Efficacy and safety of Cineole (Soledum®) in the treatment of patients with acute bronchitis: results of an open-label randomized clinical phase III study

Background Cineole has documented anti-inflammatory, expectorant, and mucolytic properties and has shown to be a valuable treatment option in different airway diseases. Our study examined whether a therapy with Cineole as add on to an antiviral therapy can relieve symptoms of acute bronchitis, and accelerate recovery in everyday practice. Methods In an open-label, randomized, parallel-group phase III clinical trial, 132 patients diagnosed with “acute bronchitis” or “acute tracheobronchitis” were included and treated with 3 × 200 mg of Cineole on top of antiviral treatment, or antiviral treatment alone (Ingavirin® 90 mg), per day for 4–9 days. The primary outcome measure was the change in cough frequency assessed in a Cough Frequency Assessment Scale, secondary outcomes were the total Bronchitis Severity Scale (BSS), as well as individual symptoms of the BSS score. Adverse events were collected for safety analysis. The study sites were located in Russia. Results After 4 days of therapy, there was a significant difference between the groups in favour of the patients treated with Cineole which persisted until the end of the study. At that time, cough during the day, assessed by the Cough Frequency Assessment Scale, was absent in 14 patients in the Cineole group (21.5%), compared to 4 (6.2%) patients in the control arm (p = 0.0203), which was replicated using the BSS individual cough score. In addition, significant improvements in the individual symptoms of the BSS in patients taking Cineole were documented. The study drug showed good tolerability without differences to antiviral treatment and results were in line with previous experiences with this drug. Conclusions Assessment after 4 days of treatment with additional Cineole showed a significant reduction of cough frequency and other symptoms of acute bronchitis compared to antiviral treatment alone. In addition, patients recovered faster from the disease. Additional treatment with Cineole is a valuable treatment option in acute bronchitis. Trial registration Ministry of Health, Russia, No. 592. Registered 19 October 2015.

Influence of Pharyngeal Anaesthesia on Post-Bronchoscopic Coughing: A Prospective, Single Blinded, Multicentre Trial

Background: Local anaesthesia of the pharynx (LAP) was introduced in the era of rigid bronchoscopy (which was initially a conscious procedure under local anaesthetic), and continued into the era of flexible bronchoscopy (FB) in order to facilitate introduction of the FB. LAP reduces cough and gagging reflex, but its post-procedural effect is unclear. This prospective multicentre trial evaluated the effect of LAP on coughing intensity/time and patient comfort after FB, and the feasibility of FB under propofol sedation alone, without LAP. Material and methods: FB was performed in 74 consecutive patients under sedation with propofol, either alone (35 patients, 47.3%) or with additional LAP (39 patients, 52.7%). A primary endpoint of post-procedural coughing duration in the first 10 min after awakening was evaluated. A secondary endpoint was the cough frequency, quality and development of coughing in the same period during the 10 min post-procedure. Finally, the ease of undertaking the FB and the patient’s tolerance and safety were evaluated from the point of view of the investigator, the assistant technician and the patient. Results: We observed a trend to a shorter cumulative coughing time of 48.6 s in the group without LAP compared to 82.8 s in the group receiving LAP within the first 10 min after the procedure, although this difference was not significant (p = 0.24). There was no significant difference in the cough frequency, quality, peri-procedural complication rate, nor patient tolerance or safety. FB, including any additional procedure, could be performed equally well with or without LAP in both groups. Conclusions: Our study suggests that undertaking FB under deep sedation without LAP does to affect post-procedural cough duration and frequency. However, further prospective randomised controlled trials are needed to further support this finding.

Feasibility and clinical utility of ambulatory cough monitoring in an outpatient clinical setting: a real world retrospective evaluation

Research questionObjective quantification of cough is rarely utilised outside of research settings and the role of cough frequency monitoring in clinical practice has not been established. This study examined the clinical utility of cough frequency monitoring in an outpatient clinical setting.MethodsThe study involved a retrospective review of cough monitor data. Participants included 174 patients referred for treatment of cough and upper airway symptoms (103 chronic cough; 50 inducible laryngeal obstruction; 21 severe asthma), and 15 controls. Measures, taken prior to treatment, included 24-h ambulatory cough frequency using the Leicester Cough Monitor, the Leicester Cough Questionnaire and Laryngeal Hypersensitivity Questionnaire. Post-treatment data was available for 50 participants. Feasibility and clinical utility were also reported.ResultsAnalysis time per recording was up to 10 min. Seventy five percent of participants could use the monitors correctly and most (93%) recordings were interpretable. The geometric mean cough frequency in patients was 10.1 (sd=2.9) compared to 2.4 (2.0) for healthy controls, (p=0.003). There was no significant difference in cough frequency between clinical groups, (p=0.080). Cough frequency decreased significantly following treatment, (p<0.001). There was a moderate correlation between cough frequency and both cough quality of life and laryngeal hypersensitivity. Cough frequency monitoring was responsive to therapy, and able to discriminate differences in cough frequency between diseases.ConclusionWhile ambulatory cough frequency monitoring remains a research tool, it provides useful clinical data that can assist in patient management. Logistical issues may preclude use in some clinical settings and additional time needs to be allocated to the process.

Predictive Value of Cough Frequency in Addition to Aspiration Risk for Increased Risk of Pneumonia in Dysphagic Stroke Survivors: A Clinical Pilot Study

Background: Post-stroke dysphagia leads to increased risk of aspiration and subsequent higher risk of pneumonia. It is important to not only diagnose post-stroke dysphagia early but also to evaluate the protective mechanism that counteracts aspiration, i.e., primarily cough. The aim of this study was to investigate the predictive value of cough frequency in addition to aspiration risk for pneumonia outcome. Methods: This was a single-center prospective observational study. Patients with first-ever strokes underwent clinical swallowing evaluation, fibreoptic endoscopic evaluation of swallowing (FEES), and overnight cough recording using LEOSound® (Löwenstein Medical GmbH & Co. KG, Bad Ems, Germany ). Penetration–Aspiration Scale (PAS) ratings and cough frequency measurements were correlated with incidence of pneumonia at discharge. Results: 11 women (37%) and 19 men (63%), mean age 70.3 years (SD ± 10.6), with ischemic stroke and dysphagia were enrolled. Correlation analysis showed statistically significant relationships between pneumonia and PAS (r = 0.521; p < 0.05), hourly cough frequency (r = 0,441; p < 0.05), and categories of cough severity (r = 0.428 p < 0.05), respectively. Logistic regression showed significant predictive effects of PAS (b = 0.687; p = 0.014) and cough frequency (b = 0.239; p = 0.041) for pneumonia outcome. Conclusion: Cough frequency in addition to aspiration risk was an independent predictor of pneumonia in dysphagic stroke survivors.

An initial assessment of the involvement of transglutaminase2 in eosinophilic bronchitis using a disease model developed in C57BL/6 mice

The detailed pathogenesis of eosinophilic bronchitis (EB) remains unclear. Transglutaminase 2 (TG2) has been implicated in many respiratory diseases including asthma. Herein, we aim to assess preliminarily the relationship of TG2 with EB in the context of the development of an appropriate EB model through ovalbumin (OVA) sensitization and challenge in the C57BL/6 mouse strain. Our data lead us to propose a 50 μg dose of OVA challenge as appropriate to establish an EB model in C57BL/6 mice, whereas a challenge with a 400 μg dose of OVA significantly induced asthma. Compared to controls, TG2 is up-regulated in the airway epithelium of EB mice and EB patients. When TG2 activity was inhibited by cystamine treatment, there were no effects on airway responsiveness; in contrast, the lung pathology score and eosinophil counts in bronchoalveolar lavage fluid were significantly increased whereas the cough frequency was significantly decreased. The expression levels of interleukin (IL)-4, IL-13, IL-6, mast cell protease7 and the transient receptor potential (TRP) ankyrin 1 (TRPA1), TRP vanilloid 1 (TRPV1) were significantly decreased. These data open the possibility of an involvement of TG2 in mediating the increased cough frequency in EB through the regulation of TRPA1 and TRPV1 expression. The establishment of an EB model in C57BL/6 mice opens the way for a genetic investigation of the involvement of TG2 and other molecules in this disease using KO mice, which are often generated in the C57BL/6 genetic background.

Eliapixant (BAY 1817080), a P2X3 receptor antagonist, in refractory chronic cough: a randomised, placebo-controlled, crossover phase 2a study

ATP acting via P2X3 receptors is an important mediator of refractory chronic cough (RCC). This phase 2a double-blinded crossover study assessed the safety, tolerability and efficacy of eliapixant (BAY 1817080), a selective P2X3 receptor antagonist, in adults with RCC attending specialist centres.In period A, patients received placebo for 2 weeks then eliapixant 10 mg for 1 week. In period B, patients received eliapixant 50, 200 and 750 mg twice daily for 1 week per dose level. Patients were randomised 1:1 to period A–B (n=20) or B–A (n=20). The primary efficacy endpoint was change in cough frequency assessed over 24 h (VitaloJAK). Primary safety endpoint was frequency and severity of adverse events (AEs).Thirty-seven patients completed randomised therapy. Mean cough frequency fell by 17.4% versus baseline with placebo. Eliapixant reduced cough frequency at doses ≥50 mg (reduction versus placebo at 750 mg, 25%: 90% confidence interval, 11.5–36.5%; p=0.002). Doses ≥50 mg also significantly reduced cough severity. AEs, mostly mild or moderate, were reported in 65% of patients with placebo and 41–49% receiving eliapixant. Cumulative rates of taste-related AEs were 3% with placebo and 5–21% with eliapixant: all were mild.Selective P2X3 antagonism with eliapixant significantly reduced cough frequency and severity, confirming this as a viable therapeutic pathway for RCC. Taste-related side-effects were lower at therapeutic doses than with the less selective P2X3 antagonist gefapixant. Selective P2X3 antagonism appears to be a novel therapeutic approach for RCC.

A novel automatic cough frequency monitoring system combining a triaxial accelerometer and a stretchable strain sensor

Objective evaluations of cough frequency are considered important for assessing the clinical state of patients with respiratory diseases. However, cough monitors with audio recordings are rarely used in clinical settings. Issues regarding privacy and background noise with audio recordings are barriers to the wide use of these monitors; to solve these problems, we developed a novel automatic cough frequency monitoring system combining a triaxial accelerator and a stretchable strain sensor. Eleven healthy adult volunteers and 10 adult patients with cough were enrolled. The participants wore two devices for 30 min for the cough measurements. An accelerator was attached to the epigastric region, and a stretchable strain sensor was worn around their neck. When the subjects coughed, these devices displayed specific waveforms. The data from all the participants were categorized into a training dataset and a test dataset. Using a variational autoencoder, a machine learning algorithm with deep learning, the components of the test dataset were automatically judged as being a “cough unit” or “non-cough unit”. The sensitivity and specificity in detecting coughs were 92% and 96%, respectively. Our cough monitoring system has the potential to be widely used in clinical settings without any concerns regarding privacy or background noise.