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| 2. |
- Andersson, Cecilia K, et al.
(author)
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Alterations in Lung Mast Cell Populations in Patients with COPD.
- 2010
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In: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 181:3, s. 206-217
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Journal article (peer-reviewed)abstract
- RATIONALE: Mast cells have important roles in innate immunity and tissue remodeling but have remained poorly studied in inflammatory airway diseases like COPD. OBJECTIVES: To perform a detailed histological characterization of human lung mast cell popu-lations at different severities of COPD, comparing with smoking and never-smoking controls. METHODS: Mast cells were analyzed in lung tissues from patients with mild to very severe COPD, GOLD IâIV (n = 25, 10 of whom were treated with corticosteroids). Never-smokers and smokers served as controls. The density, morphology and molecular characteristics of mucosal and connective tissue mast cells (MCT and MCTC, respectively) were analyzed in several lung regions. MEASUREMENTS AND MAIN RESULTS: In all compartments of COPD lungs, especially at severe stages, the MCTC population increased in density while the MCT population decreased. The net result was a reduction in total mast cell density. This phenomenon was paralleled by in-creased numbers of luminal mast cells whereas the numbers of TUNEL(+) apoptotic mast cells remained unchanged. In COPD lungs, the MCT and MCTC populations showed alterations in morphology and expression of CD88 (C5a-R), TGF-beta, and renin. Statistically significant cor-relations were found between several COPD-related mast cell alterations and lung function parameters. CONCLUSIONS: As COPD progresses to its severe stages, the mast cell population in the lung undergoes changes in density, distribution, and molecular expression. In COPD lungs, these novel histopathological features were found to be correlated to lung function and they may thus have clinical consequences.
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- Bafadhel, Mona, et al.
(author)
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Acute Exacerbations of Chronic Obstructive Pulmonary Disease : Identification of Biologic Clusters and Their Biomarkers
- 2011
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In: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 184:6, s. 662-671
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Journal article (peer-reviewed)abstract
- Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. Objectives: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. Methods: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. Measurements and Main Results: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1 beta, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83-0.95); serum CXCL10, 0.83 (95% CI, 0.70-0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78-0.93), respectively. Conclusions: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1 beta, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.
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| 4. |
- Bafadhel, Mona, et al.
(author)
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Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease A Randomized Placebo-Controlled Trial
- 2012
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In: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 186:1, s. 48-55
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Journal article (peer-reviewed)abstract
- 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.
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| 7. |
- Borges, João Batista, et al.
(author)
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The Quest for the Holy Grail : A Dead Lock
- 2010
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In: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 182:4, s. 579-580
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Journal article (peer-reviewed)
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| 9. |
- Boudier, Anne, et al.
(author)
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Ten-Year Follow-up of Cluster-based Asthma Phenotypes in Adults A Pooled Analysis of Three Cohorts
- 2013
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In: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 188:5, s. 550-560
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Journal article (peer-reviewed)abstract
- Rationale: The temporal stability of adult asthma phenotypes identified using clustering methods has never been addressed. Longitudinal cluster-based methods may provide novel insights in the study of the natural history of asthma. Objectives: To compare the stability of cluster-based asthma phenotype structures a decade apart in adults and to address the individuals' phenotypic transition across these asthma phenotypes. Methods: The latent transition analysis was applied on longitudinal data (twice, 10 yr apart) from 3,320 adults with asthma who took part in the European Community Respiratory Health Survey, the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults, or the Epidemiological Study on Genetics and Environment of Asthma. Nine variables covering personal and phenotypic characteristics measured twice, 10 years apart, were simultaneously considered. Measurements and Main Results: Latent transition analysis identifies seven asthma phenotypes (prevalence range, 8.4-20.8%), mainly [GRAPHICS] characterized by the level of asthma symptoms ( low, moderate, high), the allergic status, and pulmonary function. Phenotypes observed 10 years apart showed strong similarities. The probability of membership in the same asthma phenotype at both times varied across phenotypes from 54 to 88%. Different transition patterns were observed across phenotypes. Transitions toward increased asthma symptoms were more frequently observed among nonallergic phenotypes as compared with allergic phenotypes. Results showed a strong stability of the allergic status over time. Conclusions: Adult asthma phenotypes identified by a clustering approach, 10 years apart, were highly consistent. This study is the first to model the probabilities of transitioning over time between comprehensive asthma phenotypes.
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