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1.  Developing antitussives the clinician’s pipeline—what do we need? 
Journal of Thoracic Disease  2014;6(Suppl 7):S735-S738.
The evolving concept of cough hypersensitivity, an over activity of the afferent sensory nerves in the upper airways, has given new insights into the pathophysiology underlying chronic cough. Armed with this new information drug development aimed at reducing cough reflex sensitivity to normal has, for the first time, led to successful clinical studies. This review outlines the concepts underlying the inflammatory processes leading to cough hypersensitivity and demonstrates how knowledge of the molecular pharmacology of hypersensitivity provides a lead into drug targets. Initial hope that antagonists of TRP receptors would reduce clinical cough has been disappointing. Drugs such as theobromine, thalidomide and AF 219 which all have activity on afferent sensory nerves have shown promise in clinical trials. Large-scale phase three clinical studies are required to confirm these exciting findings.
doi:10.3978/j.issn.2072-1439.2014.08.40
PMCID: PMC4222922  PMID: 25383208
Cough; pharmacology; antitussive; hypersensitivity
2.  Changing the paradigm for cough: does 'cough hypersensitivity' aid our understanding? 
Asia Pacific Allergy  2014;4(1):3-13.
Chronic cough is a common reason for patients to seek medication attention. Over the last few decades, we have experienced significant clinical success by applying the paradigm of 'evaluating and treating the causes for chronic cough'. However, we still ask ourselves 'what underlies chronic cough. Indeed in a considerable proportion of patients cough is idiopathic, or unexplained despite vigorous evaluation. Commonly associated conditions such as rhinitis, eosinophilic bronchitis, asthma, or gastroesophageal acidic reflux may not be fundamental to cough, and thus may be triggers rather than causes. The cardinal feature of chronic cough is persistent upregulation the cough reflex, which may be driven by complex interactions between biologic, neurologic, immunologic, genetic, comorbid, and environmental factors. We suggest the new paradigm 'cough hypersensitivity syndrome' should finally bring us further advances in understanding and management of chronic cough.
doi:10.5415/apallergy.2014.4.1.3
PMCID: PMC3921869  PMID: 24527404
Cough; Respiratory hypersensitivity; Etiology; Pathophysiology
3.  Gastro‐oesophageal reflux and tachykinins in asthma and chronic cough 
Thorax  2007;62(6):468-469.
A possible new therapeutic option
doi:10.1136/thx.2006.070607
PMCID: PMC2117219  PMID: 17536026
5.  Increased Platelet Reactivity in Idiopathic Pulmonary Fibrosis Is Mediated by a Plasma Factor 
PLoS ONE  2014;9(10):e111347.
Introduction
Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls.
Methods
Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets.
Results
Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 µM ADP (1.9% positive ±0.5 (mean ± SEM) versus 0.7%±0.1; p = 0.03), 1 µM ADP (9.8%±1.3 versus 3.3%±0.8; p<0.01) and 10 µM ADP (41.3%±4.2 versus 22.5%±2.6; p<0.01). Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma.
Conclusions
IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma.
doi:10.1371/journal.pone.0111347
PMCID: PMC4206466  PMID: 25338090
6.  Is opiate action in cough due to sedation? 
Objectives:
Opiates have been used for cough suppression for centuries. It is unclear whether this antitussive action is due to their known sedative effects. We aimed to assess correlation between cough suppression and opiate usage.
Methods:
We performed a post hoc analysis of two published trials with three opioids. In study one, patients with chronic cough were treated with 4 weeks of modified release morphine sulphate (5 mg twice daily) or placebo in a double-blinded placebo-controlled fashion. Cough suppression was assessed subjectively by the Leicester Cough Questionnaire and objectively by citric acid aerosol (CAA) induced cough challenge. In study 2, normal volunteers were given single doses of placebo, codeine 30 mg or dextromethorphan 50 mg and cough suppression assessed using the CAA-induced cough challenge. Sedation was contemporaneously assessed by direct questioning.
Results:
There were 14 episodes of patient-reported sedation; 2 with modified release morphine sulphate, 9 with codeine and 3 with dextromethorphan. There was no correlation between change in the Leicester Cough Questionnaire or the CAA-induced cough challenge and reported sedation.
Conclusion:
This observational study suggests that sedation is unlikely to underlie the antitussive properties of these opioids. Eliciting the mechanism of these medications in cough may be a target for future tailored drug development.
doi:10.1177/2040622314543220
PMCID: PMC4131504  PMID: 25177477
antitussive; codeine phosphate; cough therapies dextromethorphan; morphine sulphate (MST); sedation
7.  Human TRPM8 and TRPA1 pain channels, including a gene variant with increased sensitivity to agonists (TRPA1 R797T), exhibit differential regulation by SRC-tyrosine kinase inhibitor 
Bioscience Reports  2014;34(4):e00131.
TRPM8 (transient receptor potential M8) and TRPA1 (transient receptor potential A1) are cold-temperature-sensitive nociceptors expressed in sensory neurons but their behaviour in neuronal cells is poorly understood. Therefore DNA expression constructs containing human TRPM8 or TRPA1 cDNAs were transfected into HEK (human embryonic kidney cells)-293 or SH-SY5Y neuroblastoma cells and G418 resistant clones analysed for effects of agonists and antagonists on intracellular Ca2+ levels. Approximately 51% of HEK-293 and 12% of SH-SY5Y cell clones expressed the transfected TRP channel. TRPM8 and TRPA1 assays were inhibited by probenecid, indicating the need to avoid this agent in TRP channel studies. A double-residue mutation in ICL-1 (intracellular loop-1) of TRPM8 (SV762,763EL, mimicking serine phosphorylation) or one in the C-terminal tail region (FK1045,1046AG, a lysine knockout) retained sensitivity to agonists (WS 12, menthol) and antagonist {AMTB [N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide]}. SNP (single nucleotide polymorphism) variants in TRPA1 ICL-1 (R797T, S804N) and TRPA1 fusion protein containing C-terminal (His)10 retained sensitivity to agonists (cinnamaldehyde, allyl-isothiocyanate, carvacrol, eugenol) and antagonists (HC-030031, A967079). One SNP variant, 797T, possessed increased sensitivity to agonists. TRPA1 became repressed in SH-SY5Y clones but was rapidly rescued by Src-family inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine]. Conversely, TRPM8 in SH-SY5Y cells was inhibited by PP2. Further studies utilizing SH-SY5Y may identify structural features of TRPA1 and TRPM8 involved in conferring differential post-translational regulation.
Transient receptor potential channels M8 and A1 sense the cellular environment and activate entry of Ca2+ into the cytoplasm. We identified a TRPA1 (transient receptor potential A1) variant with increased sensitivity and differential modulation of channels by a tyrosine kinase inhibitor in neuroblastoma cells.
doi:10.1042/BSR20140061
PMCID: PMC4122973  PMID: 24975826
EC50; SNP; TRPA1; TRPM8; tyrosine kinases; AITC, allyl-isothiocyanate; A1TRPM8, transient receptor potential M8; AMTB, N-(3-Aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)benzamide; HC 030031, 2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; HEK, human embryonic kidney cells; ICL-1, intracellular loop-1; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; PP3, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine; RFU, relative fluorescence unit; SNP, single nucleotide polymorphism; TRPA1, transient receptor potential; WS 12, (1R,2S)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide
8.  Unique Responses are Observed in Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and TRPV1) Co-Expressing Cells 
Cells  2014;3(2):616-626.
Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1.
doi:10.3390/cells3020616
PMCID: PMC4092848  PMID: 24921186
TRPV1; TRPA1; TRPA1; TRPV1 co-expression
9.  On the definition of chronic cough and current treatment pathways: an international qualitative study 
Background
The pathogenesis of chronic cough is not well understood and treatment options are limited. In this study we sought to explore the current understanding and management of chronic cough across an international group of specialists.
Methods
This was an international study of cross sectional qualitative design. In depth interviews were carried out with “Respiratory Specialists” experienced in treating treating Chronic Obstructive Pulmonary Disease (COPD), idiopathic pulmonary fibrosis (IPF), idiopathic chronic cough (ICC) and/or lung cancer patients and with “Disease Experts” in the field of Chronic Cough. Participants in the study were recruited from the USA, UK, Germany, Ireland, Australia and Japan. Interviews with specialists were held at research facilities and with DEs over the telephone. These were preceded by the specialists completing case records of patients recently seen. All interviews were conducted by native speaking trained moderators using a semi-structured interview guide script. This was designed to elicit the definition of chronic cough, explore the unmet needs for each disease state, define therapy goals, identify patient phenotypes and give an overview of the treatment pathway.
Results
76 specialists and 10 experts took part in the study. Over two thirds (70%) of respondents defined chronic cough as “cough lasting more than 8/12 weeks” (range 2 weeks to 2 years). Physicians emphasised three interdependent aspects of clinical assessment: impact on quality of life, type of cough (productive versus non-productive) and the underlying pathology. Specialists emphasised treating the underlying cause rather than the cough, this being most prominent in Japan. Experts as a group focussed on chronic cough independently. Evaluation of the respiratory system, GI tract and upper airway (ENT) for establishing an underlying cause was recommended. Type of cough (productive vs non-productive) and impact on quality of life influenced treatment initiation. 33% of patients with ICC were prescribed anti-tussives. With associated diagnoses of COPD, IPF or lung cancer the emphasis was on treating the underlying condition. Alternatives to pharmacological treatments were frequently considered.
Conclusion
There is significant international variation in our understanding and management of chronic cough. Further work is required to bring forth clear guidance and effective medicines for these patients.
doi:10.1186/1745-9974-10-5
PMCID: PMC4088926  PMID: 25009577
Chronic cough; Definition; Management; Qualitative research
10.  Cough in the Elderly Population: Relationships with Multiple Comorbidity 
PLoS ONE  2013;8(10):e78081.
Background
The epidemiology of cough in the elderly population has not been studied comprehensively. The present study aimed to investigate the epidemiology of cough in a community elderly population, particularly in relation with their comorbidity.
Methods
A cross-sectional analysis was performed using a baseline dataset from the Korean Longitudinal Study on Health and Aging, a community-based elderly population cohort study. Three types of cough (frequent cough, chronic persistent cough, and nocturnal cough) were defined using questionnaires. Comorbidity was examined using a structured questionnaire. Health-related quality of life was assessed using the Short Form 36 questionnaire.
Results
The prevalence was 9.3% for frequent cough, 4.6% for chronic persistent cough, and 7.3% for nocturnal cough. In multivariate logistic regression analyses, smoking, asthma and allergic rhinitis were found to be risk factors for cough in the elderly. Interestingly, among comorbidities, constipation and uncontrolled diabetes mellitus (HbA1c ≥ 8%) were also found to have positive associations with elderly cough. In the Short Form 36 scores, chronic persistent cough was independently related to impairment of quality of life, predominantly in the mental component.
Conclusions
Cough has a high prevalence and is detrimental to quality of life in the elderly. Associations with smoking, asthma and rhinitis confirmed previous findings in younger populations. Previously unrecognised relationships with constipation and uncontrolled diabetes mellitus suggested the multi-faceted nature of cough in the elderly.
doi:10.1371/journal.pone.0078081
PMCID: PMC3804463  PMID: 24205100
11.  Hypoxic Pulmonary Vasoconstriction in Humans 
BioMed Research International  2013;2013:623684.
Hypoxic pulmonary vasoconstriction is the elegant theory put forward more than six decades ago to explain regional variations in perfusion within the lung in certain animal species in response to localised restrictions in oxygenation. Although considerable progress has been made to describe the phenomenon at the macroscopic level and explain it at the microscopic level, we are far from a universal agreement about the process in humans. This review attempts to highlight some of the important evidence bases of hypoxic pulmonary vasoconstriction in humans and the significant gaps in our knowledge that would need bridging.
doi:10.1155/2013/623684
PMCID: PMC3762074  PMID: 24024204
12.  Chronic cough hypersensitivity syndrome 
Chronic cough has been suggested to be due to three conditions, asthma, post nasal drip, and reflux disease. A different paradigm has evolved in which cough is viewed as the primary condition characterised by afferent neuronal hypersensitivity and different aspects of this syndrome are manifest in the different phenotypes of cough. There are several advantages to viewing cough hypersensitivity as the unifying diagnosis; Communication with patients is aided, aetiology is not restricted and therapeutic avenues opened. Cough Hypersensitivity Syndrome is a more applicable label to embrace the clinical manifestations of this disabling disease.
doi:10.1186/1745-9974-9-14
PMCID: PMC3655896  PMID: 23668427
13.  Hyperoxic Vasoconstriction of Human Pulmonary Arteries: A Novel Insight into Acute Ventricular Septal Defects 
ISRN Cardiology  2013;2013:685735.
Objectives. Acute rises in pulmonary artery pressures following postinfarction ventricular septal defects present a challenge. We hypothesised that the abnormally high oxygen content exposure to the pulmonary arteries may be a factor. We investigated the contractile responses of human pulmonary arteries to changes in oxygen tension. Methods. Isometric tension was measured in large and medium sized pulmonary artery rings obtained from lung resections for patients with bronchial carcinoma (n = 30). Fresh rings were mounted in organ baths bubbled under basal conditions with hyperoxic or normoxic gas mixes and the gas tensions varied during the experiment. We studied whether voltage-gated calcium channels and nitric oxide signalling had any role in responses to oxygen changes. Results. Hypoxia caused a net mean relaxation of 18.1% ± 15.5 (P < 0.005) from hyperoxia. Subsequent hyperoxia caused a contraction of 19.2% ± 13.5 (P < 0.005). Arteries maintained in normoxia responded to hyperoxia with a mean constriction of 14.8% ± 3.9 (P < 0.005). Nifedipine inhibited the vasoconstrictive response (P < 0.05) whilst L-NAME had no effect on any hypoxic vasodilatory response. Conclusions. We demonstrate that hyperoxia leads to vasoconstriction in human pulmonary arteries. The mechanism appears to be dependent on voltage-gated calcium channels. Hyperoxic vasoconstriction may contribute to acute rises in pulmonary artery pressures.
doi:10.1155/2013/685735
PMCID: PMC3628186  PMID: 23606985
14.  Management of patients with chronic cough using a clinical protocol: a prospective observational study 
Background and aims
Chronic cough is a common symptom the aetiology of which can be challenging to diagnose. Diagnostic protocols for chronic cough have required the use of specialist investigations which are not always easily available. We wanted to determine whether patients with chronic cough can be successfully managed using a clinical algorithm.
Methods
112 consecutive patients with chronic cough were prospectively recruited into this study. They were assessed by history, physical examination, chest radiograph, spirometry and reversibility to nebulised salbutamol. A clinical diagnosis was made and the patient had an 8-week trial of appropriate therapy. Further therapeutic trials were carried out depending on response to treatment and the possible differential diagnoses. Investigations were carried out in cases of failed clinical trials and to exclude specific pathology. The “clinical arm” comprised patients managed on the basis of clinical assessment and without any investigations. The “investigative arm” comprised those who needed further investigations.
Results
81 (72%) were managed in the clinical arm. Of these 74 (66%) were discharged following response to therapy. 31 (28%) patients were converted to the investigative arm after failure of diagnosis in the clinical protocol. The commonest causes of cough were gastroesophageal reflux, asthma and chronic rhinitis. 51 (45.5%) patients responded to therapy based on diagnosis at initial assessment while a further 23 (20.5%) patients responded to sequential clinical trials for the commonest causes of cough. Cough severity score improved by a mean of 3.6 points on a numeric response score (from 0–10, p < 0.0001).
Conclusion
It is possible to manage a majority of chronic cough patients successfully using a protocol based on presenting symptoms and therapeutic trials for the common causes of cough.
doi:10.1186/1745-9974-9-2
PMCID: PMC3565860  PMID: 23347748
Cough; Differential diagnosis; Diagnostic techniques and procedures
15.  Chronic Cough in Musculoskeletal disorders: Using high resolution oesophageal manometry in search of an Aetiology 
Chronic cough is a common symptom carrying significant morbidity which can occur as a result of oesophageal dysmotility. Here we report 2 patients with musculoskeletal disease presenting with chronic cough to our tertiary cough clinic. Prior to referral both patients had been extensively investigated to determine the basis of their cough, with no cause found. Oesophageal studies, using high resolution oesophageal manometry, demonstrated oesophageal dysmotility with consequent airway reflux. Anti-reflux therapy resulted in a good response in both patients. These are the first reports of the recently developed technique of high resolution manometry aiding the diagnosis of chronic cough. This technique may provide important clues into aetiological mechanism in patients with conditions predisposing to reflux into the airways.
doi:10.1186/1745-9974-8-6
PMCID: PMC3500721  PMID: 23021351
Chronic cough; Airway reflux; Ehlers-Danlos; Dermatomyositis
16.  Fundoplication in chronic intractable cough 
Background
Airway reflux is a common cause of chronic cough and this is often refractory to medical therapy. Surgery in the form of Nissen fundoplication has been highly successful in the treatment of the classic reflux symptoms of heartburn and dyspepsia. There is a paucity of data regarding response to fundoplication in patients presenting with chronic cough.
Methods
We retrospectively reviewed the case notes of patients from the Hull Cough Clinic who had undergone Nissen fundoplication over the past 6 years. Demographic details, duration of symptoms, presence of other symptoms, results of oesophageal studies, outcome and complications were recorded. Patients were contacted by post and asked to complete a questionnaire detailing current symptoms. In a subgroup with continued troublesome cough 24 hour pharyngeal pH measurements were undertaken.
Results
Forty seven patients underwent fundoplication. The average duration of pre-operative cough was 8 years. Gastro intestinal symptoms were present in the majority. In 30 (64%) patients a positive response to treatment was recorded. Mild dysphagia or bloating was seen in 18 patients following surgery. Four patients needed repeat surgical intervention for modification of fundoplication. One patient developed aspiration pneumonia eight weeks following surgery and died of a myocardial infarction. Two thirds of patients with persisting cough had evidence of airway reflux on pharyngeal pH monitoring.
Conclusion
In these patients with intractable cough a long term response rate of 63% represents a useful therapeutic option. Treatment failure is more frequent than for classic peptic symptoms and may be related to persistent gaseous reflux.
doi:10.1186/1745-9974-8-3
PMCID: PMC3499264  PMID: 22812601
Chronic cough; Reflux; Fundoplication
17.  Comparison of the effect of high-dose inhaled budesonide and fluticasone on adrenal function in patients with severe chronic obstructive pulmonary disease 
Annals of Thoracic Medicine  2012;7(3):140-144.
INTRODUCTION:
Chronic obstructive pulmonary disease (COPD) is a leading cause of respiratory-related morbidity and mortality. Inhaled steroids are frequently used in patients with moderate to severe disease and may lead to adrenal suppression.
OBJECTIVES:
The aim of this study was to compare the effect of inhaled budesonide/formoterol with inhaled fluticasone/salmeterol in severe COPD.
METHODS:
It was a prospective open-label crossover study of 22 patients. Adrenal suppression was measured by overnight urinary cortisol/creatinine ratio. The measurements were taken while patients were on either combination for at least 4 weeks.
RESULTS:
A total of 12 patients completed the study. The mean age was 64 years (8 males, 4 females). The mean FEV1 was 1 L (range, 0.5-1.8). There was no significant difference in adrenal suppression measured by overnight urinary cortisol/creatinine ratio (budesonide 5.2 ± 4.3, fluticasone 4.7 ± 3.1; 95% CI -2.2 to 1.2; P = 0.52) and urinary cortisol concentration (budesonide 51 ± 53, fluticasone 43 ± 31 [nmol/l]; 95% CI -35 to 20; P = 0.56).
CONCLUSION:
Inhaled budesonide and fluticasone have no significantly different effect on adrenal function in moderate to severe COPD. The adverse event profile of high-dose inhaled steroids should not influence the choice of medication.
doi:10.4103/1817-1737.98846
PMCID: PMC3425045  PMID: 22924071
Adrenal suppression; COPD; cortisol-creatinine ratio; inhaled corticosteroids
18.  Airway Reflux, Cough and Respiratory Disease 
It is increasingly accepted that the effects of gastro-oesophageal reflux are not limited to the gastrointestinal tract. The adjacent respiratory structures are also at risk from material ejected from the proximal oesophagus as a result of the failure of anatomical and physiological barriers. There is evidence of the influence of reflux on several respiratory and otorhinological conditions and although in many cases the precise mechanism has yet to be elucidated, the association alone opens potential novel avenues of therapy to clinicians struggling to treat patients with apparently intractable respiratory complaints. This review provides a description of the airway reflux syndrome, its effects on the lung and current and future therapeutic options.
doi:10.1177/2040622311406464
PMCID: PMC3513884  PMID: 23251752
airways reflux; cough; respiratory disease; therapy
19.  Clinical expert guidelines for the management of cough in lung cancer: report of a UK task group on cough 
Background
Cough is a common and distressing symptom in lung cancer patients. The clinical management of cough in lung cancer patients is suboptimal with limited high quality research evidence available. The aim of the present paper is to present a clinical guideline developed in the UK through scrutiny of the literature and expert opinion, in order to aid decision making in clinicians and highlight good practice.
Methods
Two systematic reviews, one focusing on the management of cough in respiratory illness and one Cochrane review specifically on cancer, were conducted. Also, data from reviews, phase II trials and case studies were synthesized. A panel of experts in the field was also convened in an expert consensus meeting to make sense of the data and make clinical propositions.
Results
A pyramid of cough management was developed, starting with the treatment of reversible causes of cough/specific pathology. Initial cough management should focus on peripherally acting and intermittent treatment; more resistant symptoms require the addition of (or replacement by) centrally acting and continuous treatment. The pyramid for the symptomatic management starts from the simpler and most practical regimens (demulcents, simple linctus) to weak opioids to morphine and methadone before considering less well-researched and experimental approaches.
Conclusion
The clinical guidelines presented aim to provide a sensible clinical approach to the management of cough in lung cancer. High quality research in this field is urgently required to provide more evidence-based recommendations.
doi:10.1186/1745-9974-6-9
PMCID: PMC2978117  PMID: 20925935
20.  Validation of the ERS standard citric acid cough challenge in healthy adult volunteers 
Protocols measuring cough sensitivity can vary in terms of nebuliser, tussive agent, single and dose response. A definitive method for measuring cough sensitivity needs to be established.
The ERS guidelines recommend the KoKo DigiDoser (KD) delivery system. Study aim, was to compare the reproducibility of this citric acid (CA) cough challenge and previously established Mefar dosimeter (MD) protocol.
39 (female 26) volunteers mean age (40.4 yrs) were randomised to either KD or MD. Intra-day and inter-day reproducibility was compared.
We calculated the concentration of citric acid evoking 2 coughs (C2).
The geometric mean C2 (95%CI) was similar for both KD and MD, of 263 (200,339) mM and 209 (151,288) mM respectively.
The mean KD C2 was not significantly different. (F = 0.807, p = 0.93) from baseline over 1, 2, and 4 hrs however, the MD demonstrated significant variability (F = 7.85, P < 0.001)
Measuring mean log C2 at baseline and at 2 weeks, the KD demonstrated a stronger intraclass correlation of log C2 at baseline with 2 week log C2, ICC = 0.70 than was shown with the Mefar, ICC = 0.41
Administering CA from KD offers a reproducible cough challenge in healthy volunteers. The results correlate well with the MD challenge but offer greater intra-day and inter-day reproducibility.
Trial Registration
Current controlled trials ISRCTN98385033
doi:10.1186/1745-9974-6-8
PMCID: PMC2925329  PMID: 20698995
21.  Chronic cough associated with Crohn's disease 
A 62-year-old man presented with chronic dry cough. He was known to have Crohn's disease which was in remission. A plain chest radiograph demonstrated bilateral apical infiltrates. A HRCT of the chest showed normal proximal airways. Stenosis of medium size airways was present with post-stenotic dilation. These dilated peripheral bronchi appeared fluid filled. Patchy areas of consolidation were seen as well. These changes were thought to be due to Crohn's disease involving the lungs and responded well to treatment with cortico-steroids. We report this uncommon radiological association with Crohn's disease.
doi:10.1186/1745-9974-6-6
PMCID: PMC2924257  PMID: 20691116
22.  TRPA1 Agonists Evoke Coughing in Guinea Pig and Human Volunteers 
Rationale: Cough is the most frequent reason for consultation with a family doctor, or with a general or respiratory physician. Treatment options are limited and one meta-analysis concluded that over-the-counter remedies are ineffective. There is also increasing concern about their use in children. Environmental irritants such as air pollution and cigarette smoke are thought to evoke cough by stimulating airway sensory nerves; however, how this occurs is not fully understood.
Objectives: We hypothesized that the TRPA1 (transient receptor potential cation channel, subfamily A, member 1) receptor may have a role as a novel target for tussive agents given that many potential irritants have been shown to activate this channel.
Methods: We investigated the effect of TRPA1 ligands on vagal sensory nerve activity in vitro and in guinea pig and human tussive challenge models.
Measurements and Main Results: We demonstrated that TRPA1 agonists such as acrolein activate cloned human TRPA1 channels in HEK293 cells and also vagal sensory nerves in murine, guinea pig, and human tissues. A role for TRPA1 was confirmed, using specific inhibitors and tissue from Trpa1−/− gene–deleted animals. Finally, TRPA1 ligands evoked reproducible tussive responses in both a guinea pig model and normal volunteers.
Conclusions: This study identifies the TRPA1 receptor as a promiscuous receptor, activated by a wide range of stimuli, making it a perfect target for triggering cough and as such one of the most promising targets currently identified for the development of antitussive drugs.
doi:10.1164/rccm.200905-0665OC
PMCID: PMC2784411  PMID: 19729665
sensory nerves; cough; vagus
23.  Cough in adult cystic fibrosis: diagnosis and response to fundoplication 
Background
Gastroesophageal reflux is one of the most common causes of chronic cough in the general population. Reflux occurs frequently in patients with cystic fibrosis (CF). We undertook laparoscopic Nissen fundoplication in adult CF patients with a clinical diagnosis of reflux cough who had failed conventional medical therapies.
Objective
We determined the response to the surgical route in the treatment of intractable reflux cough in CF.
Method
Patients with refractory cough were assessed by 24 h pH monitoring and oesophageal manometry. Pre-and post-operation cough, lung function and exacerbation frequency were compared. Cough was assessed by the Leicester Cough Questionnaire (LCQ), lung function by spirometry and exacerbation frequency was defined by comparing the postoperative epoch with a similar preoperatively.
Results
Significant abnormalities of oesophageal function were seen in all patients studied. 6 patients (2 females), with the mean age of 34.5 years consented to surgery. Their mean number of reflux episodes was 144.4, mean DeMeester score was 39.2, and mean lower oesophageal sphincter pressure 12.4 mmHg. There was a small change in the FEV1 from 1.03 L to 1.17 (P = 0.04), and FVC improved from 2.62 to 2.87 (P = 0.05). Fundoplication lead to a marked fall in cough with the total LCQ score increasing from 11.9 to 18.3 (P = 0.01). Exacerbation events were reduced by 50% post operatively.
Conclusion
Whilst there is an obvious attention to respiratory causes of cough in CF, reflux is also a common cause. Fundoplication is highly effective in the control of reflux cough in CF. Significant reduction in exacerbation frequency may indicate that reflux with possible aspiration is a major unrecognised contributor to airway disease.
doi:10.1186/1745-9974-5-1
PMCID: PMC2634760  PMID: 19149907
24.  Anxiety and panic fear in adults with asthma: prevalence in primary care 
BMC Family Practice  2007;8:62.
Background
Patients may find it difficult to distinguish between the symptoms of anxiety and those of asthma. Findings are equivocal on whether there is a specific link between anxiety and asthma. The aims of this study were to i) to identify the prevalence of anxiety, depression and panic fear in adults with asthma compared with that of the general population ii) to investigate whether there is a specific relationship between asthma and anxiety.
Methods
An epidemiological survey of 872 adults with a diagnosis of asthma identified from six General Practices in Sheffield, England. Community postal survey using self-completion questionnaire.
Results
The response rate was 59%. People with asthma had higher mean Hospital Anxiety and Depression Scale (HADS) anxiety scores than UK norms with a higher proportion above the clinical cut-off. Mean HADS depression scores were significantly higher than UK norms and norms for a general population sample of people registered with the same practice. These effects were age-related with the relationship between asthma and psychological distress most marked over the age of 45. The prevalence of asthma-specific panic fear was 15.7%.
Conclusion
A significant minority of people have high levels of panic fear (as measured by the Asthma Symptom Checklist) associated with asthma. However, in adults with asthma there is also high prevalence of both generalised anxiety and depression (as measured by the HADS), suggesting that the link of anxiety to asthma may be part of a broader relationship between psychological distress and chronic disease rather than a specific one.
doi:10.1186/1471-2296-8-62
PMCID: PMC2174924  PMID: 17963505
25.  Chronic persistent cough in the community: a questionnaire survey 
Background
Chronic cough is a common symptom which causes significant levels of morbidity. It is becoming increasingly well characterised by research taking place in specialist cough clinics, where successful treatment rates are high. However, there is a paucity of data regarding the symptom complex of chronic cough in the community. This report details the results of a postal questionnaire survey sent to individuals requesting further information on chronic cough.
Methods
856 chronic cough questionnaires were sent out to members of the public who requested an information sheet following a national UK radio broadcast. Information regarding demography, history of cough, previous treatment and physical, psychological and social effects of the cough was elicited.
Results
373 completed questionnaires were returned. Mean age was 65.3 years (SD 12.0, range 9–88 years). 73% were female and 2% current smokers. Median duration of cough was 6.5 years. 66% had no other coexisting respiratory diagnosis, whilst 24% reported asthma. Of those who responded, 91% had consulted a general practitioner regarding the cough and of them, 85% had been prescribed some sort of treatment. 61% had seen at least one hospital specialist. Commonly reported associated physical symptoms included breathlessness (55%), wheeze (37%), fatigue (72%) and disturbed sleep (70%). Incontinence occurred in 55% of women. Similarly, the majority reported psychological effects such as anger or frustration (83%), anxiety (69%) and depression (55%). 64% felt that the cough interfered with their social life.
Conclusion
Chronic cough causes a high level of morbidity in the community, which results in a correspondingly high rate of healthcare utilisation. Demography and symptomatology seems to be similar to that reported from specialist centres, but successful treatment of the cough was uncommon, despite a high number of medical consultations in both primary and secondary care. If understanding of this debilitating but eminently treatable condition is enhanced, management of chronic cough will improve and many patients will be helped.
doi:10.1186/1745-9974-3-5
PMCID: PMC1847685  PMID: 17381836

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