Rachel Dockry

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING Afferent Pharmaceuticals.

Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD

IntroductionCOPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate and clinically stable COPD using a range of inflammatory biomarkers, 2 depression and 2 fatigue scales.MethodWe assessed 120 patients with moderate COPD (FEV1% 52, men 62%, age 66). Depression was assessed using the BASDEC and CES-D scales. Fatigue was assessed using the Manchester COPD-fatigue scale (MCFS) and the Borg scale before and after 6MWT. We measured systemic TNF-α, CRP, TNF-α-R1, TNF-α-R2 and IL-6.ResultsA multivariate linear model of all biomarkers showed that TNF-α only had a positive correlation with BASDEC depression score (p = 0.007). TNF-α remained positively correlated with depression (p = 0.024) after further adjusting for TNF-α-R1, TNF-α-R2, 6MWD, FEV1%, and pack-years. Even after adding the MCFS score, body mass and body composition to the model TNF-α was still associated with the BASDEC score (p = 0.044). Furthermore, patients with higher TNF-α level (> 3 pg/ml, n = 7) had higher mean CES-D depression score than the rest of the sample (p = 0.03). Borg fatigue score at baseline were weakly correlated with TNF-α and CRP, and with TNF-α only after 6MWT. Patients with higher TNF-α had more fatigue after 6MWD (p = 0.054).ConclusionThis study indicates a possible association between TNF-α and two frequent and major co-morbidities in COPD; i.e., depression and fatigue.

Depression and its relationship with poor exercise capacity, BODE index and muscle wasting in COPD

BACKGROUND The prevalence of depression in stable COPD patients varies markedly, possibly because of use of different scales. We aimed to assess depression using 2 different depression scales and to examine the association between depression and poor exercise performance, BODE index and muscle wasting in clinically stable COPD patients. METHODS 122 stable COPD patients were assessed with the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Brief Assessment Schedule Depression Cards (BASDEC). We also assessed patients with spirometry, bioelectrical impedance analysis, 6-minute walk distance (6MWD), St Georges Respiratory Questionnaire (SGRQ) and MRC dyspnoea and Borg scales. RESULTS The CES-D and BASDEC scales detected almost similar prevalence rates of depression (21% vs 17%) with a Kappa coefficient of 0.68, p<0.0001. The BASDEC scale detected more depression in women and was more closely associated with dyspnoea than the CES-D. COPD severity was associated with depression when using BODE scores but not when GOLD categories were used. Each of the CES-D and BASDEC depression scores were associated with 6MWD after adjusting for FEV1% predicted, gender, age and pack-years (p = <0.0001 and 0.001, respectively). Also, patients with a 6MWD<350 scored significantly higher on both depression scales. Wasted patients appeared to have higher depression scores, but the difference was statistically insignificant. CONCLUSION The administration of different depression scales may affect some of the characteristics of depressed patients rather than the prevalence rate of depression. Depression was associated with poor exercise performance and BODE index in COPD.

Predictors of objective cough frequency in chronic obstructive pulmonary disease.

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 ± 6.7 yr; 67.6% male; 23 smokers; 45 ex-smokers) and 24 healthy volunteers (mean age, 57.5 ± 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 = 0.018) and healthy smokers (5.3 [1.2-8.3] coughs/h; P = 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 = -0.36; P = 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 = 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.

Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: a cross-sectional study

BackgroundNon-invasive phenotyping of chronic respiratory diseases would be highly beneficial in the personalised medicine of the future. Volatile organic compounds can be measured in the exhaled breath and may be produced or altered by disease processes. We investigated whether distinct patterns of these compounds were present in chronic obstructive pulmonary disease (COPD) and clinically relevant disease phenotypes.MethodsBreath samples from 39 COPD subjects and 32 healthy controls were collected and analysed using gas chromatography time-of-flight mass spectrometry. Subjects with COPD also underwent sputum induction. Discriminatory compounds were identified by univariate logistic regression followed by multivariate analysis: 1. principal component analysis; 2. multivariate logistic regression; 3. receiver operating characteristic (ROC) analysis.ResultsComparing COPD versus healthy controls, principal component analysis clustered the 20 best-discriminating compounds into four components explaining 71% of the variance. Multivariate logistic regression constructed an optimised model using two components with an accuracy of 69%. The model had 85% sensitivity, 50% specificity and ROC area under the curve of 0.74. Analysis of COPD subgroups showed the method could classify COPD subjects with far greater accuracy. Models were constructed which classified subjects with ≥2% sputum eosinophilia with ROC area under the curve of 0.94 and those having frequent exacerbations 0.95. Potential biomarkers correlated to clinical variables were identified in each subgroup.ConclusionThe exhaled breath volatile organic compound profile discriminated between COPD and healthy controls and identified clinically relevant COPD subgroups. If these findings are validated in prospective cohorts, they may have diagnostic and management value in this disease.

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).

P159 Validation of the VitaloJAK™ 24 Hour Ambulatory Cough Monitor

Introduction Development of novel treatments for cough and its management are hampered by the lack of well validated objective cough frequency methodologies. Previous validations have been performed over limited time periods or in laboratory conditions not always representative of typical usage. We describe the rigorous validation of a semi-automated 24 hour ambulatory cough monitoring system (Vitalojak; Vitalograph; Buckinghamshire, England) operating in a manner which completely replicates routine practise. Methods In total 10 (4 female) patients (mean age 60.4 years [SD ±14.1] including 6 chronic cough, 2 asthma, 1 COPD and 1 healthy control underwent full 24 Hour ambulatory monitoring (VitaloJAK™). These recordings were manually counted by trained cough counters who also recorded the time at which each cough occurred. These 24 hour recordings were then compressed using custom designed compression software and the sensitivity to cough and the reduced file times were determined. Importantly in each case we confirmed that cough sounds identified in the compressed files were the same sounds identified by the trained manual cough counters in the full 24 hour recording. We tested the software algorithm using three distinct compression levels (1, 2 and 3). Results All results are presented as median (IQR). Sensitivities to cough (%) for compression levels 1, 2 and 3 are 100(100, 100), 100(99.53, 100) and 99.92(99.33, 100) and for reduced file times (minutes) 65.89 (62.40, 83.07), 43.21 (35.94, 57.23) and 26.30 (25.07,46.81) respectively (Table 1). Abstract P159 Table 1 Compressed output file times and sensitivities for each subject at compression levels 1, 2 and 3. Uncompressed file length=1440 minutes Output times and sensitivity Level 1 Level 2 Level3 Subject Minutes sensitivity Minutes sensitivity Minutes sensitivity 1 62.01 100.00 37.40 100.00 26.23 99.37 2 63.56 100.00 31.08 99.44 24.98 98.33 3 128.24 100.00 93.45 100.00 63.82 100.00 4 144.00 100.00 120.72 100.00 71.90 99.83 5 35.13 100.00 25.08 100.00 20.83 100.00 6 63.69 100.00 42.91 99.32 22.65 99.32 7 73.15 100.00 43.50 100.00 25.32 100.00 8 86.38 100.00 56.53 100.00 41.23 100.00 9 68.08 100.00 57.47 99.81 48.67 100.00 10 52.71 96.95 35.45 96.95 26.37 96.59 Mean 77.69 99.70 54.36 99.55 37.20 99.34 Median 65.89 100.00 43.21 100.00 26.30 99.92 Conclusions The vitaloJAK™ is a reliable, robust and efficient tool for the objective measurement of cough frequency. Importantly it reduces 24 hour recordings by up to 98% whilst preserving close to 100% of recorded cough sounds. This development facilitates efficient and speedy manual cough counting and the level of compression achieved represents significant progress towards fully automated cough monitoring.

P152 The Impact of a Selective oral TRPV1 Antagonist in Patients with Chronic Cough

Background Increased expression of TRPV1 receptors in the airways of chronic cough patients and heightened cough responses to inhaled capsaicin are suggestive of a role for TRPV1 receptors in chronic cough. We hypothesised that antagonism with a potent, selective, peripherally acting, oral TRPV1 antagonist, such as SB705498, would offer substantial cough symptom control. Methods 21 patients with unexplained chronic cough (caucasian, 71% female, mean age 53yrs) participated in a double-blind, placebo-controlled, single dose, 2-period, crossover study to investigate the relationship between pharmacokinetic (PK) derived TRPV1 receptor occupancy, change in capsaicin (C5) threshold and 24hr cough count following 600mg SB705498. PK samples were taken over the dosing interval, capsaicin threshold was determined at screening, 2hrs (Cmax) and 24hrs post-dose and 24hr objective ambulatory cough counts were recorded on each dosing day via a cough monitor (vitaloJAK™) with manual counting. In addition, CQLQ and VAS urge to cough was measured. A battery of safety and tolerability measures were also recorded, including core body temperature. Results TRPV1 receptor occupancy derived from plasma levels and factoring a plasma/lung ratio of 1, was approximately 45% at 2hrs and 25% at 24hrs. This translated to a 4 fold shift in the capsaicin C5 threshold at 2hrs (2uM to 8uM) maintained at 24hrs. However, there was no difference between hourly cough count profiles between placebo and SB705498 (see figure), with hourly counts of 20–30c/h and the characteristic nocturnal reduction. Cough counts were remarkably stable, repeated one month apart and over the 8 months of the study (including winter). Abstract P152 Figure 1 Conclusions We conclude that despite a clear relationship between receptor occupancy and engagement of the TRPV1 receptor as evidenced by the shift in the capsaicin threshold, there was no translation to any clinical efficacy parameter. This suggests peripheral TRPV1 receptor activation is not an important determinant of spontaneous cough frequency in chronic cough and that reductions in capsaicin responses do not necessarily predict anti-tussive effects.

S139 Cough responses to tussive agents in health and disease

Introduction Capsaicin or citric acid cough challenges have been used as an objective measure of cough reflex sensitivity for many decades. It remains unclear how the response to these agents differs in different diseases and how the response to one cough challenge agent differs from that to another. Prostaglandin E2 is known to result in cough when given as an inhalational agent, but has not been used as inhalational cough challenge agent. Objectives To assess the ability of individual challenges and combined challenge responses to discriminate between diagnostic groups and healthy volunteers. Methods We studied 102 subjects, median age 60.0 years (IQR 51.0–65.0) and 50% female (healthy volunteers n=21, healthy smokers n= 20, COPD n=18, asthma n=22 and chronic cough n=21). A doubling-dose, single inhalation method was used to measure the concentration of capsaicin (CAP), citric acid (CA) and prostaglandin E2 (PGE2) evoking at least 5 coughs (C5) within 15 s of administration, performed at weekly intervals. The operator was blinded to the challenge agent and each challenge contained 3 randomly interspersed placebo inhalations (saline). Data was analysed by multinomial logistic regression with healthy volunteers used as the reference category. Results Smokers (p=0.03) and COPD patients (p=0.003) had a significantly higher PGE2 logC5 than healthy volunteers. CA logC5 however was significantly lower in asthma (p=0.013), and chronic cough (p=0.001) compared with healthy volunteers. CAP logC5 was also significantly lower in chronic cough (p<0.001) but also in COPD (p=0.035) compared with healthy volunteers. Combining responses to all challenge agents suggested each individual challenge independently predicted the differences between disease groups and healthy volunteers (PGE2 p<0.001, CA p=0.018 and CAP p=0.015). Conclusions Cough responses to inhalational cough challenges can discriminate healthy controls from airway diseases. Furthermore, cough challenge agents differ in their ability to distinguish health from disease implying different underlying mechanisms drive coughing in these diagnoses. A combination of cough challenge tests appears to be better at discriminating diagnostic groups compared with any individual test in isolation.

Cough in Patients With Lung Cancer

BACKGROUND: Cough is common in patients with lung cancer, and current antitussive treatments are suboptimal. There are little published data describing cough in patients with lung cancer or work assessing clinical associations. The aim of this study is to fill that gap. METHODS: This was a longitudinal prospective observational single‐cohort study over 60 days. Patients were assessed through self‐reported validated scales and, in a subsample, ambulatory cough monitoring at study entry (day 0), day 30, and day 60. RESULTS: At study entry, 177 patients were included and 153 provided data at day 60. The median duration of cough was 52 weeks (interquartile range, 8.5‐260). Cough was described as severe enough to warrant treatment in 62% of the patients. Depending on the scale used, performance status was associated with both cough severity and cough impact (P < .001) at study entry, whereas higher cough severity at study entry was associated with female sex (P = .02), asthma (P = .035), and reflux disease (P < .001). Cough impact at study entry was additionally associated with experiencing nausea (P = .018). Cancer characteristics (ie, cancer stage, histology) were not associated with cough severity nor cough impact; neither was smoking or COPD. CONCLUSIONS: This is the first study to describe characteristics of cough in patients with lung cancer and to identify clinical associations that may be relevant for its treatment. Our data suggest that cough is a frequent and distressing symptom and an unmet clinical need. Its association with gastrointestinal symptoms in this study may improve our understanding of pathophysiology and therapeutic options for cough occurring in patients with lung cancer.