Progression Of Emphysema In Patients Research Articles

Emphysema Quantifications With CT Scan: Assessing the Effects of Acquisition Protocols and Imaging Parameters Using Virtual Imaging Trials

CT scan has notable potential to quantify the severity and progression of emphysema in patients. Such quantification should ideally reflect the true attributes and pathologic conditions of subjects, not scanner parameters. To achieve such an objective, the effects of the scanner conditions need to be understood so the influence can be mitigated. How do CT scan imaging parameters affect the accuracy of emphysema-based quantifications and biomarkers? Twenty anthropomorphic digital phantoms were developed with diverse anatomic attributes and emphysema abnormalities informed by a real COPD cohort. The phantoms were input to a validated CT scan simulator (DukeSim), modeling a commercial scanner (Siemens Flash). Virtual images were acquired under various clinical conditions of dose levels, tube current modulations (TCM), and reconstruction techniques and kernels. The images were analyzed to evaluate the effects of imaging parameters on the accuracy of density-based quantifications (percent of lung voxels with HU<-950 [LAA-950] and 15th percentile of lung histogram HU [Perc15]) across varied subjects. Paired t tests were performed to explore statistical differences between any two imaging conditions. The most accurate imaging condition corresponded to the highest acquired dose (100 mAs) and iterative reconstruction (SAFIRE) with the smooth kernel of I31, where the measurement errors (difference between measurement and ground truth) were 35 ± 3 Hounsfield Units (HU),-4%± 5%, and 26 ± 10 HU (average ± SD), for the mean lung HU, LAA-950, and Perc15, respectively. Without TCM and at the I31 kernel, increase of dose (20 to 100 mAs) improved the lung mean absolute error (MAE) by 4.2 ± 2.3 HU (average ± SD). TCM did not contribute to a systematic improvement of lung MAE. The results highlight that although CT scan quantification is possible, its reliability is impacted by the choice of imaging parameters. The developed virtual imaging trial platform in this study enables comprehensive evaluation of CT scan methods in reliable quantifications, an effort that cannot be readily made with patient images or simplistic physical phantoms.

Re-IMAGinING the Pathway for Clinical Decision Making in Rare Lung Diseases: Moving Towards a United Vision

This industry-supported symposium was held during the European Respiratory Society (ERS) International Congress and included presentations from several internationally renowned experts in rare lung diseases. The panel discussed the need to improve clinical decision making to expedite disease recognition, prognostic prediction, and early treatment in interstitial lung disease (ILD) and alpha 1 antitrypsin (AAT) deficiency-related chronic obstructive pulmonary disease (COPD). Daiana Stolz, Clinic for Pneumology, University Hospital Freiburg, Switzerland, and Marlies S. Wijsenbeek, Erasmus University Medical Centre, Rotterdam, the Netherlands, explained that although high-resolution CT (HRCT) scans may appear similar, ILD from different causes results in significantly different patient outcomes. Therefore, image analysis and the identification of sensitive and specific biomarkers are critical to improving diagnosis and monitoring treatment response and disease progression in ILD. Charlie Strange, Medical University of South Carolina, Charleston, USA, and Gerry McElvaney, Irish Centre for Genetic Lung Disease, Dublin, Ireland, described the variability in CT-based lung density measurements used to assess the progression of emphysema in patients with AAT deficiency. Clinical trial data indicate that accurate CT lung density measurements are superior to lung function measurements and other endpoints to detect disease progression. However, Strange presented data that showed the considerable impact of acute exacerbations of COPD on CT imaging measurements. One organisation working to improve the accuracy and value of imaging data in lung diseases is the Open Source Imaging Consortium (OSIC), Saugatuck, Michigan, USA. Elizabeth Estes, who works for OSIC, explained that OSIC aims to build a large, global database of anonymised patient data and CT images in ILD, with plans for future expansion into other rare lung diseases. The ultimate goals of this effort are to encourage collaboration, and to develop machine learning algorithms to improve clinical decision making in rare lung diseases.

Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative Losartan Effects on Emphysema Progression Clinical Trial.

Rationale: There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression. Methods: The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George's Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function-Short Form 20a. Measurements and Main Results: A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61-73) years and 48 (36-59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67-2.03) in the losartan group versus 0.66% (0.09-1.23) in the placebo group (P = NS). Conclusions: Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT02696564).

Coupled Immunological and Biomechanical Model of Emphysema Progression.

Chronic Obstructive Pulmonary Disease (COPD) is a disabling respiratory pathology, with a high prevalence and a significant economic and social cost. It is characterized by different clinical phenotypes with different risk profiles. Detecting the correct phenotype, especially for the emphysema subtype, and predicting the risk of major exacerbations are key elements in order to deliver more effective treatments. However, emphysema onset and progression are influenced by a complex interaction between the immune system and the mechanical properties of biological tissue. The former causes chronic inflammation and tissue remodeling. The latter influences the effective resistance or appropriate mechanical response of the lung tissue to repeated breathing cycles. In this work we present a multi-scale model of both aspects, coupling Finite Element (FE) and Agent Based (AB) techniques that we would like to use to predict the onset and progression of emphysema in patients. The AB part is based on existing biological models of inflammation and immunological response as a set of coupled non-linear differential equations. The FE part simulates the biomechanical effects of repeated strain on the biological tissue. We devise a strategy to couple the discrete biological model at the molecular /cellular level and the biomechanical finite element simulations at the tissue level. We tested our implementation on a public emphysema image database and found that it can indeed simulate the evolution of clinical image biomarkers during disease progression.

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE)

Purified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT. Patients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007. Between March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48. RAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment. CSL Behring.

Human α1-proteinase inhibitor (Respreeza®) in α1-antitrypsin deficiency emphysema: a guide to its use in the EU

Augmentation with intravenous infusions of human α1-proteinase inhibitor [Respreeza® (EU); Zemaira® (USA)] slows the progression of emphysema in patients with severe α1-antitrypsin (AAT)-deficiency emphysema. In the randomized, double-blind RAPID trial in patients with severe AAT-deficiency emphysema, Respreeza®/Zemaira® significantly reduced the mean annual rate of lung density loss based on computed tomography imaging at total lung capacity (TLC), but not at functional residual capacity (FRC) or combined TLC + FRC measurements. Respreeza®/Zemaira® is generally well tolerated, with a generally similar tolerability profile to that of placebo.

Randomized, Placebo-Controlled Trials in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a condition caused by the inheritance of two mutated SERPINA1 gene alleles. Individuals with AATD are at increased risk of injury to the liver and lungs. The pulmonary manifestations include precocious onset of pulmonary emphysema and bronchiectasis. For nearly three decades, treatment has been available to individuals with emphysema caused by AATD, but this therapy-augmentation of plasma and tissue alpha-1 antitrypsin levels by intravenous administration of human plasma-derived protein-was approved by regulatory authorities based on its biochemical efficacy. This therapy appears to slow the progression of emphysema in patients with AATD. The medical, patient, and regulatory communities have sought assurance that this expensive therapy provides measurable clinical benefit. Documenting such benefit has been difficult because of the slow progression of the underlying lung disease in AATD, the rarity of this genetic condition, and the lack of direct quantitative measurements of emphysema progression. Over the past decade, quantitative computed tomography (CT) densitometry of the lungs has been found to correlate with severity and progression of emphysema. The recent publication of a well-powered, masked, placebo-controlled study using CT densitometry to evaluate the effectiveness of augmentation therapy at slowing the progression of emphysema has provided some assurance of the clinical efficacy of this therapy.

Association of plasma adipokines with chronic obstructive pulmonary disease severity and progression.

Two adipokines, leptin and adiponectin, regulate metabolic and inflammatory systems reciprocally. The role of adiponectin in chronic obstructive pulmonary disease (COPD) has been studied. However, there are few data evaluating the relationship of plasma leptin with COPD severity or progression. The objective of this study was to evaluate the relationship of leptin, adiponectin, and the leptin/adiponectin ratio with COPD severity and progression according to COPD phenotypes. Plasma leptin and adiponectin levels were measured in 196 subjects with COPD selected from the Korean Obstructive Lung Disease cohort. Using a linear regression model and mixed linear regression, we determined the relationship of plasma leptin and adiponectin levels and the leptin/adiponectin ratio to COPD severity and progression over 3 years. The concentration of adiponectin in plasma positively correlated with percent emphysema on initial computed tomography (CT) (adjusted P = 0.022), whereas plasma leptin concentrations and the leptin/adiponectin ratio exhibited a significant inverse correlation with initial FEV1 (adjusted P = 0.013 for leptin and adjusted P = 0.041 for leptin/adiponectin ratio). Increased plasma leptin and leptin/adiponectin ratio were significantly associated with change in percent emphysema over 3 years (adjusted P = 0.037 for leptin and adjusted P = 0.029 for leptin/adiponectin ratio), whereas none of the adipokines demonstrated an association with FEV1 decline over the 3-year period. Plasma adiponectin and leptin vary according to COPD phenotypes. Plasma leptin and the leptin/adiponectin ratio, but not adiponectin, were significantly associated with changes in CT-assessed emphysema, suggesting a potential role as a biomarker in emphysema progression in patients with COPD.

Impact of Exacerbations on Emphysema Progression in Chronic Obstructive Pulmonary Disease

Low-attenuation areas assessed by computed tomography reflect the extent of pathological emphysema and correlate with airflow limitation and mortality in patients with chronic obstructive pulmonary disease. The cumulative size distribution of low-attenuation area clusters follows a power law characterized by an exponent, D. The values of D reflect the complexity of the terminal airspace geometry and sensitively detect alveolar structural changes. Exacerbations of chronic obstructive pulmonary disease have a negative impact on lung function and prognosis. However, the impact on emphysema progression remains unclear. We investigated the relationship between exacerbation and emphysema progression assessed by computed tomography in patients with chronic obstructive pulmonary disease. Exacerbations were prospectively recorded for 2 years. Annual changes in computed tomography parameters of emphysema were compared between patients with and without a history of exacerbations. In patients with exacerbations, increases in the percentage of low-attenuation areas and decreases in D were greater than in patients without exacerbations. To interpret these results, we established a novel simulation model and found that not only enlargement of preexisting low-attenuation areas but also coalescence of adjoining low-attenuation areas due to alveolar wall destruction caused emphysema progression in patients with exacerbations. This is the first longitudinal study to demonstrate that exacerbations are involved in emphysema progression in patients with chronic obstructive pulmonary disease. Emphysema progression should be evaluated as part of the outcomes of exacerbations in the management of chronic obstructive pulmonary disease.

Longitudinal Follow-up of Patients With α1-Protease Inhibitor Deficiency Before and During Therapy With IV α1-Protease Inhibitor

The efficacy of IV augmentation therapy with human alpha(1)-protease inhibitor (alpha(1)-Pi) in patients with severe alpha(1)-Pi deficiency is still under debate. To evaluate the progression of emphysema in patients with alpha(1)-Pi deficiency before and during a period in which they received treatment with alpha(1)-Pi. Multicenter, retrospective cohort study. Outpatient clinics of 26 university clinics and pulmonary hospitals. Ninety-six patients with severe alpha(1)-Pi deficiency receiving weekly augmentation therapy with human alpha(1)-Pi, 60 mg/kg of body weight, had a minimum of two lung function measurements before and two lung function measurements after augmentation therapy was started. Lung function data were followed up for a minimum of 12 months both before and during treatment (mean, 47.5 months and 50.2 months, respectively). Patients were grouped according to the severity of their lung function impairment. The change in FEV(1) was compared during nontreatment and treatment periods. In the whole group, the decline in FEV(1) was significantly lower during the treatment period (49.2 mL/yr vs 34.2 mL/yr, p = 0.019). In patients with FEV(1) > 65%, IV alpha(1)-Pi treatment reduced the decline in FEV(1) by 73.6 mL/yr (p = 0.045). Seven individuals had a rapid decline of FEV(1) before treatment, and the loss in FEV(1) could be reduced from 256 mL/yr to 53 mL/yr (p = 0.001). Some patients with severe alpha(1)-Pi deficiency and well-preserved lung function show a rapid decline in FEV(1). These patients profit from weekly IV therapy with human alpha(1)-Pi and have less rapid decline if treated. Early detection of patients at risk and early start of augmentation therapy may prevent accelerated loss of lung tissue.

O-23-340 - Therapies to prevent vasospasm after acute surgery of aneurysmal subarachnoid hemorrhage

The efficacy of IV augmentation therapywith human α1-protease inhibitor (α1-Pi) inpatients with severe α1-Pi deficiency is still underdebate.To evaluate the progressionof emphysema in patients with α1-Pi deficiency before and during a period in which they received treatment withα1-Pi.Multicenter, retrospective cohort study.Outpatientclinics of 26 university clinics and pulmonary hospitals.Ninety-six patients with severeα1-Pi deficiency receiving weekly augmentation therapywith human α1-Pi, 60 mg/kg of body weight, had a minimumof two lung function measurements before and two lung functionmeasurements after augmentation therapy was started. Lung function datawere followed up for a minimum of 12 months both before and duringtreatment (mean, 47.5 months and 50.2 months, respectively).Patients were grouped accordingto the severity of their lung function impairment. The change inFEV1 was compared during nontreatment and treatmentperiods. In the whole group, the decline in FEV1 wassignificantly lower during the treatment period (49.2 mL/yr vs 34.2mL/yr, p = 0.019). In patients with FEV1 > 65%, IVα1-Pi treatment reduced the decline in FEV1by 73.6 mL/yr (p = 0.045). Seven individuals had a rapid decline of FEV1 before treatment, and the loss in FEV1could be reduced from 256 mL/yr to 53 mL/yr (p = 0.001).Some patients with severe α1-Pideficiency and well-preserved lung function show a rapid decline inFEV1. These patients profit from weekly IV therapy with human α1-Pi and have less rapid decline if treated. Earlydetection of patients at risk and early start of augmentation therapymay prevent accelerated loss of lung tissue.