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1.  Defining Chronic Cough: A Systematic Review of the Epidemiological Literature 
Purpose
Recent evidence suggests a global burden of chronic cough in general populations. However, the definitions vary greatly among epidemiological studies, and none have been validated for clinical relevance. We aimed to examine previous epidemiological definitions in detail and explore the operational characteristics.
Methods
A systematic review was conducted for epidemiological surveys that reported the prevalence of chronic cough in general adult populations during the years 1980 to 2013. A literature search was performed on Pubmed and Embase without language restriction. Epidemiological definitions for chronic cough were classified according to their components, such as cutoff duration. Meta-analyses were performed for the male-to-female ratio of chronic cough prevalence to explore operational characteristics of epidemiological definitions.
Results
A total of 70 studies were included in the systematic review. The most common epidemiological definition was identified as 'cough ≥3 months' duration without specification of phlegm (n=50); however, it conflicted with the cutoff duration in current clinical guidelines (cough ≥8 weeks). Meta-analyses were performed for the male-to-female ratio of chronic cough among 28 studies that reported sex-specific prevalence using the most common definition. The pooled male-to-female odds ratio was 1.26 (95% confidence interval 0.92-1.73) with significant heterogeneity (I2=96%, P<0.001), which was in contrast to clinical observations of female predominance from specialist clinics. Subgroup analyses did not reverse the ratio or reduce the heterogeneity.
Conclusions
This study identified major issues in defining chronic cough in future epidemiological studies. The conflict between epidemiological and clinical diagnostic criteria needs to be resolved. The unexpected difference in the gender predominance between the community and clinics warrants further studies. Clinical validation of the existing definition is required.
doi:10.4168/aair.2016.8.2.146
PMCID: PMC4713878  PMID: 26739408
Cough; epidemiology; definition
2.  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
3.  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
4.  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
5.  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
6.  Assessment of antitussive efficacy of dextromethorphan in smoking related cough: objective vs. subjective measures 
AIMS
Using an established model of smokers cough we measured the antitussive effects of dextromethorphan compared with placebo.
METHODS
The study was a randomized, double-blind placebo controlled, crossover comparison of 22 mg 0.8 ml−1 dextromethorphan delivered pregastrically with matched placebo. Objective and subjective measurements of cough were recorded. Subjective measures included a daily diary record of cough symptoms and the Leicester quality of life questionnaire. Cough frequency was recorded using a manual cough counter. The objective measure of cough reflex sensitivity was the citric acid, dose–response cough challenge.
RESULTS
Dextromethorphan was significantly associated with an increase in the concentration of citric acid eliciting an average of two coughs/inhalation (C2) when compared with placebo, 1 h post dose by 0.49 mM (95% CI 0.05, 0.45, geometric mean 3.09) compared with placebo 0.24 mM (geometric mean 1.74) P < 0.05 and at 2 h 0.57 mM (95% CI 0.01, 0.43, geometric mean 3.75) compared with placebo 0.34 mM (geometric mean 2.19) P < 0.05). There was a highly significant improvement in the subjective data when compared with baseline. However, there was no significant difference between placebo and active treatment. No correlation was seen between cough sensitivity to citric acid and recorded cough counts or symptoms. When both subjective and objective data were compared with screening data there was evidence of a marked ‘placebo’ effect.
CONCLUSIONS
The objective measure of cough sensitivity demonstrates dextromethorphan effectively diminishes the cough reflex sensitivity. However, subjective measures do not support this. Other studies support these findings, which may represent a profound sensitivity of the cough reflex to higher influences.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTDextromethorphan is widely used as a cough suppressant in over the counter medications.Its efficacy in altering cough reflex sensitivity has been shown in healthy volunteers. In contrast evidence for an effect on clinically important cough is poor.
WHAT THIS STUDY ADDSA significant decrease in evoked cough was seen with dextromethorphan compared with placebo. However, both placebo and active treatment improved subjective data to a similar degree.We doubt the validity of currently used objective tests in the investigation of antitussives.
doi:10.1111/j.1365-2125.2008.03115.x
PMCID: PMC2432485  PMID: 18279476
antitussive; cough; dextromethorphan; smoking
7.  Cough challenge in the assessment of cough reflex 
doi:10.1046/j.0306-5251.2001.01475.x
PMCID: PMC2014577  PMID: 11678780
8.  Combating cough 
doi:10.1038/npjpcrm.2016.12
PMCID: PMC4776669  PMID: 26937873
9.  How does rhinovirus cause the common cold cough? 
BMJ Open Respiratory Research  2016;3(1):e000118.
Cough is a protective reflex to prevent aspiration and can be triggered by a multitude of stimuli. The commonest form of cough is caused by upper respiratory tract infection and has no benefit to the host. The virus hijacks this natural defence mechanism in order to propagate itself through the population. Despite the resolution of the majority of cold symptoms within 2 weeks, cough can persist for some time thereafter. Unfortunately, the mechanism of infectious cough brought on by pathogenic viruses, such as human rhinovirus, during colds, remains elusive despite the extensive work that has been undertaken. For socioeconomic reasons, it is imperative we identify the mechanism of cough. There are several theories which have been proposed as the causative mechanism of cough in rhinovirus infection, encompassing a range of different processes. Those of which hold most promise are physical disruption of the epithelial lining, excess mucus production and an inflammatory response to rhinovirus infection which may be excessive. And finally, neuronal modulation, the most convincing hypothesis, is thought to potentiate cough long after the original stimulus has been cleared. All these hypotheses will be briefly covered in the following sections.
doi:10.1136/bmjresp-2015-000118
PMCID: PMC4716235  PMID: 26835135
Cough/Mechanisms/Pharmacology; Respiratory Infection; Viral infection; Airway Epithelium
10.  A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers 
Aims
The examination of cough reflex sensitivity through inhalational challenge can be utilized to demonstrate pharmacological end points. Here we compare the effect of butamirate, dextromethorphan and placebo on capsaicin-induced cough in healthy volunteers.
Methods
In this randomized, placebo-controlled, six way crossover study the effect of dextromethrophan 30 mg, four doses of butamirate and placebo was evaluated on incremental capsaicin challenges performed at baseline and 2, 4, 6, 8, 12 and 24 h following dosing. The primary end point was the area under the curve (AUC(0,12h)) of log10 C5 from pre-dose to 12 h after dosing. Plasma butamirate metabolites were analyzed to evaluate pharmacokinetic and pharmacodynamic relationships.
Results
Thirty-four subjects (13 males, median age 25 years) completed the study. Cough sensitivity decreased from baseline in all arms of the study. Dextromethorphan was superior to placebo (P = 0.01) but butamirate failed to show significant activity with maximum attenuation at the 45 mg dose. There was no apparent relationship between pharmacokinetic and pharmacodynamic parameters for butamirate.
Conclusions
We have demonstrated for the first time that dextromethorphan attenuates capsaicin challenge confirming its broad activity on the cough reflex. The lack of efficacy of butamirate could be due to formulation issues at higher doses.
doi:10.1111/bcp.12458
PMCID: PMC4256617  PMID: 24995954
butamirate; capsaicin; cough sensitivity; dextromethorphan
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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