Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.
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SUBMITTER: Hastie AT
PROVIDER: S-EPMC5849066 | biostudies-literature | 2017 Dec
REPOSITORIES: biostudies-literature
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Association of sputum and blood eosinophil concentrations with clinical measures of COPD severity: an analysis of the SPIROMICS cohort.
Hastie Annette T AT Martinez Fernando J FJ Curtis Jeffrey L JL Doerschuk Claire M CM Hansel Nadia N NN Christenson Stephanie S Putcha Nirupama N Ortega Victor E VE Li Xingnan X Barr R Graham RG Carretta Elizabeth E EE Couper David J DJ Cooper Christopher B CB Hoffman Eric A EA Kanner Richard E RE Kleerup Eric E O'Neal Wanda K WK Paine Richard R Peters Stephen P SP Alexis Neil E NE Woodruff Prescott G PG Han MeiLan K MK Meyers Deborah A DA Bleecker Eugene R ER
The Lancet. Respiratory medicine 20171113 12
<h4>Background</h4>Increased concentrations of eosinophils in blood and sputum in chronic obstructive pulmonary disease (COPD) have been associated with increased frequency of exacerbations, reduced lung function, and corticosteroid responsiveness. We aimed to assess whether high eosinophil concentrations in either sputum or blood are associated with a severe COPD phenotype, including greater exacerbation frequency, and whether blood eosinophils are predictive of sputum eosinophils.<h4>Methods</ ...[more]
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Project description:BackgroundThe Global Initiative for Chronic Obstructive Lung Disease (GOLD) considers blood eosinophil counts < 100 cells/μL (BEC≤100) in people with COPD to predict poor inhaled corticosteroid (ICS) responsiveness. However, the BEC≤100 phenotype is inadequately characterized, especially in advanced COPD.Research questionAre there differences between GOLD group D patients with high BEC and those with low BEC regarding baseline characteristics and longitudinal outcomes?Study design and methodsWe used multivariable mixed models and logistic regression to contrast clinical characteristics and outcomes of BEC≤100 vs BEC > 100 (BEC100+) in all subjects with COPD (n = 1,414) and GOLD group D subjects (n = 185) not receiving ICS.ResultsWe identified n = 485 with BEC≤100 (n = 61 GOLD group D) and n = 929 people with BEC100+ (n = 124 GOLD group D). BEC≤100 status was stable at 6 weeks and approximately 52 weeks (intraclass correlations of 0.78 and 0.71, respectively). Compared with BEC100+, BEC≤100 comprised more women, with greater current smoking, and less frequent childhood asthma. Among all analyzed participants, the two BEC-defined subsets showed similar rates of lung function decline (mean slope, BEC≤100 vs BEC100+, -50 vs -39 mL/y; P = .140), exacerbations (0.40 vs 0.36/y; P = .098), subsequent ICS initiation (2.5% vs 4.4%; P = .071), and mortality (7.8% vs 8.4%; P = .715). However, in GOLD group D, people with BEC≤100 showed higher exacerbation rates within 365 days of enrollment (0.62 vs 0.33/y; P = .002) and total follow-up (1.16 vs 0.83/y; P = .014). They also had greater lung function decline (mean slope of -68 mL/y vs -23 mL/y; P = .036) and had greater emphysema at baseline (voxels < 950 Hounsfield units at total lung capacity of 7.46% vs 4.61%; P = .029).InterpretationIn non-ICS-treated GOLD group D COPD, people with BEC≤100 had more baseline emphysema, prospective exacerbations, and lung function decline. Our analysis has identified a particularly vulnerable subpopulation of people with COPD, suggesting the need for studies focused specifically on their therapeutic treatment.Clinical trial registrationClinicalTrials.gov; No.: NCT01969344; URL: www.Clinicaltrialsgov.
| S-EPMC10083128 | biostudies-literature
Project description:BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.
| S-EPMC7098791 | biostudies-literature
Project description:BackgroundThere is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures.MethodsP-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up.ResultsP-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up.ConclusionIn this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies.Trial registration ClinicalTrials.gov NCT01969344 (SPIROMICS).
| S-EPMC8074408 | biostudies-literature
Project description:BackgroundSubpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) is a multi-center longitudinal, observational study to identify novel phenotypes and biomarkers of chronic obstructive pulmonary disease (COPD). In a subset of 300 subjects enrolled at six clinical centers, we are performing flow cytometric analyses of leukocytes from induced sputum, bronchoalveolar lavage (BAL) and peripheral blood. To minimize several sources of variability, we use a "just-in-time" design that permits immediate staining without pre-fixation of samples, followed by centralized analysis on a single instrument.MethodsThe Immunophenotyping Core prepares 12-color antibody panels, which are shipped to the six Clinical Centers shortly before study visits. Sputum induction occurs at least two weeks before a bronchoscopy visit, at which time peripheral blood and bronchoalveolar lavage are collected. Immunostaining is performed at each clinical site on the day that the samples are collected. Samples are fixed and express shipped to the Immunophenotyping Core for data acquisition on a single modified LSR II flow cytometer. Results are analyzed using FACS Diva and FloJo software and cross-checked by Core scientists who are blinded to subject data.ResultsThus far, a total of 152 sputum samples and 117 samples of blood and BAL have been returned to the Immunophenotyping Core. Initial quality checks indicate useable data from 126 sputum samples (83%), 106 blood samples (91%) and 91 BAL samples (78%). In all three sample types, we are able to identify and characterize the activation state or subset of multiple leukocyte cell populations (including CD4+ and CD8+ T cells, B cells, monocytes, macrophages, neutrophils and eosinophils), thereby demonstrating the validity of the antibody panel.ConclusionsOur study design, which relies on bi-directional communication between clinical centers and the Core according to a pre-specified protocol, appears to reduce several sources of variability often seen in flow cytometric studies involving multiple clinical sites. Because leukocytes contribute to lung pathology in COPD, these analyses will help achieve SPIROMICS aims of identifying subgroups of patients with specific COPD phenotypes. Future analyses will correlate cell-surface markers on a given cell type with smoking history, spirometry, airway measurements, and other parameters.Trial registrationThis study was registered with ClinicalTrials.gov as NCT01969344 .
| S-EPMC4314767 | biostudies-literature
Project description:Higher blood and sputum eosinophil counts are associated with a greater response to corticosteroids in COPD. Low blood eosinophil counts exhibit greater stability over time whereas higher counts demonstrate more variability. Stability of airway eosinophil levels is less well understood. We have studied the stability of sputum eosinophil counts. Differential cell count data for COPD patients (n = 100) were analysed. Subjects with two sputum eosinophil counts, 6 months apart, were included in the analysis. Patients were stratified based on baseline sputum eosinophil count into 'low', 'intermediate' and 'high' groups: eosinophilLOW (<1%), eosinophilINT (1-3%) and eosinophilHIGH (≥3%). Sputum eosinophil counts showed good stability (rho = 0.61, p < 0.0001, ICC of 0.77), with 67.4% of eosinophilLOW patients remaining in the same category on repeat sampling. Bland-Altman analysis of the whole cohort (median difference between measurements = 0.00%, 90th percentile = -1.4 and 4.7%) showed greater variation at higher counts. This was confirmed by the wider 90th centiles in the eosinophilINT (-1.50 to 5.65) and eosinophilHIGH groups (-5.33 to 9.80) compared to the eosinophilLOW group (-0.40 to 1.40). The repeatability of sputum eosinophil counts was related to the baseline eosinophil count; sputum eosinophilLOW COPD patients were relatively stable over time, while the eosinophilHIGH group showed greater variability. These results can facilitate the identification of COPD endotypes with differential responses to treatment.
| S-EPMC9599170 | biostudies-literature
Project description:Background Accumulating evidence on the role of blood eosinophils as a biomarker prompted the Global Initiative for Chronic Obstructive Lung Disease (GOLD) committee to refine the existing treatment algorithm by incorporating eosinophil counts into treatment recommendations. However, there is a lack of data on when, why and how frequently such blood tests and other measures are being performed by German private respiratory specialists.Methods A questionnaire evaluating doctors' opinions on the use of diagnostic measures at initial diagnosis and during follow-up, including blood eosinophil count in patients with COPD, was completed by 27 respiratory specialists. Medical records from the past 12 months of 251 patients treated by the same physicians were reviewed retrospectively to investigate the use of these measures.Results Body plethysmography (100 % of doctors) and chest X-ray (96.3 %) were the most commonly used measures according to the doctor's questionnaire; other measures were COPD assessment test (CAT; 85.2 %) and blood eosinophil count (81.5 %). The evaluation of patients' medical records revealed that body plethysmography was performed in 72.7 %, the CAT in 61.8 % and chest X-ray in 40.6 % of patients. Blood eosinophil count was measured in 7.2 %.Conclusions In line with the GOLD recommendations, these results confirm that lung function, imaging and patient-reported outcome questionnaires play a crucial role in managing COPD. Our analyses reveal that measurement of the blood eosinophil count gained importance due to physicians' increased awareness of these cells as a useful biomarker. However, this test seems to be performed mainly for initial diagnosis and not on a regular basis.
| S-EPMC8093015 | biostudies-literature
Project description:RATIONALE:Rural residence is associated with poor outcomes in several chronic diseases. The association between rural residence and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear. OBJECTIVE:To determine the independent association between rural residence and COPD-related outcomes including COPD exacerbations, airflow obstruction and symptom burden. METHODS:A total of 1684 Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) participants with FEV1/FVC<0.70 had geocoding-defined rural-urban residence status determined (N=204 rural and N=1480 urban). Univariate and multivariate logistic and negative binomial regressions were performed to assess the independent association between rurality and COPD outcomes including exacerbations, lung function, and symptom burden. The primary exposure of interest was rural residence, determined by geocoding of home address to the block level at time of study enrollment. Additional covariates of interest included demographic and clinical characteristics, occupation, and occupational exposures.The primary outcome measures were exacerbations determined over the one-year course after enrollment by quarterly telephone calls and at an annual research clinic visit. Odds ratio and incidence rate of exacerbations that required treatment with medications including steroids or antibiotics (total exacerbations), and exacerbations leading to hospitalization (severe exacerbations) were determined after adjusting for relevant covariates. RESULTS:Rural residence was independently associated with 70% increase in odds of total exacerbations [OR 1.70 (95% CI 1.13-2.56); p=0.012] and 46% higher incidence rate of total exacerbations [IRR 1.46 (95% CI 1.02-2.10); p=0.039]. There was no association between rural residence and severe exacerbations. Agricultural occupation was independently associated with increased odds and incidence of total and severe exacerbations. Inclusion of agricultural occupation to analysis attenuated the association between rural residence and odds and incidence rate of total exacerbations [OR 1.52 (95% CI 1.00-2.32; p=0.05) and IRR 1.39 (95% CI 0.97 - 1.99); p=0.07]. There was no difference in symptoms or airflow obstruction between rural and urban participants. CONCLUSIONS:Rural residence is independently associated with increased odds and incidence of total, but not severe COPD exacerbations. These associations are not fully explained by agriculture-related exposures, highlighting the need for future research into potential mechanisms of increased risk of COPD exacerbations in the rural population.
| S-EPMC6207115 | biostudies-other
Project description:BackgroundForced expiratory volume in 1 second (FEV1) is central to the diagnosis of chronic obstructive pulmonary disease (COPD) but is imprecise in classifying disease burden. We examined the potential of the maximal mid-expiratory flow rate (forced expiratory flow rate between 25% and 75% [FEF25%-75%]) as an additional tool for characterizing pathophysiology in COPD.ObjectiveTo determine whether FEF25%-75% helps predict clinical and radiographic abnormalities in COPD.Study design and methodsThe SubPopulations and InteRediate Outcome Measures In COPD Study (SPIROMICS) enrolled a prospective cohort of 2978 nonsmokers and ever-smokers, with and without COPD, to identify phenotypes and intermediate markers of disease progression. We used baseline data from 2771 ever-smokers from the SPIROMICS cohort to identify associations between percent predicted FEF25%-75% (%predFEF25%-75%) and both clinical markers and computed tomography (CT) findings of smoking-related lung disease.ResultsLower %predFEF25-75% was associated with more severe disease, manifested radiographically by increased functional small airways disease, emphysema (most notably with homogeneous distribution), CT-measured residual volume, total lung capacity (TLC), and airway wall thickness, and clinically by increased symptoms, decreased 6-minute walk distance, and increased bronchodilator responsiveness (BDR). A lower %predFEF25-75% remained significantly associated with increased emphysema, functional small airways disease, TLC, and BDR after adjustment for FEV1 or forced vital capacity (FVC).InterpretationThe %predFEF25-75% provides additional information about disease manifestation beyond FEV1. These associations may reflect loss of elastic recoil and air trapping from emphysema and intrinsic small airways disease. Thus, %predFEF25-75% helps link the anatomic pathology and deranged physiology of COPD.
| S-EPMC9166328 | biostudies-literature
Project description:BackgroundQuantitative computed tomographic (QCT) imaging-based metrics enable to quantify smoking induced disease alterations and to identify imaging-based clusters for current smokers. We aimed to derive clinically meaningful sub-groups of former smokers using dimensional reduction and clustering methods to develop a new way of COPD phenotyping.MethodsAn imaging-based cluster analysis was performed for 406 former smokers with a comprehensive set of imaging metrics including 75 imaging-based metrics. They consisted of structural and functional variables at 10 segmental and 5 lobar locations. The structural variables included lung shape, branching angle, airway-circularity, airway-wall-thickness, airway diameter; the functional variables included regional ventilation, emphysema percentage, functional small airway disease percentage, Jacobian (volume change), anisotropic deformation index (directional preference in volume change), and tissue fractions at inspiration and expiration.ResultsWe derived four distinct imaging-based clusters as possible phenotypes with the sizes of 100, 80, 141, and 85, respectively. Cluster 1 subjects were asymptomatic and showed relatively normal airway structure and lung function except airway wall thickening and moderate emphysema. Cluster 2 subjects populated with obese females showed an increase of tissue fraction at inspiration, minimal emphysema, and the lowest progression rate of emphysema. Cluster 3 subjects populated with older males showed small airway narrowing and a decreased tissue fraction at expiration, both indicating air-trapping. Cluster 4 subjects populated with lean males were likely to be severe COPD subjects showing the highest progression rate of emphysema.ConclusionsQCT imaging-based metrics for former smokers allow for the derivation of statistically stable clusters associated with unique clinical characteristics. This approach helps better categorization of COPD sub-populations; suggesting possible quantitative structural and functional phenotypes.
| S-EPMC6631615 | biostudies-literature
Project description:BackgroundClassification of COPD is usually based on the severity of airflow, which may not sensitively differentiate subpopulations. Using a multiscale imaging-based cluster analysis (MICA), we aim to identify subpopulations for current smokers with COPD.MethodsAmong the SPIROMICS subjects, we analyzed computed tomography images at total lung capacity (TLC) and residual volume (RV) of 284 current smokers. Functional variables were derived from registration of TLC and RV images, e.g. functional small airways disease (fSAD%). Structural variables were assessed at TLC images, e.g. emphysema and airway wall thickness and diameter. We employed an unsupervised method for clustering.ResultsFour clusters were identified. Cluster 1 had relatively normal airway structures; Cluster 2 had an increase of fSAD% and wall thickness; Cluster 3 exhibited a further increase of fSAD% but a decrease of wall thickness and airway diameter; Cluster 4 had a significant increase of fSAD% and emphysema. Clinically, Cluster 1 showed normal FEV1/FVC and low exacerbations. Cluster 4 showed relatively low FEV1/FVC and high exacerbations. While Cluster 2 and Cluster 3 showed similar exacerbations, Cluster 2 had the highest BMI among all clusters.ConclusionsAssociation of imaging-based clusters with existing clinical metrics suggests the sensitivity of MICA in differentiating subpopulations.
| S-EPMC6145340 | biostudies-literature