What causes cough in pulmonary fibrosis, and how should we treat it?

PURPOSE OF REVIEW: To review the current understanding of the impact, mechanisms and treatments for cough in patients with interstitial lung disease (ILD). Evidence suggests that cough is a prevalent symptom in patients with ILD and has a significant impact on patients. RECENT FINDINGS: There is increasing interest in the role of cough hypersensitivity as seen in chronic refractory cough in patients with ILD, and encouraging recent results suggest that ILD-associated cough responds to opiate therapy. SUMMARY: Understanding the aetiology of cough in patients with ILD is crucial to continue to develop therapies which might be effective in reducing cough and increasing quality of life.

Feasibility and performance of the chronic obstructive pulmonary disease population screener and chronic obstructive pulmonary disease screening questionnaire in a Chinese physical examination center.

Background: Chronic obstructive pulmonary disease (COPD) affects up to 13% of the Chinese population, though it is under diagnosed throughout China. Screening among asymptomatic individual as part of routine health checks in China can facilitate early diagnosis and intervention to prevent disease progress. The COPD Population Screener (COPD-PS) or COPD Screening Questionnaire (COPD-SQ) has yet to be applied in Chinese physical examination centers (PECs) for COPD screening, and their feasibility and effectiveness should be clarified before full-scale implementation. This study is the first to apply the COPD-PS and COPD-SQ in a public hospital PEC in China to assess their feasibility and effectiveness and to identify their optimal cutoff values. Methods: People aged ≥40 years who attended the Second Affiliated Hospital of Shantou University PECs from September 2021 to December 2022 were asked to complete the COPD-PS and COPD-SQ and to undergo spirometry. The optimal cutoff values of the two questionnaires at the maximal Youden index were found, and the sensitivity and specificity were calculated. Results: Data from 198 participants were analyzed; mean [standard deviation (SD)] age of patients was 63.52 (10.94) years. Twenty-five participants (12.63%) were diagnosed with COPD. The number of COPD patients classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades 1 to 4 were 8, 12, 4, and 1, respectively. The area under the curves (AUCs) of the COPD-PS and COPD-SQ were 0.730 and 0.738, respectively. The optimal COPD-PS cutoff value of 4 points corresponded to a sensitivity of 72.00% and a specificity of 60.10%. The COPD-SQ optimal cutoff value of 15 points corresponded to a sensitivity of 76.00% and a specificity of 63.60%. Conclusions: Applying the COPD-PS and COPD-SQ in Chinese PECs is feasible, cost-effective and effective. COPD-PS and COPD-SQ can facilitate the early diagnosis of COPD, and whether they can improve the participants' quality of life would benefit a further study. It is recommended that the COPD-PS or COPD-SQ questionnaires be added to the screening of the physical examination program in PECs as part of health checks for people over 40 years old.

Qualitative assessment of sensations and triggers in chronic cough.

Qualitative interviews show a wide range of cough triggers and sensations in patients with refractory chronic cough. Knowledge of these may help us manage this complicated and impactful condition. https://bit.ly/41k9Ot5.

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.

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.

Chronic cough: is the end nigh?

Chronic cough (lasting more than 8 weeks) is a common condition with substantial psychosocial impact. Despite huge efforts following robust guidelines, chronic cough in many patients remains refractory or unexplained (RU-CC). Recent insights support a significant role for cough hypersensitivity in RU-CC, including neuropathophysiological evidence from inhalational cough challenge testing, functional magnetic resonance imaging, and airway nerve biopsy. Along with improved approaches to measuring cough, this knowledge has developed in tandem with repurposing neuromodulator medications, including gabapentin, and evidence for non-pharmacological treatments. Most significantly, there is now a pipeline for novel classes of drugs specifically for chronic cough. The P2X3 receptor antagonist gefapixant is the first such drug to be approved in Europe. However, challenges persist. The field of chronic cough needs more robust epidemiological data, enhanced diagnostic tools, further well-designed clinical trials accounting for the effects of placebo, and treatments with minimal side-effects. Addressing these challenges are novel chronic cough registries, improved International Classification of Diseases (10th revision) coding, genetic testing options and further mechanistic studies. This Viewpoint article discusses these facets and considers how, whilst the end of chronic cough may not be imminent for all patients, the evolving landscape looks increasingly optimistic.

Healthcare utilization and costs in chronic cough.

BACKGROUND: Chronic cough is a common reason for medical consultations and is associated with considerable physical and psychological morbidity. This study investigated healthcare use and cost in chronic cough and assessed its relationship with cough severity, health status, objective cough frequency (CF), and anxiety and depression. METHODS: This was a prospective study of consecutive patients with chronic cough from a specialist clinic who completed a cough severity visual analogue scale (VAS), cough-specific health status (Leicester Cough Questionnaire; LCQ) and general health status EuroQol EQ-5D-5L, Generalized Anxiety Disorder (GAD7), Patient Health Questionnaire (PHQ9), and 24-hour objective CF monitoring with Leicester Cough Monitor (LCM). Case notes were reviewed for cough-specific healthcare use 12 months before and after the first cough clinic consultation. Resource use included general practitioner and hospital clinic visits, investigations, and treatments. Unit costs for healthcare use were derived predominantly from National Health Service Reference Costs. RESULTS: One hundred participants with chronic cough were recruited (69% female, median duration 3 years, mean age 58 years). The diagnoses of cough were unexplained (57%), refractory (27%), and other (16%). Cough severity, health status, and CF were: median (IQR) VAS = 59.5 (30-79) mm, mean (SD) LCQ = 11.9 (4.0), mean (SD) EQ-5D-5L = 0.846 (0.178), and geometric mean (SD) CF = 15.3 (2.5) coughs/hr, respectively. The mean (SD) total cost per individual for cough-related healthcare utilization was £1,663 (747). Diagnostic investigations were the largest contributor to cost (63%), followed by cough clinic consultations (25%). In multivariate analysis, anxiety (GAD7) and cough-related health status (LCQ) were associated with increased cost (p ≤.001 and .037). CONCLUSION: Healthcare cost associated with chronic cough are largely due to diagnostic investigations and clinic consultations. The predictors of costs were health status (LCQ) and anxiety. Further studies should investigate the optimal management protocols for patients with chronic cough.

Noninvasive Assessment of Neuromechanical and Neuroventilatory Coupling in COPD.

This study explored the use of parasternal second intercostal space and lower intercostal space surface electromyogram (sEMG) and surface mechanomyogram (sMMG) recordings (sEMGpara and sMMGpara, and sEMGlic and sMMGlic, respectively) to assess neural respiratory drive (NRD), neuromechanical (NMC) and neuroventilatory (NVC) coupling, and mechanical efficiency (MEff) noninvasively in healthy subjects and chronic obstructive pulmonary disease (COPD) patients. sEMGpara, sMMGpara, sEMGlic, sMMGlic, mouth pressure (Pmo), and volume (Vi) were measured at rest, and during an inspiratory loading protocol, in 16 COPD patients (8 moderate and 8 severe) and 9 healthy subjects. Myographic signals were analyzed using fixed sample entropy and normalized to their largest values (fSEsEMGpara%max, fSEsMMGpara%max, fSEsEMGlic%max, and fSEsMMGlic%max). fSEsMMGpara%max, fSEsEMGpara%max, and fSEsEMGlic%max were significantly higher in COPD than in healthy participants at rest. Parasternal intercostal muscle NMC was significantly higher in healthy than in COPD participants at rest, but not during threshold loading. Pmo-derived NMC and MEff ratios were lower in severe patients than in mild patients or healthy subjects during threshold loading, but differences were not consistently significant. During resting breathing and threshold loading, Vi-derived NVC and MEff ratios were significantly lower in severe patients than in mild patients or healthy subjects. sMMG is a potential noninvasive alternative to sEMG for assessing NRD in COPD. The ratios of Pmo and Vi to sMMG and sEMG measurements provide wholly noninvasive NMC, NVC, and MEff indices that are sensitive to impaired respiratory mechanics in COPD and are therefore of potential value to assess disease severity in clinical practice.

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.

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 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.

Physical Inactivity in Pulmonary Sarcoidosis.

PURPOSE: Reduced physical activity in many chronic diseases is consistently associated with increased morbidity. Little is known about physical activity in sarcoidosis. The aim of this study was to objectively assess physical activity in patients with pulmonary sarcoidosis and investigate its relationship with lung function, exercise capacity, symptom burden, and health status. METHODS: Physical activity was assessed over one week in 15 patients with pulmonary sarcoidosis and 14 age-matched healthy controls with a tri-axial accelerometer (ActivPal™) and the International Physical Activity Questionnaire (IPAQ). All participants underwent pulmonary function tests, 6-min walk test (6MWT) and completed the Fatigue Assessment Scale (FAS), Medical Research Council (MRC) Dyspnoea Scale and the King's Sarcoidosis Questionnaire (KSQ). RESULTS: Patients with sarcoidosis had significantly lower daily step counts than healthy controls; mean (SD) 5624 (1875) versus 10,429 (2942) steps (p < 0.01) and a trend towards fewer sit-to-stand transitions each day (p = 0.095). Only two patients (13%) self-reported undertaking vigorous physical activity (IPAQ) compared to half of healthy individuals (p < 0.01). Daily step count was significantly associated with 6MWT distance in sarcoidosis (r = 0.634, p = 0.01), but not with forced vital capacity (r = 0.290), fatigue (r = 0.041), dyspnoea (r = -0.466) or KSQ health status (r = 0.099-0.484). Time spent upright was associated with fatigue (r = -0.630, p = 0.012) and health status (KSQ Lung scores r = 0.524, p = 0.045), and there was a significant correlation between the number of sit-to-stand transitions and MRC dyspnoea score (r = -0.527, p = 0.044). CONCLUSION: Physical activity is significantly reduced in sarcoidosis and is associated with reduced functional exercise capacity (6MWD). Fatigue, exertional symptoms and health status were more closely associated with time spent upright and the number of bouts of physical activity, as compared to step counts. Further studies are warranted to identify the factors that determine different physical activity profiles in sarcoidosis.

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.