Chronic Obstructive Pulmonary Disease Subtypes Research Articles

Proposed Etiotypes for Chronic Obstructive Pulmonary Disease: Controversial Issues.

The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) revised the definition of chronic obstructive pulmonary disease (COPD) to broadly include a variety of etiologies. A new taxonomy, composed of etiotypes, aims to highlight the heterogeneity in causes and pathogenesis of COPD, allowing more personalized management strategies and emphasizing the need for targeted research to understand and manage COPD better. However, controversy arises with including some diseases under the umbrella term of COPD, as their clinical presentations and treatments differ from classical COPD, which is smoking-related. COPD due to infection (COPD-I) and COPD due to environmental exposure (COPD-P) are classifications within the new taxonomy. Some disease entities in these categories show distinct clinical features and may not benefit from conventional COPD treatments, raising questions about their classification as COPD subtypes. There is also controversy regarding whether bronchiectasis with airflow limitations should be classified as an etiotype of COPD. This article discusses controversial issues associated with the proposed etiotypes for COPD in terms of COPD-I, COPD-P, and bronchiectasis. While the updated COPD definition by GOLD 2023 is a major step towards recognizing the disease's complexity, it also raises questions about the classification of related respiratory conditions. This highlights the need for further research to improve our understanding and approach to COPD management.

Assessment of Pulmonary Ventilation Using 3D Ventilation Flow Capacity-Weighted and Ventilation-Weighted Maps From 3D Ultrashort Echo Time (UTE) MRI.

Three-dimensional (3D) ventilation flow capacity-weighted (VFCW) maps together with 3D ventilation-weighted (VW) maps may help to better assess pulmonary function. To investigate the use of 3D VFCW and VW maps for evaluating pulmonary ventilation function. Prospective. Two patients (one male, 85 years old; one female, 64 years old) with chronic obstructive pulmonary disease (COPD) and nine healthy subjects (all male; 23-27 years). 3-T, 3D radial UTE imaging. 3D VFCW and VW maps were calculated from 3D UTE MRI by voxel-wise subtraction of respiratory phase images. Their validation was tested in nine healthy volunteers using slow/deep and fast/shallow breathing conditions. Additional validation was performed by comparison with single photon emission computed tomography (SPECT) ventilation maps of one healthy participant. For comparison, gravity dependence of anterior-posterior regional ventilation was assessed by one-dimensional plot of the mean signal intensity for each coronal slice. Structural similarity index measure was also calculated. Finally, VW maps and VFCW maps of two COPD patients were evaluated for emphysema lesions with reference to CT images. Wilcoxon sign-rank tests for regional Ventilation and ventilation flow capacity, analysis of variance, post-hoc t-tests and Bonferroni correction, coefficient of variation, Kullback-Liebler divergence. A P-value <0.05 was considered statistically significant. The validation of 3D VFCW and VW maps was shown by statistically significant differences in ventilation flow capacity and ventilation between the breathing conditions. Additionally, UTE-MRI and SPECT-based ventilation maps showed gravitational dependence in the anteroposterior direction. When applied to patients with COPD, the use of 3D VFCW and VW maps was able to differentiate between two patients with different phenotypes. The use of 3D VFCW and VW maps can provide regional information on ventilation function and potentially contribute to assessment of COPD subtypes and disease progression. 2 TECHNICAL EFFICACY: Stage 1.

The future landscape of immunology in COPD: A bibliometric analysis

BackgroundThis study was conducted to provide a comparative and comprehensive analysis of the last 50 years of research in the immunology of chronic obstructive pulmonary disease (COPD) and to identify future research priorities and directions. MethodsWe obtained publication information from the Web of Science Core Collection (WoSCC) database. Scimago Graphica, CiteSpace, VOSviewer, GraphPad Prism, Microsoft Excel 365, and the R package “bibliometrix” were used for bibliometric analysis. The methodologies used were burst citation, clustering and co-citation, keyword co-occurrence, and cooperative network graph clustering algorithms. ResultsA total of 2239 articles and reviews were included in the analysis. The number of annual publications showed an upward trend amidst fluctuations. The countries, institutions, journals, and authors with the highest number of publications were the USA, Imperial College London (ICL), Journal of Allergy and Clinical Immunology, and Murphy TF. There are 58 references and 13 keywords with a burst citation nature in the last 3 years, related to the study of inflammatory mechanisms. ConclusionWe used bibliometric analysis to understand the research progress regarding immune function in COPD. Meanwhile, we found that the hotspots of COPD immunology in basic research focus on the analysis of etiology and risk factors, and the exploration of the immune system; and the hotspots of COPD in clinical research focus on epidemiology, and the prevention and management of different subtypes of COPD.

Topologic Parametric Response Mapping Identifies Tissue Subtypes Associated with Emphysema Progression

Small airways disease (SAD) and emphysema are significant components of chronic obstructive pulmonary disease (COPD), a heterogenous disease where predicting progression is difficult. SAD, a principal cause of airflow obstruction in mild COPD, has been identified as a precursor to emphysema. Parametric Response Mapping (PRM) of chest computed tomography (CT) can help distinguish SAD from emphysema. Specifically, topologic PRM can define local patterns of both diseases to characterize how and in whom COPD progresses. We aimed to determine if distribution of CT-based PRM of functional SAD (fSAD) is associated with emphysema progression. We analyzed paired inspiratory-expiratory chest CT scans at baseline and 5-year follow up in 1495 COPDGene subjects using topological analyses of PRM classifications. By spatially aligning temporal scans, we mapped local emphysema at year five to baseline lobar PRM-derived topological readouts. K-means clustering was applied to all observations. Subjects were subtyped based on predominant PRM cluster assignments and assessed using non-parametric statistical tests to determine differences in PRM values, pulmonary function metrics, and clinical measures. We identified distinct lobar imaging patterns and classified subjects into three radiologic subtypes: emphysema-dominant (ED), fSAD-dominant (FD), and fSAD-transition (FT: transition from healthy lung to fSAD). Relative to year five emphysema, FT showed rapid local emphysema progression (-57.5%±1.1) compared to FD (-49.9%±0.5) and ED (-33.1%±0.4). FT consisted primarily of at-risk subjects (roughly 60%) with normal spirometry. The FT subtype of COPD may allow earlier identification of individuals without spirometrically-defined COPD at-risk for developing emphysema.

New drugs under development for COPD.

The characteristic features of chronic obstructive pulmonary disease (COPD) include inflammation and remodeling of the lower airways and lung parenchyma together with activation of inflammatory and immune processes. Due to the increasing habit of cigarette smoking worldwide COPD prevalence is increasing globally. Current therapies are unable to prevent COPD progression in many patients or target many of its hallmark characteristics which may reflect the lack of adequate biomarkers to detect the heterogeneous clinical and molecular nature of COPD. In this chapter we review recent molecular data that may indicate novel pathways that underpin COPD subphenotypes and indicate potential improvements in the classes of drugs currently used to treat COPD. We also highlight the evidence for new drugs or approaches to treat COPD identified using molecular and other approaches including kinase inhibitors, cytokine- and chemokine-directed biologicals and small molecules, anti-oxidants and redox signaling pathway inhibitors, inhaled anti-infectious agents and senolytics. It is important to consider the phenotypes/molecular endotypes of COPD patients together with specific outcome measures to target new therapies to particular COPD subtypes. This will require greater understanding of COPD molecular pathologies and a focus on biomarkers of predicting disease subsets and responder/non-responder populations.

Rationale and design of the Early Chronic Obstructive Pulmonary Disease (ECOPD) study in Guangdong, China: a prospective observational cohort study.

BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous disease and its clinically relevant subtypes are not well understood. Which clinical characteristics are more likely to be present among individuals who develop COPD remains to be studied in depth. Therefore, we designed a prospective observational cohort study, entitled the Early Chronic Obstructive Pulmonary Disease (ECOPD) study, to fill this evidence gap. The ECOPD study has four specific aims: (I) identification of characteristics, parameters, and biomarkers that may predict the development of airflow obstruction and annual decline in lung function with normal spirometry; (II) identification of clinically relevant early COPD subtypes; (III) identification of characteristics, parameters, and biomarkers that may predict disease progression in these early COPD subtypes; (IV) development and validation of machine learning models to predict development of airflow obstruction and disease progression.MethodsWe will recruit approximately 2,000 participants aged 40–80 years, including approximately 1,000 with COPD [post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.7] and approximately 1,000 without COPD, using a population-based survey for COPD. We will assess all participants using standard respiratory epidemiological questionnaires, pulmonary function tests [pre-bronchodilator and post-bronchodilator spirometry, and impulse oscillometry (IOS)], health outcomes [modified British Medical Research Council (mMRC) dyspnea scale, COPD assessment test (CAT), COPD clinical questionnaire (CCQ)], inspiratory and expiratory chest computed tomography (CT), and biomarker measurements (blood and urine), as well as satellite remote sensing pollutant exposure measures. Subgroup will additionally complete induced sputum, exercise capacity tests [6-minute walk test (6MWT) and cardiopulmonary exercise testing (CPET)] and home monitoring/personal sampling as pollutant exposure measures. Study procedures will be performed at baseline and every 1 year thereafter.DiscussionThe ECOPD study will provide insight into many aspects of early COPD and improve our understanding of COPD development, which may facilitate therapeutic interventions with the potential to modify the course of disease.Trial RegistrationChinese Clinical Trial Registry, ChiCTR1900024643. Registered on 19 July, 2019.

Identification of Mucus-Associated Molecular Subtypes of Chronic Obstructive Pulmonary Disease: A Latent Profile Analysis Based on MUC5B-Associated Genes.

BackgroundChronic obstructive pulmonary disease (COPD) is a disease with high heterogeneity, which is a major challenge in clinical individualized treatment. A mucus phenotype is one of the main characteristics of COPD.Material/MethodsGene expression profiles of lung tissue samples were from the Lung Genomics Research Consortium. MUC5B-associated gene signatures were obtained based on a nonlinear feature screening algorithm. These signatures were used to fit a latent profile analysis (LPA) model to identify COPD molecular subtypes and build a subtype classifier to verify the subtypes. Then, we explored the characteristics of cilium assembly and beating signatures, transcriptome features, immune infiltration among the 3 subtypes by xCell, single-sample gene set enrichment analysis, network perturbation amplitude, and weighted gene co-expression network analysis algorithms. An external dataset was used to verify the above COPD subtypes.ResultsThree subtypes associated with mucus were identified by LPA and verified in an external dataset. Subtype 1 displayed higher T helper type 1 (Th1) and basophil infiltration, higher Th17/regulatory T cells (Tregs) ratio, a higher level of cilium assembly and beating, and lower mast cell and Treg infiltration. The subtypes 2 and 3 demonstrated higher macrophage M2 infiltration in lung tissue, while subtype 3 had higher neutrophil and eosinophil infiltration than subtype 2.ConclusionsOverall, this work identified 3 mucus-associated molecular subtypes related to MUC5B expression, which deepens the understanding of airway mucus secretion in COPD and potentially provides valuable information for precision therapy.

Artificial intelligence in COPD: Possible applications and future prospects.

Artificial intelligence in COPD: Possible applications and future prospects.

Assessment of Ventilatory Heterogeneity in Chronic Obstructive Pulmonary Disease Using the Inspired Sinewave Test.

BackgroundThere is marked variability in the symptoms and outcomes of patients with chronic obstructive pulmonary disease (COPD) which are poorly predicted by spirometry/FEV1%pred. Furthermore, as spirometry requires the performance of potentially distressing respiratory manoeuvres which are to some extent user-effort dependent, there is need for non-invasive and simple-to-perform techniques to identify subtypes of COPD which are more closely related to clinically relevant outcomes.Materials and MethodsThe inspired sinewave test (IST) sinusoidally modulates the inspired concentration of a tracer gas (N2O) over successive tidal breaths. A single-compartment tidal-ventilation lung model processes the amplitude/phase of the expired N2O sinewave and estimates cardiopulmonary variables including: effective lung volume and indices of ventilatory heterogeneity (VH; ELV180/FRCpleth and ELV180/ELVpred). 83 COPD patients and 53 healthy controls performed the IST test, standard pulmonary function tests (Spirometry, body plethysmography and the single breath test of carbon monoxide uptake), and symptom severity questionnaires (COPD assessment test, CAT; mMRC dyspnoea-scale, mMRC-DS; Cough+Mucus score; C+M score).ResultsELV180/FRCpleth and ELV180/ELVpred were significantly lower in patients with COPD vs healthy participants (0.34±0.11 vs 0.68±0.14 and 0.7±0.27 vs 0.98±0.15, respectively; P<0.05). Multivariable regression analysis demonstrated that ELV180/FRCpleth was a stronger and independent predictor of CAT, mMRC-DS and C+M score vs FEV1%pred. ELV180/ELVpred was a stronger and independent and better predictor of C+M score vs FEV1%pred. Phenotyping patients, based upon ELV180/ELVpred and FRC%pred, uncovered significant symptomatic differences between groups.ConclusionThe IST indices of VH were superior and independent predictors of symptom severity vs FEV1%pred and has potential as a non-invasive and simple-to-perform method to stratify patients into subgroups related to clinically relevant features of COPD.

Understanding racial differences of COPD patients with an ecological model: two large cohort studies in the US and Korea.

Background:There are limited data about the racial difference in the characteristics of chronic obstructive pulmonary disease (COPD) patients who are treated at clinics. We aimed to compare sociodemographic and clinical characteristics between US and Korean COPD patients using large-scale nationwide COPD cohorts.Methods:We used the baseline demographic and clinical data of COPD patients aged 45 years or older with at least a 10 pack-per year smoking history from the Korean COPD Subtype Study (KOCOSS, n = 1686) cohort (2012–2018) and phase I (2008–2011) of the US Genetic Epidemiology of COPD (COPDGene) study (n = 4477, 3461 were non-Hispanic whites [NHW], and 1016 were African Americans [AA]).Results:Compared to NHW, AA had a significantly lower adjusted prevalence ratio (aPR) of cough >3 months (aPR: 0.67; 95% CI [confidence interval]: 0.60–0.75) and phlegm >3 months (aPR: 0.78, 95% CI: 0.70–0.86), but higher aPR of dyspnea (modified Medical Round Council scale ⩾2) (aPR: 1.22; 95% CI: 1.15–1.29), short six-minute walk distance (<350 m) (aPR: 1.98; 95% CI: 1.81–2.14), and poor quality of life (aPR: 1.10; 95% CI: 1.05–1.15). Compared to NHW, Koreans had a significantly lower aPR of cough >3 months (aPR: 0.53; 95% CI: 0.47–0.59), phlegm >3 months (aPR: 0.75; 95% CI: 0.67–0.82), dyspnea (aPR: 0.72; 95% CI: 0.66–0.79), and moderate-to-severe acute exacerbation in the previous year (aPR: 0.73; 95% CI: 0.65–0.82). NHW had the highest burden related to chronic bronchitis symptoms and cardiovascular diseases related to comorbidities.Conclusion:There are substantial differences in sociodemographic characteristics, clinical presentation, and comorbidities between COPD patients from the KOCOSS and COPDGene, which might be caused by interactions between various intrapersonal, interpersonal, and environmental factors of the ecological model. Thus, a broader and more comprehensive approach would be necessary to understand the racial differences of COPD patients.

Cigarette smoke extract induces airway epithelial cell death via repressing PRMT6/AKT signaling.

Chronic obstructive pulmonary disease (COPD) is a severe public health threat world-wide. Cigarette smoke (CS)-induced airway epithelial cell death is a major pathway of pathogenesis in emphysema, a subtype of COPD. Protein arginine methyltransferase 6 (PRMT6) is a type I PRMT that catalyzes mono- and di-methylation on arginine residues within histone and non-histone proteins to modulate a variety of life processes, such as apoptosis. However, its role in CS-induced lung epithelial death has not been fully elucidated. Here we report that PRMT6 was decreased in mouse lung tissues from a cigarette smoke extract (CSE)-mediated experimental emphysematous model and in CSE treated or cigarette smoke exposed lung epithelial cells. Depletion of PRMT6 increased the protein levels of phosphatase PTEN and PI3K regulatory subunit p85 but decreased a downstream kinase PDK1, resulting in AKT dephosphorylation and thereafter, lung epithelial cell death. Knockout of PRMT6 inhibited epithelial survival and promoted CSE-mediated epithelial cell death, while ectopic expression of PRMT6 protein partially reversed epithelial cell death via PI3K/AKT-mediated cell survival signaling in CSE cellular models. These findings demonstrate that PRMT6 plays a crucial role in CS-induced bronchial epithelial cell death that may be a potential therapeutic target against the airway cell death in CS-induced COPD.

White matter damage and altered connectivity between primary motor cortices in chronic obstructive pulmonary disease.

White matter damage and altered connectivity between primary motor cortices in chronic obstructive pulmonary disease.

The Role of Granzyme B Containing Cells in the Progression of Chronic Obstructive Pulmonary Disease.

BackgroundLung inflammation plays a vital role in the pathogenesis of chronic obstructive pulmonary disease (COPD), but the characteristics of the inflammatory process remain unclear. There is growing interest in the role of granzyme B (GzmB) because CD8+ T cells can induce apoptosis of target cells by releasing GzmB, which in turn may cause tissue injury and remodeling. However, GzmB is also expressed by regulatory cells, which are able to suppress CD8+ T cell. The role of GzmB+ cells needs to be defined in COPD.MethodsGzmB+ and CD8+ cells on alveolar wall of surgically resected lungs of microscopically classified 12 nonsmoking control, 12 panlobular emphysema (PLE) and 30 centrilobular emphysema (CLE) subjects were localized by immunohistochemical method. Positively stained cells on alveolar wall were counted and length of corresponding alveolar wall was measured. The results were expressed as mean number of positively stained cells per mm of alveolar wall in each subject.ResultsThe number of GzmB+ and CD8+ cells on alveolar wall of CLE was greater than that of control or PLE subjects (p<0.05 and p<0.001, respectively). There was a positive relationship between the number of alveolar GzmB+ cells and forced expiratory volume in 1 second (FEV1) (r=0.610, p=0.003) in CLE subjects. The number of alveolar GzmB+ cells progressively decreased with decline of FEV1.ConclusionOur finding that number of alveolar GzmB+ cells was associated with FEV1 suggests that GzmB+ cells might have protective role in the progression of lung destruction and airflow limitation in CLE, which is the predominant emphysema subtype of COPD.

Clinical phenotypes and heath-related quality of life of COPD patients in a rural setting in Malaysia \u2013 a cross-sectional study

BackgroundThe Spanish chronic obstructive pulmonary disease (COPD) guideline phenotypes patients according to the exacerbation frequency and COPD subtypes. In this study, we compared the patients’ health-related quality of life (HRQoL) according to their COPD phenotypes.MethodsThis was a cross-sectional study of COPD patients who attended the outpatient clinic of the Serian Divisional Hospital and Bau District Hospital from 23th January 2018 to 22th January 2019. The HRQoL was assessed using modified Medical Research Council (mMRC), COPD Assessment Test (CAT), and St George’s Respiratory Questionnaire for COPD (SGRQ-c).ResultsOf 185 patients, 108 (58.4%) were non-exacerbators (NON-AE), 51 (27.6%) were frequent exacerbators (AE), and the remaining 26 (14.1%) had asthma-COPD overlap (ACO). Of AE patients, 42 (82.4%) had chronic bronchitis and only 9 (17.6%) had emphysema. Of the 185 COPD patients, 65.9% had exposure to biomass fuel and 69.1% were ex- or current smokers.The scores of mMRC, CAT, and SGRQ-c were significantly different between COPD phenotypes (p < 0.001). There were significantly more patients with mMRC 2–4 among AE (68.6%) (p < 0.001), compared to those with ACO (38.5%) and NON-AE (16.7%). AE patients had significantly higher total CAT (p = 0.003; p < 0.001) and SGRQ-c (both p < 0.001) scores than those with ACO and NON-AE. Patients with ACO had significantly higher total CAT and SGRQ-c (both p < 0.001) scores than those with NON-AE.AE patients had significantly higher score in each item of CAT and component of SGRQ-c compared to those with NON-AE (all p < 0.001), and ACO [(p = 0.003–0.016; p = < 0.001–0.005) except CAT 1, 2 and 7. ACO patients had significantly higher score in each item of CAT and component of SGRQ-c (p = < 0.001–0.040; p < 0.001) except CAT 2 and activity components of SGRQ-c.ConclusionsThe HRQoL of COPD patients was significantly different across different COPD phenotypes. HRQoL was worst in AE, followed by ACO and NON-AE. This study supports phenotyping COPD patients based on their exacerbation frequency and COPD subtypes. The treatment of COPD should be personalised according to these two factors.

Severe Decline in Mir-20a and Mir-92a in the Context of the Mir-17-92 Cluster: Ideal Biomarkers of Various COPD Subtypes

Abstract- Chronic obstructive pulmonary disease (COPD) is going to be the third leading cause of death by 2020. Circulating miRNAs are among the most beneficial feasible non-aggressive biomarkers for diagnosis and treatment of many diseases. Among members of the significant miR-17-92 cluster, miR-20a and miR-92a are greatly involved in both inflammation and hypoxia (known as the main reasons for COPD comorbidities). Thus, the expression of these miRNAs was evaluated in the serum of 26 patients and 19 controls using the sensitive stem-loop RT-qPCR approach. The results revealed a significant reduction of these miRNAs in patients relative to controls (P&lt;0.001). Decreased expression of miR-20a in a patient might reflect a progressive stage of the disease. MiR-92a might be used as an early-detection biomarker of COPD. These miRNAs can be used as therapeutic targets specifically in the context of the miR-17-92 cluster to address the various clinicopathological aspects of the disease.

The association between power outage and the exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

TPS 661: Climate change: temperature effects 1, Exhibition Hall, Ground floor, August 26, 2019, 3:00 PM - 4:30 PM Background: More frequent and severe power outages (PO) are expected as potential results of climate change and increased weather extremes. Significant gaps remain in understanding the potential impact of PO on Chronic Obstructive Pulmonary Disease (COPD) hospitalizations. We examined the association between PO and COPD, as well as its variation across COPD subtypes, lag days, critical care indicators and socio-demographics. Methods: We matched the 2001-2013 daily PO data with the COPD hospitalization numbers at the New York power operating division-level. Using distributed lag nonlinear models controlling for weather and time-varying factors, we compared the number of hospitalizations during PO versus non-PO periods to determine the association of PO with COPD and its subtypes at each of 0-6 lag days, and stratified the results by socio-demographics. We also compared differences in critical care indicators including average length of stay, cost and average number of comorbidities between two periods. Results: Overall, we observed the relative risk (RR) of COPD ranged from 1.14 to 1.43 across lag days. The risk was strongest at lag 0 and lasted significantly for 6 days. Associations were stronger for acute bronchitis (RR: 1.33 to 1.63) and obstructive chronic bronchitis (RR: 1.10 to 1.47). PO impacts were significantly higher when PO coverage exceeded the 75th percentile or lasted longer than 5 days. No significant variations were observed across socio-demographics. Compared with the non-PO period, the PO period was observed to have 0.017 more COPD cases/day, $5367 increase in cost/case and 1.44 more comorbidities/case. Patients with hospital stays costing more than $30000 or having over 9 comorbidities increased to a greater extent during PO relative to other patients. Conclusion: PO was significantly associated with elevated risk of COPD as well as increased cost and comorbidities. Patients at the highest-cost and most-comorbidity groups had the highest increase among all hospitalizations.

The Difficulty Of Improving Quality Of Life In COPD Patients With Depression And Associated Factors.

ObjectivesDepression is a major comorbidity that affects clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). COPD patients with depression are hospitalized more frequently, and show more acute exacerbations, decreased physical and social activities, and higher mortality compared to their non-depressed counterparts. In the present study, we investigated the clinical impact of depressive symptoms and associated clinical factors in Korean patients with COPD by evaluating multicenter cohort data.Materials and methodsPatients with COPD enrolled in the Korean COPD Subtype Study, a multicenter observational study, from December 2011 to October 2014 were selected for evaluation. The initial evaluation of all patients included pulmonary function tests, 6 min walk distance (6MWD), the COPD Assessment Test (CAT), and the COPD-specific version of the St. George’s Respiratory Questionnaire (SGRQ-C). Significant depression was defined as a Beck Depression Inventory-II (BDI-II) score ≥17.ResultsAmong the 270 study patients, 19.6% had significant depression. The depressed group showed a higher proportion of females (41.4%), lower body mass index (BMI), and lower education level compared to the non-depressed group (p = 0.002, p = 0.008, and p = 0.019, respectively). The depressed group had significantly higher CAT and SGRQ-C scores, as well as a lower 6MWD, compared to the non-depressed group based on 6 month-interval serial measurements over 3 years. The total SGRQ-C score and the symptoms, activity, and impact domain scores were significant predictors of depression (area under curves [AUCs] of 0.699 [0.613–0.786], 0.670 [0.581–0.758], 0.680 [0.589–0.770], and 0.689 [0.603–0.776], respectively). From CAT score domains, sleep and energy scores were significant predictors of depression (AUCs of 0.619 [0.522–0.715] and 0.595 [0.504–0.685], respectively). SGRQ-C score, low BMI, and decreased 6MWD were significantly associated with depression in a multivariable analysis.ConclusionA considerable proportion of patients with COPD had depression, and a high SGRQ-C score, low BMI, and low 6MWD were significantly associated with depression. As improving quality of life in this subgroup is difficult, physicians should be more active in screening patients with significant depression.

Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene.

Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis.

Novel therapeutic targets and drug development for the precision treatment of COPD

ABSTRACTIntroduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality, morbidity, and health care expenditures worldwide. Because of the heterogeneity of COPD, subjective approach to its treatment is often unsuccessful in achieving optimal outcomes. Better understanding of its pathophysiologic mechanism may pave a more precise therapeutic approach. Such an approach should ideally consider the individual variability and incorporate the genetics, endotypes, and psychosocial aspect of the disease and indeed has become the focus of many therapeutic targets in development.Areas covered: The complexity and heterogeneity of COPD prompted the identification of several phenotypes and biomarker-based endotypes that reflect underlying pathobiological mechanisms. Although still in its infancy, precision medicine approach to treat COPD will ensure treating the right patient at the right time with the right medicine. In this review, we highlight some emerging therapeutic targets for the precision treatment of COPD.Expert opinion: Few existing therapies for COPD thus far employ a precision approach taking the individual variability of response to treatments into account. Unfortunately, biomarkers to identify different subtypes of COPD are not yet widely available. The use of such biomarkers would ensure successful drug development programs and are important for clinicians managing patients with this heterogenous disease.

Subtypes of COPD Have Unique Distributions and Differential Risk of Mortality.

Previous attempts to explore the heterogeneity of chronic obstructive pulmonary disease (COPD) clustered individual patients using clinical, demographic, and disease features. We developed continuous multidimensional disease axes based on radiographic and spirometric variables that split into an airway-predominant axis and an emphysema-predominant axis. The COPD Genetic Epidemiology study (COPDGene®) is a cohort of current and former smokers, > 45 years, with at least 10 pack years of smoking history. Spirometry measures, blood pressure and body mass were directly measured. Mortality was assessed through continuing longitudinal follow-up and cause of death was adjudicated. Among 8157 COPDGene® participants with complete spirometry and computed tomography (CT) measures, the top 2 deciles of the airway-predominant and emphysema-predominant axes previously identified were used to categorize individuals into 3 groups having the highest risk for mortality using Cox proportional hazard ratios. These groups were also assessed for causal mortality. Biomarkers of COPD (fibrinogen, soluble receptor for advanced glycation end products [sRAGE], C-reactive protein [CRP], clara cell secretory protein [CC16], surfactant-D [SP-D]) were compared by group. High-risk subtype classification was defined for 2638 COPDGene® participants who were in the highest 2 deciles of either the airway-predominant and/or emphysema-predominant axis (32% of the cohort). These high-risk participants fell into 3 groups: airway-predominant disease only (APD-only), emphysema-predominant disease only (EPD-only) and combined APD-EPD. There was 26% mortality for the APD-only group, 21% mortality for the EPD-only group, and 54% mortality for the combined APD-EPD group. The APD-only group (n=1007) was younger, had a lower forced expiratory volume in 1 second (FEV1) percent (%) predicted and a strong association with the preserved ratio-impaired spirometry (PRISm) quadrant. The EPD-only group (n=1006) showed a relatively higher FEV1 % predicted and included largely GOLD stage 0, 1 and 2 partipants. Individuals in each of the 3 high-risk groups were at greater risk for respiratory mortality, while those in the APD-only group were additionally at greater risk for cardiovascular mortality. Biomarker analysis demonstrated a significant association of the APD-only group with CRP, and sRAGE demonstrated greatest significance with both the EPD-only and the combined APD-EPD groups. Among current and former smokers, individuals in the highest 2 deciles for mortality risk on the airway-predominant axis and the emphysema-predominant axis have unique associations to spirometric patterns, different imaging characteristics, biomarkers and causal mortality.