Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis.

Importance: Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. Objective: To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023. Study Selection: Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. Data Extraction and Synthesis: Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID). Main Outcomes and Measures: Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events. Results: Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]). Conclusions and Relevance: Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

The added value of haemoglobin to height, age, and sex to predict DLCO in subjects with preserved exercise capacity.

BACKGROUND: The single breath diffusion capacity for carbon monoxide (DLCO) captures several aspects of the role of the lung in meeting the metabolic demands of the body. The magnitude of the independent contributors to the DLCO is unknown. The aim of this study was to investigate the factors that independently contribute to the DLCO. OBJECTIVES: The objective was to investigate the impact of height, age, sex and haemoglobin on DLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO). METHODS: Study participants were pre-screened based on normal exercise capacity achieved during an incremental cardio-pulmonary exercise testing (CPET) using cycle ergometry at McMaster University Medical Center between 1988-2012. Participants who had an FEV1>80% predicted, with an FEV1/FVC ≥0.7 and who achieved a maximum power output ≥80% were selected for analysis. In total, 16,298 subjects [61% male, mean height 1.70m (range 1.26-2.07), age 49 yrs (10-94), weight 79 kg (23-190) had DLCO measured while demonstrating normal spirometry and exercise capacity. RESULTS: The DLCO increased exponentially with height, was 15% greater in males, increased with age yearly until 20, then decreased yearly after the age of 35, and was 6% higher per gram of haemoglobin (5.58*Height(m)1.69*1.15 in Males*(1-0.006*Age>35)*(1+0.01*Age<20) *(1+0.06*Hb gm/dl), (r = 0.76). CONCLUSION: Height, age, sex, and haemoglobin all have independent influence on the DLCO in subjects with normal spirometry and preserved exercise capacity.

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.

Canadian Health Care Professionals' Familiarity with Chronic Cough Guidelines and Experiences with Diagnosis and Management: A Cross-Sectional Survey.

INTRODUCTION: Educational programs on chronic cough may improve patient care, but little is known about how Canadian physicians manage this common debilitating condition. We aimed to investigate Canadian physicians' perceptions, attitudes, and knowledge of chronic cough. METHODS: We administered a 10-min anonymous, online, cross-sectional survey to 3321 Canadian physicians in the Leger Opinion Panel who managed adult patients with chronic cough and had been in practice for > 2 years. RESULTS: Between July 30 and September 22, 2021, 179 physicians (101 general practitioners [GPs] and 78 specialists [25 allergists, 28 respirologists, and 25 ear/nose/throat specialists]) completed the survey (response rate: 5.4%). In a month, GPs saw a mean of 27 patients with chronic cough, whereas specialists saw 46. About one-third of physicians appropriately identified a duration of > 8 weeks as the definition for chronic cough. Many physicians reported not using international chronic cough management guidelines. Patient referrals and care pathways varied considerably, and patients frequently experienced lost to follow-up. While physicians endorsed nasal and inhaled corticosteroids as common treatments for chronic cough, they rarely used other guideline-recommended treatments. Both GPs and specialists expressed high interest in education on chronic cough. CONCLUSION: This survey of Canadian physicians demonstrates low uptake of recent advances in chronic cough diagnosis, disease categorization, and pharmacologic management. Canadian physicians also report unfamiliarity with guideline-recommended therapies, including centrally acting neuromodulators for refractory or unexplained chronic cough. This data highlights the need for educational programs and collaborative care models on chronic cough in primary and specialist care.

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.

The Impact of beta blockade on the cardio-respiratory system and symptoms during exercise.

BACKGROUND: Beta blockers prolong life in patients with cardiovascular diseases. Negative chronotropic and inotropic effects carry the potential to adversely effect peripheral skeletal and airway smooth muscle contributing to further fatigue, dyspnea and exercise intolerance. RESEARCH QUESTIONS: Do beta-blockers reduce maximal power output (MPO), VO2 max, cardiorespiratory responses, increase the perceived effort required to cycle and breath during cardiopulmonary exercise tests (CPET) and limit the capacity to exercise? METHODS: Retrospective observational study of subjects performing CPET to capacity from 1988 to 2012. Subjects with and without beta-blockers were compared: baseline physiological characteristics, MPO, VO2 max, heart rate max, ventilation responses and perceived exertion required to cycle and breathe (modified Borg scale). Forward stepwise linear additive regression was performed with MPO as the dependent factor with height, age, gender, muscle strength, FEV1 and DLCO as independent contributors. RESULTS: 42,771 subjects were included 7,787 were receiving beta-blocker [mean age 61 yrs, BMI 28.40 kg/m2, 9% airflow obstruction (FEV1/FVC<0.7)] and 34,984 were not [mean age 51yrs, BMI 27.40 kg/m2, 11% airflow obstruction]. Heart rate was lower by 18.2% (95% C.I. 18.15-18.38) (p<0.0001) while Oxygen pulse (VO2/HR) was higher by 19.5% (95% C.I. 19.3-19.7) in those receiving beta blockers. Maximum power output (MPO) was 3.3% lower in those taking beta-blockers. The perceived effort required to cycle and breathe (mBorg) was 8% lower in those taking beta-blockers. INTERPRETATION: Increases in oxygen pulse minimize the reduction in exercise intolerance and symptom handicap associated with beta-blockers.

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.