Browsing by Author "Orens, Jonathan"

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    Contemporary trends in PGD incidence, outcomes, and therapies
    (Elsevier, 2022) Cantu, Edward; Diamond, Joshua M.; Cevasco, Marisa; Suzuki, Yoshi; Crespo, Maria; Clausen, Emily; Dallara, Laura; Ramon, Christian V.; Harmon, Michael T.; Bermudez, Christian; Benvenuto, Luke; Anderson, Michaela; Wille, Keith M.; Weinacker, Ann; Dhillon, Gundeep S.; Orens, Jonathan; Shah, Pali; Merlo, Christian; Lama, Vibha; McDyer, John; Snyder, Laurie; Palmer, Scott; Hartwig, Matt; Hage, Chadi A.; Singer, Jonathan; Calfee, Carolyn; Kukreja, Jasleen; Greenland, John R.; Ware, Lorraine B.; Localio, Russel; Hsu, Jesse; Gallop, Robert; Christie, Jason D.; Medicine, School of Medicine
    Background: We sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation. Methods: Patients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders. Results: A total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p = .0002), median LAS (38.0-47.7 p = .009) and the use of ECMO salvage for PGD (5.7%-20.9%, p = .007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p = .0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p = .66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p = .0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]). Conclusions: PGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.
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    Elevated Plasma Angiopoietin-2 Levels and Primary Graft Dysfunction after Lung Transplantation
    (Public Library of Science, 2012) Diamond, Joshua M.; Porteous, Mary K.; Cantu, Edward; Meyer, Nuala J.; Shah, Rupal J.; Lederer, David J.; Kawut, Steven M.; Lee, James; Bellamy, Scarlett L.; Palmer, Scott M.; Lama, Vibha N.; Bhorade, Sangeeta M.; Crespo, Maria; Demissie, Ejigayehu; Wille, Keith; Orens, Jonathan; Shah, Pali D.; Weinacker, Ann; Weill, David; Arcasoy, Selim; Wilkes, David S.; Ware, Lorraine B.; Christie, Jason D.; Lung Transplant Outcomes Group; Medicine, School of Medicine
    Introduction: Primary graft dysfunction (PGD) is a significant contributor to early morbidity and mortality after lung transplantation. Increased vascular permeability in the allograft has been identified as a possible mechanism leading to PGD. Angiopoietin-2 serves as a partial antagonist to the Tie-2 receptor and induces increased endothelial permeability. We hypothesized that elevated Ang2 levels would be associated with development of PGD. Methods: We performed a case-control study, nested within the multi-center Lung Transplant Outcomes Group cohort. Plasma angiopoietin-2 levels were measured pre-transplant and 6 and 24 hours post-reperfusion. The primary outcome was development of grade 3 PGD in the first 72 hours. The association of angiopoietin-2 plasma levels and PGD was evaluated using generalized estimating equations (GEE). Results: There were 40 PGD subjects and 79 non-PGD subjects included for analysis. Twenty-four PGD subjects (40%) and 47 non-PGD subjects (59%) received a transplant for the diagnosis of idiopathic pulmonary fibrosis (IPF). Among all subjects, GEE modeling identified a significant change in angiopoietin-2 level over time in cases compared to controls (p = 0.03). The association between change in angiopoietin-2 level over the perioperative time period was most significant in patients with a pre-operative diagnosis of IPF (p = 0.02); there was no statistically significant correlation between angiopoietin-2 plasma levels and the development of PGD in the subset of patients transplanted for chronic obstructive pulmonary disease (COPD) (p = 0.9). Conclusions: Angiopoietin-2 levels were significantly associated with the development of PGD after lung transplantation. Further studies examining the regulation of endothelial cell permeability in the pathogenesis of PGD are indicated.
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    Preoperative plasma club (clara) cell secretory protein levels are associated with primary graft dysfunction after lung transplantation
    (Wiley Blackwell (Blackwell Publishing), 2014-02) Shah, Rupal J.; Wickersham, Nancy; Lederer, David J.; Palmer, Scott M.; Cantu, Edward; Diamond, Joshua M.; Kawut, Steven M.; Lama, Vibha N.; Bhorade, Sangeeta; Crespo, Maria; Demissie, Ejigayehu; Sonett, Joshua; Wille, Keith; Orens, Jonathan; Weinacker, Ann; Shah, Pali; Arcasoy, Selim; Wilkes, David S.; Christie, Jason D.; Ware, Lorraine B.; Department of Medicine, IU School of Medicine
    Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.
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    Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant
    (American Thoracic Society, 2018-01-15) Cantu, Edward; Diamond, Joshua M.; Suzuki, Yoshikazu; Lasky, Jared; Schaufler, Christian; Lim, Brian; Shah, Rupal; Porteous, Mary; Lederer, David J.; Kawut, Steven M.; Palmer, Scott M.; Snyder, Laurie D.; Hartwig, Matthew G.; Lama, Vibha N.; Bhorade, Sangeeta; Bermudez, Christian; Crespo, Maria; McDyer, John; Wille, Keith; Orens, Jonathan; Shah, Pali D.; Weinacker, Ann; Weill, David; Wilkes, David; Roe, David; Hage, Chadi; Ware, Lorraine B.; Bellamy, Scarlett L.; Christie, Jason D.; Medicine, School of Medicine
    RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination.
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    The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia
    (Elsevier, 2016-04) Diamond, Joshua M.; Porteous, Mary K.; Roberts, L. Jackson; Wickersham, Nancy; Rushefski, Melanie; Kawut, Steven M.; Shah, Rupal J.; Cantu, Edward; Lederer, David J.; Chatterjee, Shampa; Lama, Vibha N.; Bhorade, Sangeeta; Crespo, Maria; McDyer, John; Wille, Keith; Orens, Jonathan; Weinacker, Ann; Arcasoy, Selim; Shah, Pali D.; Wilkes, David S.; Hage, Chadi; Palmer, Scott M.; Snyder, Laurie; Calfee, Carolyn S.; Ware, Lorraine B.; Christie, Jason D.; Medicine, School of Medicine
    BACKGROUND: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. METHODS: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). RESULTS: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. CONCLUSIONS: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion.