Chronic Obstructive Lung Disease Stage Research Articles

Design of the multicentre randomised controlled BENTO trial to demonstrate patient-relevant benefit of bronchoscopic lung volume reduction using thermal vapour ablation in the German healthcare system for patients with upper lobe emphysema: a study protocol

IntroductionApplication of vapour ablation as a novel approach to lung volume reduction has positive effects in patients with severe emphysema. The BENTO study is a randomised, controlled, open, multicentre trial,...

Cigarette smoke-induced dysbiosis: comparative analysis of lung and intestinal microbiomes in COPD mice and patients

BackgroundThe impact of cigarette smoke (CS) on lung diseases and the role of microbiome dysbiosis in chronic obstructive pulmonary disease (COPD) have been previously reported; however, the relationships remain unclear.MethodsOur research examined the effects of 20-week cigarette smoke (CS) exposure on the lung and intestinal microbiomes in C57BL/6JNarl mice, alongside a comparison with COPD patients’ intestinal microbiome data from a public dataset.ResultsThe study found that CS exposure significantly decreased forced vital capacity (FVC), thickened airway walls, and induced emphysema. Increased lung damage was observed along with higher lung keratinocyte chemoattractant (KC) levels by CS exposure. Lung microbiome analysis revealed a rise in Actinobacteriota, while intestinal microbiome showed significant diversity changes, indicating dysbiosis. Principal coordinate analysis highlighted distinct intestinal microbiome compositions between control and CS-exposed groups. In the intestinal microbiome, notable decreases in Patescibacteria, Campilobacterota, Defferibacterota, Actinobacteriota, and Desulfobacterota were observed. We also identified correlations between lung function and dysbiosis in both lung and intestinal microbiomes. Lung interleukins, interferon-ɣ, KC, and 8-isoprostane levels were linked to lung microbiome dysbiosis. Notably, dysbiosis patterns in CS-exposed mice were similar to those in COPD patients, particularly of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 patients. This suggests a systemic impact of CS exposure.ConclusionIn summary, CS exposure induces significant dysbiosis in lung and intestinal microbiomes, correlating with lung function decline and injury. These results align with changes in COPD patients, underscoring the important role of microbiome in smoke-related lung diseases.

Developing and validating prediction models for severe exacerbations and readmissions in patients hospitalised for COPD exacerbation (SERCO) in China: a prospective observational study

BackgroundThere is a lack of individualised prediction models for patients hospitalised with chronic obstructive pulmonary disease (COPD) for clinical practice. We developed and validated prediction models of severe exacerbations and...

Can blood eosinophil count be used as a predictive marker for the severity of COPD and concomitant cardiovascular disease? The relationship with the 2023 Version of the Global Initiative for Chronic Obstructive Lung Disease Staging.

This study was designed to investigate the relationship between eosinophil count and cardiovascular disease (CVD) in subjects with chronic obstructive pulmonary disease (COPD) and the correlation between eosinophil count and the risk of exacerbations in COPD. The study included 405 patients who met the study inclusion criteria. Of the participants, 100 (25%) were classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) A, 105 (26%) as GOLD B, and 200 (49%) as GOLD E. Routine blood tests (including leukocyte count and differential leukocyte count, hemoglobin, and platelet count) were carried out using an automated hematology analyzer. The eosinophil count and eosinophil percentage were significantly higher in 158 patients with COPD and concurrent CVD than in the COPD patients without concurrent CVD [2.95 (2.4), p=2.309e-11, 1.9 (2), p=5.02e-08, respectively). The prevalence of CVD was higher in the GOLD E group that experienced prominent exacerbations, and while the eosinophil count was also higher (p=.03) in this group, the eosinophil percentage did not differ significantly in this group of patients. The results of our study indicate a strong relationship between eosinophils and cardiovascular events in COPD subjects, particularly in subjects at high risk of exacerbations and cardiovascular complications.

Plasma sCD146 is a potential biomarker for acute exacerbation of chronic obstructive pulmonary disease.

This study examined the levels of soluble CD146 (sCD146) in plasma samples from patients with chronic obstructive pulmonary disease (COPD) and assessed the relationship between sCD146 and the severity of COPD. A total of 97 COPD patients were recruited from 20 medical centers in Jiangsu, China, including 13 stable subjects and 84 exacerbated subjects. The plasma sCD146 level in exacerbated subjects (28.77 ± 10.80 ng/mL) was significantly lower than that in stable subjects (38.84 ± 15.00 ng/mL). In the high sCD146 group, the proportion of subjects with modified Medical Research Council (mMRC) scores of 0-1 was higher, the proportion of subjects with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 4 was lower, and the proportion of subjects with ≥1 hospitalizations in the past year was lower. The plasma sCD146 level was negatively correlated with the COPD Assessment Test (CAT) score (r = -0.2664, p = 0.0087). Logistic regression analysis showed that sCD146 was an independent risk factor for acute exacerbation of COPD (AECOPD). Receiver operating characteristic (ROC) analysis suggested that sCD146 combined with sex, age, pulmonary function, and acute exacerbations in the past year had clinical value for the accurate identification of AECOPD, with an area under the ROC curve (AUC) of 0.908 (95% CI: 0.810-1.000, p < 0.001). In addition, there was a significant negative correlation between plasma sCD146 and S100A9 (r = -0.3939, p < 0.001).

Impact of Using Global Lung Initiative Race-neutral Equations for Chronic Respiratory Disease in Western India.

The Global Lung Initiative (GLI) race-neutral equations are considered to be race agnostic, using inverse probability weight, and have lower limits of normality (LLN) different from the GLI mixed equations. In this observational study, we analyzed the impact of using GLI equations to interpret spirometry of 1,169 patients with chronic respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), COPD suspects, small airway obstruction, posttubercular lung disease, and preserved ratio with impaired spirometry (PRISm) (46% females, average age 46 years). Predicted normal and the LLN using GLI equations were significantly higher than those using Indian equations. The GLI race-neutral equations changed the category in 35.17% of males and 42.64% of females compared to Indian equations. The GLI mixed equations categorized a greater percentage of patients to have a mixed ventilatory pattern compared to the GLI race-neutral equations. There was a significant change in the grading of the severity of COPD using Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages based on the percentage of predicted values of FEV1. Although GLI race-neutral equations have greater concordance with Indian equations than GLI Mixed equations, these substantially overdiagnose abnormal ventilatory patterns on spirometry in adult Indians in western India with chronic respiratory disease. A substantial number of patients with normal or obstructive patterns on spirometry are recategorized to have mixed or restrictive patterns. The use of GLI race-neutral equations increases the severity of airflow limitation in COPD patients. GLI race-neutral predictions for FEV1 result in substantially fewer patients demonstrating postbronchodilator responsiveness (PBDR).

Characteristics and phenotypes of a COPD cohort from referral hospital clinics in Uganda

IntroductionChronic obstructive pulmonary disease (COPD) is a heterogeneous condition with varied clinical and pathophysiological characteristics. Although there is increasing evidence that COPD in low-income and middle-income countries may have different...

Tiotropium reduces clinically important deterioration in patients with mild-to-moderate chronic obstructive pulmonary disease: A post hoc analysis of the Tie-COPD study

BackgroundClinically important deterioration (CID) is a composite endpoint used to holistically assess the complex progression of chronic obstructive pulmonary disease (COPD). Tiotropium improves lung function and reduces the rate of COPD exacerbations in patients with COPD of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild) or 2 (moderate). However, whether tiotropium reduces CID risk in patients with mild-to-moderate COPD remains unclear. MethodsThis was a post hoc analysis of the 24-month Tie-COPD study comparing 18 μg tiotropium with placebo in patients with mild-to-moderate COPD. CID was defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 s, an increase of ≥2 unit in COPD Assessment Test (CAT) score, or moderate-to-severe exacerbation. The time to the first occurrence of one of these events was recorded as the time to the first CID. Subgroup analyses were conducted among patients stratified by CAT score, modified Medical Research Council (mMRC) dyspnea score, and GOLD stage at baseline. ResultsOf the 841 randomized patients, 771 were included in the full analysis set. Overall, 643 patients (83.4 %) experienced at least one CID event. Tiotropium significantly reduced the CID risk and delayed the time to first CID compared with placebo (adjusted hazard ratio = 0.58, 95 % confidence interval = 0.49–0.68, P < 0.001). Significant reductions in CID risk were also observed in various subgroups, including patients with a CAT score <10, mMRC score <2, and mild COPD. ConclusionsTiotropium reduced CID risk in patients with mild-to-moderate COPD, even in patients with fewer respiratory symptoms or mild disease, which highlights tiotropium's effectiveness in treating COPD patients with mild disease. Trial registrationThis study is registered at ClinicalTrials.gov (Tie-COPD, NCT01455129).

A Quantitative Computed Tomography Analysis of Fissure Integrity and Emphysema Destruction in Japanese Patients with Severe Chronic Obstructive Pulmonary Disease.

Objective Bronchoscopic lung volume reduction (BLVR) using a one-way endobronchial valve (EBV) can provide clinically meaningful benefits to chronic obstructive pulmonary disease (COPD) patients. Although the Japanese Pharmaceuticals and Medical Devices Agency approved EBVs in November 2022, information regarding the number of Japanese patients with severe COPD eligible for BLVR treatment is still lacking. We therefore screened computed tomography (CT) images of patients with severe COPD using a quantitative CT (QCT) analysis to estimate the proportion of candidates eligible for BLVR treatment with an EBV. Methods CT scans of COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4 were retrospectively analyzed using QCT to evaluate fissure integrity and tissue destruction. The difference in volume-weighted percentage was measured using the density scores of the target lobe and ipsilateral non-target lobe at -910 Hounsfield units. The target lobe was defined as the most affected lobe, with an emphysema destruction score of >50% for each patient. Results High-resolution CT scans of 32 patients (GOLD 3=19, GOLD 4=13) were analyzed. The target lobe could not be identified in 1 patient, whereas the target lobes for 8 patients were not surrounded by fissures with ≥80% completeness. Conversely, in 13 patients, the target lobes were surrounded by fissures with >95% completeness. The remaining 10 patients had fissure completeness between 80% and 95% at the target lobes and were considered candidates for collateral ventilation assessment. Conclusion A QCT analysis showed that 23 of 32 patients with severe COPD could be considered for a thorough examination of BLVR treatment with EBV.

Exercise training influence on cognitive capacity and mental health within chronic obstructive pulmonary disease - A pilot study.

Although pulmonary rehabilitation and regular exercise have improved negative emotions and cognitive capacity within cases of chronic obstructive pulmonary disease (COPD), influence by exercise training upon different cognitive and memory functions in COPD is still controversial. This investigation aimed to assess whether cognitive performance and mental health are affected by the benefits of exercise training within cases of COPD. This pilot investigation included thirty-three patients with Global Initiative for Chronic Obstructive Lung Disease stage ≥B. Based on the subjects' rights, all included patients could choose to join either the exercise group or the control group, according to their free will. Twelve patients were assigned to receive exercise treatment over a 2-month period, while the remaining 16 patients were assigned to the control group. Cognitive capacity outcomes were measured using the Wechsler Memory Scale-III Word List Test, Stroop task, and psychomotor vigilance task (PVT). Mood states were assessed through the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI). Most cases demonstrated major improvement for BDI and BAI scorings post-60-day therapy. During PVT, the omission rate decreased, while the hit rate increased, indicating an improvement in attention performance. Furthermore, this investigation found a significant increase in immediate verbal and recognition memory for word-list test. However, no major performance shifts were found on Stroop analysis. This investigation demonstrated that a 2-month exercise training program resulted in significant improvement in negative emotions, immediate memory, recognition memory, and attention.

Small Airway Disease in Pre-Chronic Obstructive Pulmonary Disease with Emphysema: A Cross-Sectional Study.

Rationale: Small airway disease is an important pathophysiological feature of chronic obstructive pulmonary disease (COPD). Recently, "pre-COPD" has been put forward as a potential precursor stage of COPD that is defined by abnormal spirometry findings or significant emphysema on computed tomography (CT) in the absence of airflow obstruction. Objective: To determine the degree and nature of (small) airway disease in pre-COPD using microCT in a cohort of explant lobes/lungs. Methods: We collected whole lungs/lung lobes from patients with emphysematous pre-COPD (n = 10); Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I (n = 6), II (n = 6), and III/IV (n = 7) COPD; and controls (n = 10), which were analyzed using CT and microCT. The degree of emphysema and the number and morphology of small airways were compared between groups, and further correlations were investigated with physiologic measures. Airway and parenchymal pathology was also validated with histopathology. Measurements and Main Results: The numbers of transitional bronchioles and terminal bronchioles per milliliter of lung were significantly lower in pre-COPD and GOLD stages I, II, and III/IV COPD compared with controls. In addition, the number of alveolar attachments of the transitional bronchioles and terminal bronchioles was also lower in pre-COPD and all COPD groups compared with controls. We did not find any differences between the pre-COPD and COPD groups in CT or microCT measures. The percentage of emphysema on CT showed the strongest correlation with the number of small airways in the COPD groups. Histopathology showed an increase in the mean chord length and a decrease in alveolar surface density in pre-COPD and all GOLD COPD stages compared with controls. Conclusions: Lungs of patients with emphysematous pre-COPD already show fewer small airways and airway remodeling even in the absence of physiologic airway obstruction.

Characteristics of inflammatory phenotypes in patients with chronic obstructive pulmonary disease: a cross-sectional study

BackgroundThe relationship between airway inflammation in chronic obstructive pulmonary disease (COPD) and clinical characteristics remains unclear. This study aimed to investigate the airway inflammatory phenotypes in COPD and their association...

Association of mild chronic obstructive pulmonary disease with all-cause mortality: A systematic review and meta-analysis

BackgroundIt is unclear whether patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 (mild) chronic obstructive pulmonary disease (COPD) have worse respiratory outcomes than individuals with normal spirometry. MethodsFor this systematic review and meta-analysis, we conducted a search of PubMed, Embase, and Web of Science for all literature published up to 1 March 2023. Studies comparing mortality between mild COPD and normal spirometry were included. A random-effects model was used to estimate the combined effect size and its 95% confidence interval (CI). The primary outcome was all-cause mortality. Respiratory disease-related mortality were examined as secondary outcomes. ResultsOf 5242 titles identified, 12 publications were included. Patients with mild COPD had a higher risk of all-cause mortality than individuals with normal spirometry (pre-bronchodilator: hazard ratio [HR] = 1.21, 95% CI: 1.11–1.32, I2 = 47.1%; post-bronchodilator: HR = 1.19, 95% CI: 1.02–1.39, I2 = 0.0%). Funnel plots showed a symmetrical distribution of studies and did not suggest publication bias. In jackknife sensitivity analyses, the increased risk of all-cause mortality remained consistent for mild COPD. When the meta-analysis was repeated and one study was omitted each time, the HR and corresponding 95% CI were >1. Patients with mild COPD also had a higher risk of respiratory disease-related mortality (HR = 1.71, 95% CI: 1.03–2.82, I2 = 0.0%). ConclusionsOur results suggest that mild COPD is associated with increased all-cause mortality and respiratory disease-related mortality compared with normal spirometry. Further research is required to determine whether early intervention and treatment are beneficial in mild COPD.

Guideline Alignment and Medication Concordance in COPD

Provider adherence to clinical treatment guidelines in COPD is low. However, for patients to receive guideline-aligned care, providers not only must prescribe guideline-aligned care, but also must communicate that regimen successfully to patients to ensure medication concordance. The rate of medication concordance between patients and providers and its impact on clinical management is unknown in COPD. To examine rates of guideline alignment and medication concordance and to identify patient-level factors that place patients at risk for these types of poor disease management outcomes. This study was a secondary data analysis of the Medication Adherence Research in COPD study (2017-2023). Participants were categorized into 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Medication regimens were classified as aligned or nonaligned with 2017 GOLD guidelines. Nonaligned regimens were stratified further into overuse and underuse categories. Medication concordance between provider-reported and participant-reported regimens was determined. Factors associated with guideline alignment and medication concordance were evaluated using logistic regression. Of 191 participants, 51% of provider-reported regimens were guideline aligned, with 86% of nonaligned regimens reflecting overuse with an inhaled corticosteroid (ICS). Thirty-eight percent of participants reported different regimens than their providers, of which > 80% reflected participants not reporting medications their providers reported prescribing. Participants did not report long-acting muscarinic antagonists and long-acting beta-agonists at similar rates as ICSs. Greater symptom burden and absence of a pulmonologist on the care team were associated with both guideline misalignment and medication discordance. Cognitive impairment and Black race additionally were associated with medication discordance. Guideline misalignment and medication discordance were common and were driven by overuse of ICSs and unreported medications, respectively. The patient-level factors associated with medication discordance highlight the importance of improving patient-provider communication to improve clinical management in COPD.

Relationship between Chronic Obstructive Pulmonary Disease Severity and Surface Electromyography Parameters during Fatigue Caused by Knee Extensor Contractions

Objective: Skeletal muscle dysfunction, which is characterized by decreased muscle strength and endurance, contributes to dyspnea during exercise in patients with chronic obstructive pulmonary disease (COPD), regardless of pulmonary function. This study analyzed skeletal muscle function in patients with COPD through surface electromyography (sEMG) evaluations and signal processing and attempted to determine whether sEMG parameters for muscle fatigue reflect the course of the disease. Methods: In 24 patients with COPD, maximal voluntary isometric contraction and ramp contraction were performed during isometric knee extension, and the sEMG activity of the rectus femoris muscle was measured. The patients were divided into three groups according to their modified Medical Research Council (mMRC) grade and Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Patients with mMRC grades 0 and 1 were classified into group A, grade 2 into group B, and grades 3 and 4 into group C. Patients with GOLD stage 1 were classified into group I, stage 2 into group II, and stages 3 and 4 into group III. sEMG parameters were compared between groups using one-way analysis of variance. Results: There were significant differences in the minimum median frequency and fatigue index between the mMRC groups. However, the sEMG parameters did not differ significantly among the GOLD groups. Conclusion: Muscle fatigue differs according to the severity of subjective dyspnea in COPD. sEMG evaluations and signal processing can play supplementary roles in evaluating muscle endurance and predicting functional capacity in COPD.

Early Evidence of Chronic Obstructive Pulmonary Disease Obscured by Race-Specific Prediction Equations.

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White (n = 6,766) and AA (n = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Lung volumes differentiate the predominance of emphysema versus airway disease phenotype in early COPD: an observational study of the COPDGene cohort.

Lung volumes identify the "susceptible smokers" who progress to develop spirometric COPD. However, among susceptible smokers, development of spirometric COPD seems to be heterogeneous, suggesting the presence of different pathological mechanisms during early establishment of spirometric COPD. The objective of the present study was to determine the differential patterns of radiographic pathologies among susceptible smokers. We categorised smokers with preserved spirometry (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0) in the Genetic Epidemiology of COPD (COPDGene) cohort based on tertiles (low, intermediate and high) of lung volumes (either total lung capacity (TLC), functional residual capacity FRC or FRC/TLC) at baseline visit. We then examined the differential patterns of change in spirometry and the associated prevalence of computed tomography measured pathologies of emphysema and airway disease with those categories of lung volumes. The pattern of spirometric change differed when participants were categorised by TLC versus FRC/TLC: those in the high TLC tertile showed stable forced expiratory volume in 1 s (FEV1), but enlarging forced vital capacity (FVC), while those in the high FRC/TLC tertile showed decline in both FEV1 and FVC. When participants from the high TLC and high FRC/TLC tertiles were partitioned into mutually exclusive groups, compared to those with high TLC, those with high FRC/TLC had lesser emphysema, but greater air trapping, more self-reported respiratory symptoms and exacerbation episodes and higher likelihood of progressing to more severe spirometric disease (GOLD stages 2-4 versus GOLD stage 1). Lung volumes identify distinct physiological and radiographic phenotypes in early disease among susceptible smokers and predict the rate of spirometric disease progression and the severity of symptoms in early COPD.

Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): a randomised, placebo-controlled, double-blind, investigator-initiated trial.

Although inhaled corticosteroids (ICS) are highly effective in asthma, they provide significant but modest clinical benefit in COPD. Here, we tested the hypothesis that high bronchial airway smooth muscle (ASMC) area in COPD is associated to ICS responsiveness.In this investigator-initiated and -driven, double-blind, randomised, placebo-controlled trial (HISTORIC), 190 COPD patients, GOLD stage B-D, underwent bronchoscopy with endobronchial biopsy. Patients divided in groups A and B with high ASMC area (HASMC: >20% of the bronchial tissue area) and with low ASMC area (LASMC: ≤20% of the bronchial tissue area), respectively and followed a run-in period of 6 weeks on open-label triple inhaled therapy with aclidinium/formoterol/budesonide (ACL/FOR/BUD:400/12/400 mcg/bid). Subsequently, patients were randomised to receive either ACL/FOR/BUD or ACL/FOR/Placebo and followed for 12 months. The primary end point of the study was the difference in post-bronchodilator FEV1 over 12 months between patients with LASMC and HASMC receiving or not receiving ICS.In patients with LASMC, ACL/FOR/BUD did not significantly improve FEV1 over 12 months, as compared to ACL/FOR/placebo p=0.675. In patients with HASMC, however, ACL/FOR/BUD significantly improved FEV1, as compared to ACL/FOR/placebo p=0.020. Over 12 months, the difference of FEV1 change between the group of ACL/FOR/BUD and the group of ACL/FOR/placebo was 50.6 mL·year-1 within the group of patients with LASMC and 183.0 mL·year-1 within the group of patients with HASMC.COPD patients with ΗASMC respond better to ICS than patients with LASMC, suggesting that this type of histological analysis may predict ICS responsiveness in COPD patients receiving triple therapy.

FEV1/FVC Severity Stages for Chronic Obstructive Pulmonary Disease.

The diagnosis of COPD is based on low ratio of the forced expiratory volume in one second to the forced vital capacity (FEV1/FVC) but its severity is classified using percentage predicted FEV1 (ppFEV1). To test a new severity classification scheme for COPD using FEV1/FVC, a more robust measure of airflow obstruction than ppFEV1. In COPDGene (n=10,132), the severity of airflow obstruction was categorized by GOLD Stages I-IV (ppFEV1 ≥80, ≥50-80, ≥30-50, and <30). A new severity classification (STaging of Airflow obstruction by Ratio, STAR) was tested in COPDGene: FEV1/FVC ≥0.60 to <0.70, ≥0.50 to <0.60, ≥0.40 to <0.50, and <0.40, respectively for stages I-IV, and applied to the combined Pittsburgh SCCOR and Pittsburgh Emphysema registry cohorts for replication (n=2017). Agreement (weighted Bangdiwala B) between GOLD and new FEV1/FVC severity stages was 0.89 in COPDGene and 0.88 in the Pittsburgh cohort. In both COPDGene and the Pittsburgh cohort, in comparison to GOLD staging, STAR provided significant discrimination between the absence of airflow obstruction and Stage I for all-cause mortality, respiratory-quality of life, dyspnea, airway wall thickness, exacerbations and lung function decline. No difference was noted for emphysema, small airways disease, and 6-minute walk distance. The STAR classification system identified a greater number of adults with Stage III-IV disease who would be eligible for lung transplantation and lung volume reduction evaluations. The new severity classification scheme STAR provides discrimination for mortality similar to the GOLD classification but with a more uniform gradation of disease truncated.

Blood Gene Expression and Immune Cell Subtypes Associated with Chronic Obstructive Pulmonary Disease Exacerbations.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPDs) are associated with a significant disease burden. Blood immune phenotyping may improve our understanding of a COPD endotype at increased risk of exacerbations. Objective: To determine the relationship between the transcriptome of circulating leukocytes and COPD exacerbations. Methods: Blood RNA sequencing data (n = 3,618) from the COPDGene (Genetic Epidemiology of COPD) study were analyzed. Blood microarray data (n = 646) from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study were used for validation. We tested the association between blood gene expression and AE-COPDs. We imputed the abundance of leukocyte subtypes and tested their association with prospective AE-COPDs. Flow cytometry was performed on blood in SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) (n = 127), and activation markers for T cells were tested for association with prospective AE-COPDs. Measurements and Main Results: Exacerbations were reported 4,030 and 2,368 times during follow-up in COPDGene (5.3 ± 1.7 yr) and ECLIPSE (3 yr), respectively. We identified 890, 675, and 3,217 genes associated with a history of AE-COPDs, persistent exacerbations (at least one exacerbation per year), and prospective exacerbation rate, respectively. In COPDGene, the number of prospective exacerbations in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease stage ⩾2) was negatively associated with circulating CD8+ T cells, CD4+ T cells, and resting natural killer cells. The negative association with naive CD4+ T cells was replicated in ECLIPSE. In the flow-cytometry study, an increase in CTLA4 on CD4+ T cells was positively associated with AE-COPDs. Conclusions: Individuals with COPD with lower circulating lymphocyte counts, particularly decreased CD4+ T cells, are more susceptible to AE-COPDs, including persistent exacerbations.