Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

AIMS: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

M4 muscarinic receptors mediate acetylcholine-induced suppressant effects on the cough reflex in the caudal nucleus tractus solitarii of the rabbit.

It has been shown that muscarinic acetylcholine receptors (mAChRs) located within the caudal nucleus tractus solitarii (cNTS) mediate a cholinergic inhibitory control mechanism of the cough reflex. Thus, identification of the involved mAChR subtypes could be of considerable interest for novel therapeutic strategies. In pentobarbital sodium-anesthetized, spontaneously breathing rabbits we investigated the contribution of different mAChR subtypes in the modulation of mechanically and chemically induced cough reflex. Bilateral microinjections of 1 mM muscarine into the cNTS increased respiratory frequency and decreased expiratory activity even to complete suppression. Interestingly, muscarine induced strong cough-suppressant effects up to the complete abolition of the reflex. Microinjections of specific mAChR subtype antagonists (M1-M5) into the cNTS were performed. Only microinjections of the M4 antagonist tropicamide (1 mM) prevented muscarine-induced changes in both respiratory activity and cough reflex. The results are discussed in light of the notion that cough involves the activation of the nociceptive system. They also suggest that M4 receptor agonists may have an important role in cough downregulation within the cNTS.

The P2X3 receptor antagonist filapixant in patients with refractory chronic cough: a randomized controlled trial.

BACKGROUND: P2X3 receptor antagonists seem to have a promising potential for treating patients with refractory chronic cough. In this double-blind, randomized, placebo-controlled study, we investigated the efficacy, safety, and tolerability of the novel selective P2X3 receptor antagonist filapixant (BAY1902607) in patients with refractory chronic cough. METHODS: Following a crossover design, 23 patients with refractory chronic cough (age: 60.4 ± 9.1 years) received ascending doses of filapixant in one period (20, 80, 150, and 250 mg, twice daily, 4-days-on/3-days-off) and placebo in the other. The primary efficacy endpoint was the 24-h cough frequency on Day 4 of each dosing step. Further, subjective cough severity and health-related quality of life were assessed. RESULTS: Filapixant at doses ≥ 80 mg significantly reduced cough frequency and severity and improved cough health-related quality of life. Reductions in 24-h cough frequency over placebo ranged from 17% (80 mg dose) to 37% (250 mg dose), reductions over baseline from 23% (80 mg) to 41% (250 mg) (placebo: 6%). Reductions in cough severity ratings on a 100-mm visual analog scale ranged from 8 mm (80 mg) to 21 mm (250 mg). No serious or severe adverse events or adverse events leading to discontinuation of treatment were reported. Taste-related adverse events occurred in 4%, 13%, 43%, and 57% of patients treated with filapixant 20, 80, 150, and 250 mg, respectively, and in 12% treated with placebo. CONCLUSIONS: Filapixant proved to be efficacious, safe, and-apart from the occurrence of taste disturbances, especially at higher dosages-well tolerated during the short therapeutic intervention. Clinical trial registration EudraCT, eudract.ema.europa.eu, 2018-000129-29; ClinicalTrials.gov, NCT03535168.

Cough Sensitivity to Several External Triggers is Associated with Multiple Non-respiratory Symptoms.

PURPOSE: Enhanced responsiveness to external triggers is thought to reflect hypersensitivity of the cough reflex. It may involve an enhanced sensitivity of the afferent nerves in the airways and/or an abnormal processing of the afferent information by the central nervous system (CNS). The CNS processing of cough has been shown to involve the same regions as those in symptom amplification, a phenomenon that often manifests as multiple symptoms. The main purpose of the present study was to define whether the presence of several cough triggers is associated with multiple symptoms. METHODS: 2131 subjects with current cough responding to two email surveys filled in a comprehensive questionnaire about social background, lifestyle, general health, doctors' diagnoses and visits, symptoms, and medication. Multiple symptoms was defined as three or more non-respiratory, non-mental symptoms. RESULTS: A carefully controlled multiple regression analysis revealed that the number of cough triggers was the only cough characteristic associating with multiple non-respiratory, non-mental symptoms [aOR 1.15 (1.12-1.19) per one trigger, p < 0.001]. Among the 268 subjects with current cough both in the first survey and in the follow-up survey 12 months later, the repeatability of the trigger sum was good with an intraclass correlation coefficient of 0.80 (0.75-0.84). CONCLUSION: The association between the number of the cough triggers and multiple symptoms suggests that the CNS component of cough hypersensitivity may be a manifestation of non-specific alteration in the CNS interpretation of various body sensations. The number of cough triggers is a repeatable measure of cough sensitivity.

Effects of continuous and slow tracheal tube cuff deflation on cough reflex during extubation in noncardiac surgery patients: a randomised clinical trial.

BACKGROUND: The incidence of cough reflex during extubation is 76%. Cough reflex causes severe hemodynamic fluctuations and airway complications. This prospective trial investigated the potential effects of tracheal tube cuff deflation on cough reflex during extubation. METHODS: One hundred and twenty-six patients scheduled for operations within 3 h under general anaesthesia with orotracheal intubation were randomly assigned to one of three groups: control (C), experimental (E) or syringe (S) groups. Patients in group C underwent tracheal tube cuff deflation using a 10-ml syringe in 1 s, patients in group E underwent tracheal tube cuff deflation continuously and slowly in 5 s using a cuff pressure gauge until the pressure was zero and patients in group S underwent tracheal tube cuff deflation using a 10-ml syringe at a speed of 1 ml s-1. The incidence and severity of cough reflexs during extubation and the incidence of postoperative airway complications within 48 h were assessed. RESULTS: Compared with group C (60.0%), the incidence of cough reflex in group E was 9.8% (p < 0.001) and in group S was 12.5% (p < 0.001). The severity of cough reflex was graded as 2 (1-2) in group C, 1 (1-1) in group E and 1 (1-1) in group S (p < 0.001 for group comparisons). The incidence of hoarseness in group C was 0.0%, in group E was 19.5% and in group S was 5.0% (p < 0.05 for all groups, p = 0.009 between group C and E). CONCLUSIONS: Compared with deflating a trachal tube cuff with a 10-ml syringe in 1 s, the use of a 10-ml syringe at a speed of 1 ml s-1 or a cuff pressure guage within 5 s can both reduce the incidence of cough reflex, but deflating with a cuff pressure guage can increase the incidence of postoperative hoarseness. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR2100054089, Date: 08/12/2021.

Effects of transcranial direct current stimulation on cough reflex and urge-to-cough in healthy young adults.

BACKGROUND: Chronic cough is prevalent in the clinic. The existing therapies are mostly limited to medical treatment, with poor curative effects and serious side effects. Studies have suggested that the right dorsolateral prefrontal cortex (rDLPFC) may play an active role in the inhibitory pathway of cough elicitation. Thus, this study explored the effect of transcranial direct current stimulation (tDCS) on the rDLPFC activation in relation to cough reflex and urge-to-cough sensitivity. METHODS: Twenty-three healthy young adults completed the experiment. Participants randomly received tDCS anodal stimulation, cathodal stimulation, and sham stimulation, and the interval between every two stimuli was at least one week. The tDCS (2 mA, 30 min) stimulated brain rDLPFC region. After tDCS intervention, cough reflex threshold and urge-to-cough were evaluated immediately by inhalation of citric acid-saline solution. RESULTS: Compared with sham stimulation, the cough reflex thresholds logC2 and logC5 have increased under tDCS anodal stimulation (1.78 ± 0.55 g/L vs. 1.57 ± 0.57 g/L, p < 0.05; 1.92 ± 0.53 g/L vs. 1.67 ± 0.56 g/L, p < 0.05), accompanied by the increase of the urge-to-cough threshold LogCu (0.76 ± 0.53 g/L vs. 0.47 ± 0.44 g/L, p < 0.05). In contrast, the urge-to-cough sensitivity expressed as UTC slope was not significantly changed (1.21 ± 0.86 point·L/g vs. 1.00 ± 0.37 point·L/g, p > 0.05), and there were no apparent changes in cough reflex thresholds Log C2 and logC5, urge-to-cough threshold LogCu, and urge-to-cough sensitivity UTC slope under tDCS cathodal stimulation, compared with sham stimulation. CONCLUSIONS: This study found that anodal tDCS stimulation of rDLPFC could significantly decrease cough reflex sensitivity, accompanied by the increase of urge-to-cough threshold. Further investigations targeting different brain regions using multiple central intervention techniques to explore the underlying mechanisms are warranted. Trial registration The study protocol was registered for the clinical trial in China (registration number: ChiCTR2100045618).

Gold Standard? Method of Citric Acid Solution Swallowing Test as a Screening Test for Patients with Tracheostomy.

This study aimed to apply various ranges of citric acid levels in the mouth and T-cannula to compare the validity with instrumental aspiration measures in patients with tracheostomy. Sixty-one patients underwent the citric acid cough reflex test (CRT) and videofluoroscopic swallowing study (VFSS). Citric acid was delivered via facemask and T-cannula at concentrations of 0.4 mol/L, 0.6 mol/L, and 0.8 mol/L. Further, we recorded the coughing count and presence of ≥ 2 (C2) and ≥ 5 (C5) coughs. CRT via facemask at 0.4 mol/L C2, 0.6 mol/L C5, and 0.8 mol/L C2 and C5 were significantly associated with the presence of tracheal aspiration during VFSS. The sensitivity and specificity were optimized at 0.8 mol/L C2 for mouth inhalation and at 0.8 mol/L C5 for T-cannula inhalation. There was a significant difference in the coughing count during CRT at 0.4 mol/L and 0.8 mol/L via mouth inhalation between patients with or without tracheal aspiration, but not via T-cannula. The AUC for 0.8 mol/L facemask inhalation was 0.701. The optimal cut-off value of coughing count was thrice with 84.62% sensitivity and 50.00% specificity on the ROC curve. Afferent sensory nerve desensitization around and below the tracheostomy site could affect coughing reflex initiation and decrease the sensitivity of detecting aspiration in tracheotomized patients. The citric acid CRT via facemask can reliably detect tracheal aspiration and presence of coughing reflex compared to that via T-cannula in patients with tracheostomy.

Reflux-related symptoms reflect poor asthma control and the presence of airway neuronal dysfunction.

BACKGROUND: Gastroesophageal reflux may be associated with the worsening of asthma by increasing cough reflex sensitivity. Hull Airway Reflux Questionnaire (HARQ) consists of 14 prevalent reflux-related symptoms. It may be useful in predicting the presence of cough reflex hypersensitivity in asthma. METHODS: From August 2018 to July 2020, 266 asthmatic patients completed the HARQ. They underwent blood analysis, spirometry, fraction of exhaled nitric oxide (FeNO) measurement, and the capsaicin cough challenge test. Patients were considered to have reflux-related symptoms if their HARQ scores were 13 points or higher. We evaluated the association between reflux-related symptoms and clinical asthma outcomes. Finally, we performed a multivariate analysis to determine the clinical significance of the HARQ for asthma. This study was registered in the University Hospital Medical Information Network (UMIN000040732). RESULTS: The mean HARQ scores were 13.1 (standard deviation 12.0). Patients in the high HARQ scores group (HARQ ≥13, n = 105) showed a lower prevalence of atopic predisposition, lower levels of FeNO, heightened capsaicin cough reflex sensitivity, poorer asthma control, and more frequent admissions due to asthma than those in the low HARQ groups (all p values < 0.05). The HARQ was useful in selecting patients with poor controlled asthma and those with severe cough when the cut-off value was set at 13. Multivariate analysis revealed that heightened capsaicin cough reflex sensitivity affected reflux-related symptoms, as well as lower levels of FeNO and younger age. CONCLUSIONS: Higher HARQ scores (≥13) may be useful in predicting not only poor asthma condition but also the presence of airway neuronal dysfunction in patients with asthma to some extent.

Deep Inspiration-Provoked Cough: A Sign of Cough Reflex Arc Hypersensitivity.

Deep inspiration-provoked cough (DIPC) is a form of allotussia. Allotussia is thought to be a manifestation of cough reflex arc hypersensitivity but objective evidence about this is lacking. 36 subjects with chronic cough and 25 healthy subjects underwent mannitol and citric acid cough provocation tests. DIPC was defined as two or more coughs after deep inhalation of an empty mannitol capsule. Citric acid was administered utilizing a dosimetric nebulizer during controlled tidal breathing. Nine subjects demonstrated DIPC, 8/36 subjects with chronic cough and 1/25 healthy subjects (p = 0.048). The concentration of citric acid to provoke five or more coughs (C5) was 23.4 (63.8) mM among subjects with DIPC and 750 (2941) mM among the subjects without it (p = 0.006). The number of deep inspiration-provoked coughs correlated with the citric acid C5 (Rs -0.38, p = 0.002). In conclusion, DIPC, a form of allotussia, is associated with cough reflex arc hypersensitivity.Trial Registration Number.ClinicalTrials.gov database KUH5801136.

Increased Capsaicin Sensitivity in Patients with Severe Asthma Is Associated with Worse Clinical Outcome.

Rationale: Capsaicin cough reflex sensitivity (C-CS) is associated with poorly controlled asthma, although its association with severe asthma remains unknown.Objectives: To determine the clinical impact of C-CS on severe asthma.Methods: We prospectively enrolled 157 patients with asthma (including 122 patients with severe asthma who were in step 4 or 5 according to the Global Initiative for Asthma 2015 guidelines) between November 2016 and October 2019. A capsaicin cough challenge was performed along with spirometry and assessment of biomarkers. The concentration required to induce at least five coughs by capsaicin was adopted as an index of C-CS. An Asthma Control Test and comorbidities were also evaluated. Associations of biomarkers with four clinical features of severe asthma made by the European Respiratory Society/American Thoracic Society guidelines (poor control [Asthma Control Test < 20; n = 58], frequent exacerbations [≥2/yr; n = 28], admissions [≥1/yr; n = 17], and airflow limitation [FEV1% predicted < 80%; n = 30]) were assessed.Measurements and Main Results: Heightened C-CS was associated with poor asthma control, frequent exacerbations, and admissions, particularly in patients without atopy (n = 54). Meanwhile, C-CS was not related to airflow limitation. Multivariate regression analysis has revealed that heightened C-CS (at least five coughs by capsaicin ≤ 2.44 µM) was a significant risk for poor asthma control and frequent exacerbations. Regarding general factors and comorbidities, ex-smoking status, diabetes mellitus, and chronic rhinosinusitis were associated with clinical features of severe asthma (all P < 0.05).Conclusions: Heightened C-CS is a risk factor for severe asthma. The present study suggests the association of airway neuronal dysfunction with the pathophysiology of non-type 2 severe asthma.

Dual Tasking Influences Cough Reflex Outcomes in Adults with Parkinson's Disease: A Controlled Study.

Coughing is an essential airway protective reflex. In healthy young adults, cough somatosensation changes when attention is divided (dual tasking). Whether the same is true in populations at risk of aspiration remains unknown. We present findings from a controlled study testing the effects of divided attention (via a dual-task paradigm) on measures of reflex cough in Parkinson's disease. Volunteers with Parkinson's disease (n = 14, age = 43-79 years) and 14 age-matched controls underwent five blocks of capsaicin-induced cough challenges. Within each block, capsaicin ranging from 0 to 200 µM was presented in a randomized order. Two blocks consisted of cough testing only (single task), and two blocks consisted of cough testing with simultaneous tone counting (dual task). Finally, participants completed a suppressed cough task. Measures of cough motor response, self-reported urge to cough, cough frequency, and cough airflow were collected. Historical data from healthy young adults was included for comparison. Between-group analyses revealed no differences between single- and dual-cough-task responses. However, post hoc analysis revealed a significant relationship between dual-task errors and cough frequency that was strongest in people with Parkinson's disease [p = 0.004, r2 = 0.52]. Specifically, greater errors were associated with fewer reflexive coughs. Unlike healthy participants, participants with Parkinson's disease did not change the number of coughs between the single-, dual-, and suppressed-task conditions [p > 0.05]. When distracted, people with Parkinson's disease may prioritize coughing differently than healthy controls. Abnormal cortical resource allocation may be a mechanism involved in aspiration in this population.

Determinants of response to bronchodilator in patients with cough variant asthma- A randomized, single-blinded, placebo-controlled study.

BACKGROUND: Not all patients with cough variant asthma (CVA) show responsiveness to bronchodilators (RB) in clinic. Whether there are specific clinical and pathophysiological features can indicate RB in patients with CVA needs further investigation. Thus, we aimed to investigate the RB in patients with CVA and associated factors. METHODS: Forty-two CVA patients were randomized in a 2:1 ratio to receive oral bambuterol hydrochloride (10 mg, once daily, for 3 days) or matched placebo, 36 patients (24 with bronchodilator and 12 with placebo) completed the study eventually. RB was considered when cough visual analogue scale (VAS) score decreased 30% or more after 3 days treatment. The baseline clinical and pathophysiological characteristics between patients with RB and patients without RB were compared. CRS was presented with the lowest concentration of capsaicin inducing at least 5 coughing (C5). RESULTS: The responsive rate of patients with bronchodilator was significantly higher than that with placebo (62.5% vs 16.7%, p < 0.01). Patients with RB showed a significant greater mean decline of FEV1% predicted after bronchial provocation (26.7% vs 22.4%, p < 0.05) and higher geometric mean of sputum eosinophils (1.37 vs 0.69, p < 0.05) as compared with these without RB. No significant differences in sputum neutrophil, Log C5 were found between patients with RB and patients without RB. There was a moderate correlation between the decline of FEV1% pred and RB (rs = 0.443, p < 0.05). The regression analysis showed that nocturnal cough was a predictor of RB (OR, 7.33, 95% CI: 1.11-48.26, p = 0.038). No adverse events were reported by all of the patients after the study. CONCLUSION: More than one-third of patients with CVA do not respond to bronchodilator treatment, indicating that the response to bronchodilator should not be a diagnostic requirement of CVA. CVA patients with higher airway responsiveness will more likely respond to bronchodilator. Cough of CVA might be elicited by different mechanisms, which suggests that CVA could be divided into two phenotypes according to the response to bronchodilators.

Current Status and Future Directions of Chronic Cough in China.

Chronic cough is one of the most common complaints for which patients in China seek medical attention. However, there are no nationwide data on the prevalence and socioeconomic burden of chronic cough. Although approximately 50% of Chinese men smoke, the vast majority of patients presenting for evaluation of chronic cough are never smokers. An equal sex distribution and a middle-aged predominance have been observed in the Chinese chronic cough population, despite demonstration of a higher cough reflex sensitivity in females and older patients. The role of air pollution in the distinct age and sex distribution requires further study. In terms of the etiologies of chronic cough in China, cough-variant asthma, upper airway cough syndrome, nonasthmatic eosinophilic bronchitis, and atopic cough are the most common causes, comprising 75.2% to 87.6% of cases across different regions. Chinese Guidelines for Diagnosis and Treatment of Cough were initially published in 2005, and updated in 2009 and 2016. In addition, the China Cough Coalition was established in 2016. Great progress has been made in both cough-related clinical practice and research in recent years, however, there are still challenges ahead. To facilitate optimal management of chronic cough in China, efforts promoting the dissemination and application of published guidelines will be essential, especially in community-based healthcare and in rural regions. As chronic refractory cough has been identified as a huge challenge to clinicians worldwide, continued international cooperation will be essential in optimizing evaluation and management of chronic cough.

The Relationship Between Cough Reflex Sensitivity and Exacerbation Frequency in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Cough is predictive of exacerbations of chronic obstructive pulmonary disease (COPD). Little is known about cough reflex sensitivity during exacerbation of COPD and whether it is associated with exacerbation frequency. This pilot study aimed to investigate cough reflex sensitivity during and following recovery from exacerbation of COPD, and its association with the frequency of future exacerbations. In addition, the repeatability of cough reflex sensitivity in stable COPD was investigated. METHODS: Twenty participants hospitalised with exacerbation of COPD underwent inhaled capsaicin challenge during exacerbation and after 6 weeks of recovery. The frequency of future exacerbations was monitored for 12 months. The repeatability of cough reflex sensitivity was assessed in separate participants with stable COPD, who underwent 2 capsaicin challenge tests, 6 weeks apart. RESULTS: Cough reflex sensitivity was heightened during exacerbation of COPD. Geometric mean (SD) capsaicin concentration thresholds to elicit 5 coughs (C5) during exacerbation and after 6 weeks of recovery were 1.76 (3.73) vs. 8.09 (6.25) µmol L-1, respectively (p < 0.001). The change in C5 from exacerbation to 6-week recovery was associated with the frequency of future exacerbations (ρ = - 0.687, p = 0.003). C5 was highly repeatable over 6 weeks in stable COPD, and intraclass correlation coefficient was 0.85. CONCLUSION: Cough reflex sensitivity is heightened during exacerbation of COPD and reduces after recovery. The persistence of cough reflex hypersensitivity at recovery was associated with the frequency of future exacerbations.

Cough reflex testing in acute stroke: A survey of current UK service provision and speech and language therapist perceptions.

BACKGROUND: Silent aspiration (SA)-airway entry of food, drink or other material without a cough response-is common post-stroke. Clinical swallowing examination misses up to 40% of dysphagic patients with SA. This may put these patients at risk of aspiration pneumonia, prolonged length of hospital stay and increased healthcare costs. After stroke, the laryngeal cough reflex is frequently impaired with significant relationships between pneumonia rates and reduced cough strength and sensitivity. There has been a significant amount of recent interest in cough reflex testing (CRT) as a potential means to improve clinical identification of patients at risk of SA. However, there is a lack of consensus regarding the methodology and protocols for use of CRT with widely varying outcomes reported in the literature. AIMS: To provide an overview of current practice in the UK with regards to clinical use of CRT by speech and language therapists (SLTs) in acute stroke settings and to explore the perceptions regarding its potential application in clinical dysphagia management and the barriers and facilitators associated with adopting CRT in clinical practice. METHODS & PROCEDURES: A cross-sectional web-based survey was developed, piloted and delivered. The survey targeted all UK-based SLTs working in acute stroke settings. OUTCOMES & RESULTS: A total of 129 SLTs with varying levels of experience of CRT from all regions of the UK responded. Only four SLT services in the UK were reported to be currently using CRT clinically with acute stroke patients. A total of 29% of respondents who were not using CRT were considering introducing CRT into their service's dysphagia protocol. Variation was reported in the procedures and protocols. Overall, users reported improved confidence in the clinical detection of SA and felt that the introduction of CRT had improved their patient-related outcomes. Issues included difficulties procuring citric acid, implications for SLT time (including service set-up and delivery of CRT) and restricted access to instrumental assessments. CONCLUSIONS & IMPLICATIONS: This survey gives valuable insight into the current practice and perceptions of SLTs in the UK working in acute stroke settings in relation to CRT. It highlights discrepancies between reported approaches and recommendations from existing guidelines and validation studies. The variation in responses indicates a need to develop a consensus statement and further research to guide practice. What this study adds What is already known on the subject CRT is gaining popularity as a screening tool for the clinical identification of SA with acute stroke patients. However, there is a lack of consensus in the literature regarding the methodology and protocols with widely varying outcomes. Further work needs to be done to standardize its use, especially if it is to be incorporated into dysphagia protocols for use in the acute stroke setting. What this paper adds to existing knowledge This survey of SLTs working in acute stroke settings highlights variability in practice in CRT service delivery in the UK, reflecting findings from the existing CRT literature. What are the potential or actual clinical implications of this work? The findings of this study support the need for further research relating to clinical screening tests for SA and standardization of methodology and protocols for CRT use if its use is to be continued clinically.

A systematic review of methods of citric acid cough reflex testing.

INTRODUCTION: This systematic review summarises and appraises methods of citric acid cough reflex testing (CRT) documented in published literature. METHODS: Electronic databases, MEDLINE, EMBASE, CINAHL, PsychINFO, Scopus were searched up to and including 11th February 2018. Studies reporting a method of citric acid CRT, published in peer-reviewed journals in English or Spanish, were assessed for the inclusion criteria. Of the selected studies, information on the instrumentation and CRT protocol was extracted. RESULTS: A total of 129 studies were included. Instrumentation and protocols differed widely across studies. Reporting of methods of citric acid CRT was sub-standard, with many crucial methodological components omitted from published manuscripts, preventing their full replication. CONCLUSIONS: Considerable methodological variability exists for citric acid CRT in published literature. The findings suggest that caution is warranted in comparing citric acid cough thresholds across studies. Full replication of previously published methods of citric acid CRT is limited due to crucial elements of the citric acid CRT protocol being omitted from published manuscripts. These findings have implications on the use of citric acid CRT in clinical and pharmaceutical studies to evaluate the effects of antitussive medications and cough therapies.

Quantifying test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings.

INTRODUCTION: The citric acid cough reflex test (CRT) is used to quantify cough sensitivity and evaluate the effects of cough therapies and antitussive medications. This study quantifies the test-retest variability of natural and suppressed citric acid cough thresholds and urge to cough ratings in healthy individuals. METHODS: Healthy adults (n = 16) inhaled increasing concentrations of citric acid (0.01-3.2 mol/L) on three alternate days (1, 3, 5) until C2 cough thresholds (i.e. two consecutive coughs within 3 s) or the highest concentrations of citric acid was reached. Participants were instructed to "cough if you need to" in the natural cough condition, and "try not to cough" in the suppressed cough condition. Following each inhalation, participants were asked to rate their urge to cough (UTC) using a modified Borg Scale. RESULTS: Natural cough thresholds (NCTs) increased across days 1-3 (0.87 doubling concentrations, 95% CI, 0.28, 1.44, p = 0.004) and 1-5 (0.87 doubling concentrations, 95% CI, 0.33, 1.41, p = 0.004). Suppressed cough thresholds (SCTs) increased across days 1-5 (0.64 doubling concentrations per day, 95% CI, 0.03, 1.22, p = 0.04). After taking the effect of day into account, NCTs and SCTs varied within-participants by 0.75 (95% CI, 0.53, 0.93) and 0.78 (95% CI, 0.55,0.98) doubling concentrations respectively. UTC ratings at NCT, or SCT did not significantly increase across days 1-3 or 1-5. Sub-threshold (0.05 mol/L) UTC ratings increased across days 1-3 (-1.43 ratings per day, 95% CI, -2.31, -0.5, p = 0.005) and 1-5 (-1.71 ratings per day, 95% CI, -2.59, -0.79, p = 0.001). UTC ratings at NCT, SCT, and sub-threshold varied within-participants after taking into account the effect of day by 1.34 (95% CI, 1.03, 1.71), 1.47 (95% CI, 1.10, 1.91) and 1.20 (95% CI, 0.91, 1.50) ratings. CONCLUSIONS: Natural and suppressed cough thresholds and UTC ratings are subject to test-retest variability. These data are important for the use of citric acid CRT as an outcome measure in longitudinal cough research, as they facilitate interpretation of whether changes in citric acid cough thresholds across days reflect true changes in cough sensitivity, rather than an artefact of repeating the test.

Why chronic cough in children is different.

Recently, there have been robust changes in our knowledge of the neurophysiology of cough and novel clinical etiologies. Specifically, cough hypersensitivity in adults and protracted bacterial bronchitis (PBB) in children have been increasingly investigated, and differences between chronic cough in children and adults have been widely reported. In young children, postinfectious cough, bronchiectasis, airway malacia, PBB, and asthma appear to be the main causes of cough; however, by adolescence, the causes of cough are more likely to become those common in adults, namely, gastroesophageal reflux, asthma, and upper airway syndrome. These differences are attributed to changes in various characteristics of the respiratory tract, immune system, and nervous system between children and adults. New knowledge about the neural aspects of cough has revealed a complex network of pathways that initiate cough. The effect of inflammation on cough neural processing occurs at multiple peripheral and central sites within the nervous system. Evidence exists that direct or indirect neuroimmune interaction induces a complex response, which can be altered by mediators released by the sensory or parasympathetic neurons and vice versa. During childhood, the respiratory tract and the nervous system undergo a series of anatomical and physiological maturation processes that produce the cough neural circuits. Alterations provoked by various pathological processes, noxious agents, infection, and inflammation during the developmental period can lead to persistent or irreversible modifications, which may explain why many adult patients, in addition to expressing high cough sensitivity, remain refractive to disease-specific therapies.

Interfering with airway nerves in cough associated with asthma.

Cough is a troublesome and often refractory symptom of asthma, which is associated with poor control of disease. The pathogenesis of asthmatic cough has mainly been attributed to bronchoconstriction, but recent evidence indicate that cough reflex hypersensitivity or neuronal dysfunction is a feature of asthma, even in those with mild stable disease. This is likely resistant to the mainstay treatment ICS/LABA which inhibits classic asthmatic response. Such refractory cough might manifest more predominantly in the day-time rather than night-time. Treatment options of such refractory cough or cough reflex hypersensitivity in asthma targeting the nerves (LTRAs, tiotropium, and potentially bronchial thermoplasty) are discussed.

Characteristics of Chinese chronic cough patients.

Chronic cough is one of the most common complains for patients seeking medical attention in both general practice and respiratory specialist clinics. Cough variant asthma, eosinophilic bronchitis, upper airway cough syndrome, as well as gastro-esophageal reflux disease are common conditions associated with chronic cough, and cough variant asthma, eosinophilic bronchitis account for a higher proportion of patients with chronic cough in China than in Western countries. An older female predominance has been reported in most Western countries, which may be attributed to a higher cough reflex sensitivity in females, especially those post-menopausal females. However, studies conducted in China showed that patients with chronic cough have a nearly similar gender distribution and most of them are in their late 30s or early 40s, despite the similar gender and age difference in cough reflex sensitivity as Western countries. Environmental and occupational exposures, cigarette smoking, unhealthy lifestyle might play a role in the distinct age and gender distribution of Chinese chronic cough patients, yet further study is needed to clarify it.