scholarly journals The use of treatable traits to address COPD complexity and heterogeneity and to inform the care

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210118
Author(s):  
Katarzyna Duszyk ◽  
Rebecca F. McLoughlin ◽  
Peter G. Gibson ◽  
Vanessa M. McDonald
Keyword(s):  
Respiratory Failure ◽  
Lung Function ◽  
Patient Outcomes ◽  
Clinical Presentation ◽  
Airflow Limitation ◽  
Biological Mechanisms ◽  
Lung Function Decline ◽  
Targeted Interventions ◽  
Airway Diseases ◽  
Clinical Measures

COPD is complex and heterogeneous with respect to its aetiology, clinical presentation, phenotypes and biological mechanisms. Despite this, COPD is still diagnosed and treated according to simple clinical measures, including airflow limitation, symptoms and exacerbation frequency, leading to failure to recognise the disease's heterogeneity and/or to provide targeted interventions. COPD continues to have a very large burden of disease with suboptimal outcomes for people with the disease, including frequent hospitalisation with exacerbations, rapid lung function decline, multimorbidity and death from respiratory failure. In light of this, there have been increasing calls for a renewed taxonomy with better characterisation of COPD phenotypes and endotypes. This would allow the unravelling of COPD's complexity and heterogeneity, the implementation of targeted interventions and improved patient outcomes. The treatable traits strategy is a proposed vehicle for the implementation of precision medicine in chronic airway diseases. In this review, in addition to summarising the key knowledge on the heterogeneity of COPD, we refer to the existing evidence pertaining to the treatable traits strategy as applied in COPD and discuss implementation in different settings.

scholarly journals Pulmonary involvement in Fabry disease: effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy

2018 ◽  
Vol 5 (1) ◽  
pp. e000277 ◽  
Author(s):  
Daniel Franzen ◽  
Sarah R Haile ◽  
David C Kasper ◽  
Thomas P Mechtler ◽  
Andreas J Flammer ◽  
...  
Keyword(s):  
Lung Function ◽  
Enzyme Replacement Therapy ◽  
Pulmonary Function ◽  
Fabry Disease ◽  
Replacement Therapy ◽  
Pulmonary Function Tests ◽  
Airflow Limitation ◽  
Z Score ◽  
Lung Function Decline ◽  
Enzyme Replacement

IntroductionAnderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations of GLA gene leading to reduced α-galactosidase activity and resulting in a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Plasma Lyso-Gb3 levels serve as a disease severity and treatment monitoring marker during enzyme replacement therapy (ERT).MethodsAdult patients with AFD who had yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Primary outcome measures were the change in z-score of forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. Plasma Lyso-Gb3 levels and the age of ERT initiation were investigated for their association with lung function decline.ResultsFifty-three patients (42% male, median (range) age at diagnosis of AFD 34 (6–61) years in men, 34 (13–67) in women) were included. The greatest decrease of FEV1/FVC z-scores was observed in Classic men (−0.048 per year, 95% CI −0.081 to –0.014), compared with the Later-Onset men (+0.013,95% CI −0.055 to 0.082), Classic women (−0.008, 95% CI −0.035 to +0.020) and Later-Onset women (−0.013, 95% CI −0.084 to +0.058). Cigarette smoking (P=0.022) and late ERT initiation (P=0.041) were independently associated with faster FEV1 decline. FEV1/FVC z-score decrease was significantly reduced after initiation of ERT initiation (−0.045 compared with −0.015, P=0.014). Furthermore, there was a trend towards a relevant influence of Lyso-Gb3 (P=0.098) on airflow limitation with age.ConclusionEarly ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 is maybe a useful predictor for airflow limitation. Classic men need a closer monitoring of the lung function.

scholarly journals Longitudinal decline in lung function: a community-based cohort study in Korea

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ah Young Leem ◽  
Boram Park ◽  
Young Sam Kim ◽  
Joon Chang ◽  
Sungho Won ◽  
...  
Keyword(s):  
Smoking Cessation ◽  
Lung Function ◽  
Mixed Model ◽  
Smoking Status ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Rate Of Decline ◽  
Never Smokers ◽  
Over Time

Abstract Progressive decline in lung function is the hallmark of chronic obstructive pulmonary disease (COPD). We aimed to assess the rate of decline in forced expiratory volume in 1 second (FEV1) in patients from a community cohort database in Korea. 5,865 subjects aged 40–69 years from the Ansung-Ansan cohort database I–III (2001–2006) were included in this study. We assessed the annual rate of decline in FEV1 over time in relation to smoking status, patient sex, and presence or absence of pre-bronchodilator airflow limitation using a generalized additive mixed model. The mean follow-up duration was 3.8 years. The annual mean decline in FEV1 in the entire cohort was significantly more rapid for men than women (31.3 mL vs 27.0 mL, P = 0.003). Among men without pre-bronchodilator airflow limitation, annual mean declines in FEV1 were 31.5, 35.5, and 40.1 mL for never smokers, former smokers (P = 0.09 vs. never smokers), and current smokers (P < 0.001 vs. never smokers), respectively; and 23.4, 19.7, and 33.9 mL, respectively, for men with pre-bronchodilator airflow limitation. Thus, among Korean males, smoking accelerates lung function decline over time whereas smoking cessation slows the rate of FEV1 decline regardless of pre-bronchodilator airflow limitation. This underscores the importance of smoking cessation in Koreans.

scholarly journals Fibrocyte accumulation in bronchi: a cellular hallmark of COPD

2018 ◽  
Author(s):  
Isabelle Dupin ◽  
Matthieu Thumerel ◽  
Elise Maurat ◽  
Florence Coste ◽  
Hugues Begueret ◽  
...  
Keyword(s):  
Lung Function ◽  
Ct Scan ◽  
Wall Thickness ◽  
High Density ◽  
Airflow Limitation ◽  
Normal Lung ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Control Subjects ◽  
Copd Patients

AbstractBackgroundThe remodeling mechanism and cellular players causing persistent airflow limitation in chronic obstructive pulmonary disease (COPD) remain largely elusive. We have recently demonstrated that circulating fibrocytes, a rare population of fibroblast-like cells produced by the bone marrow stroma, are increased in COPD patients during an exacerbation. It remains, however, unclear, whether fibrocytes are present in bronchial tissue of COPD patients.ObjectiveWe aimed to quantify fibrocytes density in bronchial specimens from both control subjects and COPD patients, and to define associations with clinical, functional and computed tomography relevant parameters.Methods17 COPD patients and 25 control subjects with normal lung function testing and no chronic symptoms, all of them requiring thoracic surgery, were recruited. LFT and CT-scan were performed before surgery. Using co-immunostaining and image analysis, we identify CD45+ FSP1+ cells as tissue fibrocytes and quantify their density in distal and proximal bronchial specimens from the whole series.ResultsHere, we demonstrate that fibrocytes are increased in both distal and proximal tissue specimens of COPD patients, compared to those of controls. The density of fibrocytes is negatively correlated with lung function parameters, such as FEV1 and FEV1/FVC, and positively with bronchial wall thickness assessed by CT scan. High density of distal bronchial fibrocytes predicts presence of COPD with a sensitivity of 83% and a specificity of 70%.ConclusionsOur results thus suggest that recruitment of fibrocytes in the bronchi may participate to lung function decline during COPD progression.Clinical ImplicationsHigh density of tissue fibrocytes is associated with a deteriorated lung function and an increase in airway wall thickness. A low density tissue fibrocytes virtually eliminates the presence of COPD.Capsule summaryBlood fibrocytes assessed during exacerbation is a predictor of mortality in COPD. This study shows an increase of bronchial fibrocytes, that is associated with lower lung function, increased bronchial thickness and air trapping in COPD.

scholarly journals Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yung-Che Chen ◽  
◽  
Ying-Huang Tsai ◽  
Chin-Chou Wang ◽  
Shih-Feng Liu ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Lung Function ◽  
Pulmonary Disease ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Dna Methylations

AbstractWe hypothesized that epigenetics is a link between smoking/allergen exposures and the development of Asthma and chronic obstructive pulmonary disease (ACO). A total of 75 of 228 COPD patients were identified as ACO, which was independently associated with increased exacerbations. Microarray analysis identified 404 differentially methylated loci (DML) in ACO patients, and 6575 DML in those with rapid lung function decline in a discovery cohort. In the validation cohort, ACO patients had hypermethylated PDE9A (+ 30,088)/ZNF323 (− 296), and hypomethylated SEPT8 (− 47) genes as compared with either pure COPD patients or healthy non-smokers. Hypermethylated TIGIT (− 173) gene and hypomethylated CYSLTR1 (+ 348)/CCDC88C (+ 125,722)/ADORA2B (+ 1339) were associated with severe airflow limitation, while hypomethylated IFRD1 (− 515) gene with frequent exacerbation in all the COPD patients. Hypermethylated ZNF323 (− 296) / MPV17L (+ 194) and hypomethylated PTPRN2 (+ 10,000) genes were associated with rapid lung function decline. In vitro cigarette smoke extract and ovalbumin concurrent exposure resulted in specific DNA methylation changes of the MPV17L / ZNF323 genes, while 5-aza-2′-deoxycytidine treatment reversed promoter hypermethylation-mediated MPV17L under-expression accompanied with reduced apoptosis and decreased generation of reactive oxygen species. Aberrant DNA methylations may constitute a determinant for ACO, and provide a biomarker of airflow limitation, exacerbation, and lung function decline.

scholarly journals Plasma pro-surfactant protein B and lung function decline in smokers

2015 ◽  
Vol 45 (4) ◽  
pp. 1037-1045 ◽  
Author(s):  
Janice M. Leung ◽  
John Mayo ◽  
Wan Tan ◽  
C. Martin Tammemagi ◽  
Geoffrey Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Function ◽  
Surfactant Protein ◽  
Airflow Limitation ◽  
Ct Scans ◽  
Rapid Decline ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Surfactant Protein B ◽  
Protein B

Plasma pro-surfactant protein B (pro-SFTPB) levels have recently been shown to predict the development of lung cancer in current and ex-smokers, but the ability of pro-SFTPB to predict measures of chronic obstructive pulmonary disease (COPD) severity is unknown. We evaluated the performance characteristics of pro-SFTPB as a biomarker of lung function decline in a population of current and ex-smokers.Plasma pro-SFTPB levels were measured in 2503 current and ex-smokers enrolled in the Pan-Canadian Early Detection of Lung Cancer Study. Linear regression was performed to determine the relationship of pro-SFTPB levels to changes in forced expiratory volume in 1 s (FEV1) over a 2-year period as well as to baseline FEV1 and the burden of emphysema observed in computed tomography (CT) scans.Plasma pro-SFTPB levels were inversely related to both FEV1 % predicted (p=0.024) and FEV1/forced vital capacity (FVC) (p<0.001), and were positively related to the burden of emphysema on CT scans (p<0.001). Higher plasma pro-SFTPB levels were also associated with a more rapid decline in FEV1 at 1 year (p=0.024) and over 2 years of follow-up (p=0.004).Higher plasma pro-SFTPB levels are associated with increased severity of airflow limitation and accelerated decline in lung function. Pro-SFTPB is a promising biomarker for COPD severity and progression.

scholarly journals Heterogeneity in the respiratory symptoms of patients with mild-moderate COPD

2018 ◽  
Author(s):  
Kate M. Johnson ◽  
Abdollah Safari ◽  
Wan C. Tan ◽  
Jean Bourbeau ◽  
J Mark FitzGerald ◽  
...  
Keyword(s):  
Lung Function ◽  
Respiratory Symptoms ◽  
Clinical Characteristics ◽  
Symptom Burden ◽  
Airflow Limitation ◽  
Chronic Obstructive ◽  
Lung Function Decline ◽  
Mixed Effect ◽  
Obstructive Pulmonary Disease ◽  
Logistic Regression Models

ABSTRACTBackgroundThe burden of symptoms varies markedly between patients with Chronic Obstructive Pulmonary Disease (COPD) and is only weakly correlated with lung function impairment. While heterogeneity in lung function decline and exacerbations have been previously studied, the extent of heterogeneity in symptoms and the factors associated with this heterogeneity are not well understood.MethodsA sample of the general Canadian population ≥40 years with persistent airflow limitation was followed for up to 3 years. Participants reported whether they experienced chronic coughing, phlegm, wheezing, or dyspnea during visits at 18-month intervals. We used mixed-effect logistic regression models (separately for each symptom) to assess overall heterogeneity in the occurrence of symptoms between individuals, and the proportion of variation in symptom burden explained by lung function versus all other clinical characteristics of participants.Results548 participants (54% male, mean age 67 years) contributed 1,086 visits in total, and 82% of patients reported at least one symptom during follow-up. There was substantial heterogeneity in the individual-specific probabilities for the occurrence of symptoms. This heterogeneity was highest for dyspnea and lowest for phlegm (interquartile range of probabilities: 0.15-0.77 and <0.01-0.53, respectively). FEV1 explained 82% of the variation between individuals in the occurrence of phlegm, 26% for dyspnea, 3% for cough, and <0.1% for wheeze. All clinical characteristics of participants (including FEV1) explained between 86% of heterogeneity in the occurrence of phlegm to <1% for wheeze.ConclusionThere is marked heterogeneity in the burden of respiratory symptoms between COPD patients. The ability of lung function and other commonly measured clinical characteristics to explain this heterogeneity differs between symptoms.

scholarly journals A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raymond J. Langley ◽  
Marie E. Migaud ◽  
Lori Flores ◽  
J. Will Thompson ◽  
Elizabeth A. Kean ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Acute Respiratory Failure ◽  
Patient Outcomes ◽  
Medical Intensive Care Unit ◽  
Close Association ◽  
Treatment Options ◽  
Feature Model ◽  
High Morbidity ◽  
Medical Intensive Care ◽  
Poor Outcomes

AbstractAcute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors’ biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

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