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1.  Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma 
The New England journal of medicine  2009;360(10):973-984.
BACKGROUND
Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations.
METHODS
We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV1) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum.
RESULTS
Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P = 0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P = 0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P = 0.002). There were no significant differences between the groups with respect to symptoms, FEV1 after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma.
CONCLUSIONS
Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)
doi:10.1056/NEJMoa0808991
PMCID: PMC3992367  PMID: 19264686
2.  Effect of levofloxacin on neutrophilic airway inflammation in stable COPD: a randomized, double-blind, placebo-controlled trial 
Rationale
Airway inflammation persists after smoking cessation in established chronic obstructive pulmonary disease (COPD), suggesting that other factors drive the airway inflammatory response.
Objectives
We tested the hypothesis that high levels of bacterial colonization are associated with increased levels of neutrophilic airway inflammation in stable COPD by examining the cross-sectional relationship between these measurements and by conducting a randomized, double-blind, placebo-controlled study of the effect of levofloxacin in patients with stable COPD.
Methods
Patients were randomized to receive either levofloxacin 500 mg daily or placebo for 7 days and underwent sputum induction for a differential cell count and quantitative bacterial analysis at baseline and at days 7, 14, and 28.
Results
Sputum percentage neutrophil count correlated with airway bacterial load at baseline (r=0.56; P=0.003). Levofloxacin reduced bacterial load compared with placebo by 4.9-fold (95% confidence interval, 1.4–25.7; P=0.02) at day 7 but had no effect at any point on any marker of neutrophilic airway inflammation. In patients with a baseline bacterial load of more than 106 cfu/mL, levofloxacin treatment was associated with a 26.5% (95% confidence interval, 1.8%–51.3%; P=0.04) greater reduction in the percentage neutrophil count compared with placebo at day 7. Change in percentage neutrophil count correlated significantly with baseline airway bacterial load and change in airway bacterial load.
Conclusion
In stable COPD, levofloxacin treatment causes a short-term reduction in bacterial load. This is associated with a reduction in neutrophilic airway inflammation in patients with high bacterial loads. Further studies are required to investigate whether this effect is clinically advantageous.
doi:10.2147/COPD.S55419
PMCID: PMC3923615  PMID: 24532969
bacteria; antibiotics; sputum
3.  Cluster Analysis and Clinical Asthma Phenotypes 
Rationale
Heterogeneity in asthma expression is multidimensional, including variability in clinical, physiologic, and pathologic parameters. Classification requires consideration of these disparate domains in a unified model.
Objectives
To explore the application of a multivariate mathematical technique, k-means cluster analysis, for identifying distinct phenotypic groups.
Methods
We performed k-means cluster analysis in three independent asthma populations. Clusters of a population managed in primary care (n = 184) with predominantly mild to moderate disease, were compared with a refractory asthma population managed in secondary care (n = 187). We then compared differences in asthma outcomes (exacerbation frequency and change in corticosteroid dose at 12 mo) between clusters in a third population of 68 subjects with predominantly refractory asthma, clustered at entry into a randomized trial comparing a strategy of minimizing eosinophilic inflammation (inflammation-guided strategy) with standard care.
Measurements and Main Results
Two clusters (early-onset atopic and obese, noneosinophilic) were common to both asthma populations. Two clusters characterized by marked discordance between symptom expression and eosinophilic airway inflammation (early-onset symptom predominant and late-onset inflammation predominant) were specific to refractory asthma. Inflammation-guided management was superior for both discordant subgroups leading to a reduction in exacerbation frequency in the inflammation-predominant cluster (3.53 [SD, 1.18] vs. 0.38 [SD, 0.13] exacerbation/patient/yr, P = 0.002) and a dose reduction of inhaled corticosteroid in the symptom-predominant cluster (mean difference, 1,829 μg beclomethasone equivalent/d [95% confidence interval, 307–3,349 μg]; P = 0.02).
Conclusions
Cluster analysis offers a novel multidimensional approach for identifying asthma phenotypes that exhibit differences in clinical response to treatment algorithms.
doi:10.1164/rccm.200711-1754OC
PMCID: PMC3992366  PMID: 18480428
taxonomy; corticosteroid response; multivariate classification
4.  Increased sputum and bronchial biopsy IL-13 expression in severe asthma 
Background
The importance of IL-13 in the asthma paradigm is supported by increased expression in human subjects, particularly in patients with mild-to-moderate asthma. However, the role of IL-13 in severe asthma needs to be further defined.
Objective
We sought to assess IL-13 expression in sputum and bronchial biopsy specimens from subjects with mild-to-severe asthma.
Methods
Sputum IL-13 concentrations were measured in 32 control subjects, 34 subjects with mild asthma, 21 subjects with moderate asthma, and 26 subjects with severe asthma. Enumeration of mast cells, eosinophils, and IL-13+ cells in the bronchial submucosa and airway smooth muscle (ASM) bundle was performed in 7 control subjects, 14 subjects with mild asthma, 7 subjects with moderate asthma, and 7 subjects with severe asthma.
Results
The proportion of subjects with measurable IL-13 in the sputum was increased in the mild asthma group (15/34) and severe asthma group (10/26) compared with that seen in the control group (4/32; P = .004). IL-13+ cells were increased within the submucosa in all asthma severity groups compared with control subjects (P = .006). The number of IL-13+ cells were increased within the ASM bundle in the severe asthma group compared with that seen in the other groups (P < .05). Asthma control questionnaire scores positively correlated with sputum IL-13 concentrations (Rs = 0.35, P = .04) and mast cells in the ASM bundle (Rs = 0.7, P = .007). IL-13+ cells within the submucosa and ASM correlated with sputum eosinophilia (Rs = 0.4, P ≤ .05).
Conclusions
IL-13 overexpression in sputum and bronchial biopsy specimens is a feature of severe asthma.
doi:10.1016/j.jaci.2008.01.005
PMCID: PMC3992379  PMID: 18328894
Severe asthma; IL-13; sputum; bronchus; airway smooth muscle; eosinophilia
5.  Quantitative computed tomography–derived clusters: Redefining airway remodeling in asthmatic patients☆ 
Background
Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)–assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms.
Objectives
The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes.
Methods
Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes.
Results
Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm3 [SD, 112.6 mm3], 259.0 mm3 [SD, 53.3 mm3], 366.4 mm3 [SD, 195.3 mm3], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects.
Conclusions
Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies.
doi:10.1016/j.jaci.2013.09.039
PMCID: PMC3969578  PMID: 24238646
Asthma; airway remodeling; distal airway; CT; quantitative imaging; phenotypes; cluster analysis; fractal analysis; ATS, American Thoracic Society; BSA, Body surface area; CT, Computed tomography; Dav, Averaged fractal dimension; De, Most efficient cover fractal dimension; Dsc, Slope-corrected fractal dimension; Dsce, Slope-corrected most-efficient covering fractal dimension; FRC, Functional residual capacity; HU, Hounsfield units; ICC, Intraclass correlation coefficient; LA, Lumen area; LV, Lumen volume; MLD E/I, Mean lung density expiratory/inspiratory ratio; Pi10, Hypothetical airway with internal perimeter of 10 mm; Po20, Hypothetical airways with outer airway perimeter of 20 mm; RB1, Right upper lobe apical segmental bronchus; ROI, Region of interest; RV, Residual volume; TLC, Total lung capacity; VI, Voxel index; VI−850 E-I, VI−850 change on paired inspiratory and expiratory CT scan; VI−850/−950 E-I, Voxel index change of percent voxels between −950 and −850 HU on paired inspiratory and expiratory CT scan; WA, Wall area; WV, Wall volume
6.  Pathological features and inhaled corticosteroid response of eosinophilic and non‐eosinophilic asthma 
Thorax  2007;62(12):1043-1049.
Background
Non‐eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo‐controlled studies examining the effect of inhaled corticosteroids.
Methods
Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non‐eosinophilic asthma and 10 healthy controls. The patients with non‐eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double‐blind, placebo‐controlled crossover study in which the effects of inhaled mometasone 400 μg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated.
Results
Patients with non‐eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm2 vs 23 cells/mm2 in eosinophilic asthma and 0 cells/mm2 in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 μm vs 10.3 μm in eosinophilic asthma and 5.1 μm in controls, p = 0.002). Non‐eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm2, p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC20 (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008).
Conclusions
Non‐eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short‐term response to treatment with inhaled corticosteroids.
doi:10.1136/thx.2006.073429
PMCID: PMC2094295  PMID: 17356056
7.  Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease 
Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous.
Objectives: Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations.
Methods: Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and ≤ 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms.
Measurements and Main Results: There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0–0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01–0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04).
Conclusions: The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.
Clinical trial registered with www.controlled-trials.com (ISRCTN92422949).
doi:10.1164/rccm.201108-1553OC
PMCID: PMC3400995  PMID: 22447964
chronic obstructive pulmonary disease; exacerbations; prednisolone; infection; eosinophils
8.  Primary Human Airway Epithelial Cell-Dependent Inhibition of Human Lung Mast Cell Degranulation 
PLoS ONE  2012;7(8):e43545.
Introduction
Chronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism.
Methods
HLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures.
Results
Both constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G0/Gi receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolvin D1 and D2 and lipoxin A4 attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants.
Conclusions
Primary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G0/Gi receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.
doi:10.1371/journal.pone.0043545
PMCID: PMC3428358  PMID: 22970103
9.  Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function 
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
doi:10.1164/rccm.201102-0192OC
PMCID: PMC3398416  PMID: 21965014
FEV1; FVC; genome-wide association study; modeling risk
10.  The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute) 
Introduction
Acute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID).
Methods
10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile.
Results
Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively.
Conclusion
The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.
doi:10.1186/1745-9974-7-4
PMCID: PMC3169450  PMID: 21767404
11.  IgE Sensitization to Aspergillus fumigatus Is Associated with Reduced Lung Function in Asthma 
Rationale: The importance of Aspergillus fumigatus sensitization and colonization of the airways in patients with asthma is unclear.
Objectives: To define the relationship between the clinical and laboratory features of A. fumigatus–associated asthma.
Methods: We studied 79 patients with asthma (89% classed as GINA 4 or 5) classified into 3 groups according to A. fumigatus sensitization: (1) IgE-sensitized (immediate cutaneous reactivity > 3 mm and/or IgE > 0.35 kU/L); (2) IgG-only–sensitized (IgG > 40 mg/L); and (3) nonsensitized. These were compared with 14 healthy control subjects. Sputum culture was focused toward detection of A. fumigatus and compared with clinical assessment data.
Measurements and Main Results: A. fumigatus was cultured from 63% of IgE-sensitized patients with asthma (n = 40), 39% of IgG-only–sensitized patients with asthma (n = 13), 31% of nonsensitized patients with asthma (n = 26) and 7% of healthy control subjects (n = 14). Patients sensitized to A. fumigatus compared with nonsensitized patients with asthma had lower lung function (postbronchodilator FEV1 % predicted, mean [SEM]: 68 [±5]% versus 88 [±5]%; P < 0.05), more bronchiectasis (68% versus 35%; P < 0.05), and more sputum neutrophils (median [interquartile range]: 80.9 [50.1–94.1]% versus 49.5 [21.2–71.4]%; P < 0.01). In a multilinear regression model, A. fumigatus–IgE sensitization and sputum neutrophil differential cell count were important predictors of lung function (P = 0.016), supported by culture of A. fumigatus (P = 0.046) and eosinophil differential cell count (P = 0.024).
Conclusions: A. fumigatus detection in sputum is associated with A. fumigatus–IgE sensitization, neutrophilic airway inflammation, and reduced lung function. This supports the concept that development of fixed airflow obstruction in asthma is consequent upon the damaging effects of airway colonization with A. fumigatus.
doi:10.1164/rccm.201001-0087OC
PMCID: PMC3029929  PMID: 20639442
asthma; lung function; Aspergillus fumigatus; induced sputum; neutrophil
12.  The Role of CT Scanning in Multidimensional Phenotyping of COPD 
Chest  2011;140(3):634-642.
Background:
COPD is a heterogeneous disease characterized by airflow obstruction and diagnosed by lung function. CT imaging is emerging as an important, noninvasive tool in phenotyping COPD. However, the use of CT imaging in defining the disease heterogeneity above lung function is not fully known.
Methods:
Seventy-five patients with COPD (58 men, 17 women) were studied with CT imaging and with measures of airway inflammation. Airway physiology and health status were also determined.
Results:
The presence of emphysema (EM), bronchiectasis (BE), and bronchial wall thickening (BWT) was found in 67%, 27%, and 27% of subjects, respectively. The presence of EM was associated with lower lung function (mean difference % FEV1, −20%; 95% CI, −28 to −11; P < .001). There was no difference in airway inflammation, exacerbation frequency, or bacterial load in patients with EM alone or with BE and/or BWT ± EM. The diffusing capacity of the lung for carbon monoxide/alveolar volume ratio was the most sensitive and specific parameter in identifying EM (area under the receiver operator characteristic curve, 0.87; 95% CI, 0.79-0.96). Physiologic cluster analysis identified three clusters, two of which were EM predominant and the third characterized by a heterogeneous combination of EM and BE.
Conclusions:
The application of CT imaging can be useful as a tool in the multidimensional approach to phenotyping patients with COPD.
doi:10.1378/chest.10-3007
PMCID: PMC3168858  PMID: 21454400
13.  Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial 
Background
Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure.
Methods
Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT.
Results
45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group.
Conclusions
The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years.
doi:10.1186/1471-2466-11-8
PMCID: PMC3045390  PMID: 21314924
14.  Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma 
Rationale: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.
Objectives: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting β2-agonists.
Methods: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%).
Measurements and Main Results: The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 ± 1.10; sham, 1.16 ± 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6–52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively).
Conclusions: BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period.
Clinical trial registered with www.clinialtrials.gov (NCT00231114).
doi:10.1164/rccm.200903-0354OC
PMCID: PMC3269231  PMID: 19815809
asthma; Alair Bronchial Thermoplasty System; bronchial thermoplasty; bronchoscopic procedure; Asthma Quality of Life
15.  Body Mass and Fat Mass in Refractory Asthma: An Observational 1 Year Follow-Up Study 
Journal of Allergy  2010;2010:251758.
Background. Asthma and obesity are common; however the impact of obesity upon asthma remains uncertain. Objectives. To assess relationships between obesity and fat mass with airway inflammation, lung function, and disease control in patients with refractory asthma. Methods. 151 refractory asthma patients were characterised for measures of airway inflammation, lung function, Juniper asthma control questionnaire (JACQ), body mass index (BMI), and fat mass index (FMI) derived from dual energy X-ray absorptiometry. Patients were reassessed over 12 months. Results. 74% of patients had an elevated BMI. BMI and FMI correlated (r = 0.9, P < .001). FMI and JACQ correlated in men (r = 0.3, P = .01). After 12 months 23% lost weight. Weight change over 12 months correlated with FEV1 change (r = −0.3, P = .03), but not with change in JACQ or exacerbations. Conclusion. Increased fat mass is common in refractory asthma and is associated with asthma symptom control in men. Loss of weight is associated with improvement in lung function in refractory asthma.
doi:10.1155/2010/251758
PMCID: PMC2995902  PMID: 21151697
16.  Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes 
Thorax  2010;65(9):775-781.
Background
Severe asthma is a heterogeneous condition. Airway remodelling is a feature of severe asthma and can be determined by the assessment of high-resolution computed tomography (HRCT) scans. The aim of this study was to assess whether airway remodelling is restricted to specific subphenotypes of severe asthma.
Methods
A retrospective analysis was performed of HRCT scans from subjects who had attended a single-centre severe asthma clinic between 2003 and 2008. The right upper lobe apical segmental bronchus (RB1) dimensions were measured and the clinical and sputum inflammatory characteristics associated with RB1 geometry were assessed by univariate and multivariate regression analyses. Longitudinal sputum data were available and were described as area under the time curve (AUC). Comparisons were made in RB1 geometry across subjects in four subphenotypes determined by cluster analysis, smokers and non-smokers, and subjects with and without persistent airflow obstruction.
Results
Ninety-nine subjects with severe asthma and 16 healthy controls were recruited. In the subjects with severe asthma the RB1 percentage wall area (%WA) was increased (p=0.009) and lumen area (LA)/body surface area (BSA) was decreased (p=0.008) compared with controls but was not different across the four subphenotypes. Airway geometry was not different between smokers and non-smokers and RB1 %WA was increased in those with persistent airflow obstruction. RB1 %WA in severe asthma was best associated with airflow limitation and persistent neutrophilic airway inflammation (model R2=0.27, p=0.001).
Conclusions
Airway remodelling of proximal airways occurs in severe asthma and is associated with impaired lung function and neutrophilic airway inflammation.
doi:10.1136/thx.2010.136374
PMCID: PMC2975950  PMID: 20805170
Severe asthma; airway remodelling; computed tomography; airway inflammation; quantitative analysis; asthma phenotypes; cluster analysis; imaging/CT MRI etc
17.  Genome-wide association study identifies five loci associated with lung function 
Repapi, Emmanouela | Sayers, Ian | Wain, Louise V | Burton, Paul R | Johnson, Toby | Obeidat, Ma’en | Zhao, Jing Hua | Ramasamy, Adaikalavan | Zhai, Guangju | Vitart, Veronique | Huffman, Jennifer E | Igl, Wilmar | Albrecht, Eva | Deloukas, Panos | Henderson, John | Granell, Raquel | McArdle, Wendy L | Rudnicka, Alicja R | Barroso, Inês | Loos, Ruth J F | Wareham, Nicholas J | Mustelin, Linda | Rantanen, Taina | Surakka, Ida | Imboden, Medea | Wichmann, H Erich | Grkovic, Ivica | Jankovic, Stipan | Zgaga, Lina | Hartikainen, Anna-Liisa | Peltonen, Leena | Gyllensten, Ulf | Johansson, Åsa | Zaboli, Ghazal | Campbell, Harry | Wild, Sarah H | Wilson, James F | Gläser, Sven | Homuth, Georg | Völzke, Henry | Mangino, Massimo | Soranzo, Nicole | Spector, Tim D | Polašek, Ozren | Rudan, Igor | Wright, Alan F | Heliövaara, Markku | Ripatti, Samuli | Pouta, Anneli | Naluai, Åsa Torinsson | Olin, Anna-Carin | Torén, Kjell | Cooper, Matthew N | James, Alan L | Palmer, Lyle J | Hingorani, Aroon D | Wannamethee, S Goya | Whincup, Peter H | Smith, George Davey | Ebrahim, Shah | McKeever, Tricia M | Pavord, Ian D | MacLeod, Andrew K | Morris, Andrew D | Porteous, David J | Cooper, Cyrus | Dennison, Elaine | Shaheen, Seif | Karrasch, Stefan | Schnabel, Eva | Schulz, Holger | Grallert, Harald | Bouatia-Naji, Nabila | Delplanque, Jérôme | Froguel, Philippe | Blakey, John D | Britton, John R | Morris, Richard W | Holloway, John W | Lawlor, Debbie A | Hui, Jennie | Nyberg, Fredrik | Jarvelin, Marjo-Riitta | Jackson, Cathy | Kähönen, Mika | Kaprio, Jaakko | Probst-Hensch, Nicole M | Koch, Beate | Hayward, Caroline | Evans, David M | Elliott, Paul | Strachan, David P | Hall, Ian P | Tobin, Martin D
Nature genetics  2009;42(1):36-44.
Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.
doi:10.1038/ng.501
PMCID: PMC2862965  PMID: 20010834
18.  Non‐eosinophilic asthma and the innate immune response 
Thorax  2007;62(3):193-194.
Pathological heterogeneity of asthma
doi:10.1136/thx.2006.065805
PMCID: PMC2117160  PMID: 17329554
19.  Obstructive sleep apnoea: a cause of chronic cough 
Chronic cough is a common reason for presentation to both general practice and respiratory clinics. In up to 25% of cases, the cause remains unclear after extensive investigations. We report 4 patients presenting with an isolated chronic cough who were subsequently found to have obstructive sleep apnoea. The cough improved rapidly with nocturnal continuous positive airway pressure therapy. Further studies are required to investigate the prevalence of coexistence of these common conditions.
doi:10.1186/1745-9974-3-7
PMCID: PMC1920530  PMID: 17605822

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