scholarly journals Clustering-based COPD Subtypes Have Distinct Longitudinal Outcomes and Multi-omics Biomarkers

2022 ◽  
Author(s):  
Andrew Gregory ◽  
Zhonghui Xu ◽  
Katherine Pratte ◽  
Sool Lee ◽  
Congjian Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Chronic Obstructive ◽  
Proportional Hazard ◽  
Obstructive Pulmonary Disease ◽  
Blood Gene Expression ◽  
Longitudinal Outcomes ◽  
Copd Exacerbations ◽  
Cox Proportional Hazard ◽  
Gene Expression Levels

Introduction: Chronic obstructive pulmonary disease (COPD) can progress across several domains, complicating the identification of the determinants of disease progression. In our previous work, we applied k-means clustering to spirometric and chest radiologic measures to identify four COPD-related subtypes: "Relatively resistant smokers (RRS)", "mild upper lobe predominant emphysema (ULE)", "airway-predominant disease (AD)", and "severe emphysema (SE)". In the current study, we examined longitudinal spirometric and radiologic emphysema changes and prospective risks of COPD exacerbations, incident comorbidities, and mortality of these clusters. We also compared their associations to protein and transcriptomic biomarkers. Methods: We included 8,266 non-Hispanic white and African-American smokers from the COPDGene study. We used linear regression to investigate associations to five-year prospective changes in spirometric and radiologic measures and to plasma protein and blood gene expression levels. We used Cox-proportional hazard modeling to test for associations to prospective exacerbations, comorbidities, and mortality. Results: The RRS, ULE, AD, and SE clusters represented 39%, 15%, 26%, and 20% of the studied cohort at baseline, respectively. The SE cluster had the greatest 5-year FEV1 and emphysema progression, and the highest risks of exacerbations, cardiovascular disease (CVD), and mortality. The AD cluster had the highest diabetes risk. After adjustments, only the ULE and AD clusters had elevated CVD mortality risks, while only the ULE cluster had the highest cancer-related mortality risk. These clusters also demonstrated differential protein and gene expression biomarker associations. Conclusion: COPD k-means subtypes demonstrate varying rates of disease progression, prospective comorbidities, mortality, and associations to proteomic and transcriptomic biomarkers.

The Association Between Serum Human Epididymis Protein 4 Level and Cardiovascular Events in Patients with Chronic Obstructive Pulmonary Disease

2020 ◽  
Author(s):  
Hui Lin ◽  
Jianhong Xiao ◽  
Xianghua Su ◽  
Bin Song
Keyword(s):  
Blood Pressure ◽  
Chronic Obstructive Pulmonary Disease ◽  
Logistic Regression ◽  
Hazard Analysis ◽  
Chronic Obstructive ◽  
Proportional Hazard ◽  
Obstructive Pulmonary Disease ◽  
Human Epididymis Protein 4 ◽  
Human Epididymis ◽  
Cox Proportional Hazard

Abstract Objective Serum human epididymis protein 4 (HE4) is associated with immune and inflammatory responses. This study aimed to assess the performance of serum HE4 in the early detection of cardiovascular (CV) events in patients with chronic obstructive pulmonary disease (COPD). Methods Serum HE4 levels were measured in 199 patients with COPD, all of whom were prospectively followed up for a median period of 36 months (range = 3 months–38 months). Logistic regression analysis was performed to assess the association between cardiovascular disease (CVD) history and HE4 in patients with COPD. Cox proportional hazard analysis was performed to assess the prognostic value of serum HE4 for predicting CV events. Results Serum HE4 levels were higher in patients with COPD with CV events than in those without CV events (252.6 pmol/L [186.4–366.8] vs 111.0 pmol/L [84.8–157.1]; P <.001). The multivariate logistic regression model revealed that serum HE4 (odds ratio = 1.639; 95% confidence interval [CI], 1.213–2.317; Ptrend =.009) was independently associated with CVD history after adjusting for age, sex, body mass index, current smoking status, current alcohol consumption status, admission systolic blood pressure and diastolic blood pressure, hyperlipidemia, left ventricular ejection fraction, primary diseases, and laboratory measurements in patients with COPD at baseline. The multivariate Cox proportional hazard analysis revealed that serum HE4 (hazard ratio = 2.012; 95% CI, 1.773–4.469; P <.001) was an independent prognostic factor for CV events in these patients. The Kaplan-Meier analysis showed that the rate of CV events was higher in patients with COPD with HE4 levels above the median (187.5 pmol/L) than in those with HE4 levels below the median. Conclusion Our results showed that serum HE4 was significantly and independently associated with CVD history and had independent predictive value for CV events in patients with COPD. Serum HE4 may enable early recognition of CV complication development among patients with COPD.

scholarly journals ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19

2020 ◽  
Author(s):  
Janice M. Leung ◽  
Chen X. Yang ◽  
Anthony Tam ◽  
Tawimas Shaipanich ◽  
Tillie-Louise Hackett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Current Smoking ◽  
Expression Levels ◽  
Copd Patients ◽  
Increased Risk ◽  
Lower Airways ◽  
Never Smokers ◽  
Gene Expression Levels

AbstractIntroductionCoronavirus disease 2019 (COVID-19) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This virus uses the angiotensin converting enzyme II (ACE-2) as the cellular entry receptor to infect the lower respiratory tract. Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID-19, we determined whether ACE-2 expression in the lower airways was related to COPD and cigarette smoking.MethodsUsing RNA-seq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of 6th to 8th generation airways in individuals with and without COPD. We eternally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from 6th to 12th generation airways.ResultsIn the discovery cohort (n=42 participants), we found that ACE-2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52±0.66 log2 counts per million reads (CPM) versus non-COPD= 1.70±0.51 CPM, p=7.62×10−4). There was a significant inverse relationship between ACE-2 gene expression and FEV1% of predicted (r=-0.24; p=0.035). Current smoking also significantly increased ACE-2 expression levels compared with never smokers (never current smokers=2.77±0.91 CPM versus smokers=1.78±0.39 CPM, p=0.024). These findings were replicated in the two eternal cohorts.ConclusionsACE-2 expression in lower airways is increased in patients with COPD and with current smoking. These data suggest that these two subgroups are at increased risk of serious COVID-19 infection and highlight the importance of smoking cessation in reducing the risk.

scholarly journals Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

2021 ◽  
Vol 10 (8) ◽  
pp. 1623
Author(s):  
Maria Viktoria Requardt ◽  
Dennis Görlich ◽  
Torsten Grehl ◽  
Matthias Boentert
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Disease Progression ◽  
Rating Scale ◽  
Rapid Decline ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Hazard Ratios ◽  
Sum Score ◽  
Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

scholarly journals Newborn DNA-methylation, childhood lung function, and the risks of asthma and COPD across the life course

2019 ◽  
Vol 53 (4) ◽  
pp. 1801795 ◽  
Author(s):  
Herman T. den Dekker ◽  
Kimberley Burrows ◽  
Janine F. Felix ◽  
Lucas A. Salas ◽  
Ivana Nedeljkovic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Function ◽  
Life Course ◽  
Cord Blood ◽  
Childhood Asthma ◽  
Respiratory Health ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
The Life Course

RationaleWe aimed to identify differentially methylated regions (DMRs) in cord blood DNA associated with childhood lung function, asthma and chronic obstructive pulmonary disease (COPD) across the life course.MethodsWe meta-analysed epigenome-wide data of 1688 children from five cohorts to identify cord blood DMRs and their annotated genes, in relation to forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) ratio and forced expiratory flow at 75% of FVC at ages 7–13 years. Identified DMRs were explored for associations with childhood asthma, adult lung function and COPD, gene expression and involvement in biological processes.ResultsWe identified 59 DMRs associated with childhood lung function, of which 18 were associated with childhood asthma and nine with COPD in adulthood. Genes annotated to the top 10 identified DMRs were HOXA5, PAOX, LINC00602, ABCA7, PER3, CLCA1, VENTX, NUDT12, PTPRN2 and TCL1A. Differential gene expression in blood was observed for 32 DMRs in childhood and 18 in adulthood. Genes related with 16 identified DMRs were associated with respiratory developmental or pathogenic pathways.InterpretationOur findings suggest that the epigenetic status of the newborn affects respiratory health and disease across the life course.

scholarly journals Domiciliary Cough Monitoring for the Prediction of COPD Exacerbations

Lung ◽  
2021 ◽  
Vol 199 (2) ◽  
pp. 131-137
Author(s):  
Michael G. Crooks ◽  
Albertus C. den Brinker ◽  
Susannah Thackray-Nocera ◽  
Ralph van Dinther ◽  
Caroline E. Wright ◽  
...  
Keyword(s):  
Automated System ◽  
Chronic Obstructive ◽  
Service Utilisation ◽  
Alert System ◽  
Obstructive Pulmonary Disease ◽  
Prospective Longitudinal Study ◽  
Copd Exacerbations ◽  
Cough Frequency ◽  
Copd Patients ◽  
Prospective Longitudinal

Abstract Introduction Acute exacerbations of COPD (AE-COPD) are a leading cause of health service utilisation and are associated with morbidity and mortality. Identifying the prodrome of AE-COPD by monitoring symptoms and physiological parameters (telemonitoring) has proven disappointing and false alerts limit clinical utility. We report objective monitoring of cough counts around AE-COPD and the performance of a novel alert system identifying meaningful change in cough frequency. Methods This prospective longitudinal study of cough monitoring included chronic obstructive pulmonary disease (COPD) patients experienced in telemonitoring that had two or more AE-COPD in the past year. Participants underwent cough monitoring and completed a daily questionnaire for 90 days. The automated system identified deteriorating trends in cough and this was compared with alerts generated by an established telemonitoring questionnaire. Results 28 patients [median age 66 (range 46–86), mean FEV-1% predicted 36% (SD 18%)] completed the study and had a total of 58 exacerbations (43 moderate and 15 severe). Alerts based on cough monitoring were generated mean 3.4 days before 45% of AE-COPD with one false alert every 100 days. In contrast, questionnaire-based alerts occurred in the prodrome of 88% of AE-COPD with one false alert every 10 days. Conclusion An alert system based on cough frequency alone predicted 45% AE-COPD; the low false alert rate with cough monitoring suggests it is a practical and clinically relevant tool. In contrast, the utility of questionnaire-based symptom monitoring is limited by frequent false alerts.

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