David A. Lipson

A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation

Abstract The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease

Rationale: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long‐acting &bgr;2‐agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. Objectives: We compared the effects of once‐daily triple therapy on lung function and health‐related quality of life with twice‐daily ICS/LABA therapy in patients with COPD. Methods: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double‐blind, double‐dummy study comparing 24 weeks of once‐daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 &mgr;g/62.5 &mgr;g/25 &mgr;g; ELLIPTA inhaler) with twice‐daily ICS/LABA therapy (budesonide/formoterol 400 &mgr;g/12 &mgr;g; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co‐primary endpoints were change from baseline in trough FEV1 and in St. George’s Respiratory Questionnaire (SGRQ) total score at Week 24. Measurements and Main Results: In the intent‐to‐treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and −29 ml (95% CI, −46 to −13), respectively, and mean changes from baseline in SGRQ scores were −6.6 units (95% CI, −7.4 to −5.7) and −4.3 units (95% CI, −5.2 to −3.4), respectively. For both endpoints, the between‐group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14‐51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. Conclusions: These results support the benefits of single‐inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

Pulmonary ventilation and perfusion scanning using hyperpolarized helium‐3 MRI and arterial spin tagging in healthy normal subjects and in pulmonary embolism and orthotopic lung transplant patients

Conventional nuclear ventilation/perfusion (V/Q) scanning is limited in spatial resolution and requires exposure to radioactivity. The acquisition of pulmonary V/Q images using MRI overcomes these difficulties. When inhaled, hyperpolarized helium‐3 (3He) permits MRI of gas distribution. Magnetic labeling of blood (arterial spin‐tagging (AST)) provides images of pulmonary perfusion. Three normal subjects, two patients who had undergone single lung transplantation for emphysema, and one subject with pulmonary embolism (PE), were imaged. 3He distribution and blood perfusion appeared uniform in the normal subjects and throughout the lung allografts. Gas distribution and perfusion in the emphysematous lungs were non‐uniform and paralleled radiographic abnormalities. AST imaging alone revealed a lower‐lobe wedge‐shaped perfusion defect in the patient with PE that corresponded to computed tomography (CT) imaging. Hyperpolarized 3He gas is demonstrated to provide ventilation images of the lung. Blood perfusion information may be obtained during the same examination using the AST technique. The sequential application of these imaging methods provides a novel tool for studying V/Q relationships. Magn Reson Med 47:1073–1076, 2002.

Demonstration of a compact compressor for application of metastability-exchange optical pumping of 3He to human lung imaging

Hyperpolarized gas magnetic resonance imaging has recently emerged as a method to image lungs, sinuses, and the brain. The best lung images to date have been produced using hyperpolarized 3He, which is produced by either spin‐exchange or metastability‐exchange optical pumping. For hyperpolarized gas MRI, the metastable method has demonstrated higher polarization levels and higher polarizing rates, but it requires compression of the hyperpolarized gas. Prior to this work, compression of hyperpolarized gas had only been accomplished using a large, complex and expensive apparatus. Here, human lung ventilation images are presented that were obtained using a compact compressor that is relatively simple and inexpensive. For this test, 1.1 bar‐L of 15% hyperpolarized 3He gas was produced at the National Institute of Standards and Technology using a modified commercial diaphragm pump. The hyperpolarized gas was transported to the University of Pennsylvania in a holding field provided by a portable solenoid. Magn Reson Med 43:290–294, 2000.

Hyperpolarized 13C MRI of the pulmonary vasculature and parenchyma

The study of lung perfusion in normal and diseased subjects is of great interest to physiologists and physicians. In this work we demonstrate the application of a liquid‐phase hyperpolarized (HP) carbon‐13 (13C) tracer to magnetic resonance imaging (MRI) of the pulmonary vasculature and pulmonary perfusion in a porcine model. Our results show that high spatial and temporal resolution images of pulmonary perfusion can be obtained with this contrast technique. Traditionally, pulmonary perfusion measurement techniques have been challenging because of insufficient signal for quantitative functional assessments. The use of polarized 13C in MRI overcomes this limitation and may lead to a viable clinical method for studying the pulmonary vasculature and perfusion. Magn Reson Med 57:459–463, 2007.

Detection of simulated pulmonary embolism in a porcine model using hyperpolarized 3He MRI.

Several radiological imaging modalities are available to assist with the clinical diagnosis of pulmonary embolism (PE). The most frequently used techniques—nuclear medicine ventilation‐perfusion (VP) scan, computed tomography (CT), magnetic resonance angiography (MRA), and pulmonary angiography (PA)—all have literature‐supported, substantial limitations with respect to timeliness and patient safety. Hyperpolarized 3He magnetic resonance gas distribution imaging (HP 3He MRI) recently has shown potential as a safer and faster alternative. In this study, we performed HP 3He MRI on a porcine model (N = 6) of simulated PE using selective occlusion balloon catheterization (N = 4) and nonselective aged autologous clot injection (N = 1). The technique was also performed on a normal pig and again after the animal was killed. Temporal depletion of regional HP 3He MRI signal intensity provided for a qualitative assessment of simulated PE (N = 4), and regional PAO2 (alveolar partial pressure of oxygen) was calculated in affected airspaces for a quantitative assessment of simulated PE (N = 1). The preliminary results suggest that HP 3He MRI shows promise as a means of assessing regional pulmonary perfusion abnormalities in the porcine models of simulated PE that were used in this study. Magn Reson Med 51:291–298, 2004.

Detection and localization of pulmonary air leaks using laser-polarized 3He MRI

Pulmonary air leaks were created in the lungs of Yorkshire pigs. Dynamic, 3D MRI of laser‐polarized 3He gas was then performed using a gradient‐echo pulse sequence. Coronal magnitude images of the helium distribution were acquired during gas inhalation with a voxel resolution of approximately 1.2 × 2.5 × 8 mm, and a time resolution of 5 sec. In each animal, the ventilation images reveal focal high‐signal intensity within the pleural cavity at the site of the air leaks. In addition, a wedge‐shaped region of increased parenchymal signal intensity was observed adjacent to the site of the air leak in one animal. 3He MRI may prove helpful in the management of patients with pulmonary air leaks. Magn Reson Med 44:379–382, 2000.

A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes. This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months. The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017. Treatment choices between LABA/LAMA versus ICS/LABA versus ICS/LABA/LAMA in GOLD group D subjects with COPD http://ow.ly/bg7R300C2uo

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD

BACKGROUND The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long‐acting muscarinic antagonist (LAMA), and a long‐acting β2‐agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid–LABA or LAMA–LABA), are uncertain. METHODS In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once‐daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 μg, umeclidinium (a LAMA) at a dose of 62.5 μg, and vilanterol (a LABA) at a dose of 25 μg (triple therapy) with fluticasone furoate–vilanterol (at doses of 100 μg and 25 μg, respectively) and umeclidinium–vilanterol (at doses of 62.5 μg and 25 μg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS The rate of moderate or severe exacerbations in the triple‐therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate–vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium–vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple‐therapy group was 0.13, as compared with 0.19 in the umeclidinium–vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled‐glucocorticoid groups than in the umeclidinium–vilanterol group, and the risk of clinician‐diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time‐to‐first‐event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). CONCLUSIONS Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate–vilanterol or umeclidinium–vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium–vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513.)

Quantitative assessment of emphysema using hyperpolarized 3He magnetic resonance imaging

In this experiment, Sprague–Dawley rats with elastase‐induced emphysema were imaged using hyperpolarized 3He MRI. Regional fractional ventilation r, the fraction of gas replaced with a single tidal breath, was calculated from a series of images in a wash‐in study of hyperpolarized gas. We compared the regional fractional ventilation in these emphysematous rats to the regional fractional ventilations we calculated from a previous baseline study in healthy Sprague–Dawley rats. We found that there were differences in the maps of fractional ventilation and its associated frequency distribution between the healthy and emphysematous rat lungs. Fractional ventilation tended to be much lower in emphysematous rats than in normal rats. With this information, we can use data on fractional ventilation to regionally distinguish between healthy and emphysematous portions of the lung. The successful implementation of such a technique on a rat model could lead to work toward the future implementation of this technique in human patients. Magn Reson Med 53:1341–1346, 2005.