Chronic cough: new insights and future prospects

Chronic cough is defined in adults as a cough that lasts for ≥8 weeks. When it proves intractable to standard-of-care treatment, it can be referred to as refractory chronic cough (RCC). Chronic cough is now understood to be a condition of neural dysregulation. Chronic cough and RCC result in a serious, often unrecognized, disease burden, which forms the focus of the current review.The estimated global prevalence of chronic cough is 2-18%. Patients with chronic cough and RCC report many physical and psychological effects, which impair their quality of life. Chronic cough also has a significant economic burden for the patient and healthcare systems. RCC diagnosis and treatment are often delayed for many years as potential treatable triggers must be excluded first and a stepwise empirical therapeutic regimen is recommended.Evidence supporting most currently recommended treatments is limited. Many treatments do not address the underlying pathology, are used off-label, have limited efficacy and produce significant side-effects. There is therefore a significant unmet need for alternative therapies for RCC that target the underlying disease mechanisms. Early clinical data suggest that antagonists of the purinergic P2X3 receptor, an important mediator of RCC, are promising, though more evidence is needed

Theobromine for the treatment of persistent cough: A randomised, multicentre, double-blind, placebo-controlled clinical trial

© Journal of Thoracic Disease. Background: To investigate the effect of BC1036 on health-related quality of life (QOL) in subjects with persistent cough. The secondary objective was to investigate the effect of BC1036 on subjective cough severity. Methods: This was a randomised, multicentre, double-blind, placebo-controlled, parallel-group study in 289 subjects with persistent cough. Subjects received BC1036 or placebo twice daily for 14 days. The primary endpoint comprised cough-related QOL assessed using the validated Leicester Cough Questionnaire (LCQ) at Day 14. Secondary endpoints comprised the LCQ scores at Day 7 and Day 28, cough severity VAS scores at each visit and pulmonary function tests. Results: At baseline, mean total LCQ score in the BC1036 group was lower (i.e., worse QOL) than placebo (P < 0.001), indicating significant between-group heterogeneity. Mean baseline-adjusted change in LCQ score at Day 14 was greater for BC1036 [mean (SD) 2.4±3.5] compared to placebo [mean (SD) score 2.2±3.0], but did not reach statistical significance (P=0.60). Mean cough severity VAS score decreased to a greater extent in the BC1036 group compared to placebo, but again the results were not statistically significant (-12.2±23.28 in BC1036 group and -11.0±21.34 in placebo group at Day 14, P=0.688). There was no significant change in pulmonary function measurements. The adverse event (AE) profile was similar in both groups. Conclusions: This study showed that BC1036 was well tolerated and, although the primary endpoint did not achieve statistical significance, the magnitude of improvement was greater with BC1036 compared to placebo with respect to improving QOL and reducing cough severity. Clinical trial registration: ClinicalTrials.gov: NCT01656668

Discordance in investigator-reported and adjudicated sudden death in TIOSPIR

Accurate and consistent determination of cause of death is challenging in chronic obstructive pulmonary disease (COPD) patients. TIOSPIR (N=17 135) compared the safety and efficacy of tiotropium Respimat 5/2.5 µg with HandiHaler 18 µg in COPD patients. All-cause mortality was a primary end-point. A mortality adjudication committee (MAC) assessed all deaths. We aimed to investigate causes of discordance in investigator-reported and MAC-adjudicated causes of death and their impact on results, especially cardiac and sudden death. The MAC provided independent, blinded assessment of investigator-reported deaths (n=1302) and assigned underlying cause of death. Discordance between causes of death was assessed descriptively (shift tables). There was agreement between investigator-reported and MAC-adjudicated deaths in 69.4% of cases at the system organ class level. Differences were mainly observed for cardiac deaths (16.4% investigator, 5.1% MAC) and deaths assigned to general disorders including sudden death (17.4% investigator, 24.6% MAC). Reasons for discrepancies included investigator attribution to the immediate (e.g. myocardial infarction (MI)) over the underlying cause of death (e.g. COPD) and insufficient information for a definitive cause. Cause-specific mortality varies in COPD, depending on the method of assignment. Sudden death, witnessed and unwitnessed, is common in COPD and often attributed to MI without supporting evidence

Prevalence of psychomorbidity among patients with chronic cough

BACKGROUND: Chronic cough may cause significant emotional distress and although patients are not routinely assessed for co-existent psychomorbidity, a cough that is refractory to any treatment is sometimes suspected to be functional in origin. It is not known if patients with chronic cough referred for specialist evaluation have emotional impairment but failure to recognise this may influence treatment outcomes. In this cross-sectional study, levels of psychomorbidity were measured in patients referred to a specialist cough clinic. METHODS: Fifty-seven patients (40 female), mean age 47.5 (14.3) years referred for specialist evaluation of chronic cough (mean cough duration 69.2 (78.5) months) completed the Hospital Anxiety and Depression (HAD) scale, State Trait Anxiety Inventory (STAI) and the Crown Crisp Experiential Index (CCEI) at initial clinic presentation. Subjects then underwent a comprehensive diagnostic evaluation, after which they were classified as either treated cough (TC) or idiopathic cough (IC). Questionnaire scores were compared between TC (n = 42) and IC (n = 15). RESULTS: Using the HAD scale, 33% of all cough patients were identified as anxious, while 16% experienced depression. The STAI scores suggested moderate or high trait anxiety in 48% of all coughers. Trait anxiety was significantly higher among TC (p < 0.001) and IC patients (p = 0.004) compared to a healthy adult population. On the CCEI, mean scores on the phobic anxiety, somatisation, depression, and obsession subscales were significantly higher among all cough patients than the published mean scores for healthy controls. Only state anxiety was significantly higher in IC patients compared with TC patients (p < 0.05). CONCLUSION: Patients with chronic cough appear to have increased levels of emotional upset although psychological questionnaires do not readily distinguish between idiopathic coughers and those successfully treated

Respiratory virus infection up-regulates TRPV1, TRPA1 and ASICS3 receptors on airway cells.

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