scholarly journals Effect of mesenchymal stromal cell infusions on lung function in COPD patients with high CRP levels

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Daniel J. Weiss ◽  
Karen Segal ◽  
Richard Casaburi ◽  
Jack Hayes ◽  
Donald Tashkin
Keyword(s):  
Lung Function ◽  
Time Course ◽  
Inflammatory Marker ◽  
Controlled Trial ◽  
Phase 1 ◽  
Forced Expiratory Volume ◽  
Allogeneic Mscs ◽  
Copd Exacerbations ◽  
Copd Patients ◽  
Patient Reported

Abstract Background We previously reported a Phase 1/2 randomized placebo-controlled trial of systemic administration of bone marrow-derived allogeneic MSCs (remestemcel-L) in COPD. While safety profile was good, no functional efficacy was observed. However, in view of growing recognition of effects of inflammatory environments on MSC actions we conducted a post-hoc analysis with stratification by baseline levels of a circulating inflammatory marker, C-reactive protein (CRP) to determine the effects of MSC administration in COPD patients with varying circulating CRP levels. Methods Time course of lung function, exercise performance, patient reported responses, and exacerbation frequency following four monthly infusions of remestemcel-L vs. placebo were re-assessed in subgroups based on baseline circulating CRP levels. Results In COPD patients with baseline CRP ≥ 4 mg/L, compared to COPD patients receiving placebo (N = 17), those treated with remestemcel-L (N = 12), demonstrated significant improvements from baseline in forced expiratory volume in one second, forced vital capacity, and six minute walk distance at 120 days with treatment differences evident as early as 10 days after the first infusion. Significant although smaller benefits were also detected in those with CRP levels ≥ 2 or ≥ 3 mg/L. These improvements persisted variably over the 2-year observational period. No significant benefits were observed in patient reported responses or number of COPD exacerbations between treatment groups. Conclusion In an inflammatory environment, defined by elevated circulating CRP, remestemcel-L administration yielded at least transient meaningful pulmonary and functional improvements. These findings warrant further investigation of potential MSC-based therapies in COPD and other inflammatory pulmonary diseases. Trial registration: Clinicaltrials.gov NCT00683722.

Randomised controlled trial to investigate the use of high-frequency airway oscillations as training to improve dyspnoea (TIDe) in COPD

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217072
Author(s):  
Enya Daynes ◽  
Neil Greening ◽  
Sally J Singh
Keyword(s):  
Muscle Weakness ◽  
High Frequency ◽  
Controlled Trial ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Registration Number ◽  
Randomised Controlled ◽  
Double Blinded

BackgroundChronic obstructive pulmonary disease (COPD) is characterised by symptomatic dyspnoea and reduced exercise tolerance, in part as a result muscle weakness, for which inspiratory muscle training (IMT) may be useful. Excess mucus hypersecretion commonly coexists in COPD and may lead to reduce ventilation, further impacting on breathlessness. Devices for sputum clearance may be employed to aid mucus expectoration. This trial aimed to explore the effectiveness of a combined IMT and high-frequency airway oscillating (HFAO) device in the management of dyspnoea.MethodsThis was a double-blinded, randomised sham-controlled trial which recruited symptomatic patients with COPD. Patients were randomised to either a HFAO device (Aerosure) or sham device for 8 weeks, three times a day. The primary outcome was the Chronic Respiratory Questionnaire dyspnoea (CRQ-D) domain. Pre-specified subgroup analyses were performed including those with respiratory muscle weakness, excessive sputum and frequent exacerbators.Results104 participants (68% men, mean (SD) age 69.75 years (7.41), forced expiratory volume in 1 s per cent predicted 48.22% (18.75)) were recruited to this study with 96 participants completing. No difference in CRQ-D was seen between groups (0·28, 95% CI −0.19 to 0.75, p=0.24), though meaningful improvements were seen over time in both groups (mean (SD) HFAO 0.45 (0.78), p<0.01; sham 0.73 (1.09), p<0.01). Maximal inspiratory pressure significantly improved in the HFAO group over sham (5.26, 95% CI 0.34 to 10.19, p=0.05). Similar patterns were seen in the subgroup analysis.ConclusionThere were no statistical differences between the HFAO and the sham group in improving dyspnoea measured by the CRQ-D.Trial registration numberISRCTN45695543.

scholarly journals Bronchoalveolar Lavage Fluid from COPD Patients Reveals More Compounds Associated with Disease than Matched Plasma

Metabolites ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 157 ◽  
Author(s):  
Eitan Halper-Stromberg ◽  
Lucas Gillenwater ◽  
Charmion Cruickshank-Quinn ◽  
Wanda Kay O’Neal ◽  
Nichole Reisdorph ◽  
...  
Keyword(s):  
Bronchoalveolar Lavage ◽  
Cell Metabolism ◽  
Lavage Fluid ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Exacerbations ◽  
False Discovery ◽  
Copd Patients ◽  
Clinical Covariates

Smoking causes chronic obstructive pulmonary disease (COPD). Though recent studies identified a COPD metabolomic signature in blood, no large studies examine the metabolome in bronchoalveolar lavage (BAL) fluid, a more direct representation of lung cell metabolism. We performed untargeted liquid chromatography–mass spectrometry (LC–MS) on BAL and matched plasma from 115 subjects from the SPIROMICS cohort. Regression was performed with COPD phenotypes as the outcome and metabolites as the predictor, adjusted for clinical covariates and false discovery rate. Weighted gene co-expression network analysis (WGCNA) grouped metabolites into modules which were then associated with phenotypes. K-means clustering grouped similar subjects. We detected 7939 and 10,561 compounds in BAL and paired plasma samples, respectively. FEV1/FVC (Forced Expiratory Volume in One Second/Forced Vital Capacity) ratio, emphysema, FEV1 % predicted, and COPD exacerbations associated with 1230, 792, eight, and one BAL compounds, respectively. Only two plasma compounds associated with a COPD phenotype (emphysema). Three BAL co-expression modules associated with FEV1/FVC and emphysema. K-means BAL metabolomic signature clustering identified two groups, one with more airway obstruction (34% of subjects, median FEV1/FVC 0.67), one with less (66% of subjects, median FEV1/FVC 0.77; p < 2 × 10−4). Associations between metabolites and COPD phenotypes are more robustly represented in BAL compared to plasma.

scholarly journals Maintenance Negative Pressure Ventilation Improves Survival in COPD Patients with Exercise Desaturation

2019 ◽  
Vol 8 (4) ◽  
pp. 562
Author(s):  
Hung-Yu Huang ◽  
Chun-Yu Lo ◽  
Lan-Yan Yang ◽  
Fu-Tsai Chung ◽  
Te-Fang Sheng ◽  
...  
Keyword(s):  
Lung Function ◽  
Negative Pressure ◽  
Significant Risk ◽  
Forced Expiratory Volume ◽  
Walking Distance ◽  
Chronic Obstructive ◽  
Negative Pressure Ventilation ◽  
Risk Of Death ◽  
Copd Patients

Negative pressure ventilation (NPV), when used as an adjuvant to pulmonary rehabilitation, improves lung function, increases exercise capacity, and reduces exacerbations. The aim of this study was to determine whether maintenance NPV improves long-term clinical outcomes and reduces mortality in patients with chronic obstructive pulmonary disease (COPD). Between 2003 and 2009, 341 patients were treated for COPD either with or without hospital-based NPV. We measured forced expiratory volume in one second (FEV1), 6-min walking distance (6MWD), and oxygen saturation by pulse oximetry (SpO2) during a 6-min walk test (6MWT) every 3–6 months. Desaturation (D) during the 6MWT was defined as a reduction in SpO2 of ≥10% from baseline. The NPV group had a better survival outcome than the Non-NPV group. The 8-year survival probabilities for the NPV and Non-NPV groups were 60% and 20%, respectively (p < 0.01). Baseline desaturation was a significant risk factor for death, and the risk of death increased with desaturation severity (SpO2 80~89: hazard ratios (HR) 2.7, 95% confidence interval (CI) 1.4–5.3; SpO2 < 80: HR 3.1, 95% CI 1.3–7.4). The NPV group had a slower decline in lung function and 6MWD. The NPV + D and Non-NPV+D had a threefold and fourfold increase in the risks of all-cause mortality compared with the NPV-ND, respectively. Maintenance non-invasive NPV reduced long-term mortality in COPD patients. The desaturating COPD patients had an increased mortality risk compared with non-desaturating COPD patients.

scholarly journals Flow-Volume Parameters in COPD Related to Extended Measurements of Lung Volume, Diffusion, and Resistance

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Linnea Jarenbäck ◽  
Jaro Ankerst ◽  
Leif Bjermer ◽  
Ellen Tufvesson
Keyword(s):  
Lung Function ◽  
Forced Expiratory Volume ◽  
Flow Volume ◽  
Impulse Oscillometry ◽  
Body Plethysmography ◽  
Additional Information ◽  
Single Breath ◽  
Gold Stage ◽  
Copd Patients ◽  
Helium Dilution

Classification of COPD into different GOLD stages is based on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) but has shown to be of limited value. The aim of the study was to relate spirometry values to more advanced measures of lung function in COPD patients compared to healthy smokers. The lung function of 65 COPD patients and 34 healthy smokers was investigated using flow-volume spirometry, body plethysmography, single breath helium dilution with CO-diffusion, and impulse oscillometry. All lung function parameters, measured by body plethysmography, CO-diffusion, and impulse oscillometry, were increasingly affected through increasing GOLD stage but did not correlate with FEV1within any GOLD stage. In contrast, they correlated fairly well with FVC%p, FEV1/FVC, and inspiratory capacity. Residual volume (RV) measured by body plethysmography increased through GOLD stages, while RV measured by helium dilution decreased. The difference between these RV provided valuable additional information and correlated with most other lung function parameters measured by body plethysmography and CO-diffusion. Airway resistance measured by body plethysmography and impulse oscillometry correlated within COPD stages. Different lung function parameters are of importance in COPD, and a thorough patient characterization is important to understand the disease.

Phase III study of the hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 versus everolimus in previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5094-TPS5094 ◽  
Author(s):  
Toni K. Choueiri ◽  
Laurence Albiges ◽  
Li Fan ◽  
Rodolfo F. Perini ◽  
Naseem J. Zojwalla ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Phase Iii ◽  
Once Daily ◽  
Patient Reported ◽  
Previously Treated ◽  
Metastatic Rcc

TPS5094 Background: In RCC, the Von Hippel-Lindau ( VHL) tumor suppressor gene is inactivated in most cases, resulting in the accumulation and overactivation of HIF-2α. HIF-2α is a key oncogenic driver in RCC and is involved in the activation of genes associated with angiogenesis, tumor progression, and metastasis, such as vascular endothelial growth factor A ( VEGFA), cyclin D1, and CXCR4. MK-6482 is a potent and selective small molecule inhibitor of HIF-2α, and it has shown antitumor activity in a phase 1/2 study in patients with previously treated advanced ccRCC. Methods: The current study (NCT04195750) is a phase 3, open-label, multicenter, randomized, active-controlled trial to compare the efficacy and safety of MK-6482 with everolimus in patients with previously treated advanced ccRCC. Adults aged ≥18 years will be eligible if they have unresectable, locally advanced, or metastatic ccRCC; have measurable disease per RECIST v1.1; and received ≤3 prior systemic regimens, which must include a PD-1/PD-L1 inhibitor (≥2 doses) and a VEGF-targeted therapy, for locally advanced or metastatic RCC. Approximately 736 patients will be randomly assigned 1:1 to receive MK-6482 120 mg orally once daily or everolimus 10 mg orally once daily. At randomization, patients will be stratified by International Metastatic RCC Database prognostic scores (0 vs 1-2 vs 3-6) and by the number of prior anti-VEGF–targeted therapies received for advanced RCC (1 vs 2-3). Responses will be assessed by CT or MRI per RECIST v1.1 by blinded independent central review at week 9 from the date of randomization, then every 8 weeks through week 49, and then every 12 weeks thereafter. Treatment will continue until documented disease progression, withdrawal of consent, or other discontinuation event. Dual primary endpoints are progression-free survival per RECIST v1.1 and overall survival. Key secondary endpoints include objective response rate, duration of response, patient-reported outcomes, and safety. Clinical trial information: NCT04195750 .

Impact of using different predictive equations on the prevalence of chronic byssinosis in textile workers in Pakistan

2021 ◽  
pp. oemed-2021-107680
Author(s):  
Asaad Ahmed Nafees ◽  
Muhammad Zia Muneer ◽  
Sara De Matteis ◽  
Andre Amaral ◽  
Peter Burney ◽  
...  
Keyword(s):  
Lung Function ◽  
Controlled Trial ◽  
Forced Expiratory Volume ◽  
Textile Workers ◽  
Middle Income ◽  
Low Middle Income Countries ◽  
Reference Equations ◽  
Predicted Values ◽  
Definition Of ◽  
Randomised Controlled

ObjectiveByssinosis remains a significant problem among textile workers in low/middle-income countries. Here we share our experience of using different prediction equations for assessing ‘chronic’ byssinosis according to the standard WHO classification using measurements of forced expiratory volume in 1 s (FEV1).MethodsWe enrolled 1910 workers in a randomised controlled trial of an intervention to improve the health of textile workers in Pakistan. We included in analyses the 1724 (90%) men who performed pre-bronchodilator spirometry tests of acceptable quality. We compared four different equations for deriving lung function percentage predicted values among those with symptoms-based byssinosis: the third US National Health and Nutrition Examination Survey (NHANES-III, with ‘North Indian and Pakistani’ conversion factor); the Global Lung Function Initiative (GLI, ‘other or mixed ethnicities’); a recent equation derived from survey of a western Indian population; and one based on an older and smaller survey of Karachi residents.Results58 men (3.4%) had symptoms-based byssinosis according to WHO criteria. Of these, the proportions with a reduced FEV1 (<80% predicted) identified using NHANES and GLI; Indian and Pakistani reference equations were 40%, 41%, 14% and 12%, respectively. Much of this variation was eliminated when we substituted FEV1/forced vital capacity (FVC) ratio (<lower limit of normality) as a measure of airway obstruction.ConclusionAccurate measures of occupational disease frequency and distribution require approaches that are both standardised and meaningful. We should reconsider the WHO definition of ‘chronic’ byssinosis based on changes in FEV1, and instead use the FEV1/FVC.

scholarly journals Defining asthma–COPD overlap syndrome: a population-based study

2017 ◽  
Vol 49 (5) ◽  
pp. 1602008 ◽  
Author(s):  
Tobias N. Bonten ◽  
Marise J. Kasteleyn ◽  
Renee de Mutsert ◽  
Pieter S. Hiemstra ◽  
Frits R. Rosendaal ◽  
...  
Keyword(s):  
Lung Function ◽  
Patient Characteristics ◽  
Population Based ◽  
Forced Expiratory Volume ◽  
Overlap Syndrome ◽  
Self Report ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Adjusted Incidence Rate

Asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) seems an important clinical phenotype, but multiple definitions have been proposed. This study's objectives were to assess the effect of different ACOS definitions on prevalence, patient characteristics and exacerbations.5675 individuals aged 45–65 years, with 846 asthma/COPD patients, were included in the Netherlands Epidemiology of Obesity study between 2008 and 2012, and followed-up for a median of 1.8 years. ACOS was defined by recent consensus criteria and five other definitions, based on registry, questionnaires and lung function.Prevalence of ACOS in the asthma/COPD population ranged between 4.4% and 38.3%, depending on the definition used. Agreement between registry-based and self-reported ACOS was 0.04 and 0.41 when lung function (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <0.7) was added. With registry or self-report defined ACOS, only 51% and 33% had FEV1/FVC <0.7. Patient characteristics were similar, but asthma duration was longer with self-reported compared with registry-based ACOS (mean difference 22 years (95% CI 12–33)). Exacerbation risk was highest with registry-based ACOS compared with asthma (adjusted incidence rate ratio 1.6 (95% CI 1.2–2.1)).This study adds important knowledge about agreement between ACOS definitions and their relation with exacerbations. Given the low agreement, differences in prevalence, patient characteristics and risk of exacerbations, consensus about ACOS definition in different care settings is urgently needed.

scholarly journals Stratification of eosinophilic asthma patients treated with reslizumab and GINA Step 4 or 5 therapy

2017 ◽  
Vol 3 (3) ◽  
pp. 00004-2017 ◽  
Author(s):  
Guy Brusselle ◽  
Janice Canvin ◽  
Sivan Weiss ◽  
Shawn X. Sun ◽  
Roland Buhl
Keyword(s):  
Lung Function ◽  
Patient Reported Outcomes ◽  
Secondary Analysis ◽  
Forced Expiratory Volume ◽  
Phase Iii ◽  
Eosinophilic Asthma ◽  
Interleukin 5 ◽  
Severe Eosinophilic Asthma ◽  
Patient Reported ◽  
Asthma Patients

Reslizumab, an anti-interleukin-5 monoclonal antibody, significantly reduces exacerbation frequency and improves lung function, asthma control and quality of life in adults with severe eosinophilic asthma, as demonstrated in Phase III studies.This secondary analysis assessed reslizumab's efficacy in patients receiving baseline treatment per Global Initiative for Asthma (GINA) Step 4 and Step 5 guidelines.Pooled data from duplicate, Phase III, reslizumab versus placebo studies in patients with severe eosinophilic asthma (blood eosinophils ≥400 cells·µL−1) were stratified by baseline therapy. Efficacy assessments were exacerbation rates and changes from baseline forced expiratory volume in 1 s (FEV1) and patient-reported outcomes.Of 953 patients, 69% (n=657) and 11% (n=106) were receiving Step 4 and Step 5 therapy, respectively. Compared with placebo, reslizumab reduced exacerbation rates by 53% (95% CI 0.36–0.62) and 72% (95% CI 0.15–0.52), in Step 4 and Step 5 groups respectively. By study end, reslizumab increased FEV1 in Step 4 and Step 5 groups by 103 mL (95% CI 52–154 mL) and 237 mL (95% CI 68–407 mL), respectively. Reslizumab also improved patient-reported outcomes compared with placebo in both groups.Reslizumab reduces exacerbation rates and improves lung function and patient-reported outcomes in patients with eosinophilic asthma receiving therapy per Steps 4 and 5 of the GINA guidelines.

scholarly journals Effect of TRPM8 and TRPA1 Polymorphisms on COPD Predisposition and Lung Function in COPD Patients

2021 ◽  
Vol 11 (2) ◽  
pp. 108
Author(s):  
Denis E. Naumov ◽  
Olesya O. Kotova ◽  
Dina A. Gassan ◽  
Ivana Y. Sugaylo ◽  
Evgeniya Y. Afanas’eva ◽  
...  
Keyword(s):  
Lung Function ◽  
Multiple Testing ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Bronchial Obstruction ◽  
Bronchodilator Response ◽  
Copd Patients

Certain transient receptor potential (TRP) channels including TRPM8 and TRPA1 are widely expressed in the respiratory tract and have been shown to be the receptors of cigarette smoke and particulate matter—the main causative factors of chronic obstructive pulmonary disease (COPD). The aim of the study was to investigate the effect of TRPM8 and TRPA1 polymorphisms on COPD predisposition and lung function in COPD patients. The study enrolled 143 COPD patients and 104 smokers with post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) > 70%. Lung function was measured by spirometry. TRPM8 and TRPA1 polymorphisms were genotyped by LATE-PCR. None of the polymorphisms significantly influenced COPD predisposition after correction for covariates and multiple testing. Among COPD patients, the TT genotype of TRPA1 rs7819749 was significantly associated with higher degree of bronchial obstruction. In addition, we established that carriers of the C allele of TRPM8 rs11562975 more commonly had post-bronchodilator FEV1 < 60% (OR 3.2, 95%CI (1.14–8.94), p = 0.03) and revealed the effect of TRPA1 rs959976 and TRPM8 rs17865682 on bronchodilator response in COPD. Thus, the obtained results suggest possible involvement of TRPM8 and TRPA1 in COPD pathogenesis, indicating the necessity to further investigate their functional role in this pathology.

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