Surinder S. Birring

Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease

Background: An association between the sputum eosinophil count and the response to a 2 week course of prednisolone has previously been reported in patients with chronic obstructive pulmonary disease (COPD). Whether the response to inhaled corticosteroids is related to the presence of eosinophilic inflammation is unclear. Methods: A randomised, double blind, crossover trial of placebo and mometasone furoate (800 μg/day), each given for 6 weeks with a 4 week washout period, was performed in subjects with COPD treated with bronchodilator therapy only. Spirometric tests, symptom scores, chronic respiratory disease questionnaire (CRQ), and induced sputum were performed before and after each treatment phase. Results: Ninety five patients were recruited of which 60 were randomised. Overall there were no treatment associated changes in forced expiratory volume in 1 second (FEV1), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV1 increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV1 with mometasone compared with placebo in the highest tertile was 0.11 l (95% CI 0.03 to 0.19). This improvement was not associated with a fall in the sputum eosinophil count. Conclusions: An increased sputum eosinophil count is related to an improvement in post-bronchodilator FEV1 following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

Comparison of airway immunopathology of eosinophilic bronchitis and asthma

Background: Eosinophilic bronchitis is a condition characterised by a corticosteroid responsive cough, sputum eosinophilia, and normal tests of variable airflow obstruction and airway responsiveness. We performed a detailed comparative immunopathological study to test the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma reflects differences in the nature of the lower airway inflammatory response. Methods: Exhaled nitric oxide was measured and induced sputum, bronchoscopy, bronchial wash (BW), bronchoalveolar lavage (BAL), and bronchial biopsy were performed in 16 subjects with eosinophilic bronchitis, 15 with asthma, and 14 normal controls. Results: Both eosinophilic bronchitis and asthma were characterised by an induced sputum, BW and BAL eosinophilia, an increased number of epithelial and subepithelial eosinophils, and increased reticular basement membrane thickness. The median concentration of exhaled nitric oxide was higher in those with eosinophilic bronchitis (12 ppb) or asthma (8.5 ppb) than normal controls (2 ppb) (95% CI of the difference 5 to 16, p<0.0001 and 2 to 11.3, p=0.004, respectively). There were no group differences in epithelial integrity or the number of subepithelial T lymphocytes, mast cells or macrophages. Conclusion: With the exception of our previously reported association of smooth muscle mast cell infiltration with asthma, the immunopathology of eosinophilic bronchitis and asthma are similar which suggests that eosinophilic airway inflammation, increased exhaled nitric oxide, and increased basement membrane thickening are regulated independently of airway hyperresponsiveness.

The influence of age on induced sputum differential cell counts in normal subjects.

STUDY OBJECTIVES Sputum induction is increasingly used as a research technique and as a clinical tool. In order to evaluate abnormal results, normal ranges need to be fully developed. Although a number of studies have described normal ranges, none have investigated the effect of the age of the subject on these results. This study was undertaken to assess whether there are age-related differences in sputum cell differential cell counts in a population of normal, healthy volunteers. STUDY DESIGN AND PARTICIPANTS Induced sputum samples were obtained from 66 healthy, nonsmoking subjects (24 men) with a mean age of 44 years (age range, 18 to 74 years). Differential cell counts were related to age. RESULTS Sputum neutrophil counts were found to correlate significantly with the age of the volunteers (r = 0.58; p < 0.001). Macrophage counts showed a proportionate, inverse correlation with increasing age (p < 0.01), but no correlation was seen for any other cell type. On subanalysis according to age range, the mean neutrophil differential increased from 26.9% (SD, 19.8%) [17 patients] in the group of patients who were 0 to 29 years of age to 68.5% (SD, 20.6%) [11 patients] in the group of patients who were > 60 years of age. CONCLUSION In our healthy volunteer population, the induced sputum differential neutrophil count increased significantly with age. These findings highlight the need for age matching in controlled studies.

Detection of cough signals in continuous audio recordings using hidden Markov models

Cough is a common symptom of many respiratory diseases. The evaluation of its intensity and frequency of occurrence could provide valuable clinical information in the assessment of patients with chronic cough. In this paper we propose the use of hidden Markov models (HMMs) to automatically detect cough sounds from continuous ambulatory recordings. The recording system consists of a digital sound recorder and a microphone attached to the patients chest. The recognition algorithm follows a keyword-spotting approach, with cough sounds representing the keywords. It was trained on 821 min selected from 10 ambulatory recordings, including 2473 manually labeled cough events, and tested on a database of nine recordings from separate patients with a total recording time of 3060 min and comprising 2155 cough events. The average detection rate was 82% at a false alarm rate of seven events/h, when considering only events above an energy threshold relative to each recordings average energy. These results suggest that HMMs can be applied to the detection of cough sounds from ambulatory patients. A postprocessing stage to perform a more detailed analysis on the detected events is under development, and could allow the rejection of some of the incorrectly detected events.

Multiple inflammatory hits and the pathogenesis of severe airway disease

Refractory or difficult-to-control asthma is associated with some clinical and pathological features normally associated with chronic obstructive pulmonary disease (COPD), raising the possibility that there are similarities in their pathogenesis. It is suggested that the coexistence of two or more inflammatory stimuli to the airway (multiple hits) is a key factor leading to the development of more severe airway disease. Airway inflammation in response to chronic inflammatory conditions elsewhere may be a particularly important additional inflammatory stimulus. The “multiple hit” hypothesis for the origins of severe airway disease has important implications for treatment and prevention, since identification and removal of additional inflammatory stimuli may delay progression of the underlying airway disease.

Chronic tonsillar enlargement and cough: preliminary evidence of a novel and treatable cause of chronic cough

Tonsillar enlargement is sometimes seen in patients with otherwise unexplained chronic cough although its significance is unclear. In this study, the authors set out to test the hypothesis that cough symptoms and cough reflex sensitivity will improve after tonsillectomy in patients with otherwise unexplained chronic cough and enlarged tonsils. Eight consecutive patients with unexplained chronic cough and enlarged tonsils were recruited from 236 patients seen in a cough clinic between 2000 and 2001. Six patients with enlarged tonsils and no cough who were undergoing tonsillectomy for other reasons were recruited as a control group. All patients rated cough severity on a cough visual analogue score (0–100 mm) and had capsaicin cough reflex sensitivity measurement twice before and again 3 months after tonsillectomy. Patients with a chronic cough had heightened cough reflex sensitivity compared with the control group at baseline. There was a significant improvement in mean cough visual analogue score 3 months after tonsillectomy in patients with chronic cough (mean difference 30 mm; 95% confidence interval of difference 8–51 mm). The geometric mean concentration of capsaicin required to cause five coughs increased from 4 to 207 µmol·L−1 after tonsillectomy in patients with chronic cough (mean difference from baseline 5.6 doubling concentrations; 95% confidence interval of difference 3.1–8.2). There was no change in cough reflex sensitivity in control patients after tonsillectomy. These preliminary findings suggest for the first time a possible role for tonsillectomy in patients with enlarged tonsils in whom other causes of cough have been ruled out.

Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial

Aims Unexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that long-term low-dose erythromycin reduces the induced sputum neutrophil count and 24 h cough frequency in patients with unexplained chronic cough. Methods 30 patients with an unexplained chronic cough lasting more than 8 weeks were randomly assigned to take 250 mg erythromycin once daily (n=15) or placebo (n=15) for 12 weeks in a double-blind parallel group study. Cough frequency, cough reflex sensitivity and cough severity were assessed at baseline, 6, 12 and 24 weeks. The primary outcome measure was change in 24 h cough frequency at 12 weeks. Results There was no difference in the change in cough frequency between the erythromycin and placebo groups at 12 weeks (mean difference in fold change 1.1; 95% CI 0.7 to 1.5; p=0.585) or at other times. There was a statistically significant between-treatment difference in the change in sputum neutrophils at 12 weeks (−10.2% vs +6.6% with erythromycin and placebo; mean difference 16.8%; 95% CI 1.6 to 32.1; p=0.03) but not at other times. There was no difference in the change in other measures of cough between treatments. Conclusions Treatment with low-dose erythromycin for 12 weeks reduces the induced sputum neutrophil count but not cough frequency or severity in patients with unexplained chronic cough.

Airway function and markers of airway inflammation in patients with treated hypothyroidism

Background: There is increasing evidence of an association between organ specific autoimmune diseases, particularly autoimmune thyroid disease and respiratory morbidity. A study was undertaken to determine whether patients with autoimmune thyroid disease have objective evidence of airway inflammation and dysfunction. Methods: Twenty six non-smoking women with treated hypothyroidism and 19 non-smoking controls completed a symptom questionnaire and underwent full lung function tests, capsaicin cough reflex sensitivity measurement, methacholine challenge test, and sputum induction over two visits. Results: Symptoms of cough (p = 0.01), dyspnoea (p = 0.01), sputum production (p = 0.004), and wheeze (p = 0.04) were reported more commonly in patients than controls. Patients with hypothyroidism had heightened cough reflex sensitivity compared with controls (geometric mean concentration of capsaicin causing five coughs: 40 v 108 mmol/l; mean difference 1.4 doubling doses; 95% confidence interval of difference 0.4 to 2.5; p = 0.008) and a significantly higher proportion of patients had airway hyperresponsiveness (methacholine provocative concentration (PC20) <8 mg/ml: 38% v 0%; p = 0.016). Patients with hypothyroidism also had a significantly higher induced sputum total neutrophil cell count (p = 0.01), total lymphocyte count (p = 0.02), and sputum supernatant interleukin-8 concentrations (p = 0.048). Conclusion: Patients with treated hypothyroidism report more respiratory symptoms and have objective evidence of airway dysfunction and inflammation.

CXCR6 identifies a putative population of retained human lung T cells characterised by co-expression of activation markers

Expressions of activation markers have been described on the surface of T cells in the blood and the lung in both health and disease. We have studied the distribution of activation markers on human lung T cells and have found that only certain populations exist. Importantly, the presence or absence of some markers appears to predict those of others, in particular cells which express CD103 also express CD49a and CD69, whereas cells which do not express CD69 also do not express CD49a or CD103. In view of the paucity of activation marker expression in the peripheral blood, we have hypothesised that these CD69+, CD49a+, and CD103+ (triple positive) cells are retained in the lung, possess effector function (IFNgamma secretion) and express particular chemokine receptors which allow them to be maintained in this environment. We have found that the ability of the triple negative cells to secrete IFNgamma is significantly less than the triple positive cells, suggesting that the expression of activation markers can highlight a highly specialised effector cell. We have studied the expression of 14 chemokine receptors and have found that the most striking difference between the triple negative cells and the triple positive cells is the expression of CXCR6 with 12.8+/-9.8% of triple negative cells expressing CXCR6 compared to 89.5+/-5.5% of triple positive cells. We propose therefore that CXCR6 may play an important role in the retention of T cells within the lung.

The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough.

Chronic cough is a common condition that presents to both primary and secondary care. Assessment and management are hampered by the absence of well-validated outcome measures. The present study comprises the validation of the Leicester Cough Monitor (LCM), an automated sound-based ambulatory cough monitor. Cough frequency was measured with the LCM and compared with coughs and other sounds counted manually over 2 h of a 6-h recording by two observers in nine patients with chronic cough in order to determine the sensitivity and specificity of the LCM. Automated cough frequency was also compared with manual counts from one observer in 15 patients with chronic cough and eight healthy subjects. All subjects underwent 6-h recordings. A subgroup consisting of six control and five patients with stable chronic cough underwent repeat automated measurements ≥3 months apart. A further 50 patients with chronic cough underwent 24-h automated cough monitoring. The LCM had a sensitivity and specificity of 91 and 99%, respectively, for detecting cough and a false-positive rate of 2.5 events·h−1. Mean±sem automated cough counts·patient·h−1 was 48±9 in patients with chronic cough and 2±1 in the control group (mean difference 46 counts·patient·h−1; 95% confidence interval (CI) 20–71). The automated cough counts were repeatable (intra-subject sd 11.4 coughs·patient·h−1; intra-class correlation coefficient 0.9). The cough frequency in patients undergoing 24-h automated monitoring was 19 coughs·patient·h−1; daytime (08:00–22:00 h) cough frequency was significantly greater than overnight cough frequency (25 versus 10 coughs·patient·h−1; mean difference 15 coughs·patient·h−1, 95% CI 8–22). The Leicester Cough Monitor is a valid and reliable tool that can be used to assess 24-h cough frequency in patients with cough. It should be a useful tool to assess patients with cough in clinical trials and longitudinal studies.