Biomedical subjects

Ian D Pavord

Publications and source records attributed to Ian D Pavord.

7 recordsLinked to original sources

PubMed2003

Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease.

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.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2002

Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial.

BACKGROUND: Treatment decisions in asthma are based on assessments of symptoms and simple measures of lung function, which do not relate closely to underlying eosinophilic airway inflammation. We aimed to assess whether a management strategy that minimises eosinophilic inflammation reduces asthma exacerbations compared with a standard management strategy. METHODS: We recruited 74 patients with moderate to severe asthma from hospital clinics and randomly allocated them to management either by standard British Thoracic Society asthma guidelines (BTS management group) or by normalisation of the induced sputum eosinophil count and reduction of symptoms (sputum management group). We assessed patients nine times over 12 months. The results were used to manage those in the sputum management group, but were not disclosed in the BTS group. The primary outcomes were the number of severe exacerbations and control of eosinophilic inflammation, measured by induced sputum eosinophil count. Analyses were by intention to treat. FINDINGS: The sputum eosinophil count was 63% (95% CI 24-100) lower over 12 months in the sputum management group than in the BTS management group (p=0.002). Patients in the sputum management group had significantly fewer severe asthma exacerbations than did patients in the BTS management group (35 vs 109; p=0.01) and significantly fewer patients were admitted to hospital with asthma (one vs six, p=0.047). The average daily dose of inhaled or oral corticosteroids did not differ between the two groups. INTERPRETATION: A treatment strategy directed at normalisation of the induced sputum eosinophil count reduces asthma exacerbations and admissions without the need for additional anti-inflammatory treatment.

Adult↗

PubMed2002

Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study.

Epidemiologic studies show that 5-12% of subjects with chronic obstructive pulmonary disease (COPD) are nonsmokers. Little is known about the pathophysiology of the fixed airflow obstruction in these subjects. We have prospectively identified 25 patients with COPD who had never smoked or had a less than 5 pack years smoking history and present the clinical, radiologic, and induced sputum features. Our population represented 5.7% of total referrals with fixed airflow obstruction over 2 years. Patients had a mean age of 70 years, were predominantly female (86%), and had a mean duration of respiratory symptoms of 7 years. The mean FEV(1) was 58%, and the FEV(1)/FVC was 55%. Features on high-resolution computed tomographic scanning were nonspecific and were considered typical of a wider population with COPD. An induced sputum differential inflammatory cell count suggested the presence of two distinct groups. Nine had significant sputum eosinophilia (mean, 8.1%; normal, less than 1.9%), and the remaining 13 had a normal sputum eosinophil and tended to have a raised sputum neutrophil count (mean, 70.1%; normal, less than 65%). Organ-specific autoimmune disease was present in 7 of the 22 patients (32%) and was particularly prevalent in those without sputum eosinophilia (6 of 13). In conclusion, COPD in nonsmokers predominantly affects females and has at least two pathologic subgroups, one of which may be associated with organ-specific autoimmune disease. Further investigation of this group may disclose novel mechanisms of fixed airflow obstruction.

Aged↗

PubMed2002

Mast-cell infiltration of airway smooth muscle in asthma.

BACKGROUND: Asthma and eosinophilic bronchitis are characterized by similar inflammatory infiltrates in the submucosa of the lower airway. However, eosinophilic bronchitis differs from asthma in that there is no variable airflow obstruction or airway hyperresponsiveness in the former condition. We tested the hypothesis that there were differences between the two conditions in the microlocalization of mast cells within the airway smooth muscle. METHODS: Immunohistochemical analysis of bronchial-biopsy specimens was completed in 17 subjects with asthma, 13 subjects with eosinophilic bronchitis, and 11 normal controls recruited from two centers. RESULTS: Both groups with disease had a similar degree of submucosal eosinophilia and thickening of the basement membrane and lamina reticularis. By contrast, the number of tryptase-positive mast cells in the bundles of airway smooth muscle from subjects with asthma (median, 5.1 mast cells per square millimeter of smooth muscle [range, 0 to 33.3]) was substantially higher than that in subjects with eosinophilic bronchitis (median, 0 mast cells per square millimeter; range, 0 to 4.8) and that in normal controls (median, 0 mast cells per square millimeter [range, 0 to 6.4]; P<0.001 for the comparison among the three groups). T cells and eosinophils were not usually seen in the airway smooth muscle in any of the groups. CONCLUSIONS: The infiltration of airway smooth muscle by mast cells is associated with the disordered airway function found in asthma.

Adult↗

PubMed2002

TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis.

BACKGROUND: Asthma is characterized by variable airflow obstruction and airway hyperresponsiveness in association with airway inflammation under the influence of T(H)2 cytokines. Eosinophilic bronchitis has similar immunopathology to asthma but without disordered airway physiology. Whether eosinophilic bronchitis is associated with increased expression of T(H)2 cytokines is unknown. OBJECTIVE: We sought to assess the expression of T(H)2 cytokines in eosinophilic bronchitis. METHODS: Expression of activation markers and chemokine receptors from blood and bronchoalveolar lavage (BAL) fluid T cells and the T(H)2 cytokine expression from these T cells and bronchial mucosa biopsy specimens were assessed from subjects with eosinophilic bronchitis, subjects with asthma, and healthy control subjects. RESULTS: The proportion of resting (stimulated) CD4 BAL fluid T cells expressing intracellular IL-4 was significantly higher in the subjects with eosinophilic bronchitis 7.2% (11.4%) and subjects with asthma 5.3% (5.5%) than in healthy control subjects 2.8% (3.9%) (P =.03). The number of IL-4(+) (P <.001) and IL-5(+) (P =.003) cells per square millimeter of bronchial submucosa was significantly higher in the disease groups than in the healthy control subjects. Expression of intracellular IFN-gamma was significantly higher in stimulated blood CD8 T cells from subjects with eosinophilic bronchitis (24%) and asthma (17%) than in the healthy control subjects (5%; P =.003). There were no between-group differences in expression of IFN-gamma in the BAL fluid T cells or in the bronchial submucosa and no differences in expression of activation markers or chemokine receptors. CONCLUSION: These findings support the concept of asthma as a disease associated with activation of T(H)2 lymphocytes in the airway and provide evidence that these cytokines play a role in the development of airway inflammation in eosinophilic bronchitis but suggest that the release of T(H)2 cytokines is not sufficient for the elaboration of disordered airway physiology in asthma.

Adult↗

PubMed2002

A comparison of the validity of different diagnostic tests in adults with asthma.

STUDY OBJECTIVES: Diagnosing asthma is not always easy, and there are times when objective tests can be helpful. The extent to which these tests alter the probability of asthma depends on how much more commonly the test result is positive in subjects with asthma compared to healthy subjects and particularly subjects with conditions that are commonly confused with asthma. We set out to compare the sensitivity and specificity of different tests in this setting. DESIGN: Single-center, cross-sectional, observational study. SETTING: Teaching hospital. PATIENTS: Twenty-one healthy control subjects, 69 patients with asthma, and 20 subjects referred to the hospital with a diagnosis of asthma who were found to have alternative explanations for their symptoms (i.e., pseudoasthma). INTERVENTIONS: We measured methacholine airway responsiveness, the maximum within-day peak expiratory flow amplitude mean percentage (derived from twice-daily readings for > 2 weeks), the FEV(1)/FVC ratio, the percentage change in FEV(1) 10 min after the administration of 200 microg inhaled albuterol, and the differential eosinophil count in blood and induced sputum. We derived normal ranges (from the 95% upper or lower limit for healthy subjects), sensitivity, and specificity (ie, the percentage of subjects with pseudoasthma who had negative test results). RESULTS: Most tests were less specific when the reference population was composed of subjects with conditions that can be confused with asthma. Methacholine airway responsiveness and the sputum differential eosinophil count were the most sensitive (91% and 72%, respectively) and specific (90% and 80%, respectively) tests. CONCLUSION: We conclude that methacholine airway responsiveness and the sputum differential eosinophil count are the most useful objective tests in patients with mild asthma.

Adolescent↗

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