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1.  Defining Chronic Cough: A Systematic Review of the Epidemiological Literature 
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.
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.
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.
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.
PMCID: PMC4713878  PMID: 26739408
Cough; epidemiology; definition
2.  A randomized placebo controlled trial to evaluate the effects of butamirate and dextromethorphan on capsaicin induced cough in healthy volunteers 
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.
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.
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.
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.
PMCID: PMC4256617  PMID: 24995954
butamirate; capsaicin; cough sensitivity; dextromethorphan
3.  Chronic cough: An Indian perspective 
PMCID: PMC4663888  PMID: 26664191
4.  Chronic cough: an Asian perspective. Part 1: Epidemiology 
Asia Pacific Allergy  2015;5(3):136-144.
Asia is one of the most diverse and dynamic continents. Due to recent rapid industrialisation and urbanisation, morbidity patterns are likely to be diverse in Asian populations. Chronic cough is a disease condition resulting from host-environmental interactions, and is associated with a high global epidemiological burden. However, the underlying epidemiology remains unclear, particularly in Asia. We performed a literature search to identify peer-reviewed articles on chronic cough in community-based adult Asian populations that have been published between January 2000 and June 2015. In this review, we aim to examine the epidemiological characteristics and determinants of chronic cough in several geographical areas of Asia.
PMCID: PMC4521162  PMID: 26240790
Cough; Epidemiology; Risk Factors; Asia
5.  An increasingly breathless patient 
PMCID: PMC4220337  PMID: 25378863
6.  On the definition of chronic cough and current treatment pathways: an international qualitative study 
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.
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.
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.
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.
PMCID: PMC4088926  PMID: 25009577
Chronic cough; Definition; Management; Qualitative research
7.  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.
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.
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).
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.
PMCID: PMC3565860  PMID: 23347748
Cough; Differential diagnosis; Diagnostic techniques and procedures
8.  Fundoplication in chronic intractable cough 
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.
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.
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.
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.
PMCID: PMC3499264  PMID: 22812601
Chronic cough; Reflux; Fundoplication
9.  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.
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.
The aim of this study was to compare the effect of inhaled budesonide/formoterol with inhaled fluticasone/salmeterol in severe COPD.
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.
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).
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.
PMCID: PMC3425045  PMID: 22924071
Adrenal suppression; COPD; cortisol-creatinine ratio; inhaled corticosteroids
10.  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.
PMCID: PMC2924257  PMID: 20691116
11.  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.
PMCID: PMC2784411  PMID: 19729665
sensory nerves; cough; vagus

Results 1-11 (11)