Mark Thomas Dransfield

Rationale: Conventional CT-derived pulmonary vascular metrics quantify vascular pruning but do not assess spatial heterogeneity of vascular architecture. In COPD, peripheral microvascular pruning coexists with compensatory central vessel dilation, paradoxically preserving total vessel volume while reducing effective vascular penetration into lung parenchyma. Objectives: To develop and validate Vascular Proximity Coverage (VPC), a novel distance-based CT biomarker quantifying spatial efficiency of pulmonary vascular distribution. Methods: This retrospective analysis included 7,881 COPDGene participants with complete vascular segmentations. VPC is estimated by integrating the area under the cumulative lung tissue coverage curve at distances 0–10 mm from segmented vessel voxels. Multivariable models were used to assess associations with lung function, six-minute walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ), mMRC dyspnea score and all-cause mortality adjusting for demographics, smoking, emphysema, scanner type, and BV5. We stratified the cohort into four groups defined by the median values of BV5 and VPC, yielding discordant (high-BV5/low-VPC, low-BV5/high-VPC) and concordant (high/high, low/low) vascular phenotypes. Results: VPC declined across disease severity (5.82 ± 0.50 in non-smokers to 5.21 ± 0.64 in GOLD 4; p5 ) and total vessel volume, quantify the amount of visible vasculature but do not assess how effectively vessels reach the lung parenchyma for efficient gas exchange. In COPD, peripheral microvascular pruning commonly coexists with compensatory central vessel dilation, leading to preserved or increased total vascular volume despite compromised functional vascular distribution. What This Study Adds to the Field: Vascular Proximity Coverage (VPC) is a novel distance-based CT biomarker that quantifies the spatial efficiency of pulmonary vascular distribution by measuring cumulative lung tissue coverage across distances from vessel walls. In 7,881 COPDGene participants, including non-smokers and PRISm subjects, lower VPC was independently associated with decreased lung function, reduced exercise capacity, worsened quality of life, and increased all-cause mortality over a median 10.8-year follow-up after adjusting for BV ₅ and emphysema. VPC identified a high-risk phenotype with preserved vessel volume but impaired distribution (high-BV5/low-VPC) that carried 24% increased mortality risk and detected subclinical vascular dysfunction in smokers with normal spirometry.

Background: Guidelines recommend aspirin (75–100 mg daily) for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). However, it is unknown if people with a history of ASCVD and chronic obstructive pulmonary disease (COPD) or asthma, which are independent risk factors for ASCVD, would benefit from higher dose aspirin. Methods: We evaluated the effectiveness and safety of 2 aspirin doses among individuals with and without COPD/asthma in the ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) trial. The ADAPTABLE study was an open‐label, randomized clinical trial that assigned people with ASCVD to aspirin 81 or 325 mg. We performed a secondary analysis of data from the ADAPTABLE study to investigate the difference in clinical effectiveness and safety among people with and without COPD or asthma randomized to aspirin 325 versus 81 mg. We assessed if history of COPD/asthma modified the association between aspirin dose and outcomes. Results: Among the 14 662 participants, 2778 had a history of COPD or asthma and 11 884 had no history of COPD or asthma. We observed no significant interaction between aspirin dose and history of COPD/asthma in our adjusted primary composite outcome (adjusted hazard ratio [aHR], 1.15 [95% CI, 0.92–1.43]; P value=0.349). We observed individuals with a history of COPD/asthma treated with aspirin 81 mg had a significantly higher risk of stroke (aHR, 2.41 [95% CI, 1.27–4.57]) compared with a treatment strategy of aspirin 325 mg. Conclusions: Among people with ASCVD and COPD/asthma, there were no significant differences in ASCVD outcomes based on aspirin dosing except stroke. Further evaluation of stroke prevention in this population is warranted.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) exhibit acquired CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction. CFTR modulators may improve outcomes in patients with COPD, although recent data regarding the magnitude of benefit have been inconclusive, and effects on mucociliary clearance are unknown. Objectives: We conducted a phase 2, randomized, double-blind, placebo-controlled trial to determine safety and tolerability and explore the potential mechanism of ivacaftor for the treatment of patients with COPD. Methods: We randomized 40 patients with moderate to severe COPD and symptoms of chronic bronchitis to ivacaftor (n = 30) or placebo (n = 10) 150 mg twice daily for 12 weeks. Primary endpoints included evaluation of the safety of ivacaftor and pharmacokinetics. Secondary endpoints included measures of CFTR activity and clinical outcomes. Measurements and Main Results: Ivacaftor was safe and tolerable, with similar rates of adverse events between groups. The most common adverse events were diarrhea in the ivacaftor group and acute COPD exacerbation in the placebo group. Pharmacokinetic analysis showed the mean area under the curve over 12 hours to be 72% of the previously reported value in cystic fibrosis. Treatment with ivacaftor did not improve sweat chloride, whole-lung mucociliary clearance, lung function, or respiratory symptoms. Conclusions: Ivacaftor was safe and well tolerated but did not improve measures of CFTR activity or mucus clearance. As serum concentrations achieved were lower than observed in cystic fibrosis at the same dose, and modulation of wild-type CFTR differs from G551D, further dose determination studies are needed to better understand the treatment efficacy of CFTR potentiators in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT 03085485).

Rationale: Serum IgG deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD), but it is unclear whether concentrations in the lower end of the normal range still confer risk. Objectives: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. Methods: Former and current smokers in SPIROMICS (the Subpopulations and Intermediate Outcome Measures of COPD study) (n = 1,497) were studied: 1,026 with COPD and 471 at risk for COPD. In a subset (n = 1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographic characteristics, current smoking, smoking history, FEV1 percent predicted, inhaled corticosteroids, and serum IgA. Measurements and Main Results: The 35th percentile (1,225 mg/dl in this cohort) of IgG was the best cutoff by Akaike information criterion. Below this, there was increased exacerbation risk (incidence rate ratio [IRR], 1.28; 95% confidence interval [CI], 1.08–1.51). Among subclasses, IgG1 and IgG2 below the 35th percentile (354 and 105 mg/dl, respectively) were associated with increased risks of severe exacerbation (IgG1, IRR, 1.39; 95% CI, 1.06–1.84; IgG2, IRR, 1.50; 95% CI, 1.14–1.1.97). These associations remained significant when additionally adjusting for a history of exacerbations. Conclusions: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting that subtle impairment of humoral immunity may be associated with exacerbations.

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n = 1,367) versus above 4,000 ft (1,219 m) elevation (n = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (−32.3 m [95% confidence interval, −49.8 to −14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George’s Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT 01969344).

Background: COPD has high mortality, compounded by comorbid cardiovascular disease. We investigated two ECG markers, Cardiac Infarction Injury Score (CIIS) and P pulmonale, as prognostic tools for adverse cardiopulmonary events in COPD.Methods: This was apost hocanalysis of the IMPACT trial. Outcomes included odds (odds ratio, 95% confidence intervals) of adverse cardiopulmonary events stratified by CIIS threshold (versus≥20) and P pulmonale (baseline). Events included all-cause death, hospitalisation or death, cardiovascular adverse event of special interest, severe COPD exacerbations, and moderate/severe COPD exacerbations. We also assessed the effects of fluticasone furoate/umeclidinium/vilanterolversusfluticasone furoate/vilanterol or umeclidinium/vilanterol based on CIIS and P pulmonale.Results: We included 9448 patients. Patients with CIIS ≥20 (versusCIIS versuswithout) had greater odds of all-cause death (OR 2.25, 95% CI 1.54–3.29, pversusumeclidinium/vilanterol in patients with CIIS ≥20, but not CIIS <20.Conclusions: These findings suggest the potential clinical relevance of CIIS and P pulmonale as risk indicators for adverse cardiopulmonary events in COPD.

Background: Improvements in FEV1, 6MWD and SGRQ after BLVR with Zephyr valves (EBV) were shown in the LIBERATE Study. There was a trend towards a reduction in the rate of severe COPD exacerbations (requiring hospitalization) in the longer-term (p=0.053) compared to medically managed Control group (SoC). Absolute improvements after BLVR are higher in patients that achieve a treated lobar volume reduction (TLVR) of ≥50%. Objectives: Compare rates of severe COPD exacerbations between the EBV and SoC in the year after treatment using TLVR threshold of ≥50%. Methods: Post-hoc analysis of LIBERATE study data for Clinical Events Committee adjudicated severe COPD exacerbations. Results: Of the 128 EBV subjects (mean±SD: baseline age, 64.0±6.9yrs; FEV1, 28.0±7.45% pred; RV, 224.5±42.5% pred), 70 subjects achieved ≥50% TLVR at 12months; mean RV reduction of 17.3%. Clinical outcomes at 12months for subjects with TLVR ≥50% were significantly higher and severe COPD exacerbation rate significantly reduced compared to the SoC (n=62) during the 46day to 12month post-EBV period. erj;64/suppl_68/OA2799/F1 F1 F1 Conclusions: TLVR of ≥50% after BLVR with EBV correlated with significantly fewer severe COPD exacerbations in the longer-term post-valve treatment. The improved clinical outcomes and the reduction in COPD exacerbations resulting in hospitalization has the potential to reduce the economic burden of severe COPD.

Background: Cardiovascular disease (CVD) is the most important comorbidity in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations not only contribute to COPD progression but may also elevate the risk of CVD. This study aimed to determine whether COPD exacerbations increase the risk of subsequent CVD events using up to 15 years of prospective longitudinal follow‐up data from the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. Methods and Results: The COPDGene study is a large, multicenter, longitudinal investigation of COPD, including subjects at enrollment aged 45 to 80 years with a minimum of 10 pack‐years of smoking history. Cox proportional hazards models and Kaplan‐Meier survival curves were used to assess the risk of a composite end point of CVD based on the COPD exacerbation rate. Frequent exacerbators exhibited a higher cumulative incidence of composite CVD end points than infrequent exacerbators, irrespective of the presence of CVD at baseline. After adjusting for covariates, frequent exacerbators still maintained higher hazard ratios (HRs) than the infrequent exacerbator group (without CVD: HR, 1.81 [95% CI, 1.47–2.22]; with CVD: HR, 1.92 [95% CI, 1.51–2.44]). This observation remained consistently significant in moderate to severe COPD subjects and the preserved ratio impaired spirometry population. In the mild COPD population, frequent exacerbators showed a trend toward more CVD events. Conclusions: COPD exacerbations are associated with an increased risk of subsequent cardiovascular events in subjects with and without preexisting CVD. Patients with COPD experiencing frequent exacerbations may necessitate careful monitoring and additional management for subsequent potential CVD. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00608764.