Huda Badri

Respiratory disease and the oesophagus: reflux, reflexes and microaspiration

Gastro-oesophageal reflux is associated with a wide range of respiratory disorders, including asthma, isolated chronic cough, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and cystic fibrosis. Reflux can be substantial and reach the proximal margins of the oesophagus in some individuals with specific pulmonary diseases, suggesting that this association is more than a coincidence. Proximal oesophageal reflux in particular has led to concern that microaspiration might have an important, possibly even causal, role in respiratory disease. Interestingly, reflux is not always accompanied by typical reflux symptoms, such as heartburn and/or regurgitation, leading many clinicians to empirically treat for possible gastro-oesophageal reflux. Indeed, costs associated with use of acid suppressants in pulmonary disease far outweigh those in typical GERD, despite little evidence of therapeutic benefit in clinical trials. This Review comprehensively examines the possible mechanisms that might link pulmonary disease and oesophageal reflux, highlighting the gaps in current knowledge and limitations of previous research, and helping to shed light on the frequent failure of antireflux treatments in pulmonary disease.

XEN-D0501, a novel TRPV1 antagonist, does not reduce cough in refractory cough patients

RATIONALE Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough. OBJECTIVES XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough. METHODS XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes. MEASUREMENTS AND MAIN RESULTS XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, -19.3 ± 16.4) coughs; placebo, -1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7  ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41). CONCLUSIONS XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough. Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36).

Capsaicin-evoked cough responses in asthmatic patients: Evidence for airway neuronal dysfunction

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.

The interaction between bronchoconstriction and cough in asthma

Variable airflow obstruction is a pathophysiological hallmark of asthma; however, the interactions between acute bronchoconstriction and the cough reflex are poorly understood. We performed a randomised, single-blind, placebo-controlled, crossover study to investigate the interaction between bronchoconstriction and cough in asthma. Capsaicin was administered to evoke coughs and methacholine to induce bronchoconstriction. We demonstrated that acute bronchoconstriction increased capsaicin-evoked coughs, which improved as airway calibre spontaneously resolved. However, capsaicin-evoked coughing had no impact on methacholine-induced bronchoconstriction. This study provides evidence that bronchoconstriction increases the activation of capsaicin-responsive airway nerves, but the precise mechanisms and mediators involved require further evaluation. Trial registration number ISRCTN14900082.

Airways diseases: asthma, COPD and chronic cough highlights from the European Respiratory Society Annual Congress 2018

Addressing the global morbidity associated with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough is a major unmet need for the respiratory community. Reducing exacerbations and improving lung function have remained important primary endpoints in clinical studies in asthma and COPD, however, there is also a growing momentum to show efficacy and improvements in patient reported outcomes in real-world pragmatic studies.

S35 Randomised control trial quantifying the efficacy of low dose morphine in a responder group of patients with refractory chronic cough

Introduction and objectives The pathophysiology of chronic cough remains poorly understood and treatment options are limited. Morphine sulphate can improve quality of life in refractory chronic cough,1 but its mechanism of action and effect on objective cough frequency remain unknown. Here we report morphine’s influence on cough frequency and patient reported outcomes in a group of refractory chronic cough patients who responded favourably to morphine in our tertiary clinic. Methods We recruited 22 patients (mean age 61.7 years, 18 female, mean cough duration 14 years) taking low dose morphine for refractory chronic cough into a double blinded, placebo controlled, crossover study. Volunteers withdrew their morphine therapy and were randomised to receive morphine (5–10 mg BD slow release)/matched placebo during two treatment period (5–7 days duration) separated by a 5–7 day washout. At baseline and at the end of each treatment period we assessed 24 hour cough recordings using a semi-automated cough counter (vitaloJAK), cough severity (visual analogue scales (VAS)) and the cough quality of life questionnaire (CQLQ) . For analysis we ran generalised estimating equations to compare morphine and placebo, adjusting for baseline measures and assessing any influence of treatment, sequence or period. Results Low dose morphine reduced objective cough frequency compared to placebo by 71.8% over 24 hours. Morphine significantly reduced cough frequency overnight as well as during the daytime (p<0.05) and responses were independent of baseline cough frequency. All patient reported outcomes were consistent with this effect (p<0.05). The treatment effect was not significantly influenced by period or sequence. Overall morphine was well tolerated. There was one serious adverse event, unrelated to the study treatment. Conclusions This is the first study to demonstrate a substantial objective reduction in cough frequency with low dose morphine in a clinically responsive group. Importantly this was accompanied by improvements in patient reported outcomes despite the short treatment duration used. The data suggests this population would be suitable for further investigation of the mode of action of opioids in chronic cough. Reference Morice AHet al. Opiate therapy in chronic cough. Am J Respir Crit Care Med 2007;175(4):312–5. Abstract S35 Figure 1 Median values for efficacy markers at baseline, on morphine and placebo *mean values.

P106 The use of gabapentin and pregabalin for the management of chronic cough in a tertiary cough clinic

Introduction and Objectives Chronic cough is a poorly understood condition with a limited number of treatment options available. Gabapentin and pregabalin are used in the treatment of neuropathic pain and may have some efficacy in patients with refractory chronic cough.1,2 We evaluated the real-world outcomes of using these medicines in a tertiary cough clinic. Methods We performed a retrospective review of new referrals to a tertiary cough clinic (October 2013-October 2015). Patient characteristics (age, sex, duration of cough and test results) were collected. Follow up clinic letters were reviewed until April 2017. We recorded details regarding the prescribing of gabapentin and pregabalin for patients with refractory chronic cough, their impact on cough and the associated side effects. Results 136 new patients were reviewed (mean age 56.3 years, 98 (72.1%) female) with a mean duration of cough of 7.5 years (SD 12.2). Gabapentin or pregabalin was prescribed for 38 patients (9 gabapentin and 29 pregabalin). Highest dose achieved was 1800 mg/day for gabapentin and 300 mg/day for pregabalin. Overall, fifteen patients (39%) responded favourably to these medicines initially. Fourteen (37%) tolerated them but derived no benefit and stopped the medication. Nine patients (24%) developed immediate side effects and were unable to tolerate the medications. Out of the 15 patients that tolerated these medicines, only 8 (21%) were able to continue with therapy long term, as the other seven (18%) eventually developed intolerable side effects. The most common side effect was drowsiness (see below). Abstract P106 Figure 1 Side effects/interactions reported by patients when taking gabapentin/pregablin for chronic refractory cough. Conclusions Our data suggests that in clinical practice, alpha-two delta ligands are effective in a subgroup of chronic cough patients, but side effects may outweigh their potential benefits, affecting nearly half the population trialled. Prospective work is needed to objectively quantify their anti-tussive effects and tolerability over longer treatment periods, allowing clinicians and patients to better understand the risk-benefit ratio associated with their use. References Ryan, NM, et al. Gabapentin for refractory chronic cough: A randomised, double-blind, placebo-controlled trial. Lancet2012;380(9853):1583–9. Vertigan, AE, et al. Pregabalin and speech pathology combination therapy for refractory chronic cough: A randomised controlled trial. Chest2016;149(3):639–48.

M15 Patient satisfaction in a tertiary cough service

Introduction Patient satisfaction surveys (PSS) can help identify ways of improving practice and facilitate better quality care. Patient opinion in health services research is integral but data from chronic cough populations is unknown. Aim To identify patient satisfaction in our tertiary cough service. Methods We devised a PSS containing 19 structured questions. Patients attending review consultations in two consecutive clinics were asked to consider completing the anonymous PSS. Results Fifty-two PSS were completed; an 84% response rate. Of those 43 had full responses for analysis [79% female, 58%≥55 years in age]. Patient satisfaction was extremely high (figure 1); 70% thought the care received was excellent and 95% were likely to recommend the service to friends and family. Improvement suggestions related to parking and appointment management. However 44% felt clinic locality was inconvenient, but the majority (63%) of those were not interested in Skype review consultations; response was unrelated to age. Conclusion To our knowledge, this is the first reported patient satisfaction data in chronic cough patients. Despite the refractory nature of the condition, patient satisfaction is extremely high. As a quarter of our service’s patients travel ≥25 miles, the inconvenience of clinic accessibility is not surprising. Nonetheless, patients appear to value face to face consultations and further patient consultation is required before utilising tele-health. Abstract M15 Figure 1

P238 A randomised, double-blind (sponsor-unblind), placebo controlled, cross-over study to investigate the efficacy, effect on cough reflex sensitivity, safety, tolerability and pharmacokinetics of inhaled GSK2339345 in patients with chronic idiopathic cough using an aqueous droplet inhaler

Introduction and objectives Voltage gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in the afferent sensory nerve fibres innervating the airways responsible for evoking cough. Therefore a VGSC inhibitor may be an effective anti-tussive agent, inhibiting cough irrespective of the type of stimuli. We aimed to investigate the efficacy of a novel use-and frequency-dependent VGSC inhibitor (GSK2339345) in patients with chronic idiopathic cough. Methods We performed a two-part randomised, double-blind, placebo-controlled, cross-over study recruiting patients with chronic idiopathic cough from two specialist clinics. In the first part of the study, patients were randomly assigned to receive two inhaled doses of either GSK2339345 or placebo, 4 h apart during three study periods. The primary endpoint was the objective cough frequency (VitaloJAK, Vitalograph Ltd) during the 8 h post-treatment (4 hrs following each dose). The difference between GSK2339345 and placebo in log-transformed cough counts was investigated using a mixed effects model with fixed effects terms for treatment and period, and subject fitted as a random effect. In the second part, subjects attended on four study days, and underwent full dose-response cough challenges with capsaicin and citric acid following single doses of GSK2339345 or placebo. This was analysed using dose response modelling. Results Of 16 patients enrolled (56.7 ± 9.6 yrs; 13 female), 11 completed the study. Eight hour cough counts showed a 26% increase in cough counts with GSK2339345 vs placebo. However, on exclusion of the coughs occurring within 2 min of inhalation of the study drug, there was only a 1.6% increase in coughs; see Table 1 for ratio of adjusted geometric means. There appeared to be no impact of GSK2339345 on either of the cough challenges however, the dataset was too small to draw definitive conclusions.Abstract P238 Table 1 Endpoint Treatment Adjusted geometric mean Ratio of adjusted geometric means (90% credible intervals) % Increase from placebo 8 h cough count GSK2339345 192.5 1.26 (1.10, 1.44) 26% Placebo 152.7 8 h cough count excluding transient coughs GSK2339345 153.9 1.02 (0.87, 1.19) 1.6% Placebo 151.5 Based on data from 14 subjects – 21 8h counts per treatment due to replicate period. Transient coughs are the number of coughs occurring in the first 2 min following each dose. Conclusion There was no evidence of an anti-tussive effect of GSK2339345 over the 8 h analysis for any subject, despite cough frequency being highly reproducible within patients. Inhalation of GSK2339345 had a pro-tussive effect in all subjects following actuation of the device, not seen with placebo. The novel cough challenge methodology warrants further investigation as a development tool.

S91 A randomised, double-blind, placebo-controlled crossover study to assess the efficacy of a single dose of 100 mg of VRP700 by inhalation in reducing the frequency and severity of cough in adult patients with Idiopathic Pulmonary Fibrosis

Background Cough is a common, troublesome symptom in idiopathic pulmonary fibrosis (IPF), but the underlying mechanisms are poorly understood and effective therapies are lacking. VRP700 is thought to inhibit ion-channels found on sensory afferents innervating the airways. We aimed to investigate the efficacy of VRP700 in reducing cough frequency in patients with IPF. Method A single centre double-blind randomised, placebo controlled crossover study in patients with IPF with chronic cough. Patients were randomised to receive a single inhaled dose of VRP700 (100 mg) or placebo and then crossed-over after a 7 day washout period. The primary endpoint was the number of coughs in the 4 h following the end of nebulisation for VRP700 compared with placebo, measured using an objective cough monitoring system (VitaloJAK, Vitalograph Ltd). Secondary endpoints included urge to cough visual analogue scale (VAS), cough severity VAS, and dyspnoea VAS, recorded at 1,2 and 4 h post-dose, at the end of the day and 24 hrs post-dose. Results Twenty five patients were screened, 5 were ineligible and therefore 20 were randomised [mean age 69.8(±6.9) yrs, 12 female, mean FEV1 1.97 ± 0.39 L, mean FVC 1.86 ± 0.42 L]. The geometric mean number of coughs in the 4 h following VRP700 treatment was significantly higher compared with placebo [136.8 (95% CI 80.3- 233.1) vs. 64.9 (95% CI 38.1–110.6), p < 0.001). There was no evidence of an order or period effect. The difference in cough counts was greatest during the first hour after VRP700 nebulization [63.3 (95% CI 36.4–109.8) vs. 24.1 (95% CI 13.9–41.9), p < 0.001). For reported cough severity, urge to cough, and dyspnoea severity scores there were no differences between VRP700 and placebo at almost all time-points, apart from the dyspnoea severity VAS at 24 h post-dose, where VRP700 was significantly better than placebo (p = 0.012). Conclusion VRP700, administered by nebuliser as a single inhaled dose of 100 mg, did not reduced the frequency and severity of cough in IPF patients with troublesome cough. Instead the inhalation of VRP700 seemed to evoke coughing.