Global Physiology and Pathophysiology of Cough: Part 1: Cough Phenomenology - CHEST Guideline and Expert Panel Report.

The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients.

Effect of continuous positive airway pressure on maximal exercise capacity in patients with obstructive sleep apnea: a systematic review and meta-analysis.

STUDY OBJECTIVES: Exercise capacity is impaired in obstructive sleep apnea (OSA). There are conflicting reports on the effect of continuous positive airway pressure (CPAP) on maximal exercise capacity. The objective of this review was to determine if there is a change in exercise capacity and anaerobic threshold following CPAP treatment in OSA patients. METHODS: We conducted a systematic review and meta-analyses to summarize the changes in peak rate of oxygen uptake (V̇O2 peak) or maximum rate of oxygen uptake (V̇O2 max) and anaerobic threshold (AT) during cardiopulmonary exercise testing following CPAP intervention in patients with OSA. A systematic literature review was conducted to identify published literature on markers of V̇O2 peak, V̇O2 max, and AT pre- vs post-CPAP using a web-based literature search of PubMed/MEDLINE, Embase, CINAHL, and Cochrane review (CENTRAL) databases. Two independent reviewers screened the articles for data extraction and analysis. RESULTS: The total search of all the databases returned 470 relevant citations. Following application of eligibility criteria, 6 studies were included in the final meta-analysis for V̇O2 peak, 2 studies for V̇O2 max, and five studies for AT. The meta-analysis showed a mean net difference in V̇O2 peak between pre- and post-CPAP of 2.69 mL·kg-1·min-1, P = .02, favoring treatment with CPAP. There was no difference in V̇O2 max or AT with CPAP treatment (mean net difference 0.66 mL·kg-1·min-1 [P = .78] and -144.98 mL·min-1 [P = .20] respectively). CONCLUSIONS: There is a paucity of high-quality studies investigating the effect of CPAP on exercise capacity. Our meta-analysis shows that V̇O2 peak increases following CPAP treatment in patients with OSA, but we did not observe any change in V̇O2 max or AT. Our findings should be considered preliminary and we recommend further randomized controlled trials to confirm our findings and to clarify the peak and maximum rates of oxygen uptake adaptations with CPAP therapy.

The Objective Assessment of Cough Frequency in Bronchiectasis.

INTRODUCTION: Cough in bronchiectasis is associated with significant impairment in health status. This study aimed to quantify cough frequency objectively with a cough monitor and investigate its relationship with health status. A secondary aim was to identify clinical predictors of cough frequency. METHODS: Fifty-four patients with bronchiectasis were compared with thirty-five healthy controls. Objective 24-h cough, health status (cough-specific: Leicester Cough Questionnaire LCQ and bronchiectasis specific: Bronchiectasis Health Questionnaire BHQ), cough severity and lung function were measured. The clinical predictors of cough frequency in bronchiectasis were determined in a multivariate analysis. RESULTS: Objective cough frequency was significantly raised in patients with bronchiectasis compared to healthy controls [geometric mean (standard deviation)] 184.5 (4.0) vs. 20.6 (3.2) coughs/24-h; mean fold-difference (95% confidence interval) 8.9 (5.2, 15.2); p < 0.001 and they had impaired health status. There was a significant correlation between objective cough frequency and subjective measures; LCQ r = -0.52 and BHQ r = -0.62, both p < 0.001. Sputum production, exacerbations (between past 2 weeks to 12 months) and age were significantly associated with objective cough frequency in multivariate analysis, explaining 52% of the variance (p < 0.001). There was no statistically significant association between cough frequency and lung function. CONCLUSIONS: Cough is a common and significant symptom in patients with bronchiectasis. Sputum production, exacerbations and age, but not lung function, were independent predictors of cough frequency. Ambulatory objective cough monitoring provides novel insights and should be further investigated as an outcome measure in bronchiectasis.

Sound: a non-invasive measure of cough intensity.

INTRODUCTION: Cough intensity is an important determinant of cough severity reported by patients. Cough sound analysis has been widely validated for the measurement of cough frequency but few studies have validated its use in the assessment of cough strength. We investigated the relationship between cough sound and physiological measures of cough strength. METHODS: 32 patients with chronic cough and controls underwent contemporaneous measurements of voluntary cough sound, flow and oesophageal pressure. Sound power, peak energy, rise-time, duration, peak-frequency, bandwidth and centroid-frequency were assessed and compared with physiological measures. The relationship between sound and subjective cough strength Visual Analogue Score (VAS), the repeatability of cough sounds and the effect of microphone position were also assessed. RESULTS: Sound power and energy correlated strongly with cough flow (median Spearman's r=0.87-0.88) and oesophageal pressure (median Spearman's r=0.89). Sound power and energy correlated strongly with cough strength VAS (median Spearman's r=0.84-0.86) and were highly repeatable (intraclass correlation coefficient=0.93-0.94) but both were affected by change in microphone position. CONCLUSIONS: Cough sound power and energy correlate strongly with physiological measures and subjective perception of cough strength. Power and energy are highly repeatable measures but the microphone position should be standardised. Our findings support the use of cough sound as an index of cough strength.

The development and validation of the Bronchiectasis Health Questionnaire.

Health-related quality of life or health status is significantly impaired in bronchiectasis. There is a paucity of brief, simple-to-use, disease-specific health status measures. The aim of this study was to develop and validate the Bronchiectasis Health Questionnaire (BHQ), a new health status measure that is brief and generates a single overall score.Patients with bronchiectasis were recruited from two outpatient clinics, during a clinically stable stage. The development of the questionnaire followed three phases: item generation and item reduction using Rasch analysis, validation, and repeatability testing. The BHQ was translated into 11 languages using standardised methodology.206 patients with bronchiectasis completed a preliminary 65-item questionnaire. 55 items were removed due to redundancy or poor fit to the Rasch model. The final version of the BHQ consisted of 10 items. Internal consistency was good (Cronbach's α=0.85). Convergent validity of the BHQ with the St George's Respiratory Questionnaire was high (r= -0.82; p<0.001) and moderate with lung function (forced expiratory volume in 1 s % predicted r= -0.27; p=0.001). There was a significant association between BHQ scores and number of exacerbations of bronchiectasis in the last 12 months (p<0.001), hospital admissions (p=0.001) and computed tomography scan bronchiectasis pulmonary lobe counts (p<0.001). BHQ scores were significantly worse in patients with sputum bacterial colonisation versus no colonisation (p=0.048). The BHQ was highly repeatable after 2 weeks (intraclass correlation coefficient 0.89).The BHQ is a brief, valid and repeatable, self-completed health status questionnaire for bronchiectasis that generates a single total score. It can be used in the clinic to assess bronchiectasis from the patient's perspective.

Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.

BACKGROUND: Physiotherapy, and speech and language therapy are emerging non-pharmacological treatments for refractory chronic cough. We aimed to investigate the efficacy of a physiotherapy, and speech and language therapy intervention (PSALTI) to improve health-related quality of life (HRQoL) and to reduce cough frequency in patients with refractory chronic cough. METHODS: In this multicentre randomised controlled trial, patients with refractory chronic cough were randomised to four weekly 1:1 sessions of either PSALTI consisting of education, laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and psychoeducational counselling or control intervention consisting of healthy lifestyle advice. We assessed the change in HRQoL at week 4 with the Leicester Cough Questionnaire (LCQ). Secondary efficacy outcomes included 24-hour objective cough frequency (Leicester Cough Monitor) and cough reflex sensitivity. The primary analysis used an analysis of covariance adjusted for baseline measurements with the intention-to-treat population. This study was registered at UK Clinical Research Network (UKCRN ID 10678). FINDINGS: Between December 2011 and April 2014, we randomly assigned 75 participants who underwent baseline assessment (34 PSALTI and 41 controls). In the observed case analysis, HRQoL (LCQ) improved on average by 1.53 (95% CI 0.21 to 2.85) points more in PSALTI group than with control (p=0.024). Cough frequency decreased by 41% (95% CI 36% to 95%) in PSALTI group relative to control (p=0.030). The improvements within the PSALTI group were sustained up to 3 months. There was no significant difference between groups in the concentration of capsaicin causing five or more coughs. INTERPRETATION: Greater improvements in HRQoL and cough frequency were observed with PSALTI intervention. Our findings support the use of PSALTI for patients with refractory chronic cough. TRIAL REGISTRATION NUMBER: UKCRN ID 10678 and ISRCTN 73039760; Results.

The validity of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis.

BACKGROUND: A range of questionnaires have been used to assess health-related quality of life (HRQOL) in bronchiectasis. A systematic review was conducted to evaluate their psychometric properties and assess associations between HRQOL and clinical measures. METHODS: Five electronic databases were searched. Studies eligible for inclusion were those that investigated the validity of HRQOL questionnaires and/or their association with other outcomes in adults with bronchiectasis. Patients with cystic fibrosis were excluded. The identified questionnaires were assessed for convergent, discriminant and cross-cultural translation validity; missing data, floor and ceiling effects, internal consistency, responsiveness and test-retest reliability. A meta-analysis was conducted to estimate the strength of associations between HRQOL and clinical measures. RESULTS: From 1918 studies identified, 43 studies were included in the systematic review, of which 38 were suitable for the meta-analysis. Nine HRQOL questionnaires were identified, with the most widely used being: St George's Respiratory Questionnaire, Leicester Cough Questionnaire, Quality of Life-Bronchiectasis and Short Form-36. HRQOL questionnaires had moderate to good internal consistency and good test-retest reliability. Only 8 of 18 studies that used translated HRQOL questionnaires reported or referred to the validity of the translated questionnaire. There was a stronger correlation (mean r (95% CI)) between HRQOL and subjective outcome measures, such as dyspnoea (0.55 (0.41 to 0.68)) and fatigue (0.42 (0.23 to 0.58)) compared with objective measures; exercise capacity (-0.41 (-0.54 to -0.24)), FEV1% predicted (-0.31 (-0.40 to -0.23)) and extent of bronchiectasis on CT scan (0.35 (0.03 to 0.61)); all p<0.001. CONCLUSIONS: This review supports most HRQOL questionnaires used in bronchiectasis have good psychometric properties. There was a weak to moderate association between HRQOL and objective outcome measures. This suggests that HRQOL questionnaires assess a unique aspect of health not captured by objective measures.

Predictors of objective cough frequency in pulmonary sarcoidosis.

Cough is a common symptom of pulmonary sarcoidosis. This study aimed to quantify cough frequency, and investigate its relationship with cough reflex sensitivity, pulmonary function and health status.32 patients with pulmonary sarcoidosis were compared with 40 healthy controls. Cough reflex sensitivity to capsaicin, objective 24-h cough counts, cough-specific health status, cough severity and cough triggers were measured. The predictors of cough frequency in sarcoidosis were determined in a multivariate analysis.Objective cough frequency was significantly raised in patients with sarcoidosis compared with healthy controls (p<0.001) and patients with cough had an impaired health status. Patients with pulmonary sarcoidosis had a heightened cough reflex sensitivity compared with healthy controls (p<0.001). Only cough reflex sensitivity was significantly associated with objective cough frequency in multivariate analysis, explaining 42% of the variance (p<0.001). There was no association between cough frequency, lung function, number of organs involved, chest radiograph stage or serum angiotensin-converting enzyme levels.Cough is a common and significant symptom in patients with sarcoidosis. Ambulatory objective cough monitoring provides novel insights into the determinants of cough in sarcoidosis, suggesting that cough reflex sensitivity may be more important than lung function and other measures of disease severity, and this should be investigated further.

The Intensity of Voluntary, Induced, and Spontaneous Cough.

BACKGROUND: The intensity of cough is an important determinant of cough severity. Few studies have quantified cough intensity in patients with chronic cough with objective measures. We investigated the intensity of voluntary, induced, and spontaneous cough in patients with chronic cough and healthy control subjects. METHODS: Patients with chronic cough and control subjects underwent physiologic assessment of the intensity of maximum voluntary, capsaicin-induced, and spontaneous cough. Assessments included measurement of gastric pressure (Pga) and esophageal pressure (Pes) during cough, peak cough flow (PCF), expiratory muscle strength (twitch gastric pressure [TwPga]), and cough compression phase duration (CPD). Subjective perception of cough intensity was assessed using a visual analog scale (VAS). RESULTS: Pes, Pga, and PCF during maximum voluntary cough were significantly greater in patients with chronic cough compared with control subjects (P = .003-.042). There was no difference in TwPga between patients and control subjects. CPD was increased in female patients compared with control subjects (mean ± SD, 0.50 ± 0.22 s vs 0.28 ± 0.17 s; P = .007). Mean ± SD Pes during spontaneous cough was comparable to induced cough (128 ± 28 cm H2O vs 122 ± 37 cm H2O, P = .686) but less than maximum voluntary cough (170 ± 46 cm H2O, P = .020). Median within-subject correlation coefficients between cough intensity VAS and Pes, Pga, and PCF were r = 0.82 to 0.86. CONCLUSIONS: Maximum voluntary cough intensity was increased in patients with chronic cough compared with control subjects. There was no significant difference in expiratory muscle contractility. Further studies should evaluate the compressive phase of cough in more detail. Physiologic measures of cough intensity correlated strongly with subjective perception of intensity in patients with chronic cough and may be relevant objective outcome measures for clinical studies.

A longitudinal assessment of acute cough.

RATIONALE: Cough can be assessed with visual analog scales (VAS), health status measures, and 24-hour cough frequency monitors (CF(24)). Evidence for their measurement properties in acute cough caused by upper respiratory tract infection (URTI) and longitudinal data is limited. OBJECTIVES: To assess cough longitudinally in URTI with subjective and objective outcome measures and determine sample size for future studies. METHODS: Thirty-three previously healthy subjects with URTI completed cough VAS, Leicester Cough Questionnaire (LCQ-acute), and CF(24) monitoring (Leicester Cough Monitor) on three occasions, 4 days apart. Changes in subjects' condition were assessed with a global rating of change questionnaire. The potential for baseline first-hour cough frequency (CF(1)), VAS, and LCQ to identify low CF(24) was assessed. MEASUREMENTS AND MAIN RESULTS: Mean ± SD duration of cough at visit 1 was 4.1 ± 2.5 days. Geometric mean ± log SD baseline CF(24) and median (interquartile range) cough bouts were high (14.9 ± 0.4 coughs/h and 85 [39-195] bouts/24 h). Health status was severely impaired. There was a significant reduction in CF(24) and VAS, and improvement in LCQ, from visits 1-3. At visit 3, CF(24) remained above normal limits in 52% of subjects. The smallest changes in CF(24), LCQ, and VAS that subjects perceived important were 54%, 2- and 17-mm change from baseline, respectively. The sample sizes required for parallel group studies to detect these changes are 27, 51, and 25 subjects per group, respectively. CF(1) (<20.5 coughs/h) was predictive of low CF(24). CONCLUSIONS: CF(24), VAS, and LCQ are responsive outcome tools for the assessment of acute cough. The smallest change in cough frequency perceived important by subjects is 54%. The sample sizes required for future studies are modest and achievable.

Four-hour cough frequency monitoring in chronic cough.

BACKGROUND: The recent development of automated cough monitors has enabled objective assessment of cough frequency. A study was undertaken to determine whether short-duration recordings( < 6 h) accurately reflect 24-h cough frequency and to investigate their responsiveness. METHODS: One hundred adults with chronic cough underwent 24-h cough frequency monitoring with the Leicester Cough Monitor and completed cough visual analog scales (VASs) and the Leicester Cough Questionnaire (LCQ). Cough recordings were analyzed using customized software to derive cough frequencies from 1 to 6 h and 24-h recordings. Responsiveness was assessed with repeat assessments following therapeutic trials. RESULTS: The median (interquartile range) 24-h cough frequency was 11.5 (5.8-26.6) coughs/h. Four hours was considered the shortest recording duration that represented 24-h cough frequency( ρ= 0.9, P ≤ .001). Median 4-h cough frequency was 16.6 (7.3-36.8) coughs/h. Both 4-h and 24-h cough frequency correlated moderately with cough VAS ( ρ= 0.49, P ≤ .01 and ρ= 0.44, P ≤ .01)and LCQ ( ρ = - 0.48, P ≤ .01; ρ = - 0.50, P ≤ .01). Four-hour cough frequency was responsive to improvements in cough severity following trials of therapy. CONCLUSIONS: Four-hour cough frequency correlates highly with 24-h cough frequency recordings and relates equally well with subjective measures in chronic cough. Short-duration cough monitoring could be a practical tool to validate the presence of cough and assess response to trials of therapy in the clinic setting.

The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute).

INTRODUCTION: Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID). METHODS: 10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile. RESULTS: Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively. CONCLUSION: The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.

Cough and sleep.

Cough and sleep are vital functions. The effects of cough on sleep and vice versa are important for a number of reasons. Sleep disruption is common in patients with cough and is often the reason why they seek medical attention. Sleep suppresses cough and the biological mechanisms for this action are poorly understood. Cough has recently been reported as a presenting symptom of obstructive sleep apnea. It is uncommon for healthy people to cough at night; however, approximately 50% of patients with chronic cough report sleep disruption due to cough. Cough frequency is much lower at night than during the day. There is reduced exposure to tussive stimuli at night and decreased cough reflex sensitivity. Cough is more difficult to induce in REM sleep compared to slow-wave sleep. Studies of anesthetized humans have shown that the cough reflex is suppressed; however, the expiratory reflex is less affected. The sleep-cough interaction has implications for the physician. The measurement of cough frequency with 24-h ambulatory cough monitors in patients with chronic cough suggests that the presence or absence of nocturnal cough is not helpful in establishing the etiology. Nocturnal cough may be a useful outcome parameter for clinical trials of antitussive drugs since it is under less voluntary control than daytime cough. Most antitussive drugs are sedatives. This suggests that part or all of their action may be through an effect on cortical neural pathways. Unexplained chronic cough has recently been reported as a presenting feature of obstructive sleep apnea. Patients are likely to be female and report gastroesophageal reflux and rhinitis. Continuous positive airway pressure therapy is effective in alleviating cough. Greater awareness of this condition is needed.