Cough and glottic-stop reflex sensitivity in health and disease

STUDY OBJECTIVES: Little is known about the normal ranges and repeatability of cough reflex sensitivity measurements, or the relationship of cough reflex sensitivity to other upper airway reflexes in subjects with chronic dry cough. We set out to define the normal range of cough reflex sensitivity and its repeatability in health and disease, and to assess its relationship to the glottic-stop reflex. DESIGN: Prospective, cross-sectional study. SUBJECTS AND METHODS: We measured capsaicin cough reflex sensitivity in 134 healthy subjects and 88 patients with respiratory disease, and assessed the repeatability over 2 weeks in a subgroup of individuals (healthy subjects, 15; chronic cough patients, 15). In another subgroup (healthy patients, 16; chronic cough patients, 14), we measured the sensitivity of the glottic-stop reflex (using inhaled ammonia). RESULTS: Capsaicin cough sensitivity varied widely in the population of healthy subjects, and there was considerable overlap of cough reflex sensitivity between healthy control subjects and patients with cough. The intraclass correlation coefficients for repeatability of cough sensitivity (concentration of capsaicin that causes two coughs, and concentration of capsaicin that causes five coughs) were 0.89 and 0.88, respectively. Patients with chronic cough had a significantly more sensitive glottic-stop reflex than healthy subjects (glottic-stop sensitivity threshold, 483 ppm vs 1,029 ppm, respectively; p = 0.01), and there was a significant positive correlation between glottic-stop and cough reflex sensitivity (r = 0.5; p < 0.01). CONCLUSIONS: We have shown a wide variation of cough reflex sensitivity in healthy subjects, although the measurement does have good 2-week repeatability. There was a reasonably close relationship between cough sensitivity and glottic-stop reflex sensitivity, indicating either that the cough reflex and the glottic-stop reflex share a common pathway or that subjects who have a chronic cough have a global abnormality of upper airway reflexes.     

Comparison between tidal breathing and dosimeter methods in assessing cough receptor sensitivity to capsaicin

OBJECTIVE: Dosimeter method and tidal breathing method have been used to assess cough sensitivity to inhaled capsaicin, a C-fibre ending stimulator. The aim of the present study was to evaluate the repeatability of and the agreement between the two methods. METHODOLOGY: Cough threshold, the lowest concentration of capsaicin causing five or more coughs, was measured twice 1-3 weeks apart by each method in 26 normal subjects. Increasing concentrations of capsaicin were inhaled by a single breath in the dosimeter method or by 15 s tidal breathing in the tidal breathing method in 1 min intervals. RESULTS: Coefficients of repeatability of the cough threshold measurement were 1.89 and 2.71 doubling concentration in the tidal breathing method and the dosimeter method, respectively, suggesting good repeatability in the cough threshold measurement by both methods. The cough threshold was significantly (P < 0.0001) greater by 1.75 doubling concentration on the dosimeter method than the tidal breathing method. The coefficient of agreement between the two methods was 2.53 doubling concentration. Five subjects complained of burning sensation in the throat in the dosimeter method but no patient complained about the tidal breathing method (P < 0.05). CONCLUSIONS: Although the agreement between the two methods was considered to be good, higher concentrations of capsaicin solution were required to determine the cough threshold in the dosimeter method, resulting in an unpleasant sensation in the throat.     

Effect of Tiotropium on Cough Reflex Sensitivity in Acute Viral Cough

Study Objectives Cough is the most common complaint for which patients in the United States seek medical attention. Few, if any, effective therapies exist for the most common form of acute cough, that due to viral upper respiratory tract infection (URI). The aim of this study was to evaluate the effect of the anticholinergic agent tiotropium bromide on cough reflex sensitivity in subjects with acute viral URI. Patients Otherwise healthy adult nonsmokers with acute viral URI were randomized to receive inhaled tiotropium, 18 μg once daily, or matched placebo, for 7 days. A control group of healthy volunteers underwent an identical protocol. Measurements and Results Cough reflex sensitivity to inhaled capsaicin was measured at baseline (Day 0), and 1 h after the first (Day 1) and seventh (Day 7) dose of tiotropium or placebo. Concentrations of capsaicin inducing two or more (C ₂) and five or more coughs (C ₅) were determined. In subjects with URI, tiotropium (n = 11) demonstrated inhibition of cough reflex sensitivity relative to baseline (increased log C ₂ [p = 0.004] and log C ₅ [p = 0.0004]) after the first dose. No change occurred in the placebo group (n = 10). After 7 days, mean log C ₂ was significantly increased in the tiotropium group relative to placebo (p = 0.03). Although FEF_25–75 was also increased in the tiotropium group (p = 0.016), there was no significant correlation between changes in cough reflex sensitivity and FEF_25–75. Tiotropium had no effect in healthy volunteers (n = 24). Conclusions Tiotropium inhibits cough reflex sensitivity to capsaicin in subjects with acute viral URI. The antitussive effect of tiotropium may occur through a mechanism other than bronchodilation.     

Quantifying chronic cough: objective versus subjective measurements

Background and objective: The assessment of chronic cough has been improved by the development of objective ambulatory cough monitoring systems and subjective quality of life questionnaires. Experimental induction of cough is a useful tool in the assessment of the cough reflex. We wanted to assess the reproducibility of and association between these measurements. Methods: This was a prospective observational study in patients with chronic cough of greater than 6 months' duration. All patients had an initial 24‐h cough recording. They also completed a Leicester Cough Questionnaire, a Symptom Assessment Score, a Visual Analogue Score for cough and had a capsaicin cough challenge performed. They were reviewed at 8 weeks when all assessments were repeated. Results: Twenty‐five patients (15 women) with a mean age of 54 years were included in the study. The median cough count at the second visit (302) was significantly lower compared to the first visit (381, P < 0.01). However, the cough counts at both the visits correlated well (r = 0.9, P < 0.01). All the other forms of assessment were found to be highly reproducible at 8 weeks (r = 0.6–0.9, P < 0.01). Cough counts correlated well with the other forms of assessment (r = 0.4–0.6, P < 0.01). There was good correlation between each of the subjective forms of assessment (r = 0.6, P < 0.01). Conclusions: The various forms of assessment of cough are reproducible. Cough counting correlates well with subjective assessment of cough and cough reflex sensitivity. It appears to lie between these latter two assessments of cough and may represent the best global objective synthesis of cough.     

Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non-acid gastro-oesophageal reflux

Background and objective: The aim of this study was to explore the pathogenesis of chronic cough caused by non‐acid reflux. Methods: Seven patients with chronic cough due to non‐acid reflux, 12 patients with chronic cough due to acid reflux, 10 patients with gastro‐oesophageal reflux disease without cough and 12 healthy volunteers were recruited for the study. All subjects underwent oesophageal multi‐channel intraluminal impedance measurements combined with pH monitoring, and assessment of cough reflex sensitivity to capsaicin and induced sputum cytology. The concentrations of substance P, mast cell tryptase, prostaglandin D2 and histamine in induced sputum were measured by ELISA. Results: Cough threshold C2 and C5 did not differ between patients with chronic cough due to non‐acid or acid reflux, but the values were significantly lower than those for patients with gastro‐oesophageal reflux disease without cough and healthy volunteers. Weakly acidic reflux episodes were obviously more frequent in patients with chronic cough due to non‐acid reflux than in the other three groups. Sputum substance P and mast cell tryptase concentrations were remarkably increased in patients with chronic cough, but were similar for those with cough due to non‐acid or acid reflux. There were significant inverse correlations between substance P levels and cough threshold C2 or C5 in patients with cough due to non‐acid or acid reflux, and between mast cell tryptase levels and cough threshold C2 in patients with cough due to acid reflux. Conclusions: Chronic cough due to non‐acid reflux may be related to cough reflex hypersensitivity caused by neurogenic airway inflammation and mast cell activation, in which weakly acidic reflux is possibly a major factor.     

Ethnic and gender differences in cough reflex sensitivity.

BACKGROUND: Although recent studies have suggested that the cough reflex is more sensitive in women than in men, ethnic differences in cough reflex sensitivity have not previously been investigated. OBJECTIVES: To evaluate ethnic and gender differences in cough reflex sensitivity. METHODS: We performed capsaicin cough challenge testing in 182 healthy volunteers of three distinct ethnic groups: Caucasian (white, non-Hispanic, of European origin), Indian (originating from the Indian subcontinent) and Chinese. The concentration of capsaicin inducing 2 or more (C2) and 5 or more coughs (C5) was determined in each subject. RESULTS: Mean (+/-SEM) values for log C5 demonstrated that, within each ethnic group, the cough reflex was more sensitive in women: p = 0.00002 for Caucasian subjects; p = 0.003 for Indian volunteers; and p = 0.002 for Chinese subjects. Examination of C2 data yielded similar results. When subjects were evaluated by gender, multivariate analysis of variance demonstrated no ethnic differences in sensitivity to capsaicin. CONCLUSION: Our data do not support the presence of significant ethnic differences in cough reflex sensitivity, but do confirm previous data demonstrating lower cough thresholds in women.     

Cough challenge tests involving mechanical stimulation of the cervical trachea in patients with cough as a leading symptom

Background and objective: Challenge tests involving chemical stimulation by inhalation of capsaicin or citric acid are currently used to assess cough sensitivity. We investigated the clinical usefulness of cough challenge tests based on mechanical stimulation. Methods: A total of 347 patients (126 men and 221 women) were enrolled in the study, including 161 patients with asthma, 116 with cough‐variant asthma, 27 with acute upper respiratory tract viral infections, 25 with acute bronchitis, four with pneumonia, three with chronic bronchitis and 11 with cough of unknown aetiology. Three modes of mechanical stimulation were assessed: the cervical trachea was compressed softly with the fingers several times (tracheal compression test); the trachea was stretched by retroflexion of the neck for 5 s (tracheal stretch test); and a vibrating tuning fork was placed on the cervical trachea for 20 s (tuning fork test). The relationships between phonation‐induced cough and the results of these tests were assessed. Results: The cough detection rate was 27.7% with the tracheal compression test, 39.8% with the tracheal stretch test and 36.9% with the tuning fork test. An itchy sensation with or without cough was noted by about 50% of subjects undergoing each of the tests. Provocation of cough and an itchy sensation during each test was significantly more frequent in subjects with phonation‐induced cough. Tests were usually negative after improvement of the cough with treatment. Conclusions: Mechanical stimulation of the cervical trachea is a feasible cough challenge test that may be useful for evaluating disease activity.     

The effect of codeine on the Urge-to-Cough response to inhaled capsaicin

We have shown previously in normal subjects that a sensory measure, the Urge-to-Cough rating, increases at concentrations of inhaled capsaicin that are lower than those necessary to elicit reflex cough. This finding suggests that the Urge-to-Cough may represent an index of the cough response. Research on cough in the human has most often employed challenge with inhaled capsaicin to induce reflex cough. Current measures of cough sensitivity in the human provide no information regarding the intensity of cough. The influence of codeine on cough perceptual sensitivity and the relationship to cough intensity with capsaicin-induced cough in normal subjects has not been evaluated. This study determined the effect of codeine on capsaicin-induced cough perceptual sensitivity and motor response in normal subjects in a double-blind, placebo-controlled, crossover study. This approach investigated the relevance of cough sensitivity, intensity, and sensory modalities in the assessment of cough suppression in humans. This study consisted of three experimental trials: administration of placebo, 30 mg codeine and 60 mg codeine. The study was double-blinded. The order of the three trials was randomized. Respiratory motor pattern was recorded with EMGs from the rectus abdominis, lateral abdominal muscles and eighth intercostal space. The subjects leaned into a fume hood to inspire deeply for 2 s once through a mouthpiece connected to the nebulizer. A modified Borg scale was used to estimate their Urge-to-Cough. The experimental trial consisted of eight test solutions of 0-200 microM capsaicin. Each solution was presented three times in a randomized block order for a total of 24 presentations. The lowest capsaicin concentration to elicit a cough was determined. The lowest capsaicin concentration to elicit an Urge-to-Cough greater than zero was identified. The Urge-to-Cough sensitivity was determined from the log-log slope. For placebo, the Urge-to-Cough was zero with inhalation of the vehicle and no coughs were observed. The threshold capsaicin concentration for subjects to report an Urge-to-Cough was 15.6 microM (+/-2.6 SEM). The capsaicin concentration threshold for eliciting a cough was significantly greater, 39.3 microM (+/-5.6 SEM). As the capsaicin concentration increased, the magnitude estimation of the Urge to-Cough increased. The slope of the log-log relationship for the Urge-to-Cough was 0.94 (+/-0.07 SEM). As the capsaicin concentration increased, the number and intensity of the coughs increased. The administration of 30 and 60 mg codeine had no significant effect on the threshold capsaicin concentration for the Urge-to-Cough. There was also no significant codeine effect on the slope of the log-log Urge-to-Cough relationship. Thirty and sixty milligram codeine had no significant effect on the relationship between the capsaicin concentration and the number and intensity of the coughs. The results of this study demonstrate that the threshold for a subject to perceive an Urge-to-Cough was less than the capsaicin concentration that elicits the cough motor response. There was a direct relationship between the sensory intensity (magnitude estimation of the Urge-to-Cough) and the cough number and intensity. Thus, as the sense of an Urge-to-Cough increased the cough motor response increased. Neither the 30 nor 60 mg codeine affected the perceptual or motor sensitivity to capsaicin-induced cough. These results showed that the initial threshold for responding to capsaicin-induced cough is the perception of an Urge-to-Cough, followed by a motor cough response if the capsaicin is increased above the perceptual threshold. As the capsaicin concentration increases, both the perceptual need to cough and the cough motor response increase. The response of subjects to inhalation of capsaicin consisted of both a sensory component leading to perception of an Urge-to-Cough and motor cough behavior.     

Acute sustained hypoxia suppresses the cough reflex in healthy subjects

RATIONALE: An intact cough reflex is important to protect the lung from injurious substances and to clear excess secretions. A blunted cough reflex may be harmful or even fatal in respiratory disease. Hypoxia is common in respiratory disorders and has been shown to have depressant effects on respiratory sensation and ventilation. We hypothesized that it might also suppress the cough reflex. OBJECTIVES: To determine if acute hypoxia increases cough threshold and cough tachyphylaxis to inhaled capsaicin. METHODS: On two occasions, 16 healthy subjects inhaled a saline control followed by doubling doses of capsaicin aerosol (range, 0.49-500 microM) every minute for 15 s during controlled ventilation (approximately 190% baseline) with isocapnic hypoxia (SpO2, approximately 80%) or isocapnic normoxia, in random order. When a subject responded to a dose with five or more coughs, the next doubling dose of capsaicin was administered continuously for 60 s to assess acute tachyphylaxis. MAIN RESULTS: The capsaicin concentration required to elicit five coughs was significantly higher during isocapnic hypoxia compared with normoxia (29.6 +/- 16.0 vs. 23.4 +/- 15.6 microM, p = 0.01). During continuous capsaicin inhalation, significantly more coughs were evoked in the first 10 s compared with the last (2.3 +/- 0.3 vs. 1.3 +/- 0.3, p < 0.01), indicating cough tachyphylaxis. However, the decrease was the same during hypoxia and normoxia (-1.3 +/- 0.4 vs. -0.9 +/- 0.6, p = 0.54). CONCLUSIONS: Acute isocapnic hypoxia suppresses cough reflex sensitivity to inhaled capsaicin. This finding raises the possibility that the cough reflex may be impaired during acute exacerbations of hypoxic-respiratory disorders.     

Chronic cough management: dealing with a sensation of irritation in the throat

Among the various types of laryngeal paraesthesia suffered by chronic cough patients, we often encounter ‘a sensation of irritation in the throat (SIT)’. Our study indicated that capsaicin cough threshold was significantly (P < 0.05) lower in the SIT‐positive group (13.9 μmol/L) than in the SIT‐negative group (49.6 μmol/L). The establishment of treatment strategies for SIT would be advantageous for treating chronic cough patients suffering from this laryngeal sensation.     

Sensitivity of the cough reflex in patients with chronic cough.

Cough may occur in association with excess bronchial secretions and may, therefore, be productive. However, in a proportion of patients the cough is non-productive and a possible association with an enhanced response of the cough reflex has been postulated. Using the irritant capsaicin, the sensitivity of the cough reflex was measured in 363 individuals. A questionnaire was used to divide subjects into three groups: Group A) non-coughing controls; Group B) subjects with non-productive cough; and Group C) subjects with productive cough. The group means (+/- 99% confidence interval (CI)) of the log capsaicin concentration causing two or more coughs (C2) for groups A, B, C were 0.98 (+/- 0.08), 0.64 (+/- 0.09) and 1.04 (+/- 0.23), respectively. The log capsaicin concentration causing five or more coughs (C5) for groups A, B, C were 1.78 (+/- 0.1), 1.16 (+/- 0.12) and 1.54 (+/- 0.25), respectively. Group B was significantly more sensitive to inhaled capsaicin than the other groups (p less than 0.01). No significant difference was observed between groups A and C. Some differences were found when subgroups were examined within groups B and C. In group B, patients with post-nasal drip were found to have a normal sensitivity of the cough reflex and were, therefore, different from the remainder of patients with non-productive cough. In group C, patients with bronchiectasis and current infection showed an increase in the sensitivity of their cough reflex. It is concluded that cough can occur in association with either excess mucus production leading to productive cough or an increase in the sensitivity of the cough reflex, possibly leading to non-productive cough.     

Effect of capsaicin on airway responsiveness to hypertonic saline challenge in asthmatic and non-asthmatic children

Recurrent cough and asthma are common problems in children. In the evaluation of children with recurrent cough, the sequential measurements of airway responsiveness (AR) and capsaicin cough receptor sensitivity may be useful. However, the effect of capsaicin on AR induced by an indirect stimulus such as hypertonic saline (HS) is not known. Current evidence suggests that a common pathway is involved in both capsaicin and HS challenges. This study was designed to determine whether inhalation of capsaicin for the cough receptor sensitivity test before HS challenge will alter AR of asthmatic and non-asthmatic children to that challenge. Twenty-one children (12 asthmatics, 9 non-asthmatics; mean age, 11.3 years) performed the HS challenge alone or 2 min after capsaicin inhalation on 2 different days in random order. The end point of the capsaicin inhalation was when ≥5 coughs were stimulated from a single inhalation. The power of the study was >90% at a significance level of 0.05. Capsaicin inhalation prior to HS challenge did not alter the AR of normal children. In the asthmatic group, the PD₁₅ (provocation dose causing a fall in forced expiratory volume in 1 s of ≥15% from the baseline) without prior inhalation of capsaicin (mean, 2.44 ± SEM 1.21 ml) was not significantly different from that when HS challenge was performed after capsaicin inhalation (mean, 2.19 ± SEM 0.83 ml). The mean of the difference in log PD₁₅ of the HS challenge with and without capsaicin was −0.02 (95% Cl, −0.16, 0.12), i.e. within the equivalence range of the HS challenge in children with asthma. We conclude that in normal and asthmatic children, capsaicin inhalation does not alter AR to HS; consequently the capsaicin cough sensitivity test can be performed validly before an HS challenge. Pediatr. Pulmonol. 1997; 23:412–416. © 1997 Wiley-Liss, Inc.     

Down-regulation of cough sensitivity after eucapnic dry air provocation in chronic idiopathic cough

Down-regulation of cough sensitivity in humans is rarely discussed in terms other than pharmacological treatment of cough or hypersensitive cough reflex. Chronic cough and increased cough sensitivity could be due to a number of airway and other diseases. When such conditions are excluded, there still remains a group of patients with no evident medical explanation for persistent coughing; such patients are often described as having “chronic idiopathic cough”.The aim of this study was to use a standardized eucapnic dry air provocation among patients with chronic idiopathic cough in order to study physiological parameters and measure their possible influence on capsaicin cough sensitivity. Fourteen female patients with chronic idiopathic cough and ten healthy controls underwent a capsaicin inhalation provocation on two occasions. In all patients, irritating environmental factors were known to induce cough and airway symptoms. One of the two capsaicin provocations was preceded by a eucapnic dry air provocation. Number of coughs, spirometry, respiratory rate, pulse rate, end-tidal CO₂, and oxygen saturation by pulse oximetry (PSaO₂) were registered and compared. The patients showed increased capsaicin sensitivity compared with the control subjects. This sensitivity was decreased when the capsaicin test was preceded by a eucapnic dry air provocation. Before the dry air provocation and after the capsaicin provocations, end-tidal CO₂ was decreased among the patients in comparison with the controls. After dry air provocation, spirometry values remained unchanged.The results suggest that in patients with chronic idiopathic cough, physiological down-regulation of the cough sensitivity is possible with a eucapnic dry air provocation.     

Capsaicin troche for swallowing dysfunction in older people

OBJECTIVES: To determine whether oral capsaicin troche supplementation with every meal upregulates the impairment of upper respiratory protective reflexes such as the swallowing reflex and the cough reflex. DESIGN: Randomized, controlled study with recruitment through nursing homes. SETTING: Sendai, Japan, from September 2002 through December 2003. PARTICIPANTS: Sixty-four participants in nursing homes with a mean age+/-standard deviation of 81.9+/-1.0 with stable physical status. INTERVENTION: Participants were randomly assigned to the program for the supplementation of capsaicin trochisci or placebo trochisci before every meal for 4 weeks. MEASUREMENTS: Assessment of individual latency time of the swallowing reflex (LTSR) and cough reflex sensitivity. RESULTS: Before the commencement of this study, there were no significant baseline differences in multiple parameters between the intervention group and control group. LTSR in participants in the intervention group was significantly shorter than in the control group (P<.05). The odds ratio (OR) of the shortening of the LTSR of more than 1 minute in the intervention group was 3.4 (95% confidence interval (CI)=1.1-10.4), compared with the control group (P=.03). In particular, daily capsaicin supplementation significantly increased the ratio of LTSR reduction at 4 weeks after the study to baseline LTSR in the high-risk group (baseline LTSR >6.0 seconds) compared with the low-risk group (baseline LTSR <3.0 seconds) and the intermediate group (3.0 seconds 相似文献   

Heightened cough response to bronchoconstriction in cough variant asthma

Background and objective: The pathophysiology of cough variant asthma (CVA) is poorly understood. We compared bronchoconstriction‐triggered cough between CVA patients and normal control (NC) subjects. Methods: There were two protocols in the study. We measured bronchial responsiveness to methacholine (MCh) and counted the number of coughs in nine CVA patients and seven NC subjects (Study A). Using partial and full flow–volume curves, expiratory flow of the partial flow–volume curve at 40% above residual volume level (PEF40) and FEV₁ were used to measure bronchoconstriction. Mild bronchoconstriction was defined as a 35% fall in PEF40 (PC₃₅‐PEF40), and more severe bronchoconstriction as a 20% fall in FEV₁ (PC₂₀‐FEV₁). In study B, the same measurements were obtained in six CVA patients before and after therapy. Results: In study A, more coughs were provoked at PC₃₅‐PEF40 in CVA patients (median, 60 coughs/32 min post challenge; range, 12–135) than in NC subjects (median, 0/32 min; range, 0–13; P < 0.05). At PC₂₀‐FEV₁, more coughs were provoked in CVA patients (median, 60/32 min; range, 12–150) than in NC subjects (median, 20/32 min; range, 0–54; P < 0.05). In study B, the six CVA patients who underwent re‐examination after treatment had less coughs at PC₃₅‐PEF40 (median, 3/32 min; range, 0–14) and PC₂₀‐FEV1 (median, 13/32 min; range, 3–26) after therapy than before therapy (median, 54/32 min; range, 33–125 and 52/32 min, 45–96, respectively; P < 0.05). Conclusions: We identified heightened cough response to bronchoconstriction as a feature of CVA.     

Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown.After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected.Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E₂, substance P, and leukotriene B₄, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced.These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted.     

Cough reflex testing with inhaled capsaicin in the study of chronic cough

OBJECTIVES: To assess the utility of capsaicin test in the differential diagnosis of non-productive causes of chronic cough and to examine the effects of treatment on this reflex. PARTICIPANTS: 86 healthy volunteers and 101 patients with chronic cough: asthma (n: 54) gastroesophageal reflux (n: 35) and post-nasal drip syndrome (n: 12). DESIGN: Prospective intervention trial. Spirometry, bronchoprovocation test with histamine (PC20), and cough challenge with ascending concentrations of capsaicin (0.49-500 microM) were initially performed in all subjects. Patients were treated for 3 months according to the origin of the cough. Concentrations that elicited two (C2) and five or more coughs (C5) were determined before and after treatment. RESULTS: In healthy subjects, cough sensitivity to capsaicin was not influenced by gender or smoking status; however, women with chronic cough were more sensitive to cough challenge than men. C2 and C5 were significantly lower in patients with asthma or gastroesophageal reflux than in post-nasal drip syndrome. No significant correlation was observed between the capsaicin cough threshold and PC20. Cough sensitivity did not improve significantly in most patients with asthma or gastroesophageal reflux despite adequate medical treatment during 3 months. Discriminative value of capsaicin test to differentiate healthy subjects from patients with asthma or reflux was poor. CONCLUSIONS: Cough sensitivity to inhaled capsaicin is a safe and reproducible tool in the study of chronic cough. However, its usefulness for the management and differential diagnosis is limited.     

Changes in cough reflex sensitivity after cessation and resumption of cigarette smoking

Previous studies have shown that healthy cigarette smokers have diminished cough reflex sensitivity compared to healthy nonsmokers. We have recently demonstrated that cough reflex sensitivity is enhanced soon after smoking cessation, suggesting that diminished cough sensitivity in smokers results from chronic cigarette smoke-induced desensitization of airway cough receptors. In this study, we evaluated cough reflex sensitivity to capsaicin (C(5)) in 11 chronic smokers who had discontinued smoking for at least 2 weeks, and then resumed smoking. Two weeks after smoking cessation there was a significant enhancement of cough reflex sensitivity; mean (+/-SEM) log C(5) decreased from 1.77+/-0.18 to 1.47+/-0.14 (p=0.01). All subjects resumed smoking after 2-12 weeks of abstinence. Repeat capsaicin cough challenge was performed 14-23 days after resumption of smoking. Mean log C(5) increased compared to the last value obtained during the smoking cessation period: 1.42+/-0.15 vs. 1.77+/-0.16 (p=0.0004). Mean log C(5) after resumption of smoking returned to almost exactly the baseline value. Our findings suggest that the sensitivity of airway cough receptors is a dynamic phenomenon, promptly affected and modulated by changes in environmental conditions, such as the presence or absence of cigarette smoke.     

Airway cough sensitivity to inhaled capsaicin and bronchial responsiveness to methacholine in asthmatic and bronchitic subjects

The objective of this study was to evaluate the effect of chronic airway inflammation on airway cough sensitivity and non-specific bronchial responsiveness, and the relationship between them. The capsaicin cough threshold, defined as the lowest concentration of capsaicin causing five or more coughs, and non-specific bronchial responsiveness, defined as the methacholine concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1) (PC20-FEV1), were measured in 18 asthmatic, 13 bronchitic (sinobronchial syndrome) and 28 healthy non-atopic subjects. All subjects were non-smoking men. The geometric mean values (mumol) of the cough threshold were 18.9 (GSEM 1.29), 8.69 (GSEM 1.29) and 27.6 (GSEM 1.31) in asthmatic, bronchitic and normal subjects, respectively. The value in bronchitic subjects was significantly lower (P < 0.02) than that in normal subjects. The geometric mean value of PC20-FEV1 in asthmatic subjects (0.48 mg/ml (GSEM 1.38)) was significantly lower than that in bronchitic subjects (18.5 mg/ml (GSEM 1.75)) (P < 0.001). There was no correlation between cough threshold and PC20-FEV1 values (correlation coefficient (r) = 0.155). These results indicate that cough sensitivity is potentiated by chronic airway inflammation in bronchitis but not in asthma, and suggest that cough sensitivity and bronchial responsiveness may be independently potentiated by different mechanisms resulting from chronic airway inflammation.     

'Free' surfactant in gastric aspirates and bronchoalveolar lavage in children with and without reflux oesophagitis

Aim: Dipalmitoylphosphatidycholine (DPPC) is the characteristic and main constituent of surfactant. Adsorption of surfactant to epithelial surfaces may be important in the masking of receptors. The aims of the study were to (i) compare the quantity of free DPPC in the airways and gastric aspirates of children with gastroesophageal reflux disease (GORD) to those without and (ii) describe the association between free DPPC levels with airway cellular profile and capsaicin cough sensitivity. Methods: Children aged <14 years were defined as ‘coughers’ if a history of cough in association with their GORD symptoms was elicited before gastric aspirates and nonbronchoscopic bronchoalveolar lavage (BAL) were obtained during elective flexible upper gastrointestinal endoscopy. GORD was defined as histological presence of reflux oesophagitis. Spirometry and capsaicin cough‐sensitivity test was carried out in children aged >6 years before the endoscopy. Results: Median age of the 68 children was 9 years (interquartile range (IQR) 7.2). Median DPPC level in BAL of children with cough (72.7 μg/mL) was similar to noncoughers (88.5). There was also no significant difference in DPPC levels in both BAL and gastric aspirates of children classified according to presence of GORD. There was no correlation between DPPC levels and cellular counts or capsaicin cough‐sensitivity outcome measures. Conclusion: We conclude that free DPPC levels in the airways and gastric aspirate is not influenced by presence of cough or GORD defined by histological presence of reflux oesophagitis. Whether quantification of adsorbed surfactant differs in these groups remain unknown. Free DPPC is unlikely to have a role in masking of airway receptors.