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Biomedical subjects

I D Pavord

Publications and source records attributed to I D Pavord.

At least 19 recordsLinked to original sources
PubMed2006

Comparison of asthma treatment given in addition to inhaled corticosteroids on airway inflammation and responsiveness.

There is increasing evidence that the assessment of eosinophilic airway inflammation using induced sputum and measurement of airway hyperresponsiveness provides additional, clinically important information concerning asthma control. The aim of this study was to directly compare the effects of different treatments on these markers in patients with asthma and persistent symptoms, despite the use of low-dose inhaled corticosteroids. A double-blind four-way crossover study was performed, which compared a 1-month treatment with budesonide 400 mug b.i.d., additional formoterol, additional montelukast and placebo in 49 patients with uncontrolled asthma despite budesonide 100 mug b.i.d., with each treatment separated by a 4-week washout period. The change in sputum eosinophil count with formoterol (2.4 to 3.8% change, 0.6-fold reduction, 95% confidence interval (CI) 0.5-0.9) differed significantly from placebo (2.8 to 2.5% change, 1.1-fold reduction, 95% CI 0.7-1.6) and high-dose budesonide (2.7 to 1.6% change, 1.6-fold reduction, 95% CI 1.2-2.2). The effects of montelukast did not differ from placebo. The changes in methacholine airway responsiveness were small and did not differ between treatments. High-dose budesonide had the broadest range of beneficial effects on other outcomes, including symptom scores, morning peak expiratory flow and forced expiratory volume in one second. In conclusion, treatment given in addition to low-dose inhaled corticosteroids results in modest benefits. Formoterol and high-dose budesonide have contrasting effects on eosinophilic airway inflammation.

Acetates↗
PubMed2006

Variability of bronchial inflammation in chronic obstructive pulmonary disease: implications for study design.

There is variability in the distribution of inflammatory cells in bronchial tissue in chronic obstructive pulmonary disease (COPD). Better strategies for biopsy sampling of the airway mucosa may improve the capacity to show a difference between study populations where variability in distribution exists. The current authors have examined sources of biological variability in the quantification of inflammatory cells in endobronchial biopsies using immunostained samples taken from 51 subjects with COPD, with a mean forced expiratory volume in one second of 1.71 L, 55% predicted. The distribution of variance contributed by different sources was similar for different inflammatory cell types. For CD8+ cells, a key inflammatory cell in COPD, the largest contribution to intra-subject variability (39%) was time (i.e. 10 weeks between biopsies of placebo-treated subjects), followed by airway generation (23%), biopsy (2.5%), zone (within section; 1.4%) and section (0.4%). Power calculations demonstrated that examining one section from one biopsy, from each of two airway generations, would require a sample size of 32 subjects per group to show a difference of one doubling or halving in CD8+ cells, compared with 47 subjects per group if only one airway generation was sampled. Therefore, biopsies from more than one airway generation should be examined in order to maximise statistical power to detect a difference between study groups.

Adult↗
PubMed2006

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.

Asthma↗
PubMed2005

Sputum eosinophilia in idiopathic pulmonary fibrosis.

OBJECTIVES AND DESIGN: Cough is a common symptom in idiopathic pulmonary fibrosis that is difficult to treat and has a major impact on quality of life. We tested the hypothesis that the cough and increased cough reflex sensitivity seen in patients with idiopathic pulmonary fibrosis may be due to airway inflammation in a prospective, cross-sectional study. SUBJECTS AND METHODS: We measured the induced sputum inflammatory cell profile and cell-free supernatant inflammatory mediator concentrations in 15 patients with idiopathic pulmonary fibrosis, 17 healthy controls and 15 patients with chronic obstructive pulmonary disease. RESULTS: Both the geometric mean sputum differential eosinophil cell count and median eosinophilic-cationic-protein concentration were significantly higher in patients with idiopathic pulmonary fibrosis than controls (2.1% vs 0.3%; p <0.001 and 1.1 mg/ml versus 0.2 mg/ml; p=0.03 respectively). There were no significant differences in sputum eosinophil counts and eosinophilic-cationic-protein concentrations between patients with idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Sputum leukotriene-B4 concentrations were significantly lower in patients with idiopathic pulmonary fibrosis (p=0.03) and chronic obstructive pulmonary disease (p=0.008) compared to controls. CONCLUSIONS: Idiopathic pulmonary fibrosis is characterised by the presence of active eosinophilic airway inflammation raising the possibility that airway inflammation may contribute to symptoms such as cough.

Aged↗
PubMed2005

Observational study of the natural history of eosinophilic bronchitis.

BACKGROUND: Eosinophilic bronchitis is an important cause of chronic cough. Treatment with inhaled corticosteroids is associated with a short-term improvement in cough and reduced sputum eosinophil count but the long-term outcome is uncertain. OBJECTIVE: To determine the long-term outcome in patients diagnosed with and treated for eosinophilic bronchitis. METHODS: We have performed a longitudinal study of symptoms, eosinophilic airway inflammation, spirometry and airway hyper-responsiveness in all patients diagnosed with eosinophilic bronchitis over 7 years. RESULTS: We identified 52 patients with eosinophilic bronchitis and longitudinal data of greater than 1 year (mean 3.1 years) was available in 32 patients, all of whom were treated with inhaled steroids. Three (9%) patients developed symptoms consistent with asthma and a methacholine PC20<8 mg/mL on one or more occasion. Five (16%) patients developed fixed airflow obstruction defined by a persistent post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity<70%. One (3%) patient had complete resolution of symptoms and eosinophilic airway inflammation off treatment. The remaining patients had ongoing eosinophilic airway inflammation and/or continuing symptoms. Multiple linear regression identified smoking, female gender and area under the curve of sputum eosinophil count over time as the most important predictors of decline in FEV1. CONCLUSIONS: The most common outcome in eosinophilic bronchitis is continuing disease and complete resolution is rare. Asthma and fixed airflow obstruction developed in relatively few patients. The most important factors associated with a more rapid decline in FEV1 were female gender, smoking and prolonged eosinophilic airway inflammation.

Administration, Inhalation↗
PubMed2005

The use of exhaled nitric oxide concentration to identify eosinophilic airway inflammation: an observational study in adults with asthma.

BACKGROUND: Assessment of eosinophilic airway inflammation may be helpful in the management of asthma. Nitric oxide (NO) has potential advantages as a tool to monitor airway inflammation although little is known about the relationship between NO and eosinophilic airway inflammation and the factors which influence it. METHODS: We set out to define the relationship between exhaled NO and the sputum eosinophil count, identify the exhaled NO concentration that best identified a sputum eosinophil count >3% and investigate the impact of several potential confounding factors in 566 consecutive patients with varying severity of asthma. Finally we examined the ability of exhaled NO concentrations measured at differing exhalation flows to identify the presence of a sputum eosinophilia. RESULTS: We found a significant positive relationship between exhaled NO and sputum eosinophil count (R(2)=0.26, P<0.001) which was best described using a non-linear model. There were no clinically important confounding factors to this model. In non-smokers an exhaled NO concentration of >8.3 p.p.b. at 250 mL/s gave 71% sensitivity and 72% specificity for identifying a sputum eosinophil count of >3%. CONCLUSIONS: This value of exhaled NO would seem to be the best for identifying significant eosinophilic airway inflammation. It is applicable to a wide range of non-smoking patients with asthma; exhalation flow does not alter the ability of exhaled NO concentration to detect a sputum eosinophilia.

Adolescent↗
PubMed2005

Multi-dimensional phenotyping: towards a new taxonomy for airway disease.

All the real knowledge which we possess, depends on methods by which we distinguish the similar from the dissimilar. The greater the number of natural distinctions this method comprehends the clearer becomes our idea of things. The more numerous the objects which employ our attention the more difficult it becomes to form such a method and the more necessary. Classification is a fundamental part of medicine. Diseases are often categorized according to pre-20th century descriptions and concepts of disease based on symptoms, signs and functional abnormalities rather than on underlying pathogenesis. Where the aetiology of disease has been revealed (for example in the infectious diseases) a more precise classification has become possible, but in the chronic inflammatory diseases, and in the inflammatory airway diseases in particular, where pathogenesis has been stubbornly difficult to elucidate, we still use broad descriptive terms such as asthma and chronic obstructive pulmonary disease, which defy precise definition because they encompass a wide spectrum of presentations and physiological and cellular abnormalities. It is our contention that these broad-brush terms have outlived their usefulness and that we should be looking to create a new taxonomy of airway disease-a taxonomy that more closely reflects the spectrum of phenotypes that are encompassed within the term airway inflammatory diseases, and that gives full recognition to late 20th and 21st century insights into the disordered physiology and cell biology that characterizes these conditions in the expectation that these will map more closely to both aetiology and response to treatment. Development of this taxonomy will require a much more complete and sophisticated correlation of the many variables that make up a condition than has been usual to employ in an approach that encompasses multi-dimensional phenotyping and uses complex statistical tools such as cluster analysis.

Animals↗
PubMed2005

Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease.

BACKGROUND: Chemokine receptors (CR) play an important role in T cell migration, but their contribution to lung trafficking is unclear. OBJECTIVE: We hypothesized that if a particular CR was involved in T cell homing its expression would be enriched on lung T cells compared with peripheral blood T cells (PBT). METHODS: We have measured the CR expression on BAL T cells from patients with sarcoid, other interstitial lung diseases (ILD), asthma and healthy volunteers. RESULTS: Of 14 CR studied in sarcoid, CXCR6 expression was the most markedly increased in the lung compared with the blood, a finding that was also seen in ILD patients. A striking although lesser increase was also seen in asthmatics and healthy controls. Analysis of expression of the CXCR6 ligand, CXCL16, by immunohistochemistry suggested that alveolar macrophages (AM) were the major source of CXCL16 in the lung. AM expressed mRNA for CXCL16 and released nanogram quantities after adhesion to plastic as shown by RT-PCR, Western blotting and ELISA. Bronchoalveolar lavage (BAL) fluid from all subjects contained large amounts of CXCL16. The full-length CXCL16 was the predominant isoform in AM lysates, supernatants and BAL. CONCLUSION: This data suggests that CXCR6 and CXCL16 may play a role in T cell recruitment to the lung.

Adult↗
PubMed2005

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 microg/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 (FEV(1)), total CRQ, or sputum characteristics. After stratification into tertiles by baseline eosinophil count, the net improvement in post-bronchodilator FEV(1) increased with mometasone compared with placebo progressively from the least to the most eosinophilic tertile. The mean change in post-bronchodilator FEV(1) 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 FEV(1) following treatment with inhaled mometasone in COPD, but the improvement is not associated with a reduction in the sputum eosinophil count.

Administration, Inhalation↗
PubMed2005

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 (PC(20)) <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.

Biomarkers↗
PubMed2005

Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma.

Recent studies have suggested that alveolar nitric oxide (NO) concentration is a noninvasive test of distal lung inflammation. The current study determined whether alveolar NO concentration can be measured in patients with asthma of varying severity, tested the hypothesis that there is an association between alveolar NO and bronchoalveolar lavage (BAL) eosinophil count and determined whether refractory asthma is characterised by a raised alveolar NO concentration. Finally, the present authors assessed the effect of 2 weeks of prednisolone (30 mg q.d.) on alveolar NO concentration. Alveolar NO concentration was both measurable and repeatable in patients with refractory asthma. A positive correlation was found between alveolar NO concentration and BAL eosinophil count but not with bronchial wash or sputum eosinophil count. Alveolar NO concentration was increased in patients with refractory asthma (7.1 ppb) compared with mild-to-moderate asthma (3.4 ppb) and normal controls (3.4 ppb) and reduced by treatment with prednisolone. In conclusion, these findings support the hypothesis that alveolar nitric oxide is a measure of distal airway inflammation and suggest that distal lung inflammation is present in refractory asthma.

Administration, Inhalation↗
PubMed2004

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 micromol 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.

Administration, Inhalation↗