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Joshua M. Diamond - One of the best experts on this subject based on the ideXlab platform.
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lung innate lymphoid cell composition is altered in primary Graft Dysfunction
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Laurel A Monticelli, Elia Tait D Wojno, Steven A Saenz, David Artis, Mary K. Porteous, Edward Cantu, Joshua M. Diamond, Jason D. ChristieAbstract:Rationale: Primary Graft Dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the alloGraft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, alloGraft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: AlloGraft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after alloGraft reperfusion.Conclusions: The composition of donor ILC subsets is altered after alloGraft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
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primary Graft Dysfunction pgd following lung transplantation
Seminars in Respiratory and Critical Care Medicine, 2018Co-Authors: Rupal J. Shah, Joshua M. DiamondAbstract:Primary Graft Dysfunction (PGD) is a form of acute lung injury that results from ischemia reperfusion injury (IRI) and is the major cause of early posttransplant morbidity and mortality. Patients who survive PGD have decreased quality of life, an increased risk of chronic lung alloGraft Dysfunction, specifically bronchiolitis obliterans syndrome, and a significantly increased risk of death. In 2017, the International Society for Heart and Lung Transplantation released updated consensus statements on the PGD definition, most up-to-date PGD risk factors, mechanisms of PGD development, and the state-of-the-art for PGD therapeutics. Risk factor identification has led to the development of PGD predictive algorithms, although their clinical utility remains limited. Ongoing areas of controversy and discussion include further refinements to the PGD grading scheme to account for technologic advances such as extracorporeal membrane oxygenation and the increased utilization of high flow nasal cannula, the use of PGD as an outcome measure in clinical trials of ex vivo lung perfusion, enhancement of predictive algorithms incorporating biochemical risk factors, and the need for development of therapies targeted at improving PGD outcomes.
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cell free hemoglobin promotes primary Graft Dysfunction through oxidative lung endothelial injury
JCI insight, 2018Co-Authors: Ciara M Shaver, Joshua M. Diamond, David J. Lederer, Nancy Wickersham, Brennan J Mcneil, Hiromasa Nagata, Adam Miller, Stuart R Landstreet, Jamie L Kuck, Steven M. KawutAbstract:Primary Graft Dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23-6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue-labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.
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peripheral blood gene expression changes associated with primary Graft Dysfunction after lung transplantation
American Journal of Transplantation, 2017Co-Authors: Joshua M. Diamond, Mary K. Porteous, Edward Cantu, David J. Lederer, Y Suzuki, Keith C Meyer, Rita K Milewski, Selim M Arcasoy, F Dovidio, Matthew BacchettaAbstract:Recipient responses to primary Graft Dysfunction (PGD) after lung transplantation may have important implications to the fate of the alloGraft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of alloGraft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the alloGraft.
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diastolic Dysfunction increases the risk of primary Graft Dysfunction after lung transplant
American Journal of Respiratory and Critical Care Medicine, 2016Co-Authors: Mary K. Porteous, Jason D. Christie, Joshua M. Diamond, Rupal J. Shah, James N Kirkpatrick, Russell T Shinohara, James Lee, Steven M. KawutAbstract:Rationale: Primary Graft Dysfunction (PGD) is a significant cause of early morbidity and mortality after lung transplant and is characterized by severe hypoxemia and infiltrates in the alloGraft. The pathogenesis of PGD involves ischemia-reperfusion injury. However, subclinical increases in pulmonary venous pressure due to left ventricular diastolic Dysfunction may contribute by exacerbating capillary leak.Objectives: To determine whether a higher ratio of early mitral inflow velocity (E) to early diastolic mitral annular velocity (e), indicative of worse left ventricular diastolic function, is associated with a higher risk of PGD.Methods: We performed a retrospective cohort study of patients in the Lung Transplant Outcomes Group who underwent bilateral lung transplant at our institution between 2004 and 2014 for interstitial lung disease, chronic obstructive pulmonary disease, or pulmonary arterial hypertension. Transthoracic echocardiograms obtained during evaluation for transplant listing were analyzed...
Vibha N. Lama - One of the best experts on this subject based on the ideXlab platform.
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objective estimates improve risk stratification for primary Graft Dysfunction after lung transplantation
American Journal of Transplantation, 2015Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, Judd D Flesch, Jonathan B Orens, David S. WilkesAbstract:Primary Graft Dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002–2010; with separate validation in 382 subjects accrued from 2011–2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 hours, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed 3 prediction models, where low-risk recipients had a normal BMI (18.5–25 kg/m2), COPD/CF, and absent or mild PH (mPAP< 40mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4–7%, and high-risk a predicted PGD risk of 15–18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5–25%. We conclude that valid estimates of PGD risk can be produced using readily-available clinical variables.
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latent class analysis identifies distinct phenotypes of primary Graft Dysfunction after lung transplantation
Chest, 2013Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, David S. Wilkes, Jonathan B Orens, Sangeeta BhoradeAbstract:Background There is significant heterogeneity within the primary Graft Dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung Dysfunction and patterns of resolution. Methods Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. Results Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent Dysfunction (class 1), (2) complete resolution of Dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P Conclusions There are distinct phenotypes of resolution of Dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of Graft Dysfunction.
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clinical risk factors for primary Graft Dysfunction after lung transplantation
Journal of Heart and Lung Transplantation, 2013Co-Authors: Joshua M. Diamond, James C. Lee, Edward Cantu, David J. Lederer, Steven M. Kawut, Rupal J. Shah, Scarlett L. Bellamy, Benjamin A Kohl, A R Localio, Vibha N. LamaAbstract:Purpose Primary Graft Dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies of PGD risk factors have produced conflicting results due to small sample sizes, inconsistencies in PGD phenotype, inability to control for multiple confounders, and use of retrospective, single center, or administrative data. We sought to identify donor, recipient, and peri-operative risk factors for PGD. Methods and Materials We performed a 10 center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was grade 3 PGD at 48 or 72 hrs post transplant. The association of risk factors with PGD was analyzed using multivariable conditional logistic regression. Results 1255 patients were enrolled; 211 subjects (16.8%) developed PGD. In multivariable models, risk factors for PGD were any history of donor smoking (OR=1.8, 95%CI 1.2, 2.6, p=0.002), FiO2 at alloGraft reperfusion (OR=1.1 per 10% increase in FiO2, 95%CI 1.0, 1.2; p=0.01), single lung transplant (OR=2.0, 95%CI 1.2, 3.3; p=0.008), cardiopulmonary bypass (OR=3.4, 95%CI 2.2, 5.3; p Conclusions We identified important PGD risk factors, including donor smoking, recipient factors of pre-transplant diagnosis and BMI, and perioperative treatment variables, including use of cardiopulmonary bypass, blood transfusion volume, and FiO2 at reperfusion. Several of these risk factors are potentially modifiable, and thus may suggest preventative strategies, while other risk factors should be prioritized for future mechanistic research efforts.
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clinical risk factors for primary Graft Dysfunction after lung transplantation
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: Joshua M. Diamond, James C. Lee, Edward Cantu, David J. Lederer, Steven M. Kawut, Rupal J. Shah, Scarlett L. Bellamy, Russell A Localio, Benjamin A Kohl, Vibha N. LamaAbstract:Rationale: Primary Graft Dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during alloGraft reperfusion (OR, 1.1 per 10% ...
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construct validity of the definition of primary Graft Dysfunction after lung transplantation
Journal of Heart and Lung Transplantation, 2010Co-Authors: Jason D. Christie, Nancy Robinson, James C. Lee, Lorraine B. Ware, David J. Lederer, Keith M. Wille, Scarlett L. Bellamy, Russell A Localio, Denis Hadjiliadis, Vibha N. LamaAbstract:Background This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary Graft Dysfunction (PGD) grades with lung injury biomarker profiles and survival. Methods The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade. Results PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation ( p p p p Conclusions The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.
Rupal J. Shah - One of the best experts on this subject based on the ideXlab platform.
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primary Graft Dysfunction pgd following lung transplantation
Seminars in Respiratory and Critical Care Medicine, 2018Co-Authors: Rupal J. Shah, Joshua M. DiamondAbstract:Primary Graft Dysfunction (PGD) is a form of acute lung injury that results from ischemia reperfusion injury (IRI) and is the major cause of early posttransplant morbidity and mortality. Patients who survive PGD have decreased quality of life, an increased risk of chronic lung alloGraft Dysfunction, specifically bronchiolitis obliterans syndrome, and a significantly increased risk of death. In 2017, the International Society for Heart and Lung Transplantation released updated consensus statements on the PGD definition, most up-to-date PGD risk factors, mechanisms of PGD development, and the state-of-the-art for PGD therapeutics. Risk factor identification has led to the development of PGD predictive algorithms, although their clinical utility remains limited. Ongoing areas of controversy and discussion include further refinements to the PGD grading scheme to account for technologic advances such as extracorporeal membrane oxygenation and the increased utilization of high flow nasal cannula, the use of PGD as an outcome measure in clinical trials of ex vivo lung perfusion, enhancement of predictive algorithms incorporating biochemical risk factors, and the need for development of therapies targeted at improving PGD outcomes.
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diastolic Dysfunction increases the risk of primary Graft Dysfunction after lung transplant
American Journal of Respiratory and Critical Care Medicine, 2016Co-Authors: Mary K. Porteous, Jason D. Christie, Joshua M. Diamond, Rupal J. Shah, James N Kirkpatrick, Russell T Shinohara, James Lee, Steven M. KawutAbstract:Rationale: Primary Graft Dysfunction (PGD) is a significant cause of early morbidity and mortality after lung transplant and is characterized by severe hypoxemia and infiltrates in the alloGraft. The pathogenesis of PGD involves ischemia-reperfusion injury. However, subclinical increases in pulmonary venous pressure due to left ventricular diastolic Dysfunction may contribute by exacerbating capillary leak.Objectives: To determine whether a higher ratio of early mitral inflow velocity (E) to early diastolic mitral annular velocity (e), indicative of worse left ventricular diastolic function, is associated with a higher risk of PGD.Methods: We performed a retrospective cohort study of patients in the Lung Transplant Outcomes Group who underwent bilateral lung transplant at our institution between 2004 and 2014 for interstitial lung disease, chronic obstructive pulmonary disease, or pulmonary arterial hypertension. Transthoracic echocardiograms obtained during evaluation for transplant listing were analyzed...
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objective estimates improve risk stratification for primary Graft Dysfunction after lung transplantation
American Journal of Transplantation, 2015Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, Judd D Flesch, Jonathan B Orens, David S. WilkesAbstract:Primary Graft Dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002–2010; with separate validation in 382 subjects accrued from 2011–2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 hours, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed 3 prediction models, where low-risk recipients had a normal BMI (18.5–25 kg/m2), COPD/CF, and absent or mild PH (mPAP< 40mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4–7%, and high-risk a predicted PGD risk of 15–18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5–25%. We conclude that valid estimates of PGD risk can be produced using readily-available clinical variables.
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latent class analysis identifies distinct phenotypes of primary Graft Dysfunction after lung transplantation
Chest, 2013Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, David S. Wilkes, Jonathan B Orens, Sangeeta BhoradeAbstract:Background There is significant heterogeneity within the primary Graft Dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung Dysfunction and patterns of resolution. Methods Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. Results Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent Dysfunction (class 1), (2) complete resolution of Dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P Conclusions There are distinct phenotypes of resolution of Dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of Graft Dysfunction.
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clinical risk factors for primary Graft Dysfunction after lung transplantation
Journal of Heart and Lung Transplantation, 2013Co-Authors: Joshua M. Diamond, James C. Lee, Edward Cantu, David J. Lederer, Steven M. Kawut, Rupal J. Shah, Scarlett L. Bellamy, Benjamin A Kohl, A R Localio, Vibha N. LamaAbstract:Purpose Primary Graft Dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies of PGD risk factors have produced conflicting results due to small sample sizes, inconsistencies in PGD phenotype, inability to control for multiple confounders, and use of retrospective, single center, or administrative data. We sought to identify donor, recipient, and peri-operative risk factors for PGD. Methods and Materials We performed a 10 center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was grade 3 PGD at 48 or 72 hrs post transplant. The association of risk factors with PGD was analyzed using multivariable conditional logistic regression. Results 1255 patients were enrolled; 211 subjects (16.8%) developed PGD. In multivariable models, risk factors for PGD were any history of donor smoking (OR=1.8, 95%CI 1.2, 2.6, p=0.002), FiO2 at alloGraft reperfusion (OR=1.1 per 10% increase in FiO2, 95%CI 1.0, 1.2; p=0.01), single lung transplant (OR=2.0, 95%CI 1.2, 3.3; p=0.008), cardiopulmonary bypass (OR=3.4, 95%CI 2.2, 5.3; p Conclusions We identified important PGD risk factors, including donor smoking, recipient factors of pre-transplant diagnosis and BMI, and perioperative treatment variables, including use of cardiopulmonary bypass, blood transfusion volume, and FiO2 at reperfusion. Several of these risk factors are potentially modifiable, and thus may suggest preventative strategies, while other risk factors should be prioritized for future mechanistic research efforts.
Jason D. Christie - One of the best experts on this subject based on the ideXlab platform.
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lung innate lymphoid cell composition is altered in primary Graft Dysfunction
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Laurel A Monticelli, Elia Tait D Wojno, Steven A Saenz, David Artis, Mary K. Porteous, Edward Cantu, Joshua M. Diamond, Jason D. ChristieAbstract:Rationale: Primary Graft Dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the alloGraft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, alloGraft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: AlloGraft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after alloGraft reperfusion.Conclusions: The composition of donor ILC subsets is altered after alloGraft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
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diastolic Dysfunction increases the risk of primary Graft Dysfunction after lung transplant
American Journal of Respiratory and Critical Care Medicine, 2016Co-Authors: Mary K. Porteous, Jason D. Christie, Joshua M. Diamond, Rupal J. Shah, James N Kirkpatrick, Russell T Shinohara, James Lee, Steven M. KawutAbstract:Rationale: Primary Graft Dysfunction (PGD) is a significant cause of early morbidity and mortality after lung transplant and is characterized by severe hypoxemia and infiltrates in the alloGraft. The pathogenesis of PGD involves ischemia-reperfusion injury. However, subclinical increases in pulmonary venous pressure due to left ventricular diastolic Dysfunction may contribute by exacerbating capillary leak.Objectives: To determine whether a higher ratio of early mitral inflow velocity (E) to early diastolic mitral annular velocity (e), indicative of worse left ventricular diastolic function, is associated with a higher risk of PGD.Methods: We performed a retrospective cohort study of patients in the Lung Transplant Outcomes Group who underwent bilateral lung transplant at our institution between 2004 and 2014 for interstitial lung disease, chronic obstructive pulmonary disease, or pulmonary arterial hypertension. Transthoracic echocardiograms obtained during evaluation for transplant listing were analyzed...
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lung size mismatch and primary Graft Dysfunction after bilateral lung transplantation
Journal of Heart and Lung Transplantation, 2013Co-Authors: Michael Eberlein, Joshua M. Diamond, Keith M. Wille, Jonathan B Orens, Robert M Reed, Servet Bolukbas, Roy G Brower, Jason D. ChristieAbstract:Background Donor-to-recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC) ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC ratio is associated with the risk of primary Graft Dysfunction (PGD) after bilateral LTx (BLT). Methods We calculated the pTLC ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between March 2002 to December 2010. Patients were stratified by pTLC ratio >1.0 ("oversized") and pTLC ratio ≤1.0 ("undersized"). PGD was defined as any ISHLT Grade 3 PGD (PGD3) within 72 hours of reperfusion. We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size-matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories. Results In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, 0.45-0.85, p = 0.003). In a multivariate model accounting for center-effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38 to 0.88, p = 0.01). The risk-adjusted point estimate was similar for the non-COPD diagnosis groups (OR 0.52, 95% CI 0.32 to 0.86, p = 0.01); however, there was no detected association within the COPD group (OR 0.72, 95% CI 0.29 to 1.78, p = 0.5). Conclusion Oversized alloGrafts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients.
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construct validity of the definition of primary Graft Dysfunction after lung transplantation
Journal of Heart and Lung Transplantation, 2010Co-Authors: Jason D. Christie, Nancy Robinson, James C. Lee, Lorraine B. Ware, David J. Lederer, Keith M. Wille, Scarlett L. Bellamy, Russell A Localio, Denis Hadjiliadis, Vibha N. LamaAbstract:Background This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary Graft Dysfunction (PGD) grades with lung injury biomarker profiles and survival. Methods The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade. Results PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation ( p p p p Conclusions The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.
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risk factors for early primary Graft Dysfunction after lung transplantation a registry study
Clinical Transplantation, 2009Co-Authors: Catherine L Kuntz, Robert M. Kotloff, Vivek N. Ahya, Alberto Pochettino, Denis Hadjiliadis, James D Lewis, Jason D. ChristieAbstract:: Background: Primary Graft Dysfunction (PGD) is a leading cause of early morbidity and mortality in lung transplantation. We sought to identify risk factors for PGD using the United Network for Organ Sharing/International Society for Heart and Lung Transplant (UNOS/ISHLT) Registry. Methods: A total of 6984 lung transplants between 1994 and 2002 were available for analysis. Potential risk factors were tested for association with PGD and multivariable logistic regression was applied to adjust for confounding. Results: The overall incidence of PGD was 10.7% (95% CI 9.9–11.4). In multivariable analyses, factors independently associated with PGD were donor age >45 yr (p 25 kg/m2 (p = 0.005); recipient female gender (p = 0.001); use of Eurocollins preservation solution (p = 0.001); single lung transplant (p = 0.005); increased ischemic time (p < 0.001); and elevated recipient pulmonary artery systolic pressure at transplant (p < 0.001). Recipient transplant diagnosis was strongly associated with PGD, with primary or secondary pulmonary hypertension (p < 0.001 for both), and idiopathic (p < 0.001) or secondary pulmonary fibrosis (p = 0.011) as significant and independent risk factors for PGD. Conclusions: Risk factors for PGD in the UNOS/ISHLT registry are consistent with prior smaller studies. Recipient, donor, and therapy variables are independently associated with PGD, as defined in a large registry.
Edward Cantu - One of the best experts on this subject based on the ideXlab platform.
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lung innate lymphoid cell composition is altered in primary Graft Dysfunction
American Journal of Respiratory and Critical Care Medicine, 2020Co-Authors: Laurel A Monticelli, Elia Tait D Wojno, Steven A Saenz, David Artis, Mary K. Porteous, Edward Cantu, Joshua M. Diamond, Jason D. ChristieAbstract:Rationale: Primary Graft Dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the alloGraft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, alloGraft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: AlloGraft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after alloGraft reperfusion.Conclusions: The composition of donor ILC subsets is altered after alloGraft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
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early Graft Dysfunction after lung transplantation
Current Pulmonology Reports, 2018Co-Authors: Justin Rosenheck, Colleen Pietras, Edward CantuAbstract:Purpose of review Primary Graft Dysfunction is an acute lung injury syndrome occurring immediately following lung transplantation. This review aims to provide an overview of the current understanding of PGD, including epidemiology, immunology, clinical outcomes and management. Recent findings Identification of donor and recipient factors allowing accurate prediction of PGD has been actively pursued. Improved understanding of the immunology underlying PGD has spurred interest in identifying relevant biomarkers. Work in PGD prediction, severity stratification and targeted therapies continue to make progress. Donor expansion strategies continue to be pursued with ex vivo lung perfusion playing a prominent role. While care of PGD remains supportive, ECMO has established a prominent role in the early aggressive management of severe PGD. Summary A consensus definition of PGD has allowed marked advances in research and clinical care of affected patients. Future research will lead to reliable predictive tools, and targeted therapeutics of this important syndrome.
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peripheral blood gene expression changes associated with primary Graft Dysfunction after lung transplantation
American Journal of Transplantation, 2017Co-Authors: Joshua M. Diamond, Mary K. Porteous, Edward Cantu, David J. Lederer, Y Suzuki, Keith C Meyer, Rita K Milewski, Selim M Arcasoy, F Dovidio, Matthew BacchettaAbstract:Recipient responses to primary Graft Dysfunction (PGD) after lung transplantation may have important implications to the fate of the alloGraft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of alloGraft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the alloGraft.
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objective estimates improve risk stratification for primary Graft Dysfunction after lung transplantation
American Journal of Transplantation, 2015Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, Judd D Flesch, Jonathan B Orens, David S. WilkesAbstract:Primary Graft Dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002–2010; with separate validation in 382 subjects accrued from 2011–2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 hours, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed 3 prediction models, where low-risk recipients had a normal BMI (18.5–25 kg/m2), COPD/CF, and absent or mild PH (mPAP< 40mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4–7%, and high-risk a predicted PGD risk of 15–18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5–25%. We conclude that valid estimates of PGD risk can be produced using readily-available clinical variables.
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latent class analysis identifies distinct phenotypes of primary Graft Dysfunction after lung transplantation
Chest, 2013Co-Authors: Rupal J. Shah, James C. Lee, Edward Cantu, Joshua M. Diamond, David J. Lederer, Ann Weinacker, Vibha N. Lama, David S. Wilkes, Jonathan B Orens, Sangeeta BhoradeAbstract:Background There is significant heterogeneity within the primary Graft Dysfunction (PGD) syndrome. We aimed to identify distinct grade 3 PGD phenotypes based on severity of lung Dysfunction and patterns of resolution. Methods Subjects from the Lung Transplant Outcomes Group (LTOG) cohort study with grade 3 PGD within 72 h after transplantation were included. Latent class analysis (LCA) was used to statistically identify classes based on changes in PGD International Society for Heart & Lung Transplantation grade over time. Construct validity of the classes was assessed by testing for divergence of recipient, donor, and operative characteristics between classes. Predictive validity was assessed using time to death. Results Of 1,255 subjects, 361 had grade 3 PGD within the first 72 h after transplantation. LCA identified three distinct phenotypes: (1) severe persistent Dysfunction (class 1), (2) complete resolution of Dysfunction within 72 h (class 2), and (3) attenuation, without complete resolution within 72 h (class 3). Increased use of cardiopulmonary bypass, greater RBC transfusion, and higher mean pulmonary artery pressure were associated with persistent PGD (class 1). Subjects in class 1 also had the greatest risk of death (hazard ratio, 2.39; 95% CI, 1.57-3.63; P Conclusions There are distinct phenotypes of resolution of Dysfunction within the severe PGD syndrome. Subjects with early resolution may represent a different mechanism of lung pathology, such as resolving pulmonary edema, whereas those with persistent PGD may represent a more severe phenotype. Future studies aimed at PGD mechanism or treatment may focus on phenotypes based on resolution of Graft Dysfunction.
