Cough: meeting the needs of a growing field

There has been a rapidly increasing volume of research undertaken in the field of acute and chronic cough at both basic scientific and clinical levels. However, until now there has been no journal dedicated to publishing work in this field. In this editorial, we introduce the new online, open-access journal entitled Cough which has been founded specifically for this purpose. We also review the clinical problems posed by acute and chronic cough and highlight some of the current issues that are being tackled by cough researchers

Glucocorticoid insensitivity as a future target of therapy for chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal and chronic inflammatory response in the lung that underlies the chronic airflow obstruction of the small airways, the inexorable decline of lung function, and the severity of the disease. The control of this inflammation remains a key strategy for treating the disease; however, there are no current anti-inflammatory treatments that are effective. Although glucocorticoids (GCs) effectively control inflammation in many diseases such as asthma, they are less effective in COPD. The molecular mechanisms that contribute to the development of this relative GC-insensitive inflammation in the lung of patients with COPD remain unclear. However, recent studies have indicated novel mechanisms and possible therapeutic strategies. One of the major mechanisms proposed is an oxidant-mediated alteration in the signaling pathways in the inflammatory cells in the lung, which may result in the impairment of repressor proteins used by the GC receptor to inhibit the transcription of proinflammatory genes. Although these studies have described mechanisms and targets by which GC function can be restored in cells from patients with COPD, more work is needed to completely elucidate these and other pathways that may be involved in order to allow for more confident therapeutic targeting. Given the relative GC-insensitive nature of the inflammation in COPD, a combination of therapies in addition to a restoration of GC function, including effective alternative anti-inflammatory targets, antioxidants, and proresolving therapeutic strategies, is likely to provide better targeting and improvement in the management of the disease

No effect of omeprazole on pH of exhaled breath condensate in cough associated with gastro-oesophageal reflux

BACKGROUND: Endogenous airway acidification evaluated as pH in exhaled breath condensate (EBC) has been described in patients with chronic cough. Proton pump inhibitors improve gastro-oesophageal reflux (GOR)-associated cough. METHODS: We examined pH levels in EBC and capsaicin cough response in 13 patients with chronic cough (mean age 41 years, SD 9) associated with GOR before and after omeprazole treatment (40 mg/day for 14 days) and its relationship with clinical response. RESULTS: Omeprazole abolished symptoms associated with GOR. Patients with chronic cough had an EBC pH of 8.28 (SD 0.13) prior to treatment but this did not change with omeprazole treatment. There was a significant improvement in the Leicester Cough Questionnaire symptom scores from 80.8 points (SD 13.2) to 95.1 (SD 17) (p = 0.02) and in a 6-point scale of cough scores, but there was no change in capsaicin cough response. CONCLUSION: An improvement in GOR-associated cough was not associated with changes in EBC pH or capsaicin cough response. These parameters are not useful markers of therapeutic response

Increase in airway neutrophils after oral but not inhaled corticosteroid therapy in mild asthma

SummaryBackground: Neutrophils, in addition to eosinophils, are prominent in the airways of patients with severe asthma who are usually on long-term oral and inhaled corticosteroid treatment. We determined whether inhaled or oral corticosteroid therapy can induce airway neutrophilia.Methods: We performed two separate placebo-controlled studies in which patients with mild asthma were treated with either prednisolone (30mg per day for 7 days; n=9) or placebo tablets (n=8), or with either inhaled budesonide (800μg twice daily for 4 weeks; n=6) or inhaled placebo (n=6). Fiberoptic bronchoscopy was performed before treatment and at day 7 of oral treatment, and at day 28 of inhaled therapy. Bronchial sections were immunostained with an antibody to major basic protein for eosinophils, and with an antibody to neutrophil elastase for neutrophils. Induced sputum was obtained in the prednisolone study.Results: Neutrophils in airway submucosa increased after prednisolone from median 76 to 140/mm2 (P=0.05); this change was higher than that after placebo (P=0.04). Eosinophils decreased from 24 to 9/mm2 (P=0.03), but this was not significantly different from placebo. Eosinophils and neutrophils, and levels of IL-8 and myeloperoxidase in induced sputum did not change after prednisolone. There was no change in neutrophil counts after budesonide, but the reduction in eosinophils was greater than placebo (P=0.05). Budesonide improved bronchial responsiveness, but prednisolone did not.Conclusion: Corticosteroid therapy by the oral but not inhaled route can induce neutrophil recruitment into the airways of patients with mild asthma. This could explain the increase in airway neutrophils observed in severe asthmatics treated with oral corticosteroids

Mouth breathing, dry air, and low water permeation promote inflammation, and activate neural pathways, by osmotic stresses acting on airway lining mucus

Respiratory disease and breathing abnormalities worsen with dehydration of the upper airways. We find that humidification of inhaled air occurs by evaporation of water over mucus lining the upper airways in such a way as to deliver an osmotic force on mucus, displacing it towards the epithelium. This displacement thins the periciliary layer of water beneath mucus while thickening topical water that is partially condensed from humid air on exhalation. With the rapid mouth breathing of dry air, this condensation layer, not previously reported while common to transpiring hydrogels in nature, can deliver an osmotic compressive force of up to around 100 cm H2O on underlying cilia, promoting adenosine triphosphate secretion and activating neural pathways. We derive expressions for the evolution of the thickness of the condensation layer, and its impact on cough frequency, inflammatory marker secretion, cilia beat frequency and respiratory droplet generation. We compare our predictions with human clinical data from multiple published sources and highlight the damaging impact of mouth breathing, dry, dirty air and high minute volume on upper airway function. We predict the hypertonic (or hypotonic) saline mass required to reduce (or amplify) dysfunction by restoration (or deterioration) of the structure of ciliated and condensation water layers in the upper airways and compare these predictions with published human clinical data. Preserving water balance in the upper airways appears critical in light of contemporary respiratory health challenges posed by the breathing of dirty and dry air

MyAirCoach: The use of home-monitoring and mHealth systems to predict deterioration in asthma control and the occurrence of asthma exacerbations; Study protocol of an observational study

© Published by the BMJ Publishing Group Limited. Introduction Asthma is a variable lung condition whereby patients experience periods of controlled and uncontrolled asthma symptoms. Patients who experience prolonged periods of uncontrolled asthma have a higher incidence of exacerbations and increased morbidity and mortality rates. The ability to determine and to predict levels of asthma control and the occurrence of exacerbations is crucial in asthma management. Therefore, we aimed to determine to what extent physiological, behavioural and environmental data, obtained by mobile healthcare (mHealth) and home-monitoring sensors, as well as patient characteristics, can be used to predict episodes of uncontrolled asthma and the onset of asthma exacerbations. Methods and analysis In an 1-year observational study, patients will be provided with mHealth and home-monitoring systems to record daily measurements for the first-month (phase I) and weekly measurements during a follow-up period of 11 months (phase II). Our study population consists of 150 patients, aged ≥18 years, with a clinician's diagnosis of asthma, currently on controller medication, with uncontrolled asthma and/or minimally one exacerbation in the past 12 months. They will be enrolled over three participating centres, including Leiden, London and Manchester. Our main outcomes are the association between physiological, behavioural and environmental data and (1) the loss of asthma control and (2) the occurrence of asthma exacerbations. Ethics This study was approved by the Medical Ethics Committee of the Leiden University Medical Center in the Netherlands and by the NHS ethics service in the UK. Trial registration number NCT02774772

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

Domiciliary fractional exhaled nitric oxide and spirometry in monitoring asthma control and exacerbations

Background: Domiciliary measurements of airflow obstruction and inflammation may assist healthcare teams and patients in determining asthma control and facilitate self-management. Objective: To evaluate parameters derived from domiciliary spirometry and fractional exhaled nitric oxide (FENO) in monitoring asthma exacerbations and control. Methods: Patients with asthma were provided with hand-held spirometry and FENO devices in addition to their usual asthma care. Patients were instructed to perform twice-daily measurements for 1 month. Daily symptoms and medication change were reported through a mobile health system. The Asthma Control Questionnaire was completed at the end of the monitoring period. Results: One hundred patients had spirometry, of which 60 were given additional FENO devices. Compliance rates for twice-daily measurements were poor (median [interquartile range], 43% [25%-62%] for spirometry; 30% [3%-48%] for FENO); at least 15% of patients took little or no spirometry measurements and 40% rarely measured FENO. The coefficient of variation (CV) values in FEV1 and FENO were higher, and the mean % personal best FEV1 lower in those who had major exacerbations compared with those without (P < .05). FENO CV and FEV1 CV were associated with asthma exacerbation during the monitoring period (area under the receiver-operating characteristic curve, 0.79 and 0.74, respectively). Higher FENO CV also predicted poorer asthma control (area under the receiver-operating characteristic curve, 0.71) at the end of the monitoring period. Conclusions: Compliance with domiciliary spirometry and FENO varied widely among patients even in the setting of a research study. However, despite significant missing data, FENO and FEV1 were associated with asthma exacerbations and control, making these measurements potentially clinically valuable if used