Patient Perception of Cough in Interstitial Lung Disease; Impact of Cough Hypersensitivity.

INTRODUCTION: Cough is common in interstitial lung disease (ILD) and is associated with disease progression, yet its mechanisms are understudied. We investigated cough hypersensitivity features and impact in ILD. METHODS: Participants with ILD and cough (n = 195) completed a multiple choice and free text questionnaire on cough sensations/triggers and impacts. RESULTS: The majority of participants were male (54%), aged > 65 (64%), with idiopathic pulmonary fibrosis (IPF, 75%). Common cough triggers were body position (74%), physical activity (72%), and talking (62%). Common laryngeal sensations were globus (43%), and itch/tickle (42%). Cough impacted everyday life in 55%, and all activities in 31%, causing exhaustion (59%), social embarrassment (70%), urinary incontinence (46% females), and syncope/pre-syncope (12%). The total number of cough-provoking sensations/triggers correlated with impacts; ρ = 0.73, p < 0.001. CONCLUSION: Cough hypersensitivity symptoms are prevalent in ILD and detrimentally affect quality of life. Further studies investigating mechanisms of cough hypersensitivity and targeted pharmacotherapy are warranted.

Chronic Cough and Obstructive Sleep Apnea.

Chronic cough, defined as a cough lasting more than 8 weeks, is a common medical condition occurring in 5% to 10% of the population. Its overlap with another highly prevalent disorder, obstructive sleep apnea (OSA), is therefore not surprising. The relationship between chronic cough and OSA extends beyond this overlap with higher prevalence of OSA in patients with chronic cough than in the general population. The use of continuous positive airway pressure can result in improvement in chronic cough although further studies are needed to understand which patients will experience benefit in their cough from the treatment of comorbid OSA.

Profile of cough triggers and their relationship with capsaicin cough sensitivity in chronic cough.

BACKGROUND: Cough hypersensitivity is an important part of the neurophysiology of cough, which presents with increased cough response to a lower level of stimuli or triggers. Classification of stimuli might bring about additional insight into the underlying mechanisms and management. OBJECTIVES: This study investigated the profile of cough triggers in chronic cough patients and their relationship with capsaicin cough sensitivity. DESIGN: This was a cross-sectional observational study. METHODS: We enrolled patients with different causes of chronic cough from 2006 to 2021. Cough triggers were defined as cough response to chemical triggers, mechanical triggers, meal triggers, or thermal trigger. Cough sensitivity to capsaicin was evaluated by the capsaicin challenge test, which was expressed as the lowest concentration of capsaicin inducing 5 or more coughing (C5). RESULTS: Among 1211 patients with chronic cough, 1107 (91.4%) patients reported at least one cough trigger. Chemical triggers (66.9%) were the most common cough triggers, followed by thermal exposure (50.6%), mechanical triggers (48.2%), and meal triggers (21.2%). There was no difference in the proportion of chemical triggers among different etiologies. Patients with refractory chronic cough reported the highest prevalence of cough triggers (97.1%). A higher number of meal triggers (34.9%) was associated with gastroesophageal reflux-related cough, and meal triggers and mechanical triggers were more common in refractory chronic cough. Among 254 patients who completed capsaicin challenge test, both the number of total triggers and the number of chemical triggers had a significant but mild correlation with capsaicin cough sensitivity. CONCLUSION: Cough hypersensitivity as reflected by a variety of cough triggers is a common feature in chronic cough patients, but different etiologies present specific profiles of cough triggers, which could not be evaluated comprehensively by capsaicin cough sensitivity.

Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity.

Chronic cough is characterized by a state of cough hypersensitivity. We analyze the process of transpiration, by which water appears to evaporate from laryngeal and tracheal mucus as from the surface of a leaf, as a potential cause of cough hypersensitivity. In this process, osmotic pressure differences form across mucus, pulling water toward the air, and preventing mucus dehydration. Recent research suggests that these osmotic differences grow on encounter with dry and dirty air, amplifying pressure on upper airway epithelia and initiating a cascade of biophysical events that potentially elevate levels of ATP, promote inflammation and acidity, threaten water condensation, and diminish mucus water permeability. Among consequences of this inflammatory cascade is tendency to cough. Studies of isotonic, hypotonic, and hypertonic aerosols targeted to the upper airways give insights to the nature of mucus transpiration and its relationship to a water layer that forms by condensation in the upper airways on exhalation. They also suggest that, while hypertonic NaCl and mannitol may provoke cough and bronchoconstriction, hypertonic salts with permeating anions and non-permeating cations may relieve these same upper respiratory dysfunctions. Understanding of mucus transpiration and its role in cough hypersensitivity can lead to new treatment modalities for chronic cough and other airway dysfunctions promoted by the breathing of dry and dirty air.

Use of central neuromodulators in chronic cough / 中国临床药理学与治疗学

Chronic cough is a common condition that imposes significant physical, psychological, and social burdens on patients. Although chronic cough is often associated with underlying conditions such as asthma, gastroesophageal reflux disease, and eosinophilic bronchitis, some patients experience uncontrollable coughing that is difficult to attribute to a specific cause. Many of these patients exhibit clinical features of cough hypersensitivity syndrome, providing new directions for research into the treatment of chronic cough. As the pathophysiological mechanisms of chronic cough are further elucidated, treatment approaches for chronic cough are entering a new stage of development. This article summarizes and discusses the mechanisms and clinical evidence of central neuromodulators used in the treatment of chronic cough, suggesting promising clinical applications for these drugs in the future.

Mechanisms and management of cough in interstitial lung disease.

INTRODUCTION: Many patients with interstitial lung diseases (ILDs), especially fibrotic ILDs, experience chronic cough. It negatively impacts both physical and psychological well-being. Effective treatment options are limited. AREAS COVERED: The pathophysiology of chronic cough in IPF is complex and involves multiple mechanisms, including mechanical distortion of airways, parenchyma, and nerve fibers. The pathophysiology of cough in other fibrosing ILDs is poorly understood and involves various pathways. The purpose of this review is to highlight mechanisms of chronic cough and to present therapeutic evidence for its management in the most commonly occurring diffuse fibrosing lung diseases including idiopathic pulmonary fibrosis (IPF), connective tissue disease-related interstitial lung disease (CTD-ILD), sarcoidosis-related ILD (Sc-ILD), chronic hypersensitivity pneumonitis-related ILD (CHP-ILD), and post-COVID-19-related interstitial lung disease (PC-ILD). EXPERT OPINION: This review guides the management of chronic cough in fibrosing ILDs. In this era of precision medicine, chronic cough management should be individualized in each interstitial lung disease.

New Insights Into Refractory Chronic Cough and Unexplained Chronic Cough: A 6-Year Ambispective Cohort Study.

PURPOSE: Only limited studies have depicted the unique features and management of refractory chronic cough (RCC) and unexplained chronic cough (UCC). These led to the initiation of this study, which reported the demographic characteristics, manifestations, and long-term outcomes on a large series of consecutive RCC/UCC patients, providing a guideline-led real-world clinical experience. METHODS: Retrospective baseline information was obtained from Clinical Research Database (January 2016 to May 2021). At least 6 months after the last clinic visit, included subjects were prospectively followed up. RESULTS: Three hundred and sixty-nine RCC and UCC patients (199 females, 53.9%) were analyzed. The median cough duration was 24.0 (12.0-72.0) months. Laryngeal symptoms were reported in 95.9% of the patients. The common triggers for coughing were talking (74.9%), pungent odors (47.3%), eating (45.5%), and cold air (42.8%). RCC was considered in 38.2%, and the remainder of 228 patients had UCC, with an equal sex distribution (P = 0.66). Among the 141 RCCs, 90.8% (128) had refractory reflux cough, which was more responsive to current treatments (P < 0.01). Although most features and test results between RCC and UCC were similar, UCC was more commonly inappropriately treated (P < 0.01). Nineteen (7.7-41.1) months after the final clinic visit, 31.2% still coughed persistently, while 68.8% reported cough improvement or remission. RCC reported more favorable treatment outcomes (including cough improvement, control, and spontaneous remission) than UCC (P < 0.01). Coughs with long duration before the initial cough clinic visit (P < 0.01), frequent urinary incontinence (P < 0.01), and being sensitive to "talking" (P < 0.01) or "cold air" (P < 0.01) were less likely to be solved. CONCLUSIONS: The current treatments only improve cough symptoms in two-thirds of patients. Clinical indicators for treatment failure were those coughing for long duration and being sensitive to "talking" or "cold air."

Effects of Pregabalin as a Neural Pathway Inhibitor for the Treatment of Resistant Subacute and Chronic Cough: A Pilot Clinical Trials Study.

BACKGROUND: Cough hypersensitivity syndrome is one of the causes of chronic cough. Small clinical trials have suggested the effects of pregabalin as a neural pathway inhibitor in treating subacute and chronic cough resistance. METHODS: This study is an 8-week, pilot study randomized, double-blind clinical trial on 30 patients' resistant to treatment of the underlying cause who were referred to an ultra-specialized lung clinic, Shahid Beheshti Hospital, between 2021-2022. The samples were randomly divided into control (dextromethorphan and placebo) and intervention (dextromethorphan and pregabalin). Patients were evaluated at the beginning, during, and after eight weeks of treatment, using the modified standard Leicester Cough Questionnaire (LCQ) regarding the changes and the rate of recovery compared to before Participation in the study. FINDINGS: The quality of life score of patients eight weeks after treatment had a significant difference and was higher in the intervention group (In the pregabalin group) than in the control group (p =0.006). The recovery rate of cough in 26% of patients was equal to 70%, but others were reported up to 50%. CONCLUSION: Pregabalin increases the quality of life in patients with subacute and chronic cough resistant to standard treatment and increases the rate of recovery in these patients.

Patterns of Cough Medication Prescribing among Patients with Chronic Cough in Florida: 2012-2021.

Among patients with chronic cough (CC) in the 2012-2021 statewide OneFlorida Clinical Research Consortium database, we examined trends in cough medication (CM) prescribing prevalence over time in repeated cross-sectional analyses and identified distinct CM utilization trajectories using group-based trajectory modeling (GBTM) in a retrospective cohort study. Among eligible adults (≥18 years) without cancer/benign respiratory tumor diagnoses, we identified CC patients and non-CC patients with any cough-related diagnosis. In the GBTM analysis, we calculated the number of monthly prescriptions for any CMs (excluding gabapentinoids) during the 12 months from the first qualifying cough event to identify distinct utilization trajectories. From 2012 to 2021, benzonatate (9.6% to 26.1%), dextromethorphan (5.2% to 8.6%), and gabapentinoid (5.3% to 14.4%) use increased among CC patients, while opioid antitussive use increased from 2012 to 2015 and decreased thereafter (8.4% in 2012, 14.7% in 2015, 6.7% in 2021; all p < 0.001). Of 15,566 CC patients and 655,250 non-CC patients identified in the GBTM analysis, CC patients had substantial burdens of respiratory/non-respiratory comorbidities and healthcare service and concomitant medication use compared to non-CC patients. Among CC patients, GBTM identified three distinct CM utilization trajectories: (1) no CM use (n = 11,222; 72.1%); (2) declining CM use (n = 4105; 26.4%); and (3) chronic CM use (n = 239; 1.5%). CC patients in Florida had limited CM use with increasing trends in use of benzonatate, dextromethorphan, and gabapentinoids and a decreasing trend in opioid antitussive use. CC patients, particularly with chronic prescription CM use, experienced substantial disease burden.

Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers.

Chronic cough (CC) is associated with many conditions, so identifying contributing causes poses a diagnostic challenge. However, guidelines written for US physicians do not explicitly outline suggested roles for primary care providers (PCPs) in the approach to patients with CC, including refractory or unexplained CC. The objective of this review is to describe the role of PCPs in the diagnosis and treatment of CC in adults. This narrative review draws upon literature (identified via a PubMed search performed January 9, 2023, using primary care/disease state-related terms) and expertise from specialist physicians to provide recommendations for CC management in primary care. Cough is one of the top reasons patients seek care from PCPs; accordingly, PCPs are often the first physicians to conduct workup and initiate treatment. Patients with CC often experience a burdensome cough that lasts for years, have high healthcare resource utilization (HCRU), undergo multiple or failed treatment trials, and have limited success finding an etiology. Although specialist referral may be needed for many diagnostic tests, initial aspects of CC workup and management should be completed in primary care. Often more accessible than specialists, real-world evidence on HCRU suggests PCPs are important stakeholders in diagnosing and managing CC, including during initial workup and treatment for the most common causes of CC (i.e. upper-airway cough syndrome, asthma, noneosinophilic asthmatic bronchitis, and gastroesophageal reflux disease). Thorough workup at the primary care level may facilitate earlier identification of CC cause(s), improving patient journey to diagnosis and management.

Unravelling vagal hypersensitivity in chronic cough: A distinct disease.

Chronic cough (CC) is a common but poorly understood disease that has a negative impact on quality of life. For years, clinicians have been trying to find the underlying diagnosis and using existing disease models to describe the patients' illness. This presents a confusing picture of CC. Most patients with CC present with hypersensitivity of the cough reflex, which is characterised by laryngeal paraesthesia and an increased response to the tussive stimuli or an innocuous stimulus that would not trigger coughing in healthy people. Recently, it has been proposed that CC is a unique disease characterised by vagal hypersensitivity that projects to the central nervous system altering responsiveness. The evidence supports the hypothesis that CC is primarily a neurological disorder, consisting of different phenotypes.

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.

Similarities and differences between the cough suppression test and the cough challenge test.

In recent years, a new test method namely the cough suppression test has been proposed to measure cough suppression in patients with chronic cough. The cough suppression test is a modified test based on capsaicin tussive challenge. There are similarities and differences between it and the more established cough challenge test in detection method, purpose and clinical significance. In this article, we will introduce and compare the concepts, application and methodology of the cough suppression test and the cough challenge test, summarize this research progress and problems of the two methods, and predict the possible role of both in the further study of chronic cough.

Cough desensitization treatment for patients with refractory chronic cough: results of a second pilot randomized control trial.

OBJECTIVE: The purpose of this study was to collect pilot efficacy data on a novel treatment for refractory chronic cough (RCC), which we call cough desensitization treatment (CDT). DESIGN AND METHODS: In this parallel cohort, sham-controlled, randomized controlled trial, 21 adults with RCC were randomly assigned to 12 sessions of either CDT (progressive doses of aerosolized capsaicin while behaviorally suppressing cough; n = 11) or a sham treatment (repeated exposure to aerosolized saline; n = 9). The Leicester Cough Questionnaire (LCQ) was the primary outcome measure. Perceived cough severity with a visual analogue scale and cough challenge testing (for measuring cough-reflex sensitivity) were secondary outcome measures. Data were analyzed with mixed effects linear regression and follow-up contrasts. RESULTS: Results on all measures favored CDT. Excluding one sham participant, whose baseline LCQ scores were deemed unreliable, mean change in LCQ at 3-weeks post treatment was 6.35 and 2.17 in the CDT and sham groups, respectively. There was moderate to strong evidence of a greater improvement in the CDT group in total LCQ score (p = .058) and LCQ Psychological domain (p = .026) and Physical domain (p = .045) scores. Strong evidence was found for a greater reduction in urge-to-cough during CCT in the CDT group (p = .037) and marginal for a reduction in the capsaicin cough-reflex sensitivity (p = .094). There was weak evidence of a greater reduction in cough severity in the CDT group (p = .103). DISCUSSION: Although the study is limited due to the small sample size, the data provide additional evidence supporting further research on CDT. CDT resulted in a greater change in the primary efficacy measure (LCQ) than both pharmaceutical and behavioral treatments currently found in the literature. TRIAL REGISTRATION: This trial (NCT05226299) was registered on Clinicaltrials.gov on 07/02/2022.

Chronic cough in adults: recommendations from an Italian intersociety consensus.

BACKGROUND: Chronic cough (CC) is a burdensome health problem in adult and older people, with a major impact on quality of life. Its management is often troublesome, and many guidelines have been released. Notwithstanding, a proportion of cases still do not reach a definite diagnosis and resolutive treatment. A coordinated approach between different specialists would be highly recommended, but its implementation in clinical practice suffers from the lack of shared protocols and poor awareness of the problem. The present consensus document has been implemented to address these issues. AIMS: To develop evidence-based recommendations for the management of adults with CC. METHODS: A 12-member expert task force of general practitioners, geriatricians, pneumologists, allergologists, otorhynolaringologists and gastroenterologists was established to develop evidence-based recommendations for the diagnostic and therapeutic approach to subjects with CC. A modified Delphi approach was used to achieve consensus, and the US Preventive Services Task Force system was used to rate the strength of recommendations and the quality of evidence. RESULTS: A total of 56 recommendations were proposed, covering 28 topics and concerning definitions and epidemiology, pathogenesis and etiology, diagnostic and therapeutic approach along with the consideration of specific care settings. CONCLUSION: These recommendations should ease the management of subjects with CC by coordinating the expertise of different specialists. By providing a convenient list of topics of interest, they might assist in identifying unmet needs and research priorities.

ATP, an attractive target for the treatment of refractory chronic cough.

Chronic cough is the most common complaint in respiratory clinics. Most of them have identifiable causes and some may respond to common disease-modifying therapies. However, there are many patients whose cough lacks effective aetiologically targeted treatments or remains unexplained after thorough assessments, which have been described as refractory chronic cough. Current treatments for refractory chronic cough are limited and often accompanied by intolerable side effects such as sedation. In recent years, various in-depth researches into the pathogenesis of chronic cough have led to an explosion in the development of drugs for the treatment of refractory chronic cough. There has been considerable progress in the underlying mechanisms of chronic cough targeting ATP, and ongoing or completed clinical studies have confirmed the promising antitussive efficacy of P2X3 antagonists for refractory cough. Herein, we review the foundation on which ATP target was developed as potential antitussive medications and provide an update on current clinical progresses.