Receptors implicated in cough hypersensitivity are transient receptor potential vanilloid 1 (TRPV1), transient receptor potential cation channel, Subfamily A, Member 1 (TRPA1) and acid sensing ion ...channel receptor 3 (ASIC3). Respiratory viruses, such as respiratory syncytial virus (RSV) and measles virus (MV) may interact directly and/or indirectly with these receptors on sensory nerves and epithelial cells in the airways. We used in vitro models of sensory neurones (SHSY5Y or differentiated IMR-32 cells) and human bronchial epithelium (BEAS-2B cells) as well as primary human bronchial epithelial cells (PBEC) to study the effect of MV and RSV infection on receptor expression. Receptor mRNA and protein levels were examined by qPCR and flow cytometry, respectively, following infection or treatment with UV inactivated virus, virus-induced soluble factors or pelleted virus. Concentrations of a range of cytokines in resultant BEAS-2B and PBEC supernatants were determined by ELISA. Up-regulation of TRPV1, TRPA1 and ASICS3 expression occurred by 12 hours post-infection in each cell type. This was independent of replicating virus, within the same cell, as virus-induced soluble factors alone were sufficient to increase channel expression. IL-8 and IL-6 increased in infected cell supernatants. Antibodies against these factors inhibited TRP receptor up-regulation. Capsazepine treatment inhibited virus induced up-regulation of TRPV1 indicating that these receptors are targets for treating virus-induced cough.
More infants with bronchopulmonary dysplasia (BPD) now survive to adulthood, but little is known regarding persisting respiratory impairment. We report respiratory symptoms, lung function and ...health-related quality of life (HRQoL) in adult BPD survivors compared with preterm (non-BPD) and full-term controls. Respiratory symptoms (European Community Respiratory Health Survey) and HRQoL (EuroQol (EQ)-5D) were measured in 72 adult BPD survivors (mean ± sd study age 24.1 ± 4.0 years; mean ± sd gestational age 27.1 ± 2.1 weeks; and mean ± sd birth weight 955 ± 256 g) cared for in the regional neonatal intensive care unit, Royal Maternity Hospital, Belfast, UK (between 1978 and 1993). These were compared with 57 non-BPD controls (mean ± sd study age 25.3 ± 4.0 years; mean ± sd gestational age 31.0 ± 2.5 weeks; and mean ± sd birth weight 1238 ± 222 g) and 78 full-term controls (mean ± sd study age 25.7 ± 3.8 years; mean ± sd gestational age 39.7 ± 1.4 weeks; and mean ± sd birth weight 3514 ± 456 g) cared for at the same hospital. Spirometry was performed on 56 BPD, 40 non-BPD and 55 full-term participants. BPD subjects were twice as likely to report wheeze and three times more likely to use asthma medication than controls. BPD adults had significantly lower forced expiratory volume in 1 s and forced expiratory flow at 25-75% of forced vital capacity than both the preterm non-BPD and full-term controls (all p<0.01). Mean EQ-5D was 6 points lower in BPD adults compared to full-term controls (p<0.05). BPD survivors have significant respiratory and quality of life impairment persisting into adulthood.
Background
The extent to which objective and subjective tools has been used to measure the characteristics and burden of cough in patients with asthma has not been reported.
Objective
To review the ...large and extensive body of literature in asthma with the specific hypothesis that the characteristics of cough and clinical impact in this disease has only occasionally been studied.
Methods
For this systematic review, we searched EMBASE and MEDLINE databases using a combination of MeSH terms for “cough” and “asthma” for studies published up to and including end of August 2021. Studies included for analysis were confined to those undertaken in adult patients (≥ 18 years) with asthma of any severity where any tool or method to specifically measure cough was employed.
Results
Of 12,090 citations identified after our initial search, 112 full-text articles met criteria for inclusion in our analysis. We found that a broad range of objective and subjective measures have been used albeit with a lack of consistency between studies. Clinically important levels of cough associated with impaired health status were identified in patients with asthma.
Conclusion
Although cough is a common symptom in asthma, the clinical features and accompanying healthcare burden have been studied infrequently. In studies where cough was measured, the methods employed varied considerably. A more consistent use of cough-specific measurement tools is required to better determine the nature and burden of cough in asthma.
The purpose of this systematic literature review was to examine current empirical research on general and respiratory health outcomes in adult survivors of bronchopulmonary dysplasia (BPD).
We ...searched seven databases up to the end of November 2010 (MEDLINE, PubMed, EMBASE, PsycINFO, Maternity and Infant Care, Cumulative Index of Nursing and Allied Health Literature, and Web of Knowledge). We independently screened and included only those studies concerning the assessment of outcome measures in adult survivors of BPD. Data on methodologic design and findings were extracted from each included study; in addition, the methodologic quality of each study was assessed using the Critical Appraisal Skills Programme checklist.
Fourteen cohort studies met the review criteria. Of those, a total of eight studies were considered to be of high quality (score 9-12), five of moderate quality (score 5-8), and only one was of low quality (score 0-4). In all studies of adult survivors of BPD, differences were found between the index and control groups, suggesting that many adults survivors of BPD who were born preterm or with very low birth weight had more respiratory symptoms and pulmonary function abnormalities compared with their peers. Five studies concerning radiologic findings reported structural changes persisting into adulthood. Findings from three studies suggested impairment in exercise capacity, although firm conclusions were limited by the small sample size in the studies reviewed.
Compared with adults born at term, adult survivors of BPD have more impairment in general and respiratory health, which does not seem to diminish over time.
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.
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.
Nonadherence to inhaled corticosteroid therapy (ICS) is a major contributor to poor control in difficult asthma, yet it is challenging to ascertain.
Identify a test for nonadherence using fractional ...exhaled nitric oxide (Fe(NO)) suppression after directly observed inhaled corticosteroid (DOICS) treatment.
Difficult asthma patients with an elevated Fe(NO) (>45 ppb) were recruited as adherent (ICS prescription filling >80%) or nonadherent (filling <50%). They received 7 days of DOICS (budesonide 1,600 μg) and a test for nonadherence based on changes in Fe(NO) was developed. Using this test, clinic patients were prospectively classified as adherent or nonadherent and this was then validated against prescription filling records, prednisolone assay, and concordance interview.
After 7 days of DOICS nonadherent (n = 9) compared with adherent subjects (n = 13) had a greater reduction in Fe(NO) to 47 ± 21% versus 79 ± 26% of baseline measurement (P = 0.003), which was also evident after 5 days (P = 0.02) and a Fe(NO) test for nonadherence (area under the curve = 0.86; 95% confidence interval, 0.68-1.00) was defined. Prospective validation in 40 subjects found the test identified 13 as nonadherent; eight confirmed nonadherence during interview (three of whom had excellent prescription filling but did not take medication), five denied nonadherence, two had poor inhaler technique (unintentional nonadherence), and one also denied nonadherence to prednisolone despite nonadherent blood level. Twenty-seven participants were adherent on testing, which was confirmed in 21. Five admitted poor ICS adherence but of these, four were adherent with oral steroids and one with omalizumab.
Fe(NO) suppression after DOICS provides an objective test to distinguish adherent from nonadherent patients with difficult asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 01219036).
Treatment options for adults with chronic cough (CC) are limited. This study reports on the health status and experiences of patients with recent healthcare evaluation for CC.
This prospective, UK, ...cross-sectional study surveyed adults with a CC evaluation within the previous 12 months. All were never smokers (or ex-smokers for ≥12 months). Subjects completed five validated patient-reported outcome measures: cough visual analogue scale (VAS), EuroQoL 5 dimension, 5 level (EQ-5D-5L), EQ-5D VAS, Leicester Cough Questionnaire (LCQ), and Work Productivity and Activity Impairment (WPAI) questionnaire.
A total of 101 participants were recruited: 71% were female, mean age was 54.9 ± 15.2 years. Median (IQR) CC duration was 36 (11, 120) months. Mean self-reported CC severity (Cough-VAS) was 51.3 ± 22.9 over the previous 2 weeks and 62.9 ± 23.7 on the worst day of coughing. EQ-5D values were lower for CC patients than population norms. Subanalyses revealed that EQ-5D and LCQ scores were significantly impacted by CC duration and the number of healthcare providers (HCPs) visited. WPAI analysis showed a 27.6% work time impairment because of participants' CC. The number of HCP attendances ranged from 1 to 10 (3.3 ± 2.8) before diagnosis was confirmed. Treatment was being prescribed to 87% of participants and comprised mainly steroids (nasal 19% and inhaled 25%), beta agonists (24%), and proton pump inhibitors (21%); 44% of patients were dissatisfied with treatment efficacy.
Real-world data from a nationally representative UK population show significant unmet needs associated with CC, including multiple healthcare visits and limited treatment effectiveness, resulting in inadequate cough control and impaired health status.
Chronic obstructive pulmonary disease (COPD) is a debilitating heterogeneous disease characterised by unregulated proteolytic destruction of lung tissue mediated via a protease-antiprotease ...imbalance. In COPD, the relationship between the neutrophil serine protease, neutrophil elastase, and its endogenous inhibitor, alpha-1-antitrypsin (AAT) is the best characterised. AAT belongs to a superfamily of serine protease inhibitors known as serpins. Advances in screening technologies have, however, resulted in many members of the serpin superfamily being identified as having differential expression across a multitude of chronic lung diseases compared to healthy individuals. Serpins exhibit a unique suicide-substrate mechanism of inhibition during which they undergo a dramatic conformational change to a more stable form. A limitation is that this also renders them susceptible to disease-causing mutations. Identification of the extent of their physiological/pathological role in the airways would allow further expansion of knowledge regarding the complexity of protease regulation in the lung and may provide wider opportunity for their use as therapeutics to aid the management of COPD and other chronic airways diseases.
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