INTRODUCTION:Breathlessness is common and impairs the quality of life of people with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung diseases (ILD). We report the findings of a multicentre, fast-track (wait-list), mixed-methods, randomised controlled, feasibility study of a complex breathlessness intervention in breathless IPF and non-IPF fibrotic ILD patients. METHODS:Breathless IPF and non-IPF fibrotic ILD patients were randomised to receive the intervention within 1 week (fast-track) or after 8 weeks (wait-list). The intervention comprised two face-to-face and one telephone appointment during a 3-week period covering breathing control, handheld fan-use, pacing and breathlessness management techniques, and techniques to manage anxiety. Feasibility and clinical outcomes were assessed to inform progression to, and optimal design for, a definitive trial. A qualitative substudy explored barriers and facilitators to trial and intervention delivery. RESULTS:47 patients (M:F 38:9, mean (SD) age 73.9 (7.2)) were randomised with a recruitment rate of 2.5 participants per month across three sites. The adjusted mean differences (95% CI) for key clinical outcomes at 4 weeks post randomisation were as follows: Chronic Respiratory Questionnaire breathlessness mastery domain (0.45 (-0.07, 0.97)); and numerical rating scales for 'worst' (-0.93 (-1.95, 0.10)), 'best' (-0.19 (-1.38, 1.00)), 'distress caused by' (-1.84 (-3.29, -0.39)) and 'ability to cope with' (0.71 (-0.57, 1.99)) breathlessness within the past 24 hours. The qualitative substudy confirmed intervention acceptability and informed feasibility and acceptability of study outcome measures. CONCLUSION:A definitive trial of a complex breathlessness intervention in patients with IPF and non-IPF fibrotic ILD is feasible with preliminary data supporting intervention effectiveness. TRIAL REGISTRATION NUMBER:ISRCTN13784514.

In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. Trial registration: EudraCT 2019-000580-24 (17 May 2019)

The primary endpoint in many cough studies is 24 hour objective cough counting. When this is compared to our Patient Reported Outcomes (PROs) such as a Visual Analogue Scale (VAS) or cough diary data then a correlation of approxiamately 60% is observed. This suggests that cough counting does not reflect the full patient experience. We hypothesised that periods free from cough maybe a more accurate reflection of the patients perceived improvement in cough. The treatment of cystic fibrosis has been radically changed by the introduction of modulator therapy. We undertook 24-hour cough monitoring in patients prior to and 1 month post initiation of Kaftrio, utilising a semi-automated system for analysis (gift of Professor Birring). Total 24hr cough counts, mean hourly cough counts/24hrs and cough free hours were analysed in 14 patients (5 female, 9 male; mean age 31 years). Analysis revealed cough free hours/24hrs prior to treatment ranged from 0-14 (mean 7.2) which significantly improved, along with all other parameters measured, to a range of 7-19 (mean 13.8) hours cough free post treatment (p<0.01). These results suggest that the improvement in time free of cough is a sensitive index of drug efficacy and maybe more representative of the true patient perception of cough improvement.

Aims: To determine whether superior laryngeal nerve (SLN) block with lidocaine and steroids would reduce cough in patients with long term refractory cough. Methods: This was a retrospective review of 8 patients with long term refractory cough, undergoing unilateral SLN block. Pre and post measures of 24 hr cough, cough visual analogue scale (VAS) and Hull airway Reflux Questionnaire (HARQ) were measured. Results: 8 (7 female) patients, mean age 61 were studied prior and following unilateral block of the suerior laryngeal nerve. Effectiveness of the procedure was measured using subjective scores of cough intensity/frequency using VAS and HARQ and objectively, by measuring 24 hr ambulatory cough with the Hull Cough Recorder with analysis via leicester cough monitoring system. 24hr cough was significantly reduced from mean 427.4 to 225.3 1week post treatment (p<0.05), returning back to 472.3 at 1 month post treatment. There was a similar fall in both the mean VAS scores and HARQ total scores at 1 week, but these didnt reach significance. Conclusion: SLN block could be a possible effective treatment for patients with refractory cough. Indicating superior laryngeal neuropathy may contribute in part to hightened cough in these patients. Further study of bilateral SLN nerve block and longterm effects, aswell as characterisitcs of patients responding to the procedure needs to be undertaken.

Cough is a common symptom is cystic fibrosis (CF). Many patients demonstrate characteristics of cough hypersensitivity suggesting vagal nerve excitability. The introduction of CF modulator therapy has demonstrated beneficial response in a number of clinical parameters, particularly exacerbation rate and nutritional status. We hypothesised that the improvement in respiratory function with Kaftrio would be associated with a reduction in objectively measured cough. Ambulatory cough monitoring using a 24 hour recording system can be analysed in a semi-automated system (a kind gift from Professor S Birring). We recorded total cough count and average hourly cough count over 24 hours in patients at baseline and 1 month post initiation of Kaftrio. 14 patients were studied with a mean age of 31 years (5 female, 9 male). Total cough counts at baseline ranged from 29-2985 (median of 290) coughs over 24 hours. One month post initiation of Kaftrio objevtive cough counting was reduced in all patients to a range of 8-149 (median 22.5) total coughs over 24hours (p<0.05). These findings illustrate the usefulness of objective 24 hour cough counting in the monitoring of cystic fibrosis patients. The magnitude and speed of change provides a useful guide to therapeutic response and may provide simple objective measurement of clinical improvement in cystic fibrosis.

Introduction Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency. Methods This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire. Results 28 patients [median age 66 (range 46–86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days. Conclusion An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts.

Background: Chronic cough is a distressing symptom for many people with pulmonary sarcoidosis. Continuous treatment with a macrolide antibiotic may improve cough. We aimed to assess the potential efficacy of azithromycin in patients with sarcoidosis and self-reported cough. Methods: We conducted a noncontrolled, open-label clinical trial of azithromycin 250 mg once daily for 3 months in patients with pulmonary sarcoidosis who reported a chronic cough. The primary outcome was number of coughs in 24 h. Secondary outcomes were cough visual analogue scales and quality of life measured using the Leicester Cough Questionnaire and King's Sarcoidosis Questionnaire. Safety outcomes included QTc interval on ECG. Measurements were made at baseline and after 1 and 3 months of treatment. Results: All 21 patients were white, median age 57 years, 9 males, 12 females, median 3 years since diagnosis. Five were taking oral corticosteroids and none were taking other immunosuppressants. Twenty patients completed the trial. The median (range) number of coughs in 24 h was 228 (43-1950) at baseline, 122 (20-704) at 1 month, and 81 (16-414) at 3 months (p=0.002, Friedman's test). The median reduction in cough count at 3 months was 49.6%. There were improvements in all patient-reported outcomes. Azithromycin was well tolerated. Conclusion: In a noncontrolled open-label trial in people with sarcoidosis who reported a chronic cough, 3 months of treatment with azithromycin led to improvements in a range of cough metrics. Azithromycin should be tested as a treatment for sarcoidosis cough in a randomised placebo-controlled trial.

We thank J.A. Smith and co-workers for their interest in our paper [1]. Perhaps an even more ancient truth, that of William of Occam [2], should be applied to this discussion. The human cough reflex has separate, distinct pathways http://bit.ly/2PZgybq

Introduction: Acute exacerbations of COPD (AECOPD) often lead to health service utilisation and have associated morbidity and mortality. Telemonitoring is proposed to facilitate early treatment by identifying and alerting clinicians to deterioration; but existing strategies have proven disappointing. Cough commonly increases at the time of AECOPD. We have previously described a system to monitor cough trends over time. Aim: To assess cough count around AE-COPD and develop a system to alert clinicians to a meaningful change in cough frequency. Methods: This prospective longitudinal study of cough monitoring included COPD patients that had ≥2 AECOPD within the last year. Participants underwent continual cough monitoring and completed a daily questionnaire for 90 days. AECOPD were identified by self-reporting, prescribing and hospital attendance data. A novel alert system based on cough monitoring was compared with a symptom based strategy. Results: 28 patients completed the study (16 males; median age 66 [range 46-86]; mean [SD] FEV-1 % predicted 36 [18]%; CAT score 28 [8]) and had a total of 43 moderate and 15 severe AECOPD. Mean cough count increased during AE-COPD. Alerts based on cough monitoring occurred in the prodrome of 45% of AE-COPD with 1 false alert every 100 days. Questionnaire based alerts occurred in the prodrome of 88% of AE-COPD with 1 false alert every 10 days. Conclusion: Cough monitoring can detect change in cough frequency around AECOPD. The low false alert rate with cough monitoring means it has the potential to be a clinically useful tool to identify an impending AE-COPD and facilitate an early response. The utility of symptom monitoring is limited by frequent false alerts.

A retrospective case series was undertaken on all patients initiated on Octreotide from March 2014-May 2019 following referral to the Cough Clinic at Castle Hill Hospital. Patients were identified from the Octreotide records, which were analysed for cough and spirometry data, patient-reported outcomes, and details of adverse events. Medical records were analysed for patient demographics. 21 patients were initiated on 50mcg subcutaneous Octreotide. Prior to 4-weeks completion, 3 patients discontinued, 1 patient was non-compliant, and 1 patient had incomplete data. All patients completed the Hull Airway Reflux Questionnaire (HARQ) and Visual Analogue Symptom Score (SS.) 24-hour cough count was also recorded for 6/16 patients. We therefore report the effects of 4 weeks of therapy on these patients, 2 males and 4 females, with a mean age of 55.3 and a mean % of predicted FEV1 of 52.6%. Mean 24-hour cough count fell from 867 to 282 (67% decrease.) Cough count was reduced in 5/6 patients. Mean SS fell from 34/45 to 24/45 and mean HARQ score from 47/70 to 35/70. 3/6 patients experienced distressing GI side effects. Of all patients initiated on Octreotide, 15 (71%) experienced GI symptoms and 6 (29%) later discontinued – 3 prior to and 3 at 4 weeks. Octreotide is effective in reducing cough count and improving patient-reported outcomes in some patients. The proposed mechanism is through improving oesophageal dysmotility by interacting with motilin. Due to adverse effects, it is unsuitable for routine use, however in refractory cough it may be considered for a 4-week trial.

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge. In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking >= 2 coughs (C2) and >= 5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs.h(-1)) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored. 24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p <= 0.001) and 3.7-fold (C5, p= 0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p= 0.113; C5, p= 0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients). ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.

Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease that causes breathlessness and cough that worsen over time, limiting daily activities and negatively impacting quality of life. Although treatments are now available that slow the rate of lung function decline, trials of these treatments have failed to show improvement in symptoms or quality of life. There is an immediate unmet need for evidenced-based interventions that improve patients' symptom burden and make a difference to everyday living. This study aims to assess the feasibility of conducting a definitive randomised controlled trial of a holistic, complex breathlessness intervention in people with IPF. Methods and analysis The trial is a two-centre, randomised controlled feasibility trial of a complex breathlessness intervention compared with usual care in patients with IPF. 50 participants will be recruited from secondary care IPF clinics and randomised 1:1 to either start the intervention within 1 week of randomisation (fast-track group) or to receive usual care for 8 weeks before receiving the intervention (wait-list group). Participants will remain in the study for a total of 16 weeks. Outcome measures will be feasibility outcomes, including recruitment, retention, acceptability and fidelity of the intervention. Clinical outcomes will be measured to inform outcome selection and sample size calculation for a definitive trial. Ethics and dissemination Yorkshire and The Humber – Bradford Leeds Research Ethics Committee approved the study protocol (REC 18/YH/0147). Results of the main trial and all secondary end-points will be submitted for publication in a peer-reviewed journal.

Introduction: Studies have shown hypersensitivity of the cough reflex in acute cough associated with Upper Respiratory Tract Infection (URTI), the physiopathology of this mechanism is not known. Objectives: To assess the effect of a single-dose ambroxol hydrochloride (HCL) 20 mg lozenge on cough reflex sensitivity to cough challenge; cough severity and urge-to-cough Visual analogue scale (VAS) and comparing cough reflex sensitivity during URTI to post-recovery. Methods: Response to cough challenge using capsaicin, citric acid, ATP and distilled water was measured at baseline and at 30 and 90 min post ambroxol. Patient´s perception of their acute cough severity and urge-to-cough were measured. ANOVA analysis to compare baseline, 30 min and 90 min post dose test results and 95% CIs were calculated. In addition Paired t-test and Wilcoxon signed-rank test were used to compare cough challenge results during URTI (baseline) and post-recovery. 14 subjects (23 to 61 years) were recruited. No effect of ambroxol in reducing cough reflex sensitivity to cough challenge was shown. A significant reduction in severity of cough VAS (p<0.01, p<0.001) and urge-to-cough VAS (p<0.001, p<0.001) was shown versus baseline at 30 min and 90 min post-dose. Cough sensitivity to ATP and distilled water was reduced 1 month post-recovery from URTI (p<0.05). No change in cough sensitivity to capsaicin or citric acid was observed. Conclusion: Although the cough model was unable to detect changes in cough reflex sensitivity following ambroxol. There was evidence of decreased cough sensitivity to cough challenge post recovery, supporting the use of challenge agents in future studies.

Introduction: Citric acid has been used for over six decades to induce cough; however the mechanism of its protussive effect is still not fully understood. We assessed the response to inhalation of citric acid at varying levels of acidity to determine if the pH of the solution plays a role in the induction of cough. Data was collected from both healthy volunteers and patients with chronic cough. Methods: 20 chronic cough patients and 20 healthy volunteers were recruited and underwent three cough challenges on separate days. Each visit involved 5 repeated one second inhalations of 300 mM citric acid solution. The concentration of the citrate cation remained constant, but the pH of the solution altered by the addition of sodium bicarbonate to 3, 5 and 6, representing the plc values of the individual acid moieties. The total number of coughs elicited was recorded for each inhalation. Results: Two subjects withdrew and were not included in the analysis. Participants were gender matched, each group consisting of 12 females. 74% of chronic coughers coughed at pH 3 (mean coughs 16), 89% coughed at pH 5 (18) and 63% coughed at pH 6 (7). In healthy volunteers, 60% of subjects coughed at pH 3 (9), 30% of subjects coughed at pH 5 (3), and 10% of subjects coughed at pH 6 (0). Thus chronic cough patients coughed more than healthy volunteers and did not exhibit a clear pH concentration response. There was also a greater variability in their response to individual challenges.

Background: Capsaicin (CAP), Citric Acid (CA), Fog and ATP cough challenges have been routinely used to assess cough reflex sensitivity (CRS). Whether these agents can be utilised on a single challenge protocol or if cross-tachyphylaxis prevents the accurate determination of challenge sensitivity is unknown. Aim: To determine whether order of cough challenge effects CRS. Methods: CRS was studied in 23 chronic cough (CC) and 12 healthy volunteers. Cough challenges were performed in a random sequence and in accordance with ERS guidelines. The first challenge with each agent was then compared with subsequent challenges. C2 was log transformed (logC2) and compared by ANOVA. Results: First challenge did not influence the logC2 concentration of subsequent challenges (Table 1). This was also the case when CC and healthy volunteers were analysed separately. However, all three chemical agents caused significantly greater response in chronic cough patients. Mean difference in logC2 concentrations for CAP, CA and ATP were 0.64 (95% CI 0.25 – 1.03), 0.90 (95% CI 0.36 -1.44), 1.02 (95% CI 0.39 – 1.65) all p < 0.01 respectively. Conclusion: First cough challenge did not effect subsequent cough CRS. Protocols using multiple challenge methodology may be used to assess pharmacodynamics and target engagement of anti-tussive drugs. Table 1. Values for mean (± SD) logC2, grouped by the first cough challenge performed.

BACKGROUND:Whether the fraction of exhaled nitric oxide (FeNO) measurement can predict the response to anti-inflammatory treatment in chronic cough is unknown. OBJECTIVE:To explore whether the effectiveness of treatment with 10 mg of montelukast or 20 mg of prednisolone in patients with chronic cough is predicted by FeNO level. METHODS:In this randomized, open-label, controlled pilot study conducted in the Clinical Trial Unit in Castle Hospital in the United Kingdom, 50 nonsmoking patients with a cough that lasted more than 8 weeks were sequentially enrolled in the study. Thirty patients with high FeNO levels (≥30 ppb) were randomized in a 1:1 ratio to receive 10 mg of montelukast or 20 mg of prednisolone for 2 weeks followed by 10 mg of montelukast for 2 weeks. Twenty patients with a low FeNO level (≤20 ppb) received 10 mg of montelukast. The primary objective was to determine the effectiveness of treatment on 24-hour cough counts. RESULTS:The 24-hour cough counts decreased in both groups by approximately 50% (P < .005), indicating that FeNO did not predict treatment response. However, it was a good marker for eosinophilic inflammation with a high degree of correlation with blood and sputum eosinophilia (P < .001). CONCLUSION:These results suggest that prior investigation may not predict response to anti-inflammatory treatment, which may be consequent on localized leukotriene-mediated inflammation. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02479074.

Capsaicin, the hot component of chilli peppers, is a well-known tussive agent, which is regularly used as a tool to study cough and antitussives (1). Capsaicin is known to activate the transient receptor potential vanilloid 1 (TRPV1) cation channel which is thought to be involved in pain perception, inflammation, itch and cough (2-4). These functions within the body make TRPV1 an exciting target for research and drug development.

To evaluate whether exhaled nitric oxide measurement can facilitate in the assessment of chronic cough patients based on their airway inflammatory phenotype. We have studied consecutive patients attending a specialist cough clinic. 30 patients with high FeNO (> 30 ppb) and 20 patients with low FeNO (< 20 ppb) were recruited. There was a significant correlation between FeNO, B-Eos and sputum eosinophil count (p < 0.001). The number of recorded coughs in 24 h and HARQ scores were significantly (p < 0.05) higher in patients with a low FeNO. In contrast to the high FeNO group (48%), the greater proportion of these patients were women (90%). LCQ scores were worse in the low FeNO group but it was not significant. A strong relationship between FeNO, blood eosinophils and sputum eosinophils confirming phenotypic identity was observed. Whether the observed gender disparity accounts for the different cough frequency characteristics is unknown.