Burden of Disease Associated with Refractory and Unexplained Chronic Cough in Canada: Results from a National Survey.

INTRODUCTION: Chronic cough (persisting for ≥ 8 weeks) is a common disorder that includes refractory chronic cough (RCC; cough that persists despite treatment of underlying disease) and unexplained chronic cough (UCC; cough with no identifiable cause). We evaluated self-reported health-related quality of life (HR-QoL) and work/activity impairment associated with RCC/UCC in Canada. METHODS: Our exploratory study included Canadians in the Leger Opinion Panel with RCC or UCC. Key entry criteria were ≥ 18 years of age, cough for ≥ 8 weeks, not currently smoking/quit ≥ 1 year ago, no serious respiratory disease or lung cancer, and not taking angiotensin-converting enzyme inhibitors. Respondents completed a 30-min online survey with general and cough-specific HR-QoL questionnaires, including the EuroQol (EQ) visual analogue scale (VAS), EQ-5-dimension 5-level (EQ-5D-5L), cough severity VAS, Leicester Cough Questionnaire (LCQ), and Work Productivity and Activity Impairment-Specific Health Problem (WPAI-SPH). RESULTS: Of 49,076 individuals who completed the chronic cough screening questionnaire (July 30-September 1, 2021), 1,620 (3.3%) met entry criteria for RCC/UCC and 1,046 (2.1%) completed the survey. The mean age of respondents was 45 years and 61% were female. Respondents reported impairments in global HR-QoL (EQ-VAS 73.8, 61% with anxiety/depression on the EQ-5D-5L) and cough-specific HR-QoL (mean cough severity VAS score 29.7, LCQ index 15.2). Work and non-work activities were reduced by 34% and 30%, respectively, on the WPAI-SPH. CONCLUSION: RCC/UCC is prevalent in Canada and associated with impaired HR-QoL, particularly in mental health domains. Additional support and management options may be required to fully address this burden.

Burden of chronic cough on social participation, healthcare resource utilisation and activities of daily living in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Chronic cough is a common troublesome condition, but it is unclear whether dry or productive chronic cough and sex, impacts the burden of cough differently. METHODS: The Canadian Longitudinal Study on Aging is a nationally generalizable, stratified random sample of adults aged 45-85 years. Chronic cough was identified based on a self-reported daily cough in the last 12 months assessed at baseline (2011-2015) and follow-up (2015-2018). Odds ratios (95 % CI) for cough status and change in social participation activities (SPA), healthcare resource utilisation (HCRU), basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were estimated using a weighted generalised estimating equation (WGEE). Results were stratified by sex, and adjusted for age, sex, smoking, body mass index, education, respiratory diseases and retirement status. RESULTS: Overall, chronic cough was associated with less SPA, greater HCRU and impaired ADL/IADLs. Productive chronic cough in males was associated with SPA limited by health, ED visits and hospitalisation. Females with productive chronic cough was associated with reduced frequency of SPA and ED visit. Dry chronic cough in females was associated with SPA limited by health and ED visits. Both types of cough was associated with at least 1 impaired basic ADL, but only in females with productive chronic cough was there an association with any impairment in IADLs. CONCLUSION: Chronic cough is associated with a greater burden on social participation, healthcare use and personal care.

Emerging drugs in the treatment of chronic cough.

INTRODUCTION: Chronic cough is a debilitating condition that is among the most common reasons for seeking medical attention yet remains challenging to manage. Identifying an underlying respiratory, nasal, or upper gastrointestinal disease triggering cough is the first step in assessment, but once this has been ruled out or adequately treated, many patients remain troubled with chronic cough. AREAS COVERED: This narrative review discusses the role of existing treatments and describes the current research landscape for the development of new therapies for chronic cough greater than 8 weeks that is refractory (RCC) or unexplained (UCC). The literature search includes published studies found on pubmed and conference abstracts until 2023. EXPERT OPINION: RCC/UCC can occur due to neuronal dysregulation of the vagus nerve or central nervous system. Hence, novel anti-tussives have targeted ion channels involved in the neuronal signaling which triggers cough. Although some therapies targeting receptors such as TRPV1 have failed to show efficacy, P2X3 antagonists have emerged as the most promising therapy for patients impacted by chronic cough. Disease-specific therapies such as for idiopathic pulmonary fibrosis are in early development.

Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Aerosol delivery, but not intramuscular injection, of adenovirus-vectored tuberculosis vaccine induces respiratory-mucosal immunity in humans.

BackgroundAdenovirus-vectored (Ad-vectored) vaccines are typically administered via i.m. injection to humans and are incapable of inducing respiratory mucosal immunity. However, aerosol delivery of Ad-vectored vaccines remains poorly characterized, and its ability to induce mucosal immunity in humans is unknown. This phase Ib trial evaluated the safety and immunogenicity of human serotype-5 Ad-vectored tuberculosis (TB) vaccine (AdHu5Ag85A) delivered to humans via inhaled aerosol or i.m. injection.MethodsThirty-one healthy, previously BCG-vaccinated adults were enrolled. AdHu5Ag85A was administered by single-dose aerosol using Aeroneb Solo Nebulizer or by i.m. injection. The study consisted of the low-dose (LD) aerosol, high-dose (HD) aerosol, and i.m. groups. The adverse events were assessed at various times after vaccination. Immunogenicity data were collected from the peripheral blood and bronchoalveolar lavage samples at baseline, as well as at select time points after vaccination.ResultsThe nebulized aerosol droplets were < 5.39 µm in size. Both LD and HD of AdHu5Ag85A administered by aerosol inhalation and i.m. injection were safe and well tolerated. Both aerosol doses, particularly LD, but not i.m., vaccination markedly induced airway tissue-resident memory CD4+ and CD8+ T cells of polyfunctionality. While as expected, i.m. vaccination induced Ag85A-specific T cell responses in the blood, the LD aerosol vaccination also elicited such T cells in the blood. Furthermore, the LD aerosol vaccination induced persisting transcriptional changes in alveolar macrophages.ConclusionInhaled aerosol delivery of Ad-vectored vaccine is a safe and superior way to elicit respiratory mucosal immunity. This study warrants further development of aerosol vaccine strategies against respiratory pathogens, including TB and COVID-19.Trial registrationClinicalTrial.gov, NCT02337270.FundingThe Canadian Institutes for Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada funded this work.

Impact of productive and dry chronic cough on mortality in the Canadian Longitudinal Study on Aging (CLSA).

Background: Chronic cough is a common troublesome condition and accounts for a high burden on quality of life. Previous data investigating the mortality associated with chronic cough has been derived in patients with chronic bronchitis. No data exists on chronic dry cough. Therefore, we investigated if chronic dry and productive cough is independently associated with increased mortality. Methods: The Canadian Longitudinal Study on Ageing (CLSA) is a prospective, nationally generalizable, stratified random sample of adults aged 45-85 years at baseline recruited between 2011-2015 and followed up three years later. Chronic cough was identified based on a self-reported daily cough in the last 12 months. Deaths were confirmed by the Ministry of Health and/or completion of descendent questionnaire by a family member. Models were investigated for dry and productive chronic cough and was adjusted for age, sex, smoking, body mass index (BMI), and respiratory diseases. Results: Of the 30,016 participants, 4,783 (15.9%) reported chronic cough at baseline; 2,724 (57%) had a dry cough, and 2,059 (43%) had productive chronic cough. There was a total of 561 deaths between baseline and follow-up-1 (3 years later). There was a 49% higher risk of death in participants with chronic productive cough {adjusted odds ratio (aOR) 1.49 [95% confidence intervals (CI): 1.08-2.07]}, but not dry chronic cough [aOR 0.85 (0.60-1.20)]. The effects of chronic productive cough on mortality were persistent in those with no airflow obstruction [chronic productive cough aOR 1.90 (1.09-3.31)]. Conclusions: Chronic productive cough is associated with a higher risk of death, while chronic dry cough has no impact on mortality risk of death in middle-aged and older adults. This highlights the importance of careful evaluation of patients with chronic cough.

Effects of cigarette smoke exposure on pulmonary physiology, muscle strength and exercise capacity in a retrospective cohort with 30,000 subjects.

BACKGROUND: The effects of long-term cigarette smoke exposure on pulmonary physiology and how those effects lead to reduced exercise capacity are not well established. METHODS: We retrospectively analyzed the spirometry, single-breath gas transfer (DLCO), peripheral muscle strength, and maximum exercise capacity data in patients referred to McMaster University Medical Centre for cardiopulmonary exercise testing between 2000 and 2012. RESULTS: 29,441 subjects underwent CPET and had a recorded smoking history [58% male, mean age 51.1 years (S.D.±19.6), BMI 27.4 kg/m2(±5.8)]. 7081 (24%) were current or former smokers and were divided into 4 categories by packs years (mean ±S.D.): <10 (5.8±3.3), 10-20 (17.1±2.9), 20-30 (27.1±2.8), 30-40 (37.3±2.8), and >40 (53.9±12.8). Patients with greater cigarette smoke exposure had lower expiratory flow rates (FEV1, FEF50, FEF75, PEFR), DLCO, and maximum power output (MPO) during exercise. There was no association between smoke exposure and muscle strength. Modeling MPO (kpm/min) output as a function of demographic and physiologic variables showed that the data are well explained by muscle strength (kg), FEV1 (L), and DLCO (mmHg/min/mL) in similar magnitude (MPO = 42.7*Quads0.34*FEV10.34 * DLCO0.43; r = 0.84). CONCLUSIONS: Long-term cigarette smoke exposure is associated with small airway narrowing and impaired diffusion capacity but not with peripheral muscle weakness. The effects of smoking, age, and gender on maximum power output are mediated by reductions in FEV1, muscle strength and DLCO. Exercise capacity in smokers may benefit from therapies targeting all 3 variables.

Prevalence, incidence and characteristics of chronic cough among adults from the Canadian Longitudinal Study on Aging.

The global prevalence of chronic cough is highly variable, ranging from 2% to 18%. There is a lack of data on the prevalence and incidence of chronic cough in the general population. The objective of this study was to investigate the prevalence and incidence of chronic cough in a sample of Canadian adults, and how these are influenced by age, sex, smoking, respiratory symptoms, medical comorbidities and lung function. Participants with chronic cough were identified from the Canadian Longitudinal Study on Aging (CLSA) based on self-reported daily cough in the past 12 months. This is a prospective, nationally generalisable, stratified random sample of adults aged 45-85 years at baseline recruited between 2011 and 2015, and followed-up 3 years later. The prevalence and incidence per 100 person-years are described, with adjustments for age, sex and smoking. Of the 30 097 participants, 29 972 completed the chronic cough question at baseline and 26 701 did so at follow-up. The prevalence of chronic cough was 15.8% at baseline and 17.6% at follow-up with 10.4-17.1% variation across seven provinces included in the CLSA comprehensive sample. Prevalence increased with age and current smoking, and was higher in males (15.2%), Caucasians (14%) and those born in North America, Europe or Oceania (14%). The incidence of chronic cough adjusted for age, sex and smoking was higher in males and in underweight and obese subjects. Subjects with respiratory symptoms, airway diseases, lower forced expiratory volume in 1 s (% predicted), cardiovascular diseases, psychological disorders, diabetes and chronic pain had a higher incidence of chronic cough. The prevalence and incidence of chronic cough is high in the CLSA sample with geographic, ethnic and gender differences, influenced by a number of medical comorbidities.

Prognostic factors associated with small for gestational age babies in a tertiary care hospital of Western Nepal: A cross-sectional study.

BACKGROUND: Small for gestational age (SGA) is common among newborns in low-income countries like Nepal and has higher immediate mortality and morbidities. OBJECTIVES: To study the prevalence and prognostic factors of SGA babies in Western Nepal. METHODS: A cross-sectional study (November 2016-October 2017) was conducted in a tertiary care hospital in Western Nepal. Socio-demographic, lifestyle factors including diet, and exposures including smoking and household air pollution in mothers who delivered newborns appropriate for gestational age (AGA), SGA and large for gestational age (LGA) were recorded. Logistic regression was carried out to find the odds ratio of prognostic factors after adjusting for potential confounders. RESULTS: Out of 4000 delivered babies, 77% (n = 3078) were AGA, 20.3% (n = 813) were SGA and 2.7% (n = 109) were LGA. The proportion of female-SGA was greater in comparison to male-SGA (n = 427, 52.5% vs n = 386, 47.5%). SGA babies were born to mothers who had term, preterm, and postterm delivery in the following proportions 70.1%, 19.3%, and 10.6%, respectively. The average weight gain (mean ± SD) by mothers in AGA pregnancies was 10.3 ± 2.4 kg, whereas in SGA were 9.3 ± 2.4 kg. In addition to low socioeconomic status (OR 1.9, 95% CI 1.1, 3.2), other prognostic factors associated with SGA were lifestyle factors such as low maternal sleep duration (OR 5.1, CI 3.6, 7.4) and monthly or less frequent meat intake (OR 5.0, CI 3.2, 7.8). Besides smoking (OR 8.8, CI 2.1, 36.3), the other major environmental factor associated with SGA was exposure to household air pollution (OR 5.4, 4.1, 6.9) during pregnancy. Similarly, some of the adverse health conditions associated with a significantly higher risk of SGA were anemia, oligohydramnios, and gestational diabetes. CONCLUSIONS: SGA is common in Western Nepal and associated with several modifiable prognostic factors.

Investigations and management of chronic cough: a 2020 update from the European Respiratory Society Chronic Cough Task Force.

Chronic cough affects approximately 10% of the general population, is highest amongst people aged 50 to 60 years, and is twice as common in women than men. It is described to last 8 weeks or longer in adults and does not respond well to treatment with over-the-counter medications and those targeting potential associated conditions. This is a debilitating condition with physical, social, and psychological consequences. The purpose of this review was to highlight the key messages on the management of chronic cough from the task force commissioned by the European Respiratory Society. The assessment of patients with chronic cough should include a thorough detailed history and examination to identify potential causes. The impact and severity can be assessed in a clinic using questionnaires. Potential causes of the condition vary and include, for example, angiotensin­converting enzyme inhibitors, smoking, asthma, nonasthmatic eosinophilic bronchitis, gastroesophageal reflux disease, and upper airways cough syndrome. In many patients, coughing is persistent despite optimum medical therapy of the underlying medical condition and is hence referred to as refractory chronic cough. In some cases, no cause can be found and the cough is classified as unexplained chronic cough. If treatment of any underlying disease is unsuccessful at controlling cough, then neuromodulatory treatment such as a low­dose opioid, gabapentin, pregabalin or speech and language therapy may be considered. There is no licensed treatment for chronic cough, but a new class of treatment targeting the purinergic P2X3 receptor is currently in phase 2 and 3 of development.

Prevalence and contribution of respiratory viruses in the community to rates of emergency department visits and hospitalizations with respiratory tract infections, chronic obstructive pulmonary disease and asthma.

BACKGROUND: The individual and combined contribution of viral prevalence in the community to Emergency Department (ED) visits and hospitalizations with respiratory tract infections (RTIs), chronic obstructive pulmonary disease (COPD) and asthma is unclear. METHODS: A retrospective analysis on daily viral positive tests and daily ED visits and hospitalizations between 01/01/2003 to 31/12/2013 in Ontario, Canada. Viral data was collected from the Centre for Immunization and Respiratory Infectious Diseases (CIRID). The Canadian Institute for Health Information reports daily ED visits and hospitalizations for RTIs, COPD and asthma as a primary diagnosis. RESULTS: There were 4,365,578 ED visits with RTIs of which 321,719 (7.4%) were admitted to hospital; 817,141 ED visits for COPD of which 260,665 (31.9%) were admitted and 649,666 ED visits with asthma of which 68,626 (10.6%) were admitted. The percentage of positive tests to influenza A and B, respiratory syncytial virus (RSV), parainfluenza and adenovirus prevalence explained 57.4% of ED visits and 63.8% of hospitalizations for RTI, 41.4% of ED visits and 39.2% of hospitalizations with COPD but only 1.5% of ED visits and 2.7% of hospitalizations for asthma. The further addition of human metapneumovirus, rhinovirus and coronavirus over the final 3 years accounted for 66.7% of ED visits and 74.4% of hospitalizations for RTI, 52.5% of visits and 48.2% of hospitalizations for COPD, and only 13.3% of visits and 10.4% of hospitalizations for asthma. CONCLUSIONS: Community respiratory viral epidemics are major drivers of ED visits and hospitalizations with RTIs and COPD but only a modest contributor to asthma.

Under- and over-diagnosis of COPD: a global perspective.

Globally, chronic obstructive pulmonary disease (COPD) is the fourth major cause of mortality and morbidity and projected to rise to third within a decade as our efforts to prevent, identify, diagnose and treat patients at a global population level have been insufficient. The European Respiratory Society and American Thoracic Society, along with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document, have highlighted key pathological risk factors and suggested clinical treatment strategies in order to reduce the mortality and morbidity associated with COPD. This review focuses solely on issues related to the under- and over-diagnosis of COPD across the main geographical regions of the world and highlights some of the associated risk factors. Prevalence of COPD obtained mainly from epidemiological studies varies greatly depending on the clinical and spirometric criteria used to diagnose COPD, i.e. forced expiratory volume in 1 s to forced vital capacity ratio <0.7 or 5% below the lower limit of normal, and this subsequently affects the rates of under- and over-diagnosis. Although under-utilisation of spirometry is the major reason, additional factors such as exposure to airborne pollutants, educational level, age of patients and language barriers have been widely identified as other potential risk factors. Co-existent diseases, such as asthma, bronchiectasis, heart failure and previously treated tuberculosis, are reported to be the other determinants of under- and over-diagnosis of COPD. KEY POINTS: Globally, there is large variation in the prevalence of COPD, with 10-95% under-diagnosis and 5-60% over-diagnosis (table 1) due to differences in the definition of diagnosis used, and the unavailability of spirometry in rural areas of low- and middle-income countries where the prevalence of COPD is likely to be high.In order to be diagnosed with COPD, patients must have a combination of symptoms with irreversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of <0.7 or below the fifth centile of the lower limit of normal (LLN), and with a history of significant exposure to a risk factor. Repeat spirometry is recommended if the ratio is between 0.6 and 0.8.Not performing spirometry is the strongest predictor for an incorrect diagnosis of COPD; however, additional factors, such as age, gender, ethnicity, self-perception of symptoms, co-existent asthma, and educational awareness of risk factor by patients and their physician, are also important.COPD can be associated with inhalation of noxious particles other than smoking tobacco. EDUCATIONAL AIMS: To summarise the global prevalence of over- and under-diagnosis of COPD.To highlight the risk factors associated with the under- and over-diagnosis of COPD.To update readers on the key changes in the recent progress made regarding the correct diagnosis of COPD.