Angela Kelsall

Acoustic Cough?Reflux Associations in Chronic Cough: Potential Triggers and Mechanisms

BACKGROUND & AIMS Central sensitization is thought to play a role in chronic cough and might explain the temporal association between cough and gastroesophageal reflux (GOR) in patients in whom non-GOR causes have been excluded. Using our novel simultaneous acoustic cough recording and impedance/pH monitoring technique, we aimed to explore this further by assessing such temporal associations and their relationship to the acidity, duration, and proximal extent of reflux and the presence of erosive disease and cough reflex sensitivity in unselected patients (ie, including non-GOR causes) with chronic cough. METHODS Twenty-four hour ambulatory acoustic cough monitoring with simultaneous impedance/pH recording was carried out in 71 unselected patients with chronic cough, aged 51-64 years (47 female). In addition, all patients underwent cough reflex sensitivity testing to citric acid, and 66 patients underwent gastroscopy. Temporal associations between cough and reflux were expressed using the symptom association probability. RESULTS Seventy percent of patients exhibited temporal associations, with 48% having a positive symptom association probability (SAP(R-C)) for cough preceded by reflux (mainly distal), 56% a positive symptom association probability (SAP(C-R (2 min))) for reflux preceded by cough, and 32% both. Moreover, SAP(R-C) positive patients had a more sensitive cough reflex (P = .03) but similar esophageal reflux exposure and erosive disease, together with similar prevalence of extraesophageal causes of cough compared with SAP(R-C) negative patients. Reflux immediately following cough was rare. CONCLUSIONS Cough temporally associates with reflux irrespective of proposed diagnoses, may be self-perpetuating in some patients, and is likely to be driven by central processes.

Chronic cough: how do cough reflex sensitivity and subjective assessments correlate with objective cough counts during ambulatory monitoring?

Background: Cough reflex sensitivity, subjective estimates of cough frequency and cough-related quality of life have been used to assess cough and monitor treatment responses. The relationships between these measures and objective cough monitoring remain unclear and the usefulness of subjective assessments remains questionable. Subjects: 62 patients with chronic cough (39 women) were studied. Mean age of patients was 54.9 (SD 12.2) years, with a median duration of cough of 5.5 (range 1–30) years. Methods: Cough reflex sensitivity testing (C5; citric acid) was performed in all patients before fully ambulatory day-time and night-time cough recordings. Patients scored the frequency and severity of their cough (Visual Analogue Scales (VAS) and 0–5 score) for each recording period and completed a cough-related quality-of-life questionnaire, Leicester Cough Questionnaire (LCQ). Ambulatory cough recordings were manually counted and reported in terms of cough seconds per hour (cs/h). Cough rates were log10 transformed for analysis. Results: The median time spent coughing was 11.36 (range 1.06–46) cs/h with median day rates of 15.59 (range 2–74.8) cs/h and median night rates of 2.94 (range 0–26.67) cs/h. An inverse relationship was seen between day cough rates and log10 C5 (r = −0.452, p⩽0.001). Subjective cough scores and visual analogue scales were only moderately associated with objective time spent coughing, with night-time being scores more strongly associated than day-time scores. The strongest correlation with objective cough frequency was cough-related quality of life (LCQ), (r = −0.622, p⩽0.001), mediated through the psychological domain. Conclusions: Subjective measures of cough and cough reflex sensitivity are only moderately related to objective time spent coughing, and hence cannot be used as surrogate markers for objective cough-frequency measurements. Cough-related quality of life (LCQ) is most strongly related to objectively counted cough, and may be a useful adjunct to objective measures in the assessment of cough.

Sex differences and predictors of objective cough frequency in chronic cough

Background: Women are consistently over-represented in specialist cough clinics and known to have a more sensitive cough reflex than men. Whether female sex and other patient characteristics are associated with higher cough rates is not known. A study was conducted to determine the predictors of objective cough frequency in patients presenting to a tertiary referral clinic with chronic cough. Methods: 100 subjects (65 women) of mean (SD) age 55.8 (11.0) years and median cough duration 4 years (IQR 2.0–10.0) with unexplained chronic cough completed flow-volume loops (mean (SD) forced expiratory volume in 1 s 103 (15.2)% predicted; forced expiratory flow (FEF50) 68.8 (24.1)% predicted), methacholine challenge (42% positive), citric acid cough reflex sensitivity (C5; 0.12 M (IQR 0.06–0.50)) and the Leicester Cough Questionnaire. 24-h ambulatory cough monitoring was performed in 86 subjects; manually counted coughs were quantified as the number of explosive cough sounds per hour. Results: Women coughed significantly more than men (geometric mean 16.6 coughs/h (95% CI 13.1 to 21.0) vs 9.4 coughs/h (95% CI 6.4 to 13.9), p = 0.01)). The cough reflex was also more sensitive in women than in men (median logC5 −0.9 M vs −0.6 M, p = 0.002), but cough-related quality of life was similar in women and men (12.0 (3.6) and 12.2 (3.2), respectively, p = 0.76). Linear regression analysis showed that 38.6% of the variation in cough rate was predicted by sex (p = 0.01), logC5 (p<0.001) and age (p = 0.002) but not lung function or bronchial hyper-reactivity. Conclusions: Ambulatory objective cough monitoring provides novel insights into factors modulating chronic cough. These findings suggest that effects of sex and age must be taken into account in the study of cough and when designing clinical trials testing novel antitussive agents.

How to quantify coughing: Correlations with quality of life in chronic cough

Different methods are used for quantifying coughing in sound recordings, but as yet no method has been shown to be more valid than any other. In the present study, the relationships between three different units of cough were examined and their ability to predict subjective ratings of cough and cough-related quality of life were evaluated. In total, 70 subjects (mean±sd age 55±11.7 yrs, 51 (73%) females) with chronic unexplained cough (median duration 4.8 yrs, interquartile range 2.5–10.1 yrs) performed fully ambulatory 24-h sound recordings, which were manually counted by trained observers and quantified by 1) explosive phases, 2) cough seconds and 3) cough epochs. Subjects also completed cough visual analogue scales (VAS) and the Leicester Cough Questionnaire (LCQ). All units of cough were strongly correlated; explosive phases and cough seconds correlated slightly more strongly than cough seconds with cough epochs or explosive phases with cough epochs. LCQ scores correlated moderately with explosive phases and seconds; epochs correlated slightly less well. Cough VAS scores showed a similar pattern. Explosive phases and seconds are interchangeable units of cough, moderately related to subjective measures and cough-related quality of life; epochs are a less satisfactory alternative.

Chest wall dynamics during voluntary and induced cough in healthy volunteers

Non‐technical summary  Cough is the commonest symptom for which people seek medical advice and has significant impact upon quality of life. Moreover ineffective coughing is associated with significant morbidity and mortality. A better understanding of cough mechanics is important for dealing with the complications of both excessive and impaired cough. This study investigates how the mechanical changes during coughing are influenced by the amount of air inhaled prior to coughing (operating volume), examining chest and abdominal motion, pressures and flow. We have shown that operating volume is the most important determinant of the flow achieved and volume expelled during single voluntary coughs and peals of voluntary coughs. Coughs within a peal appear to have a different motor pattern, producing similar pressures and flows but more rapidly than single coughs and therefore may be more efficient. Future studies investigating cough mechanics should control for the influence of operating volume.

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

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

Chronic Cough: Relationship Between Microaspiration, Gastroesophageal Reflux, and Cough Frequency

BACKGROUND Microaspiration is often considered a potential cause of cough. The aim of this study was to investigate the relationship between microaspiration, the degree and type of gastroesophageal reflux, and the frequency of coughing in patients with chronic cough. METHODS One hundred patients with chronic cough (mean [± SD] age, 55.8 years [± 11.0 years]; 65 women) and 32 healthy volunteers (median age, 43.5 years [interquartile range (IQR), 30-50.8 years]; 16 women) were recruited. Patients with chronic cough performed 24-h objective cough frequency with simultaneous esophageal impedance/pH monitoring and measurement of pepsin concentrations in sputum and BAL. Twelve healthy volunteers underwent bronchoscopy/BAL, and 20 underwent impedance/pH monitoring. RESULTS Patients with chronic cough had significantly more reflux episodes than healthy volunteers (median, 63.5 reflux episodes [IQR, 52.5-80.0] vs 59.0 [IQR, 41.8-66.0]; P = .03), although the absolute difference was small, and there was no difference in numbers of events extending into the proximal esophagus (median, 17.2% [IQR, 8.0%-26.0%] vs 20.3% [IQR, 5.1%-32.1%]; P = .36). BAL pepsin levels were also similar in chronic cough to control subjects (median, 18.2 ng/mL [range, 0-56.4 ng/mL] vs 9.25 ng/mL [range, 0-46.9 ng/mL]; P = .27). Sputum but not BAL pepsin weakly correlated with the number of proximally occurring reflux events (r = 0.33, P = .045) but was inversely related to cough frequency (r = −0.52, P = .04). Sputum pepsin was, therefore, best predicted by combining the opposing influences of cough and proximal reflux (r = 0.50, P = .004). CONCLUSIONS Proximal gastroesophageal reflux and microaspiration into the airways have limited roles in provoking chronic cough. Indeed, coughing appears to be protective, reducing pepsin concentration in the larger airways of patients with chronic cough.

A Novel Approach to Studying the Relationship Between Subjective and Objective Measures of Cough

BACKGROUND Currently, no data are available on the relationship between changes in objective and subjective measures of cough, the magnitude of change in cough frequency perceived by patients as clinically meaningful, or the sample sizes required to show significant changes in cough therapeutic trials. Because patients anecdotally report reductions in cough severity while undergoing esophageal testing, we aimed to address these issues by assessing objective and subjective measures of cough with and without an esophageal catheter. METHODS Twenty-four-hour cough monitoring was performed on two occasions, with and without esophageal impedance/pH monitoring in 62 patients with chronic cough (mean age 56.8 years [SD±10.8]; 43 women; median cough duration 3.3 years [interquartile range (IQR), 2.0-10.0]). Cough was assessed objectively measuring coughs per hour and subjectively using a numerical cough score and a visual analog scale (VAS), scored separately for day and night, and then averaged to represent each 24-h period. RESULTS Objective cough frequency was reduced by a median of 33.3% (IQR, -68.8% to -13.0%; P<.001) with the catheter. The averaged day and night cough scores and VAS scores also significantly decreased, but changes in these did not correlate with decreases in cough frequency. Sample-size calculations suggested that crossover designs using objective cough frequency may be preferable in therapeutic trials. CONCLUSIONS These observations provide useful information on the reduction in objective cough frequency scored as an improvement by patients with chronic cough and offer guidance for the design and powering of future therapeutic trials. TRIAL REGISTRY ISRCTN; No.: ISRCTN62337037; URL: http://www.controlled-trials.com.

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).

Objective measurement of cough in otherwise healthy volunteers with acute cough

Cough is one of the commonest reasons for medical consultation and acute cough associated with upper respiratory tract infections (URTIs) is a global problem. In otherwise healthy volunteers complaining of cough associated with symptoms of URTI, we aimed to assess objective and subjective measures of cough and their repeatability and perform power calculations for the design of future studies to test therapies. We studied 54 otherwise healthy volunteers with acute cough (<3 weeks) (median age 22 yrs (interquartile range 21–26 yrs), 64% female, mean forced expiratory volume in 1 s 97.6±10.5% predicted). All subjects performed 24-h ambulatory cough monitoring and reported cough frequency and severity using visual analogue scales (VAS) on 2 consecutive days. Sample size calculations were performed for crossover and parallel group study designs. Objective cough frequency was high (session 1: geometric mean 12.1 coughs·h−1 (95%CI 9.7–15.2)) and fell significantly (session 2: 9.0 coughs·h−1 (95%CI 6.9–11.6); p<0.001). Repeatability was higher for objective cough frequency (intra-class correlation coefficient (ICC)=0.94, p<0.001) than reported cough frequency (daytime VAS ICC=0.784, p<0.001). Crossover/parallel studies require <15 and <41 subjects per arm to detect a 50% reduction in cough frequency with 90% power, respectively. Acute cough frequency is highly repeatable over any 48-h period, allowing small sample sizes to be used when investigating the effectiveness of novel anti-tussives.