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PubMed2004

Cough in chronic obstructive pulmonary disease.

Patients with chronic obstructive pulmonary disease (COPD) most commonly complain of cough, production of phlegm and breathlessness. The cough reflex sensitivity is heightened compared with that in healthy volunteers and is similar to that in subjects with asthma. The degree of airflow obstruction does not predict cough reflex sensitivity or objective cough counts, implying an independent process. Objective cough rates seem to be relatively low in COPD, despite frequent reporting of the symptom by patients. The relative contribution of cough to disability in COPD seems to be small, if assessed by subjective reporting. Effective treatments for cough in COPD have not yet been identified. Improved outcome measures of cough, a better understanding of the mechanisms underlying cough, and the importance of cough to patients is required to progress in this field.

Clinical Trials as Topic↗
PubMed2004

Cough and asthma.

Cough variant asthma and the closely related corticosteroid responsive cough syndromes eosinophilic bronchitis and atopic cough are common causes of chronic cough. The diagnosis is often not overt but detailed investigation of airway responsiveness and airway inflammation can be helpful. Cough variant asthma, eosinophilic bronchitis and atopic cough are all associated with eosinophilic airway inflammation, which is similar to that seen in non-cough predominant asthma. However, evidence of activated mast cells and increased concentrations of mast cell products appears to be confined to the conditions associated with cough, suggesting a role for mast cell degranulation in the superficial airway structures in the pathogenesis of cough. Cough variant asthma is typically corticosteroid responsive; leukotriene antagonists and antihistamines also help. Further study of this interesting asthma variant may increase our understanding of the relationship between airway inflammation and airway dysfunction.

Adrenal Cortex Hormones↗
PubMed2006

The problem of cough and development of novel antitussives.

Cough is a very common clinical symptom and current therapies are largely ineffective, indicating a major unmet medial need. There is a pressing need to develop novel and safe antitussive therapies. This is likely to arise from better understanding of the sensory nerves involved in cough and the signalling pathways that are activated. A major therapeutic target should be sensitization of the cough reflex which is a feature of patients with both acute (virally induced) cough and chronic cough, including chronic idiopathic cough. Studies on human cough mechanisms are limited. There are several novel therapeutic approaches that are currently being explored. Perhaps the most promising drugs are transient receptor potential vanilloid-1 (TRPV(1)) antagonists, selective cannabinoid agonists (CB2 agonists), maxi-K channel openers and P2X3 antagonists. New cough therapies may target airway nerve sensitization and may best be delivered as inhalers to minimize any systemic effects. Understanding the intercellular signalling pathways involved in nociception may lead to novel drugs, such as p38 mitogen-activated protein (MAP) kinase inhibitors, being used in the treatment of cough in the future. It is also likely that several novel treatments that are developed as analgesics will also prove to be beneficial in the treatment of cough.

Acute Disease↗
PubMed2006

Supramedullary influences on cough.

The evidence for supramedullary influences on cough is largely indirect. Cough can be voluntarily induced or inhibited, functions usually thought to reside in the cerebral cortex. A sensation of 'urge-to-cough' usually precedes cough due to an airway irritant stimulus, and this may well involve the cerebral cortex. In conditions with interruption of the pathways between the cortex and the brainstem, such as strokes and Parkinson's disease, voluntary cough may be inhibited without disruption of reflex cough from the larynx or lower airways. 'Habit cough', like Tourette's syndrome, is assumed to be cortically mediated. Placebos and many treatments based on complementary medicine are effective in inhibiting clinical cough, and the site of action is likely to be the cerebral cortex. In sleep and in anaesthesia cough is depressed and, again, this seems likely to be at a cortical level. However there are few or no experimental or clinical observation as to the localization and functions of supramedullary areas responsible for cough. It is a field of research wide open for exploration.

Animals↗
PubMed1993

Influence of simulated mucus on cough sounds in cats.

Although in the clinic the presence of mucus in the airways is known to be an important factor influencing the sound of coughing in pathological conditions, this observation has not been established experimentally. We have substituted mucus in the airways of anaesthetized cats with 0.5 ml of natural undiluted egg albumin (EA) from hens' eggs, or with 1 ml of 10% pig gastric mucin (PGM) in saline. There were obvious changes in the character of cough sounds and significant increases in the intensity of the sounds (+76% with EA, +36% with PGM). The intensity of cough efforts significantly increased but only in the cats with addition of PGM (mean 30%). Removal of EA or PGM caused the opposite effects, a decrease in cough sounds (-41%) and intensity of cough effort (-52%), with simultaneous changes in the character of the cough sounds. There were no clear-cut patterns of cough sounds as has been described for humans. The cough sounds were often present not only during the expiratory phase of cough but also during the inspiratory phase. The results establish an important role of mucus in the airways in the creation of cough sounds.

Animals↗
PubMed2000

Chronic cough in children: bronchoalveolar lavage findings.

Isolated chronic cough in childhood is a common complaint. Although the symptom cough is included in the definition of clildhood asthma, there is debate as to whether the majoritv of these children have asthma. The authors studied children with isolated chronic cough looking for evidence of airway inflammation typical of asthma, with increased numbers of airway eosinophils as assessed from bronchoalveolar lavage (BAL). The investigations were carried out on 23 children (median age: 6.7 yrs; range: 1.7-12.75 yrs), attending the Royal Belfast Hospital for Sick Children for elective surgery, who also had a chronic unexplained cough. Written informed consent was obtained from the parent(s) and a nonbronchoscopic BAL was performed. BAL samples were analysed for total and differential white cell counts and also for the inflammatory mediators, eosinophil cationic protein (ECP) and histamine. Results were compared with a group of normal nonatopic children and also a group of atopic asthmatic children, who had been recruited for other studies on airway inflammation. There was a small but statistically significant increase in BAL percentage eosinophils in the children with chronic cough compared with nonasthmatic controls (0.28% versus 0.10%, p=0.03). However, the children with cough had lower percentage eosinophils than the atopic asthmatic controls (0.28% versus 0.66%, p=0.01). Three out of 23 children with chronic cough had BAL eosinophils greater than the normal upper 95% reference interval in BAL. There was a small but statistically significant increase in percentage neutrophils in the children with cough compared with the nonasthmatic controls (5.85% versus 3.21%, p=0.03). Four out of the 23 children had BAL neutrophils greater than the normal upper 95% reference interval in BAL. The authors conclude that only a minority of children with chronic unexplained cough have asthmatic-type airway inflammation. It is speculated that the increased percentage neutrophils in bronchoalveolar lavage from children with cough could relate to underlying persistent airways infection.

Asthma↗
PubMed2003

Effect of carbocysteine on cough reflex to capsaicin in asthmatic patients.

AIMS: Cough, one of the main symptoms of bronchial asthma, is a chronic airway inflammatory disease with functionally damaged bronchial epithelium. Recently, we established an animal model with cough hypersensitivity after antigen challenge and clearly showed the protective effect of carbocysteine in this model. This study was designed to investigate the clinical effect of carbocysteine for cough sensitivity in patients with bronchial asthma. METHODS: The effects of the two orally active mucoregulatory drugs, carbocysteine and ambroxol hydrochloride, on cough response to inhaled capsaicin were examined in 14 patients with stable asthma. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough sensitivity. RESULTS: Geometric mean values of the cough threshold at run-in (baseline) and after 4 weeks' treatment of placebo, 1500 mg day-1 of carbocysteine and 45 mg day-1 of ambroxol hydrochloride were 12.8 micro M (95% confidence interval [CI] 5.5, 29.6), 11.0 micro M (95% CI 4.4, 27.5), 21.0 micro M (95% CI 8.8, 50.2) and 11.6 micro M (95% CI 5.8, 23.3), respectively. The cough threshold for carbocysteine was significantly greater than those of ambroxol hydrochloride (P = 0.047) and placebo (P = 0.047), respectively. CONCLUSIONS: These findings indicate that carbocysteine administration may be a novel therapeutic option for asthmatic patients, especially with cough variant asthma.

Adult↗
PubMed1994

Gastroesophageal reflux and chronic cough: which comes first?

We evaluated the relationship between gastroesophageal (GE) reflux and chronic cough using prolonged pH monitoring and the standard acid reflux study in a retrospective case review. Ten patients were referred to our clinical esophageal laboratory for prolonged pH monitoring to determine whether GE reflux was the cause of chronic cough. In addition, we report one patient referred for a standard acid reflux test as a clear example of spontaneous cough inducing GE reflux. Of the 10 patients having prolonged pH monitoring, 182 of 221 (80.9 +/- 4.6%) of cough episodes had no correlation with GE reflux (p = 0.0001). Of those cough episodes that appeared to be related to GE reflux, 27 of 39 (69.2 +/- 11.7%) occurred before GE reflux and 12/39 (30.8 +/- 10.3%) occurred after GE reflux (p = 0.06). In the single patient GE reflux after spontaneous cough occurred five of seven times during a standard acid reflux test. In our series, cough and reflux were not related in the majority of episodes. Where there was a relationship, it appeared that the cough preceded GE reflux twice as often as reflux preceded cough. We conclude that GE reflux does not appear to be a frequent cause of chronic cough.

Aged↗
PubMed2005

Rhinitis is an independent risk factor for developing cough apart from colds among adults.

BACKGROUND: In cross-sectional clinical studies, rhinitis has been shown to be strongly associated with co-existing chronic cough. However, to date, this association has been poorly delineated from a prospective and epidemiological standpoint. METHODS: We used data from the 'Pisa Prospective Study', a population-based longitudinal cohort study composed of a baseline and a follow-up survey taken approximately 5 years apart from each other. Information on cough, rhinitis, and other risk factors was collected by standardized questionnaire. Cough apart from colds was defined as either 'chronic' (most days for at least 3 months for at least two consecutive years) or 'occasional' (if the three above temporal conditions were not met). 'Any' cough was defined as the presence of either occasional or chronic cough. RESULTS: Complete information was available for 1670 subjects who were > or =15 years old and had no positive history of cough apart from colds at the baseline survey. Among them, 299 (18%) had rhinitis at baseline. By the follow-up survey, 16% of the subjects with rhinitis had developed any cough apart from colds, as compared with only 10% of the subjects without rhinitis (OR 1.7, 95% CI 1.2-2.5, P < 0.005). After adjustment for age, gender, asthma status, smoking, and occupational exposure, rhinitis remained significantly associated with an increased risk both for any cough (OR 1.8, 95% CI 1.2-2.6) and for occasional and chronic cough separately (OR 2.2, 95% CI 1.1-4.5, and OR 1.7, 95% CI 1.1-2.6, respectively). CONCLUSIONS: Rhinitis is a significant and independent risk factor for developing cough among adults. Further research is needed to assess potential implications in terms of prevention.

Chronic Disease↗
PubMed2005

Weakly acidic reflux in patients with chronic unexplained cough during 24 hour pressure, pH, and impedance monitoring.

BACKGROUND AND AIMS: Acid gastro-oesophageal reflux is one of the most important causes of chronic cough. The response to acid suppression in these patients is not as good as in patients with heartburn but improvement with antireflux surgery has been reported, suggesting the involvement of a non-acidic gastric component in the refluxate. Less acidic reflux may produce symptoms such as regurgitation or chest pain. We investigated whether chronic cough might be associated with weakly acidic reflux. METHODS: We studied 28 patients with chronic cough using 24 hour ambulatory pressure-pH-impedance monitoring. Manometry was used for precise recognition of cough and impedance-pHmetry to detect acid (pH <4), weakly acidic (pH 7-4), and weakly alkaline (impedance drops, pH >/=7) reflux. A symptom association probability (SAP) analysis was performed for each type of reflux. RESULTS: Analysis was completed in 22 patients with 24 cough events (5-92)/patient. The majority of cough events (69.4%) were considered "independent" of reflux whereas 30.6% occurred within two minutes of a reflux episode. Half of these (49%) were "reflux cough" sequences, involving acid (65%), weakly acidic (29%), and weakly alkaline (6%) reflux. Ten patients (45%) had a positive SAP between reflux and cough: five with acid, two with acid and weakly acidic, and three only with weakly acidic reflux. CONCLUSIONS: Ambulatory pressure-pH-impedance monitoring with SAP analysis allowed precise determination of the temporal association between cough and gastro-oesophageal reflux (acid, weakly acidic, and weakly alkaline) and identification of a subgroup of patients with chronic cough clearly associated with weakly acidic gastro-oesophageal reflux.

Adult↗
PubMed1998

Cough responsiveness in neurogenic dysphagia.

OBJECTIVES: In neurogenic dysphagia a good cough is important for airway protection. If triggering of cough, or its effectiveness, is impaired this might result in an increased aspiration risk. Capsaicin, an agent which induces cough through sensory nerve stimulation, was used to test cough sensitivity in groups of patients with and without neurogenic dysphagia. METHODS: On the basis of swallowing speed (ml/s) in a validated water test 28 alert neurological inpatients (16 women, aged 22-71 years) were classified into 13 with abnormal and 15 with normal swallowing (median swallowing speed 23% and 99%, median volume/swallow 43% and 106% of that predicted for age and sex respectively: p<0.001). Capsaicin nebulised on air in saline was inhaled via a low resistance valve using a mouthpiece and noseclip. Up to seven incremental concentrations of capsaicin ranging from 0.07-20.0 x 10(-4) mol/l were each inhaled for up to a minute. A pneumotachograph connected to the expiratory limb gave a paper recording of expiratory air flow. Coughs were recorded as high flow expirations of short duration. Capsaicin concentrations at first cough (threshold) were recorded; concentrations at frequencies of 10 and 20 coughs/minute were interpolated from the dose-response curve. RESULTS: Cough threshold tended to be lower in those with abnormal swallowing (non-significant): the (log) concentration of capsaicin producing 10 or 20 coughs/ minute also tended to be lower (p=0.12 and 0.07 respectively) in those with abnormal swallowing. CONCLUSION: Contrary to expectation, these results suggest that cough responsiveness is enhanced in alert patients with neurogenic dysphagia even after allowing for diagnostic category, the possible presence of a bulbar upper motor neuron lesion, or voluntary respiratory capacity. It is concluded that these patients with neurogenic dysphagia do not have a reduced sensitivity of cough triggering.

Adult↗
PubMed1996

Diagnosis and management of chronic persistent dry cough.

Cough is one of the commonest symptoms of lung disease and is a frequent problem encountered in general practice as well as in hospital practice. A wide range of disease processes may present with cough and definitive treatment depends on making an accurate diagnosis of the cause. A diagnostic work-up for patients with persistent dry cough is presented. The most common associated conditions are post-viral cough, asthma, rhinosinusitis (post-nasal drip or 'nasal catarrh') and gastro-oesophageal reflux. Treatment with angiotensin-converting enzyme inhibitors can also lead to a persistent dry cough. Specific treatment of the cause should control the cough, but this may not occur in all cases and in a sizeable proportion of patients, no associated cause can be found. An increased sensitivity of the cough reflex can be observed in patients with persistent dry cough. Symptomatic relief must be considered when the cough interferes with the patient's health and sleep but the most effective antitussive opiates cause sedation and may be addictive. Treatment of persistent dry cough remains a challenge in some patients and there is still scope for improvement in its diagnosis and effective therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2004

Reduced pH and chloride levels in exhaled breath condensate of patients with chronic cough.

BACKGROUND: Increased hydrogen and reduced chloride ionic environments of the airways are conducive to the stimulation of cough. However, the constituents of the local milieu of the airways of patients with chronic cough are unknown. METHODS: The pH and chloride levels in exhaled breath condensate and capsaicin cough threshold (C5) were measured in 50 patients with chronic cough and in 16 healthy controls. pH and chloride measurements were repeated after capsaicin challenge in those with cough. The cause of cough was asthma (n = 13), postnasal drip/rhinitis (n = 7), gastro-oesophageal reflux (n = 5), bronchiectasis (n = 5), but remained unidentified in 20. RESULTS: Compared with controls, patients with chronic cough had lower pH (mean 7.9 v 8.3, 95% CI of difference -0.5 to -0.2, p<0.0001), chloride levels (median 4 v 6 mmol/l, 95% CI -3.1 to -0.2, p = 0.007), and C5 (median 3.9 v 125 micro M, 95% CI -270.0 to -17.6, p = 0.002). The pH levels were different in the six subgroups including controls, and were reduced in all diagnostic subgroups of patients with cough compared with controls but did not differ between them. Chloride levels were significantly different in the six subgroups but were lower than controls in only the gastro-oesophageal reflux subgroup. There was a weak but significant correlation between chloride levels and C5 when all participants were analysed together, but not between pH and C5 or chloride levels. pH and chloride levels did not change after capsaicin challenge. CONCLUSIONS: The epithelial lining fluid of patients with chronic cough has a reduced pH and reduced chloride levels which could contribute to the enhanced cough reflex.

Adult↗
PubMed2006

Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms.

BACKGROUND: The prevalence and severity of chronic cough in the community is uncertain. In a large population of representative normal subjects, we explored the relationship between self-reported cough severity and frequency, and factors known to be related to the aetiology of chronic cough. In particular, we have examined the relative association between cough and symptoms of gastrointestinal disease. METHODS: A cross-sectional survey was undertaken in 36 general practices with subjects randomly selected from practice computer databases. Baseline lifestyle and demographic characteristics were recorded. Participants were asked how often in the previous 2 months they had experienced bouts or spasms of coughing. Cough symptom status was dichotomised into symptomatic using a cut off of bouts or spasms of coughing at a frequency of between once a week and once a day or above. Gastrointestinal data were collected using validated methodology. RESULTS: Questionnaires were sent to 6416 subjects and 4003 (62%) responded. The prevalence of chronic cough was 12%, and was severe in 7%. Following multivariate analysis, regurgitation (OR 1.71; 99% CI 1.20 to 2.45) and irritable bowel syndrome (OR 2.00; 99% CI 1.47 to 2.72) were strong predictors of cough. Smoking (OR 1.61; 99% CI 1.18 to 2.19), declining social class (OR 1.63; 99% CI 1.04 to 2.57), and quality of life at baseline (OR 1.63; 99% CI 1.13 to 2.35) were also significantly associated. CONCLUSION: Chronic cough is a common symptom in the general population. Its strong association with gastrointestinal disease may have aetiological significance.

Adult↗
PubMed2001

Iron supplementation inhibits cough associated with ACE inhibitors.

Dry cough is the most common limiting factor of ACE inhibitor (ACEI) use. Generation of NO, a proinflammatory substance on bronchial epithelial cells, is increased by ACEI. Using a randomized, double-blind, placebo-controlled trial, we tested the hypothesis that supplementing iron, an inhibitor of NO synthase, may reduce the cough associated with ACEI use. The subjects were 19 patients who had developed ACEI-induced cough. After a 2-week observation period, they were randomized to a daily morning dose of either 256-mg ferrous sulfate as a tablet or placebo for a treatment period of 4 weeks. The subjects were requested to fill out a cough diary by scoring the daily severity of the cough on a scale of 0 to 4. Mean daily cough scores for the last week of the observation and treatment period were compared. Changes in blood cell count and serum iron and ferritin concentration between the 2 periods were evaluated. Mean daily cough scores during the observation and treatment periods were 3.07+/-0.70 and 1.69+/-1.10, respectively, for the iron group and 2.57+/-0.80 and 2.35+/-1.22, respectively, for the placebo group, showing a significant reduction in cough scores with iron supplementation (P<0.01) but not with placebo. Three subjects in the iron group showed almost complete cough abolition. No significant changes in laboratory data were observed in either group. In conclusion, iron supplementation successfully decreases ACEI-induced cough. This effect may be related to the decrease of NO generation associated with the inhibition of NO synthase activity in bronchial epithelial cells.

Adult↗
PubMed1999

Eosinophilic bronchitis is an important cause of chronic cough.

Eosinophilic bronchitis presents with chronic cough and sputum eosinophilia, but without the abnormalities of airway function seen in asthma. It is important to know how commonly eosinophilic bronchitis causes cough, since in contrast to cough in patients without sputum eosinophilia, the cough responds to inhaled corticosteroids. We investigated patients referred over a 2-yr period with chronic cough, using a well-established protocol with the addition of induced sputum in selected cases. Eosinophilic bronchitis was diagnosed if patients had no symptoms suggesting variable airflow obstruction, and had normal spirometric values, normal peak expiratory flow variability, no airway hyperresponsiveness (provocative concentration of methacholine producing a 20% decrease in FEV(1) ([PC(20)] > 8 mg/ml), and sputum eosinophilia (> 3%). Ninety-one patients with chronic cough were identified among 856 referrals. The primary diagnosis was eosinophilic bronchitis in 12 patients, rhinitis in 20, asthma in 16, post-viral-infection status in 12, and gastroesophageal reflux in seven. In a further 18 patients a diagnosis was established. The cause of chronic cough remained unexplained in six patients. In all 12 patients with eosinophilic bronchitis, the cough improved after treatment with inhaled budesonide 400 micrograms twice daily, and in eight of these patients who had a follow-up sputum analysis, the eosinophil count decreased significantly, from 16.8% to 1.6%. We conclude that eosinophilic bronchitis is a common cause of chronic cough, and that sputum induction is important in the investigation of cough.

Administration, Inhalation↗
PubMed2004

Increased expression of transient receptor potential vanilloid-1 in airway nerves of chronic cough.

Transient receptor potential vanniloid-1 (TRPV-1) mediates the cough response induced by the pepper extract capsaicin and is expressed in sensory nerves that innervate the airway wall. We determined the expression of TRPV-1 in the airways of patients with chronic persistent cough of diverse causes and with an enhanced capsaicin cough response. We obtained airway mucosal biopsies by fiberoptic bronchoscopy in 29 patients with chronic cough and 16 healthy volunteers without a cough. Immunostaining for nerve profiles with anti-protein gene product (PGP)-9.5 antibody showed no increase in nerve profiles in the airway epithelium of patients with chronic cough; however, with an anti-TRPV-1 antibody, there was a fivefold increase of TRPV-1 staining nerve profiles (p < 0.001). There was a significant correlation between capsaicin tussive response and the number of TRPV-1-positive nerves within the patients with cough. Our findings indicate that TRPV-1 receptors may contribute to an enhanced cough reflex and the cough response in chronic persistent cough of diverse causes.

Adult↗
PubMed1989

Recombinant human enkephalinase (neutral endopeptidase) prevents cough induced by tachykinins in awake guinea pigs.

To determine whether recombinant enkephalinase (neutral endopeptidase, EC 3.4.24.11) prevents cough induced by exogenously applied and endogenously released neuropeptides, we measured cough responses to aerosolized solutions of substance P or of capsaicin for 2 min in random-source guinea pigs before or after exposing them to aerosolized recombinant human enkephalinase. Substance P (10(-16) M) increased coughing compared with its vehicle. Enkephalinase (120 micrograms) inhibited cough induced by subsequent exposure to substance P compared with the response to substance P alone, but after further exposure to the enkephalinase inhibitor leucine-thiorphan (10(-5) M), substance P increased cough significantly. Similar results were obtained for capsaicin-induced cough. In pathogen-free guinea pigs, after they inhaled inactive recombinant enkephalinase (33 micrograms), capsaicin (10(-13) M) increased cough significantly. In contrast, after they inhaled active recombinant enkephalinase (33 micrograms), capsaicin increased cough only slightly. These results suggest that aerosolized enkephalinase reaches the sites of release or actions of endogenous neuropeptides and, by degrading them, prevents cough induced by their release. Furthermore, these studies suggest that recombinant enkephalinase might be useful in the treatment of cough and other symptoms of diseases involving peptides cleaved by this enzyme.

Aerosols↗