Showing papers by "Ian D. Pavord published in 2003"

Development of a symptom specific health status measure for patients with chronic cough: Leicester Cough Questionnaire (LCQ)

Abstract: BACKGROUND: Chronic cough is a common condition which has a significant impact on quality of life. Assessment and management are hampered by the absence of well validated outcome measures. The development and validation of the Leicester Cough Questionnaire (LCQ), a self-completed health related quality of life measure of chronic cough, is presented. METHODS: Patients with chronic cough were recruited from outpatient clinics. The development of the LCQ consisted of three phases: phase 1 (item generation); phase 2 (item reduction, allocation of items to domains and validation of questionnaire); phase 3 (repeatability and responsiveness testing of final version of questionnaire). RESULTS: Phase 1: Literature review, multidisciplinary team meeting and 15 structured interviews with chronic cough patients generated 44 items (LCQ1) with a 7 point Likert response scale. Phase 2: 104 chronic cough outpatients completed the LCQ1 along with an importance rating for each item. The clinical impact factor method was used for item reduction to 19 items (LCQ2: final version). These items were divided into three domains (physical, psychological and social) following expert opinion. Internal reliability, as assessed using Cronbach's alpha coefficients, varied between 0.79 and 0.89. Concurrent validity was high when the LCQ2 (n=56) was compared with a cough visual analogue score (r=-0.72). There was a moderate relationship with response to the St George's Respiratory Questionnaire (r=-0.54) and SF36 total score (r=0.46). Phase 3: Two week repeatability (n=24) was high with intraclass correlation coefficients for domains varying between 0.88 and 0.96. Responsiveness in nine patients whose cough was successfully treated varied within domains from an effect size of 0.84 to 1.75. CONCLUSION: The LCQ is a valid, repeatable 19 item self-completed quality of life measure of chronic cough which is responsive to change. It should be a useful tool in clinical trials and longitudinal studies.

Comparison of airway immunopathology of eosinophilic bronchitis and asthma

Abstract: 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.

Antiinflammatory Effects of the Phosphodiesterase-4 Inhibitor Cilomilast (Ariflo) in Chronic Obstructive Pulmonary Disease

Abstract: Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.

Interleukin-4 and -13 expression is co-localized to mast cells within the airway smooth muscle in asthma.

Abstract: Background: Airway smooth muscle infiltration by mast cells is a feature of asthma and not eosinophilic bronchitis. In asthma, Th2 cytokines have been implicated as playing a critical role in the development of airway inflammation and hyper-responsiveness. Whether inflammatory cells within the airway smooth muscle release these cytokines is unknown. Methods: We have undertaken a comparative immunohistochemical study in bronchial biopsies from 14 subjects with asthma, 10 with eosinophilic bronchitis and eight normal controls recruited from two centres. Results: The median number of IL-4+ cells/mm2 smooth muscle was significantly higher in subjects with asthma than eosinophilic bronchitis and normal controls for both the anti-IL-4 mAb 3H4 (2.4, 0, 0, respectively; P=0.001) and anti-IL-4 mAb 4D9 (1.6, 0, 0, respectively; P=0.02). There were no group differences in the number of IL-5+ cells (P=0.31). In six subjects with asthma, IL-13 expression by cells within the airway smooth muscle was studied. The median (range) of IL-13+cells was 2 (0.9–2.7). Ninety-four percent of the cells expressing IL-4 (3H4), 92% of those expressing IL-4 (4D9) and 100% expressing IL-13 in the airway smooth muscle were mast cells. Fifty-five percent of the mast cells within the airway smooth muscle co-localized to IL-4 (3H4), 29% to IL-4 (4D9) and 17% to IL-13. Conclusions: In asthma, IL-4+ and IL-13+ cells were present within the airway smooth muscle and were expressed predominantly by mast cells, suggesting that IL-4 and IL-13 may play an important role in mast cell–airway smooth muscle interactions.

Idiopathic chronic cough: association with organ specific autoimmune disease and bronchoalveolar lymphocytosis

Abstract: Background: We have recently reported a strong association between organ specific autoimmune disease and idiopathic chronic cough and have suggested that cough may be caused by airway inflammation secondary to aberrant homing of activated lymphocytes to the lung. An immunopathological study was undertaken to test the hypothesis that idiopathic chronic cough is associated with lymphocytic airway inflammation. Methods: Bronchoscopy, bronchial biopsies, bronchoalveolar lavage (BAL), and peripheral blood and BAL flow cytometry were performed in 19 patients with idiopathic chronic cough, 14 with explained chronic cough, and 11 normal subjects. Results: Organ specific autoimmune disease or positive autoantibodies were present in eight of the 19 patients with idiopathic cough, in one of the 14 patients with explained cough, and in one of the 11 normal subjects. Median BAL fluid differential lymphyocyte counts were significantly higher in patients with idiopathic cough (10.0%) than in normal subjects (6.3%, 95% confidence interval of difference 1.5 to 11.9, p = 0.01) or patients with explained cough (5.2%, 95% CI of difference 2.0 to 10.4, p = 0.001). There were no differences in bronchial biopsy T lymphocyte counts between the groups. The mean (SE) proportion of CD3+ peripheral blood mononuclear cells expressing CD4 was significantly higher in normal subjects than in patients with idiopathic cough (69 (3)% v 58 (3)%, mean difference 11%, 95% CI of difference 2 to 20, p<0.02) but not than those with explained chronic cough (63 (2)%). There were no differences in BAL T lymphocyte phenotype between groups. Conclusion: BAL fluid lymphocytosis occurs in some patients with idiopathic chronic cough. The association of idiopathic chronic cough with organ specific autoimmune disease raises the possibility that this might be caused by lymphocyte homing from the primary site of autoimmune inflammation or the result of an autoimmune process in the lung.

Respiratory symptoms in patients with treated hypothyroidism and inflammatory bowel disease

Abstract: Background: Patients with idiopathic chronic cough and unexplained airflow obstruction in non-smokers have been shown to have an increased prevalence of hypothyroidism and other organ specific autoimmune disorders. Whether patients with hypothyroidism have an increased prevalence of respiratory symptoms is unknown. Methods: The prevalence of respiratory symptoms was assessed in 124 patients with treated hypothyroidism recruited from primary and secondary care, 64 outpatients with inflammatory bowel disease, and 1346 control adults recruited randomly from the electoral register in a case-control study. Respiratory symptoms and smoking history were assessed by a respiratory symptom questionnaire. Results: After adjustment for age, sex and smoking, symptoms of breathlessness and sputum production were more prevalent in both patient populations than in controls (odds ratios for hypothyroidism and inflammatory bowel disease; breathlessness: 3.1 (95% CI 2.1 to 4.6) and 3.4 (95% CI 2.0 to 6.0), respectively; sputum production: 2.7 (95% CI 1.6 to 4.5) and 2.5 (95% CI 1.2 to 5.0), respectively). Cough during the day and night was significantly more prevalent in patients with hypothyroidism (1.8 (95% CI 1.2 to 2.9)) and approached significance in those with inflammatory bowel disease (1.8 (95% CI 1.0 to 3.4)). Wheeze and nocturnal cough were no more prevalent in either disease population than in controls. Conclusion: There is a significantly increased prevalence of respiratory symptoms in patients with hypothyroidism or inflammatory bowel disease compared with controls recruited from the general population. Further work is required to determine whether similar differences are seen in comparison with hospital based controls. These findings support the hypothesis that there is a link between autoimmune hypothyroidism and respiratory disease.

Management of asthma in adults: current therapy and future directions

Abstract: Asthma is increasing in prevalence worldwide and results in significant use of healthcare resources. Although most patients with asthma can be adequately treated with inhaled corticosteroids, an important number of patients require additional therapy and an increasing number of options are available. A further minority of patients develop severe persistent asthma which remains difficult to manage despite current pharmacological therapies. This review discusses the various treatment options currently available for each stage of asthma severity, highlights some of the limitations of current management, and outlines directions which may improve the management of asthma in the future.

Eosinophilic bronchitis: clinical features, management and pathogenesis.

Abstract: Eosinophilic bronchitis is a common and treatable cause of chronic cough. The major pathological feature is eosinophilic airway inflammation, similar to that seen in asthma. However, the associated airway dysfunction is quite different, with evidence of heightened cough reflex sensitivity, but no variable airflow obstruction or airway hyperresponsiveness. Recent evidence suggests that the differences in functional association are related to differences in localization of mast cells in airway wall, with airway smooth muscle infiltration occurring in asthma and epithelial infiltration in eosinophilic bronchitis. Diagnosis is usually made with induced sputum analysis after exclusion of other causes for chronic cough on clinical, radiological and lung function assessment. The cough responds well to inhaled corticosteroids but dose and duration of treatment remain unclear. Little is known about the natural history of this condition. However, some patients with COPD without a history of previous asthma have sputum eosinophilia, so one possibility is that some cases of eosinophilic bronchitis may develop fixed airflow obstruction. Further study of this interesting condition will increase our understanding of airway inflammation and airway responsiveness, leading to novel targets for therapeutics for both eosinophilic bronchitis and asthma.

Cough and asthma

Abstract: 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.

Recent insights into the relationship between airway inflammation and asthma.

Abstract: There have been important recent advances in our understanding of the relationship between eosinophilic airway inflammation and airway dysfunction. Observational studies have shown that eosinophilic airway inflammation is not always present in asthma nor is it an exclusive feature of asthma. Its presence seems to be more closely linked to the presence of corticosteroid responsive airways disease and the occurrence of severe exacerbations than the presence of symptoms or the extent of airway dysfunction--indeed recent evidence suggests that in asthma these features may be more closely linked to the site of localisation of mast cells in the airway wall. One implication of this new understanding of the significance of eosinophilic airway inflammation is that it predicts that measuring airway inflammation might provide information that it is not readily available from a more traditional clinical assessment, and that patients might do better if this information is available. Recent studies support this view, showing a marked reduction in asthma exacerbation in patients with moderate to severe disease who are managed with reference to markers of airway inflammation as well as symptoms and simple tests of airway function. The development of new agents that have the potential to modulate specific aspects of airway inflammation, together with refinements in non-invasive techniques to assess the efficacy of these agents offers the prospect of further refining our understanding of the role of this aspect of the inflammatory response in asthma and other airway diseases.