Chronic Cough Smith, Jaclyn A; Woodcock, Ashley
New England journal of medicine/The New England journal of medicine,
2016-Oct-20, Letnik:
375, Številka:
16
Journal Article
In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current ...unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored.
Summary Background Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could ...mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. Methods We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov , number NCT01432730. Findings Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. Interpretation P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. Funding Afferent Pharmaceuticals
How often do healthy people cough? Holt, Kimberley J; Smith, Jaclyn A
Respiratory research,
11/2023, Letnik:
24, Številka:
1
Journal Article
Recenzirano
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Objective cough frequency has been reported in several respiratory conditions but the amount that healthy individuals cough daily is unclear. Seventy-nine healthy volunteers (38 males, median IQR age ...41y IQR 30-53) completed 24-hour ambulatory cough monitoring (VitaloJAK™). The audio recording was filtered using a custom written algorithm to remove non-cough sounds and then all individual explosive cough sounds in the filtered file were tagged electronically by trained cough counters. Most coughing occurred during the day and cough numbers over 24 h were generally low (geometric mean of 4.6 coughs) but there was large variability; ranging from 0 to 136 coughs overall. Cough frequency was independent of participant characteristics apart from sex with males coughing significantly, 4-5 fold, more than females during the day and over 24 h (median IQR 16.1 3.8-33.4 vs. 4.1 1.0-15.0 total coughs; p = 0.015). This is the first report to describe cough frequency in a balanced group of healthy adults using an accurate cough monitoring system. The data reveal a further example of sexual dimorphism in cough, which warrants additional investigation.
In 2011, a European Respiratory Society Task Force embarked on a process to determine the position and clinical relevance of the cough hypersensitivity syndrome, a disorder characterised by ...troublesome coughing often triggered by low levels of thermal, mechanical or chemical exposure, in the management of patients with chronic cough. A 21-component questionnaire was developed by an iterative process supported by a literature review. 44 key opinion leaders in respiratory medicine were selected and interviewed as to their opinions. There was a high degree of unanimity in the responses obtained, with all opinion leaders supporting the concept of cough hypersensitivity as a clinically useful paradigm. The classic stratification of cough into asthmatic, rhinitic and reflux-related phenotypes was supported. Significant disparity of opinion was seen in the response to two questions concerning the therapy of chronic cough. First, the role of acid suppression in reflux cough was questioned. Secondly, the opinion leaders were split as to whether a trial of oral steroids was indicated to establish a diagnosis of eosinophilic cough. The cough hypersensitivity syndrome was clearly endorsed by the opinion leaders as a valid and useful concept. They considered that support of patients with chronic cough was inadequate and the Task Force recommends that further work is urgently required in this neglected area.
Background Sensory nerves innervating the airways play an important role in regulating various cardiopulmonary functions, maintaining homeostasis under healthy conditions and contributing to ...pathophysiology in disease states. Hypo-osmotic solutions elicit sensory reflexes, including cough, and are a potent stimulus for airway narrowing in asthmatic patients, but the mechanisms involved are not known. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is widely expressed in the respiratory tract, but its role as a peripheral nociceptor has not been explored. Objective We hypothesized that TRPV4 is expressed on airway afferents and is a key osmosensor initiating reflex events in the lung. Methods We used guinea pig primary cells, tissue bioassay, in vivo electrophysiology, and a guinea pig conscious cough model to investigate a role for TRPV4 in mediating sensory nerve activation in vagal afferents and the possible downstream signaling mechanisms. Human vagus nerve was used to confirm key observations in animal tissues. Results Here we show TRPV4-induced activation of guinea pig airway–specific primary nodose ganglion cells. TRPV4 ligands and hypo-osmotic solutions caused depolarization of murine, guinea pig, and human vagus and firing of Aδ-fibers (not C-fibers), which was inhibited by TRPV4 and P2X3 receptor antagonists. Both antagonists blocked TRPV4-induced cough. Conclusion This study identifies the TRPV4-ATP-P2X3 interaction as a key osmosensing pathway involved in airway sensory nerve reflexes. The absence of TRPV4-ATP–mediated effects on C-fibers indicates a distinct neurobiology for this ion channel and implicates TRPV4 as a novel therapeutic target for neuronal hyperresponsiveness in the airways and symptoms, such as cough.
Background Cough in asthmatic patients is a common and troublesome symptom. It is generally assumed coughing occurs as a consequence of bronchial hyperresponsiveness and inflammation, but the ...possibility that airway nerves are dysfunctional has not been fully explored. Objectives We sought to investigate capsaicin-evoked cough responses in a group of patients with well-characterized mild-to-moderate asthma compared with healthy volunteers and assess the influences of sex, atopy, lung physiology, inflammation, and asthma control on these responses. Methods Capsaicin inhalational challenge was performed, and cough responses were analyzed by using nonlinear mixed-effects modeling to estimate the maximum cough response evoked by any concentration of capsaicin (Emax ) and the capsaicin dose inducing half-maximal response (ED50 ). Results Ninety-seven patients with stable asthma (median age, 23 years interquartile range, 21-27 years; 60% female) and 47 healthy volunteers (median age, 38 years interquartile range, 29-47 years; 64% female) were recruited. Asthmatic patients had higher Emax and lower ED50 values than healthy volunteers. Emax values were 27% higher in female subjects ( P = .006) and 46% higher in patients with nonatopic asthma ( P = .003) compared with healthy volunteers. Also, patients with atopic asthma had a 21% lower Emax value than nonatopic asthmatic patients ( P = .04). The ED50 value was 65% lower in female patients ( P = .0001) and 71% lower in all asthmatic patients ( P = .0008). ED50 values were also influenced by asthma control and serum IgE levels, whereas Emax values were related to 24-hour cough frequency. Age, body mass index, FEV1 , PC20 , fraction of exhaled nitric oxide, blood eosinophil counts, and inhaled steroid treatment did not influence cough parameters. Conclusion Patients with stable asthma exhibited exaggerated capsaicin-evoked cough responses consistent with neuronal dysfunction. Nonatopic asthmatic patients had the highest cough responses, suggesting this mechanism might be most important in type 2–low asthma phenotypes.
Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and ...safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough.
COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2).
From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 33×3% with placebo, 244 33×4% with gefapixant 15 mg twice per day, and 243 33×3% with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 33×1% with placebo, 440 33×5% with gefapixant 15 mg twice per day, and 439 33×4% with gefapixant 45 mg twice per day). Participants were mostly female (542 74×2% of 730 in COUGH-1 and 984 74×9% of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% 95% CI 32·9–0·9; p=0·041) and at week 24 in COUGH-2 (14·6% 26·1–1·4; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 4·9% of 730 in COUGH-1 and 86 6·5% of 1314 in COUGH-2), dysgeusia (118 16·2% in COUGH-1 and 277 21·1% in COUGH-2), hypergeusia (3 0·4% in COUGH-1 and 6 0×5% in COUGH-2), hypogeusia (19 2·6% in COUGH-1 and 80 6·1% in COUGH-2), and taste disorder (28 3·8% in COUGH-1 and 46 3·5% in COUGH-2).
Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough.
Merck Sharp & Dohme.
Reports from individual centres suggest a preponderance of females with chronic cough. Females also have heightened cough reflex sensitivity. Here we have reviewed the age and sex of unselected ...referrals to 11 cough clinics. To investigate the cause of any observed sex dimorphism, functional magnetic resonance imaging of putative cough centres was analysed in normal volunteers. The demographic profile of consecutive patients presenting with chronic cough was evaluated. Cough challenge with capsaicin was undertaken in normal volunteers to construct a concentration-response curve. Subsequent functional magnetic resonance imaging during repeated inhalation of sub-tussive concentrations of capsaicin observed areas of activation within the brain and differences in the sexes identified. Of the 10,032 patients presenting with chronic cough, two-thirds (6591) were female (mean age 55 years). The patient profile was largely uniform across centres. The most common age for presentation was 60-69 years. The maximum tolerable dose of inhaled capsaicin was lower in females; however, a significantly greater activation of the somatosensory cortex was observed. Patients presenting with chronic cough from diverse racial and geographic backgrounds have a strikingly homogeneous demographic profile, suggesting a distinct clinical entity. The preponderance of females may be explained by sex-related differences in the central processing of cough sensation.
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