significant changes (p < or = 0.05) were observed only in FEV(1) (4.1%) and MMEF (14.6%) at 100 microg and sGaw (25.6%) and R20 (8.3%) at 200 microg. In mild asthmatics significant changes were observed in sGaw (15.9%) at 10 microg, X5 (23%), RF (20.3%) and MMEF (15.7%) at 20 microg, R5 (13.9%) and R20 (9.4%) at 100 microg and FEV(1) (7.1%) at 200 microg. All measurements except R20 demonstrated significant changes at 10 micro g in moderate asthmatics. The most sensitive test for assessing bronchodilatation is different in healthy subjects and asthmatics, and varies with severity of airflow obstruction.