- Email: [email protected]
Relationship between Phenotypic Characteristics from the Donors, Predictive Biomarkers from the Donor Grafts and the Development of Primary Graft Dysfunction in Lung Transplant Recipients
S328
The Journal of Heart and Lung Transplantation, Vol 39, No 4S, April 2020
Table 1 Select Donor and Recipient Characteristics of Patients Undergoing Lung Transplantation
Positive donor smoking history Positive donor heavy alcohol use Graft ischemic time (min) Intaoperative IVF (ml) Recipient BMI Intraoperative RBC (ml) Intraoperative FFP (ml) Intraoperative platelets (ml) Intraoperative cryoprecipitate (ml) Intraoperative RBC >1000ml Use of intraoperative ECMO (vs CPB) Preoperative use of OCS Recipient gender (female) Recipient age (yrs) Donor etiology of respiratory failure Cystic fibrosis COPD ILD / IPF Other
No PGD (n = 81)
PGD (n= 18)
p value
11 (13.6%) 20 (24.7%) 343 (204-851) 2031 (400-4700) 24.8 (17.2-31.6) 0 (0-8700) 292 (0-5880) 204 (0-2554) 0 (0-620) 12 (14.8%) 12 (14.8) 8 (9.88%) 42 (51.9%) 58.1 (24.1-69.3)
2 (11.1%) 2 (11.1%) 364 (191-843) 1800 (507-3800) 26.1 (17.9-30.9) 475 (0-3300) 611 (0-2974) 528 (0-2072) 158 (0-836) 7 (38.9%) 5 (27.8%) 2 (11.1%) 7 (38.9%) 56.7 (24.3-69.3)
>0.999 0.347 0.577 0.576 0.253 0.032 0.048 0.037 0.017 0.041 0.297 >0.999 0.463 0.737 0.031
16 (19.8%) 28 (34.5%) 35 (43.2%) 2 (2.4%)
3 (16.7%) 1 (5.56%) 13 (72.2%) 1 (5.56%)
(812) Primary Graft Dysfunction is Associated with Increased Radiographic Atelectasis at Three Months Post-Lung Transplant D. Li, A. Kapasi, D.C. Lien, A. Hirji, J. Weinkauf and K. Halloran Department of Medicine, University of Alberta, Edmonton, AB, Canada. Purpose: Primary graft dysfunction (PGD) contributes to mortality and impaired lung function after lung transplant but little is known about future radiographic manifestations. We assessed radiographic features on 3-month post-transplant chest computed tomography (CT) studies and the association with future risk of baseline lung allograft dysfunction (BLAD) and chronic lung allograft dysfunction (CLAD). We hypothesized radiographic abnormalities would be more frequent after PGD and be associated with increased risk of BLAD and CLAD. Methods: We studied double-lung transplant recipients from 2010-2016. Grade 3 PGD (PGD3) was defined as CXR edema + PaO2/ FiO2<200mmHg at 48/72 hours. We reviewed 3-month chest CTs for eight abnormalities: effusion, ground glass, centrilobular nodules, interlobular septal thickening (ILS), atelectasis, consolidation (all as number of involved lobes [0-5]) and presence of fibrosis or air trapping (binary). We assessed for clinically relevant microbiology on 3-month bronchoscopy as potential radiographic confounders. We used trend tests and chi squared tests for the relationship between PGD3 and CT features. We tested relationships between associated CT features and future risk of BLAD (failure to reach both FEV1 and FVC>80%) and CLAD (ISHLT 2019 definition) using logistic and Cox models respectively. Results: 237 patients met inclusion criteria, 50 (21%) of whom developed post-operative PGD3. PGD3 was associated with more frequent and/or widely distributed ILS (p=0.0389) and atelectasis (p<0.0001) on 3-month CT, but only atelectasis remained after multiple testing correction (threshold p = 0.05/8 = 0.00625). We found no association with lung microbiology on 3 month bronchoscopy. Atelectasis at 3 months increased the risk of BLAD both unadjusted (odds ratio 3.83 [95% CI 1.90-8.03], p=0.0002) and adjusted for PGD3 status (OR 3.44 [95% CI 1.68-7.28], p=0.0007). Neither the unadjusted nor adjusted risk of CLAD was affected. Conclusion: Grade 3 PGD is associated with radiographic atelectasis at 3months post-transplant. Atelectasis increases the risk of BLAD but not CLAD. This latter finding is plausible given the injury of PGD is confined to the post-operative period rather than sustained. Post-PGD atelectasis may suggest persistent surfactant/type II pneumocyte dysfunction, but this requires further study.
(813) Relationship between Phenotypic Characteristics from the Donors, Predictive Biomarkers from the Donor Grafts and the Development of Primary Graft Dysfunction in Lung Transplant Recipients D. Adam,1 C. Landry,2 D. Corado-Castillo,1 A. Jalbert,1 A. Prive,3 M. Merjaneh,3 N. Noiseux,4 B. Nasir,4 E. Charbonney,5 M. Chasse,2 C. Poirier,2 P. Ferraro,4 and E. Brochiero.1 1Departement de Medecine, Universite de Montreal, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 2Departement de Medecine, Universite de Montreal, Centre Hospitalier de l’Universite de Montreal / Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 3Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 4 Departement de Chirurgie, Universite de Montreal, Centre Hospitalier de l’Universite de Montreal / Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; and the 5Departement de Medecine, Universite de Montreal, Centre de Recherche de l’H^opital du Sacre-Cúur de Montreal, Montreal, QC, Canada. Purpose: Lung transplantation is the only therapeutic option for patients with a terminal lung condition. Unfortunately, survival rates at 5-yrs after transplantation remains too low. Primary graft dysfunction (PGD) is the first cause of death in the perioperative period and is associated with acute respiratory distress syndrome (ARDS), higher risk of lung infections, chronic rejection and lower survival rates. We hypothesized that the alveolar epithelial dysfunction in donor grafts and then in the recipient, is a critical component of PGD pathophysiology. Our goal is to identify phenotypic factors from donors, associated with markers of alveolar damage and dysfunction in the donor grafts, and then the development of the PGD within the recipients. Methods: We collected human samples and the clinical data from 136 donors and their recipients at different time points (before, during and after lung transplant, in the perioperative period in the ICU and follow-ups at the transplantation clinic). We isolated alveolar epithelial cells from donor lung biopsies to assess by immunostaining the expression of functionality biomarkers such as ENaC channels, which play a critical function in the resorption of lung edema, a key feature of ARDS/PGD. Results: Among our cohort of 136 lung transplants, suffering from various lung diseases (64 cystic fibrosis, 37 pulmonary fibrosis, 17 chronic obstructive pulmonary disease, 8 arterial pulmonary hypertension or 5 emphysema), 33% developed a PGD. Several phenotypic factors from donors and intervention parameters of the donor grafts were studied and we found a statistically longer cold ischemic time of the graft in recipients developing a PGD. We also demonstrated in alveolar cells, from donor grafts within recipients developing a PGD, a severe decrease in ENaC expression. Interestingly, this reduced ENaC expression is related to higher cold ischemia duration and PGD risk. Conclusion: This study provides novel insights on epithelial dysfunction within donor graft associated with PGD development and pave the way for the identification of novel biomarkers. Our ultimate goal is to develop strategies for the restoration of alveolar integrity and functionality by targeting proteins involved in these mechanisms and thus to prevent the PGD.
(814) Effect of Time of Intraoperative Circulatory Support on Incidence of High-Grade Primary Graft Dysfunction (PGD): Multicenter Analysis on Use of Extracorporeal Life Support (ECLS) during Lung Transplantation M. Hartwig,1 G. Loor,2 B. Bottiger,1 G. Warnecke,3 W. Sommer,3 A. Frick,4 A. Neyrinck,4 M. Villavicencio-Theoduloz,5 K. Drezek,5 D. Daoud,2 Q. Wei,2 S. Huddleston,6 M. Landeweer,6 Y. Toyoda,7 M.A. Kashem,7 S. Chandrashekaran,8 T.N. Machuca,8 R. Plascencia,2 M.A. Smith,9 and D. Van Raemdonck.4 1Duke University Health System, Durham, NC; 2Baylor College of Medicine, Houston, TX; 3Hannover Medical School, Hannover, Germany; 4University Hospital Leuven, Leuven, Belgium; 5Massachusetts General Hospital, Boston, MA; 6 University of Minnesota Medical School, Minneapolis, MN; 7Temple
The Journal of Heart and Lung Transplantation, Vol 39, No 4S, April 2020
Table 1 Select Donor and Recipient Characteristics of Patients Undergoing Lung Transplantation
Positive donor smoking history Positive donor heavy alcohol use Graft ischemic time (min) Intaoperative IVF (ml) Recipient BMI Intraoperative RBC (ml) Intraoperative FFP (ml) Intraoperative platelets (ml) Intraoperative cryoprecipitate (ml) Intraoperative RBC >1000ml Use of intraoperative ECMO (vs CPB) Preoperative use of OCS Recipient gender (female) Recipient age (yrs) Donor etiology of respiratory failure Cystic fibrosis COPD ILD / IPF Other
No PGD (n = 81)
PGD (n= 18)
p value
11 (13.6%) 20 (24.7%) 343 (204-851) 2031 (400-4700) 24.8 (17.2-31.6) 0 (0-8700) 292 (0-5880) 204 (0-2554) 0 (0-620) 12 (14.8%) 12 (14.8) 8 (9.88%) 42 (51.9%) 58.1 (24.1-69.3)
2 (11.1%) 2 (11.1%) 364 (191-843) 1800 (507-3800) 26.1 (17.9-30.9) 475 (0-3300) 611 (0-2974) 528 (0-2072) 158 (0-836) 7 (38.9%) 5 (27.8%) 2 (11.1%) 7 (38.9%) 56.7 (24.3-69.3)
>0.999 0.347 0.577 0.576 0.253 0.032 0.048 0.037 0.017 0.041 0.297 >0.999 0.463 0.737 0.031
16 (19.8%) 28 (34.5%) 35 (43.2%) 2 (2.4%)
3 (16.7%) 1 (5.56%) 13 (72.2%) 1 (5.56%)
(812) Primary Graft Dysfunction is Associated with Increased Radiographic Atelectasis at Three Months Post-Lung Transplant D. Li, A. Kapasi, D.C. Lien, A. Hirji, J. Weinkauf and K. Halloran Department of Medicine, University of Alberta, Edmonton, AB, Canada. Purpose: Primary graft dysfunction (PGD) contributes to mortality and impaired lung function after lung transplant but little is known about future radiographic manifestations. We assessed radiographic features on 3-month post-transplant chest computed tomography (CT) studies and the association with future risk of baseline lung allograft dysfunction (BLAD) and chronic lung allograft dysfunction (CLAD). We hypothesized radiographic abnormalities would be more frequent after PGD and be associated with increased risk of BLAD and CLAD. Methods: We studied double-lung transplant recipients from 2010-2016. Grade 3 PGD (PGD3) was defined as CXR edema + PaO2/ FiO2<200mmHg at 48/72 hours. We reviewed 3-month chest CTs for eight abnormalities: effusion, ground glass, centrilobular nodules, interlobular septal thickening (ILS), atelectasis, consolidation (all as number of involved lobes [0-5]) and presence of fibrosis or air trapping (binary). We assessed for clinically relevant microbiology on 3-month bronchoscopy as potential radiographic confounders. We used trend tests and chi squared tests for the relationship between PGD3 and CT features. We tested relationships between associated CT features and future risk of BLAD (failure to reach both FEV1 and FVC>80%) and CLAD (ISHLT 2019 definition) using logistic and Cox models respectively. Results: 237 patients met inclusion criteria, 50 (21%) of whom developed post-operative PGD3. PGD3 was associated with more frequent and/or widely distributed ILS (p=0.0389) and atelectasis (p<0.0001) on 3-month CT, but only atelectasis remained after multiple testing correction (threshold p = 0.05/8 = 0.00625). We found no association with lung microbiology on 3 month bronchoscopy. Atelectasis at 3 months increased the risk of BLAD both unadjusted (odds ratio 3.83 [95% CI 1.90-8.03], p=0.0002) and adjusted for PGD3 status (OR 3.44 [95% CI 1.68-7.28], p=0.0007). Neither the unadjusted nor adjusted risk of CLAD was affected. Conclusion: Grade 3 PGD is associated with radiographic atelectasis at 3months post-transplant. Atelectasis increases the risk of BLAD but not CLAD. This latter finding is plausible given the injury of PGD is confined to the post-operative period rather than sustained. Post-PGD atelectasis may suggest persistent surfactant/type II pneumocyte dysfunction, but this requires further study.
(813) Relationship between Phenotypic Characteristics from the Donors, Predictive Biomarkers from the Donor Grafts and the Development of Primary Graft Dysfunction in Lung Transplant Recipients D. Adam,1 C. Landry,2 D. Corado-Castillo,1 A. Jalbert,1 A. Prive,3 M. Merjaneh,3 N. Noiseux,4 B. Nasir,4 E. Charbonney,5 M. Chasse,2 C. Poirier,2 P. Ferraro,4 and E. Brochiero.1 1Departement de Medecine, Universite de Montreal, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 2Departement de Medecine, Universite de Montreal, Centre Hospitalier de l’Universite de Montreal / Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 3Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; 4 Departement de Chirurgie, Universite de Montreal, Centre Hospitalier de l’Universite de Montreal / Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, QC, Canada; and the 5Departement de Medecine, Universite de Montreal, Centre de Recherche de l’H^opital du Sacre-Cúur de Montreal, Montreal, QC, Canada. Purpose: Lung transplantation is the only therapeutic option for patients with a terminal lung condition. Unfortunately, survival rates at 5-yrs after transplantation remains too low. Primary graft dysfunction (PGD) is the first cause of death in the perioperative period and is associated with acute respiratory distress syndrome (ARDS), higher risk of lung infections, chronic rejection and lower survival rates. We hypothesized that the alveolar epithelial dysfunction in donor grafts and then in the recipient, is a critical component of PGD pathophysiology. Our goal is to identify phenotypic factors from donors, associated with markers of alveolar damage and dysfunction in the donor grafts, and then the development of the PGD within the recipients. Methods: We collected human samples and the clinical data from 136 donors and their recipients at different time points (before, during and after lung transplant, in the perioperative period in the ICU and follow-ups at the transplantation clinic). We isolated alveolar epithelial cells from donor lung biopsies to assess by immunostaining the expression of functionality biomarkers such as ENaC channels, which play a critical function in the resorption of lung edema, a key feature of ARDS/PGD. Results: Among our cohort of 136 lung transplants, suffering from various lung diseases (64 cystic fibrosis, 37 pulmonary fibrosis, 17 chronic obstructive pulmonary disease, 8 arterial pulmonary hypertension or 5 emphysema), 33% developed a PGD. Several phenotypic factors from donors and intervention parameters of the donor grafts were studied and we found a statistically longer cold ischemic time of the graft in recipients developing a PGD. We also demonstrated in alveolar cells, from donor grafts within recipients developing a PGD, a severe decrease in ENaC expression. Interestingly, this reduced ENaC expression is related to higher cold ischemia duration and PGD risk. Conclusion: This study provides novel insights on epithelial dysfunction within donor graft associated with PGD development and pave the way for the identification of novel biomarkers. Our ultimate goal is to develop strategies for the restoration of alveolar integrity and functionality by targeting proteins involved in these mechanisms and thus to prevent the PGD.
(814) Effect of Time of Intraoperative Circulatory Support on Incidence of High-Grade Primary Graft Dysfunction (PGD): Multicenter Analysis on Use of Extracorporeal Life Support (ECLS) during Lung Transplantation M. Hartwig,1 G. Loor,2 B. Bottiger,1 G. Warnecke,3 W. Sommer,3 A. Frick,4 A. Neyrinck,4 M. Villavicencio-Theoduloz,5 K. Drezek,5 D. Daoud,2 Q. Wei,2 S. Huddleston,6 M. Landeweer,6 Y. Toyoda,7 M.A. Kashem,7 S. Chandrashekaran,8 T.N. Machuca,8 R. Plascencia,2 M.A. Smith,9 and D. Van Raemdonck.4 1Duke University Health System, Durham, NC; 2Baylor College of Medicine, Houston, TX; 3Hannover Medical School, Hannover, Germany; 4University Hospital Leuven, Leuven, Belgium; 5Massachusetts General Hospital, Boston, MA; 6 University of Minnesota Medical School, Minneapolis, MN; 7Temple