Cough in chronic lung disease: a state of the art review.

Chronic cough (CC; ≥8 weeks in duration) is a common and burdensome feature of respiratory diseases. The understanding of cough has progressed significantly in recent years, albeit largely in refractory (unexplained) chronic cough (RCC) in the absence of other respiratory conditions. The prevalence of CC in respiratory diseases is poorly described, but estimates have been reported: asthma (8-58%), chronic obstructive pulmonary disease (COPD; 10-74%), bronchiectasis (82-98%), interstitial lung disease (ILD; 50-89%) and sarcoidosis (3-64%). CC in respiratory conditions generally predicts impaired health status and more severe disease. It is associated with increased symptom burden and disease severity in asthma, COPD, bronchiectasis and ILD, higher exacerbation frequency in asthma and bronchiectasis, and increased mortality and lung transplantation in idiopathic pulmonary fibrosis (IPF). Physiologically, heightened cough reflex sensitivity (CRS) has been reported and postulated to be mechanistic in isolated RCC. Cough reflex hypersensitivity (CRH) has also been reported in asthma, COPD, bronchiectasis, ILD and sarcoidosis. Unlike recent advances in isolated RCC, there are limited studies and understanding of central cough neuropathways in other respiratory conditions. Of note, dysfunctional central voluntary cough suppression neuropathways and physiology were observed in isolation in RCC; cough suppression is preserved in COPD. Understanding in the mechanism of RCC cannot be simply extrapolated to other respiratory conditions. The restricted understanding of cough mechanisms in these conditions has limited cough-specific therapeutic options in this context. There is currently an unmet need to expand our understanding of cough in chronic respiratory conditions, both in order to improve the quality of life of patients, and to improve knowledge of cough in general. This review aims to describe the prevalence, impact, pathophysiology and management of CC in asthma, COPD, bronchiectasis, ILD and sarcoidosis.

Chronic Cough as a Genetic Neurological Disorder? Insights from Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS).

Chronic cough is common, and in many cases unexplained or refractory to otherwise effective treatment of associated medical conditions. Cough hypersensitivity has developed as a paradigm that helps to explain clinical and research observations that frequently point towards chronic cough as a neuropathic disorder. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described neurological condition whose clinical features include gait ataxia, unsteadiness, peripheral neuropathy, and autonomic dysfunction. Chronic cough is also a common feature of the syndrome, with features of hypersensitivity, often preceding core neurological symptoms by up to 30 years or more. The genetic basis in a majority of cases of CANVAS appears to be biallelic variable repeat intron expansion sequences within RFC1, a gene normally involved in the regulation of DNA replication and repair. The same polymorphism has now been identified at an increased frequency in patients with unexplained or refractory chronic cough in the absence of defining clinical features of CANVAS. This review expands on these points, aiming to increase the awareness of CANVAS amongst clinicians and researchers working with chronic cough. We discuss the implications of a link between RFC1 disease and cough. Improved understanding of CANVAS may lead to an enhanced grasp of the pathophysiology of chronic cough, and new approaches to antitussive treatments.

Patient Global Impression of Severity Scale in Chronic Cough: Validation and Formulation of Symptom Severity Categories.

BACKGROUND: The Patient Global Impression of Severity (PGI-S) scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough (CC). OBJECTIVE: This study aimed to establish validity, repeatability, and responsiveness of the PGI-S scale in CC and use the scale to define discrete categories of severity when measured with other commonly used patient-reported outcome (PRO) tools. METHODS: Consecutive patients with CC completed the PGI-S scale, cough severity and urge to cough visual analog scales (VAS), and cough-specific health status Leicester Cough Questionnaire (LCQ) at a clinic visit. Validity, repeatability, and responsiveness were assessed, and threshold scores for PRO severity categories determined. RESULTS: A total of 482 participants completed the assessments; the median (interquartile range [IQR]) age was 57 (46-67) years, 71% were female, and the median (IQR) duration of cough was 48 (24-120) months. They reported a median (IQR) PGI-S score of 3 (3-4; moderate severity), cough severity VAS of 57 (31-75) mm, urge to cough VAS of 62 (40-81) mm, and LCQ of 11.5 (8.7-14.4). There were strong associations between PGI-S scores and cough severity VAS (ρ = 0.81), urge to cough VAS (ρ = 0.73), and LCQ (ρ = -0.73) (all P < .001). Repeatability of the PGI-S scale was high (n = 77); the intraclass correlation coefficient (95% confidence interval) was 0.85 (0.77-0.91) (P < .001). The PGI-S scale was responsive in participants with a treatment response (P < .001). The suggested PRO thresholds to define severe cough are ≥61 mm (cough severity VAS), ≥71 mm (urge to cough VAS), and ≤10 (LCQ). CONCLUSION: The PGI-S scale is a simple and valid tool that characterizes cough severity and is repeatable and responsive in CC. The proposed categorical severity thresholds for VAS and LCQ can provide intuitive meaning for patients and clinicians.

Cough hypersensitivity and suppression in COPD.

Cough reflex hypersensitivity and impaired cough suppression are features of chronic refractory cough (CRC). Little is known about cough suppression and cough reflex hypersensitivity in cough associated with chronic obstructive pulmonary disease (COPD). This study investigated the ability of patients with COPD to suppress cough during a cough challenge test in comparison to patients with CRC and healthy subjects. This study also investigated whether cough reflex hypersensitivity is associated with chronic cough in COPD.Participants with COPD (n=27) and CRC (n=11) and healthy subjects (n=13) underwent capsaicin challenge tests with and without attempts to self-suppress cough in a randomised order over two visits, 5 days apart. For patients with COPD, the presence of self-reported chronic cough was documented, and objective 24-h cough frequency was measured.Amongst patients with COPD, those with chronic cough (n=16) demonstrated heightened cough reflex sensitivity compared to those without chronic cough (n=11): geometric mean±sd capsaicin dose thresholds for five coughs (C5) 3.36±6.88 µmol·L-1 versus 44.50±5.90 µmol·L-1, respectively (p=0.003). Participants with CRC also had heightened cough reflex sensitivity compared to healthy participants: geometric mean±sd C5 3.86±5.13 µmol·L-1 versus 45.89±3.95 µmol·L-1, respectively (p<0.001). Participants with COPD were able to suppress capsaicin-evoked cough, regardless of the presence or absence of chronic cough: geometric mean±sd capsaicin dose thresholds for 5 coughs without self-suppression attempts (C5) and with (CS5) were 3.36±6.88 µmol·L-1 versus 12.80±8.33 µmol·L-1 (p<0.001) and 44.50±5.90 µmol·L-1 versus 183.2±6.37 µmol·L-1 (p=0.006), respectively. This was also the case for healthy participants (C5 versus CS5: 45.89±3.95 µmol·L-1 versus 254.40±3.78 µmol·L-1, p=0.033), but not those with CRC, who were unable to suppress capsaicin-evoked cough (C5 versus CS5: 3.86±5.13 µmol·L-1 versus 3.34±5.04 µmol·L-1, p=0.922). C5 and CS5 were associated with objective 24-h cough frequency in patients with COPD: ρ= -0.430, p=0.036 and ρ= -0.420, p=0.041, respectively.Patients with COPD-chronic cough and CRC both had heightened cough reflex sensitivity but only patients with CRC were unable to suppress capsaicin-evoked cough. This suggests differing mechanisms of cough between patients with COPD and CRC, and the need for disease-specific approaches to its management.

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.

Methods of Cough Assessment.

The accurate and consistent assessment of cough is essential not only for optimum standards of clinical care but also to drive forward advances in our understanding of cough. A range of tools for the subjective and objective measurement of cough exists, and their ongoing development has coincided with growth in clinical and preclinical research in cough, resulting in novel findings and promising new treatments. The most widely used and most fruitful approaches to assessing cough are discussed, along with some newer and preliminary techniques and directions for the future. These include methods for measuring cough-specific quality of life, subjective severity, cough frequency, intensity, and sensitivity of the underlying cough reflex. Ongoing development and more widespread adoption of cough assessment tools should help describe the heterogeneity of cough phenotypes, and may better guide treatment by enabling prediction of responses to pharmacological and nonpharmacological antitussive therapies. More detailed assessments of cough may also bring benefits in measuring the transmission of respiratory infections, or in managing reduced airway protection in neuromuscular disease. Population-wide assessments should also help understand the epidemiology of cough and assist in screening for disease.

Impaired cough suppression in chronic refractory cough.

Functional brain imaging in individuals with chronic cough demonstrates reduced activation in cortical regions associated with voluntary cough suppression. Little is known about the ability of patients with chronic cough to suppress cough. This study aimed to compare the ability to voluntarily suppress cough during inhaled capsaicin challenge in participants with chronic refractory cough with that in healthy controls. In addition, this study aimed to assess the repeatability of capsaicin challenge test with voluntary cough suppression.Participants with chronic refractory cough and healthy controls underwent inhaled capsaicin challenge tests while attempting to suppress their cough responses. After 5 days, either a conventional capsaicin challenge test with no cough suppression attempt, or a repeat test with an attempt at cough suppression was performed. Threshold capsaicin concentrations required to elicit one, two and five coughs were calculated by interpolation. Objective 24-h cough frequency was measured in individuals with chronic refractory cough.Healthy controls were able to suppress capsaicin-evoked cough while participants with chronic refractory cough were not. Geometric mean±sd capsaicin dose thresholds for five coughs with (CS5) and without (C5) suppression attempts were 254.40±3.78 versus 45.89±3.95 µmol·L-1, respectively, in healthy controls (p=0.033) and 3.34±5.04 versus 3.86±5.13 µmol·L-1, respectively, in participants with chronic refractory cough (p=0.922). Capsaicin dose thresholds for triggering five coughs with self-attempted cough suppression were significantly lower in participants with chronic refractory cough than in healthy controls; geometric mean±sd 4.94±4.43 versus 261.10±4.34 µmol·L-1, respectively; mean difference (95% CI) 5.72 (4.54-6.91) doubling doses (p<0.001). Repeatability of cough suppression test in both patients and healthy controls was high; intraclass correlation coefficients of log(CS5) values 0.81 and 0.87, respectively. CS5 was associated with objective cough frequency (ρ=-0.514, p=0.029).Participants with chronic refractory cough were less able to voluntarily suppress capsaicin-evoked cough compared to healthy controls. This may have important implications for the pathophysiology and treatment of chronic cough.

Tuberculosis Infectiousness and Host Susceptibility.

The transmission of tuberculosis is complex. Necessary factors include a source case with respiratory disease that has developed sufficiently for Mycobacterium tuberculosis to be present in the airways. Viable bacilli must then be released as an aerosol via the respiratory tract of the source case. This is presumed to occur predominantly by coughing but may also happen by other means. Airborne bacilli must be capable of surviving in the external environment before inhalation into a new potential host-steps influenced by ambient conditions and crowding and by M. tuberculosis itself. Innate and adaptive host defenses will then influence whether new infection results; a process that is difficult to study owing to a paucity of animal models and an inability to measure infection directly. This review offers an overview of these steps and highlights the many gaps in knowledge that remain.

Chronic cough and a normal chest X-ray - a simple systematic approach to exclude common causes before referral to secondary care: a retrospective cohort study.

Chronic cough is common in the community and can cause significant morbidity. It is not clear how closely treatment guidelines are used in general practice, or how often specialist referral is indicated. We aimed to assess the management of chronic cough in primary care before referral to a cough clinic, and to assess the outcome of managing chronic cough with an approach of simple investigation and empirical treatment trials. Data were extracted from the records of all patients attending a district general hospital respiratory clinic over a two-year period with isolated chronic cough lasting ⩾8 weeks. The clinic assessed symptoms with a cough-severity visual analogue scale and the Leicester Cough Questionnaire. Among 266 patients, the most frequent diagnoses were asthma (29%), gastro-oesophageal reflux (22%) and angiotensin-converting enzyme inhibitor use (14%). In all, 12% had unexplained chronic cough. Common diagnoses had often not been excluded in primary care: only 21% had undergone spirometry, 86% had undergone chest radiography and attempts to exclude asthma with corticosteroids had been made only in 39%. In the clinic few investigations were conducted that were not available in primary care. Substantial improvements in symptoms occurred with a median (interquartile range) total of 2 (2-3) clinic visits. We estimated that 87% of patients could have been managed solely in primary care; we did not identify distinguishing characteristics among this group. Most cases of chronic cough referred to secondary care could be managed with a simple and systematic approach, which is potentially transferrable to a community setting.

Cough and the transmission of tuberculosis.

Cough is a predominant feature of respiratory infection and, in tuberculosis, is of prime importance for transmitting infection. Tuberculosis is transmitted by the air, yet the process by which bacilli are aerosolized has received little attention. Features of cough may account for differences in transmission rates from source cases of pulmonary disease. We review the literature on the mechanisms and characteristics of cough in tuberculosis in the context of the dissemination of infection. Coughing is probably more important than other respiratory maneuvers, and characteristics of mucus may have an important role but data are scarce. Direct mechanisms of cough in tuberculosis are unknown, as are temporal and other patterns that correlate with the release of viable airborne bacilli. Other than antituberculous chemotherapy and masks, there are few methods of modulating cough in tuberculosis. This is an increasingly important area for research.

How to count coughs? Counting by ear, the effect of visual data and the evaluation of an automated cough monitor.

BACKGROUND: Cough causes morbidity and transmits disease yet has been under-researched. The best method for recognising and counting coughs remains unclear. We tested the accuracy of the human ear and measured the influence of visual data on cough counting. We also evaluated PulmoTrack®, a potentially fully-automated cough monitor. METHODS: Consistency amongst listeners and the effect of visual data: Three 14­22-min sequences containing 45­79 coughs were played to 15 respiratory physicians on at least two occasions. Only sound was played on the first occasions but on the final occasion a simultaneous display of audio activity was included. Counts of cough sounds across methods and listeners were compared. Evaluation of PulmoTrack®: 20-h recordings were made from 10 patients with cough. Automated counts were compared with assessment by one investigator. RESULTS: Agreement among listeners was high. The intraclass correlation coefficient (ICC) for cough counts by ear alone was 0.89 (95% CI, 0.65­1.00). With a concurrent visual display of sound amplitude it was 0.94 (0.80­1.00). 4.8% (0.6­9.5) fewer coughs were counted using visual data than by listening alone (mean [SD] total coughs: 190.2 [3.4] vs 200.7 [14.6]; p = 0.04). Cough frequencies reported by PulmoTrack® and the researcher differed substantially (ICC 0.23, −0.51 to 0.34, p = 0.87); PulmoTrack® had a sensitivity of 26% for detecting coughs identified by ear. CONCLUSION: Coughs are well recognised by different listeners. The method used to count coughs should be clearly described as visual information has a significant influence. Non-automated cough counting remains the gold standard method of quantifying cough.