Publications by authors named "Daniel Kreisel"

206 Publications

Editorial: COVID-19 immunology and organ transplantation.

Curr Opin Organ Transplant 2021 Apr;26(2):258-265

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

Purpose Of Review: The aim of this study was to provide a critical appraisal of the literature on the effects of the COVID-19 pandemic on organ transplantation, with a specific focus on lung transplantation given the predominant pulmonary involvement of the virus.

Recent Findings: There was a significant decrease in lung transplant volumes during the first wave of the COVID-19 pandemic due to a combination of reduced availability of donors and an imbalance between waitlist additions and inactivations. SARS-CoV-2 infection was subsequently associated with an exuberant immune response that can lead to the development of postinfectious fibrotic lung disease. Few lung transplants have been performed in previously infected recipients and long-term outcomes remain unknown. Although the lung transplant volume rebounded during the second wave, it is unclear what the long-term effects of healthcare resource limitation and public health measures will have on transplant volumes in the future. Outcomes after SARS-CoV-2 infection in previous lung transplant recipients appear to be worse than the general public, and, although an immunosuppressed state likely contributes to these outcomes, whether immunosuppression should be altered in those exposed to or infected with SARS-CoV-2 remains unanswered in the absence of unequivocal data.

Summary: The COVID-19 pandemic has presented a number of challenges for lung transplant programs across the globe. Multiple research questions remain to be answered in order to optimally manage lung transplant recipients in the context of this pandemic.
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http://dx.doi.org/10.1097/MOT.0000000000000862DOI Listing
April 2021

Different-Team Procurements: A Potential Solution for the Unintended Consequences of Change in Lung Allocation Policy.

Am J Transplant 2021 Feb 27. Epub 2021 Feb 27.

Department of Surgery, Division of Cardiothoracic Surgery, Washington University, St. Louis, MO, USA.

The new lung allocation policy has led to an increase in distant donors and consequently enhanced logistical burden of procuring organs. Though early single-center studies noted similar outcomes between same-team transplantation (ST, procuring team from transplanting center) and different-team transplantation (DT, procuring team from different center), the efficacy of DT in the contemporary era remains unclear. In this study, we evaluated the trend of DT, rate of transplanting both donor lungs, 1-year graft survival, and risk of Grade 3 primary graft dysfunction (PGD) using the Scientific Registry of Transplant Recipient (SRTR) database from 2006 to 2018. A total of 21619 patients (DT 2085, 9.7%) with 19837 donors were included. Utilization of DT decreased from 15.9% in 2006 to 8.5% in 2018. Proportion of two-lung donors was similar between the groups, and DT had similar 1-year graft survival as ST for both double (DT, HR 1.108, 95% CI 0.894 - 1.374) and single lung transplants (DT, HR 1.094, 95% CI 0.931 - 1.286). Risk of Grade 3 PGD was also similar between ST and DT. Given our results, expanding DT may be a feasible option for improving lung procurement efficiency in the current era, particularly in light of the COVID-19 pandemic.
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http://dx.doi.org/10.1111/ajt.16553DOI Listing
February 2021

Crosstalk between non-classical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment.

JCI Insight 2021 Feb 23. Epub 2021 Feb 23.

Division of Thoracic Surgery, Northwestern University, Chicago, United States of America.

Primary Graft Dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular non-classical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flowcytometry revealed that depletion of donor NCM abrogated CM recruitment, single-cell RNA-seq identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine knockouts and chimeras indicated that IL1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL1β production by NCM was NLRP3 inflammasome-dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL1R-dependent activation of the PKC and NFκB-pathway. Accordingly, we show that IL1β-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL1β or IL1R antagonism, and inflammasome inhibition, abrogated recruitment of CM as well as PGD, and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.
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http://dx.doi.org/10.1172/jci.insight.147282DOI Listing
February 2021

Clinical Outcomes of Lung Transplants From Donors With Unexpected Pulmonary Embolism.

Ann Thorac Surg 2020 Oct 22. Epub 2020 Oct 22.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University, Saint Louis, Missouri. Electronic address:

Background: Pulmonary embolism (PE) is unexpectedly detected in some donor lungs during organ procurement for lung transplantation. Anecdotally, such lungs are usually implanted; however, the impact of this finding on recipient outcomes remains unclear. We hypothesized that incidentally detected donor PE is associated with adverse short-term and long-term outcomes among lung transplant recipients.

Methods: We analyzed a prospectively maintained database of all lung donors procured by a single surgeon and transplanted at our institution between 2009 and 2018. A standardized approach was used for all procurements and included antegrade and retrograde flush. Pulmonary embolism was defined as macroscopic thrombus seen in the pulmonary artery during the donor procurement operation.

Results: A total of 501 consecutive lung procurements were performed during the study period. The incidence of donor PE was 4.4% (22 of 501). No organs were discarded owing to PE. Donors with PE were similar to donors without PE in baseline characteristics and Pao. Recipients in the two groups were also similar. Pulmonary embolism was associated with a higher likelihood of acute cellular rejection grade 2 or more (10 of 22 [45.5%] vs 120 of 479 [25.1%], P = .03). Multivariable Cox modeling demonstrated an association between PE and the development of chronic lung allograft dysfunction (hazard ratio 2.02; 95% confidence interval, 1.23 to 3.30; P = .005).

Conclusions: Lungs from donors with incidentally detected PE may be associated with a higher incidence of recipient acute cellular rejection as well as reduced chronic lung allograft dysfunction-free survival. Surgeons must use caution when transplanting lungs with incidentally discovered PE. These preliminary findings warrant corroboration in larger data sets.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.040DOI Listing
October 2020

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19.

JCI Insight 2021 02 22;6(4). Epub 2021 Feb 22.

Division of Cardiothoracic Surgery, Department of Surgery.

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345.
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http://dx.doi.org/10.1172/jci.insight.143299DOI Listing
February 2021

The Specialized Donor Care Facility (SDCF) Model and Advances in Management of Thoracic Organ Donors.

Ann Thorac Surg 2021 Jan 6. Epub 2021 Jan 6.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine.

Background: Donor hearts and lungs are more susceptible to the inflammatory physiologic changes that occur after brain death. Prior investigations have shown that protocolized management of potential organ donors can rehabilitate donor organs that are initially deemed unacceptable. In this review, we discuss advances in donor management models with particular attention to the specialized donor care facility (SDCF) model. In addition, we review specific strategies to optimize donor thoracic organs and improve organ yield in thoracic transplantation.

Methods: We performed a literature review by searching the Pubmed database for MeSH terms associated with organ donor management models. We also communicated with our local organ procurement organization to gather published and unpublished information first-hand.

Results: The SDCF model has been shown to improve the efficiency of organ donor management and procurement while reducing costs and minimizing travel and its associated risks. Lung protective ventilation, recruitment of atelectatic lung, and hormone therapy (e.g., glucocorticoids and T3/T4) are associated with improved lung utilization rates. Stroke volume-based volume resuscitation is associated with improved heart utilization rates, while studies evaluating hormone therapy (e.g., glucocorticoids and T3/T4) have shown variable results.

Conclusions: Lack of high-quality prospective evidence results in conflicting practices across organ procurement organizations and best practices remain controversial. Future studies should focus on prospective, randomized investigations to evaluate donor management strategies. The SDCF model fosters a collaborative environment that encourages academic inquiry and is an ideal setting for these investigations.
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http://dx.doi.org/10.1016/j.athoracsur.2020.12.026DOI Listing
January 2021

Donor management using a specialized donor care facility is associated with higher organ utilization from drug overdose donors.

Clin Transplant 2020 Dec 4:e14178. Epub 2020 Dec 4.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, MO, USA.

Drug overdoses have tripled in the United States over the last two decades. With the increasing demand for donor organs, one potential consequence of the opioid epidemic may be an increase in suitable donor organs. Unfortunately, organs from donors dying of drug overdose have poorer utilization rates than other groups of brain-dead donors, largely due to physician and recipient concerns about viral disease transmission. During the study period of 2011 to 2016, drug overdose donors (DODs) account for an increasingly greater proportion of the national donor pool. We show that a novel model of donor care, known as specialized donor care facility (SDCF), is associated with an increase in organ utilization from DODs compared to the conventional model of hospital-based donor care. This is likely related to the close relationship of the SDCF with the transplant centers, leading to improved communication and highly efficient donor care.
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http://dx.doi.org/10.1111/ctr.14178DOI Listing
December 2020

Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction.

JCI Insight 2020 Dec 3;5(23). Epub 2020 Dec 3.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into μMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory μ-chain (μs) double-KO (AID-/-μs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.
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http://dx.doi.org/10.1172/jci.insight.136533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714414PMC
December 2020

Economic evaluation of the specialized donor care facility for thoracic organ donor management.

J Thorac Dis 2020 Oct;12(10):5709-5717

Division of Cardiothoracic Surgery, Washington University School of Medicine, Saint Louis, MO, USA.

Background: Over the last decade two alternative models of donor care have emerged in the United States: the conventional model, whereby donors are managed at the hospital where brain death occurs, and the specialized donor care facility (SDCF), in which brain dead donors are transferred to a SDCF for medical optimization and organ procurement. Despite increasing use of the SDCF model, its cost-effectiveness in comparison to the conventional model remains unknown.

Methods: We performed an economic evaluation of the SDCF and conventional model of donor care from the perspective of U.S. transplant centers over a 2-year study period. In this analysis, we utilized nationwide data from the Scientific Registry of Transplant Recipients and controlled for donor characteristics and patterns of organ sharing across the nation's organ procurement organizations (OPOs). Subgroup analysis was performed to determine the impact of the SDCF model on thoracic organ transplants.

Results: A total of 38,944 organ transplants were performed in the U.S. during the study period from 13,539 donors with an observed total organ cost of $1.36 billion. If every OPO assumed the cost and effectiveness of the SDCF model, a predicted 39,155 organ transplants (+211) would have been performed with a predicted total organ cost of $1.26 billion (-$100 million). Subgroup analysis of thoracic organs revealed that the SDCF model would lead to a predicted 156 additional transplants with a cost saving of $24.6 million.

Conclusions: The U.S. SDCF model may be a less costly and more effective means of multi-organ donor management, particularly for thoracic organ donors, compared to the conventional hospital-based model.
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http://dx.doi.org/10.21037/jtd-20-1575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656378PMC
October 2020

Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance.

J Clin Invest 2020 12;130(12):6718-6727

Departments of Surgery.

Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.
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http://dx.doi.org/10.1172/JCI136057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685742PMC
December 2020

Impact of Nighttime Lung Transplantation on Outcomes and Costs.

Ann Thorac Surg 2020 Oct 13. Epub 2020 Oct 13.

Department of Surgery, Division of Cardiothoracic Surgery, Washington University, St. Louis, MO, USA. Electronic address:

Background: Previous studies in the field of organ transplantation have shown a possible association between nighttime surgery and adverse outcomes. We aim to determine the impact of nighttime lung transplantation on postoperative outcomes, long-term survival, and overall cost.

Methods: We performed a single center retrospective cohort analysis of adult lung transplant recipients who underwent transplantation between January 2006 and December 2017. Data were extracted from our institutional Lung Transplant Registry and Mid-America Transplant services database. Patients were classified into two strata (daytime 5AM to 6PM; nighttime 6PM to 5AM) based upon time of incision. Major postoperative adverse events, 5-year overall survival and 5-year BOS-free survival were examined after propensity score matching. Additionally, we compared overall cost of transplantation between nighttime and daytime groups.

Results: Of the 740 patients included in this study, 549 (74.2%) patients underwent daytime transplantation (DT) and 191 (25.8%) patients underwent nighttime transplantation (NT). Propensity score matching yielded 187 matched pairs. NT was associated with a higher risk of having any major postoperative adverse event (adjusted OR=1.731, 95% CI 1.093-2.741, P=0.019), decreased 5-year overall survival (adjusted HR=1.798, 95% CI 1.079-2.995, P=0.024), as well as decreased 5-year BOS-free survival (adjusted HR=1.556, 95% CI 1.098-2.205, P=0.013) in doubly robust multivariable analyses following propensity score matching. Overall cost for NT and DT were similar.

Conclusions: NT was associated with higher risk of major postoperative adverse events, decreased 5-year overall survival and decreased 5-year BOS-free survival. Our findings suggest potential benefits of delaying NT to daytime.
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http://dx.doi.org/10.1016/j.athoracsur.2020.07.060DOI Listing
October 2020

Assessment of Preoperative Opioid Use Prevalence and Clinical Outcomes in Pulmonary Resection.

Ann Thorac Surg 2020 Oct 1. Epub 2020 Oct 1.

Washington University School of Medicine, Division of Cardiothoracic Surgery.

Background: Preoperative opioid use is associated with increased healthcare utilization after elective abdominal surgery. However, the scope of preoperative opioid use and its association with outcomes have not been described in elective pulmonary resection. We aimed to characterize prevalent preoperative opioid use in patients undergoing elective pulmonary resection and compare clinical outcomes between patients with and without preoperative opioid exposure.

Methods: We assembled a retrospective cohort of adult patients undergoing elective pulmonary resection using the IBM® Watson Health MarketScan® Database (2007-2015). We compared opioid-naïve patients to those with a history of preoperative opioid exposure (>0 morphine milligram equivalent prescription filled within 90 days prior to surgery). Multivariable logistic and linear regression adjusting for patient sociodemographic, comorbidity, and operative characteristics were used to compare odds of postoperative complication, prolonged length-of-stay (>14 days), 30-day post-discharge emergency room visits, 90-day readmissions, and 90-day costs.

Results: We identified 14,373 patients, of which 4,502 (31.3%) had opioid exposure prior to pulmonary resection. In multivariable regression, patients with preoperative opioid exposure had significantly higher odds of experiencing prolonged length-of-stay (OR: 1.32, 95% CI: 1.11-1.58), 30-day emergency room visits (OR: 1.24, 95% CI: 1.01-1.41), and 90-day readmissions (OR: 1.41, 95% CI: 1.28-1.55). Adjusted 90-day costs were approximately 5% higher for patients with preoperative opioid use (p<0.0001).

Conclusions: One-third of pulmonary resection patients used opioids preoperatively and were at risk of experiencing adverse outcomes and having significantly higher health care utilization. They represent a unique high-risk population that will require novel, targeted interventions.
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http://dx.doi.org/10.1016/j.athoracsur.2020.07.043DOI Listing
October 2020

Local versus distant lung donor procurement does not influence short-term clinical outcomes.

J Thorac Cardiovasc Surg 2020 Aug 27. Epub 2020 Aug 27.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St Louis, Mo.

Objective: The purpose of this study was to recognize clinically meaningful differences in lung transplant outcomes based on local or distant lung procurement. This could identify if the lung allocation policy change would influence patient outcomes.

Methods: This single-center retrospective cohort study analyzed adult patients who underwent lung transplant from 2006 to 2017. Donor and recipient data were abstracted from a collaborative, prospective registry shared by our local organ procurement organization, and tertiary medical center. Short-term outcomes, 1-year survival, and hospitalization costs were compared between local and distant lung transplants defined by donor service area.

Results: Of the 722 lung transplants performed, 392 (54%) had local donors and 330 (46%) had distant donors. Donors were similar in age and cause of death. Recipients were significantly different in diagnosis and local recipients had lower median lung allocation scores (local, 37.3 and distant, 44.9; P < .01). Distant lung transplants had longer total ischemic times (local, 231 ± 52 minutes and distant, 313 ± 48 minutes; P < .01). The rate of major complications, length of hospital stay, and 1-year survival were similar between groups. Distant lung transplants were associated with higher median overall cost (local, $183,542 and distant, $229,871; P < .01). Local lung transplants were more likely to be performed during daytime (local, 333 out of 392 [85%] and distant, 291 out of 330 [61%]; P < .01).

Conclusions: Local lung transplants are associated with shorter ischemic times, lower cost, and greater likelihood of daytime surgery. Short- and intermediate-term outcomes are similar for lung transplants from local and distant donors. The new lung allocation policy, with higher proportion of distant lung transplants, is likely to incur greater costs but provide similar outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2020.07.115DOI Listing
August 2020

Molecular T-cell‒mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss.

J Heart Lung Transplant 2020 Dec 26;39(12):1327-1337. Epub 2020 Aug 26.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying T-cell‒mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival.

Methods: We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB-TBB, mucosal-mucosal, and TBB-mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies.

Results: The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies, molecular TCMR was associated with graft loss, whereas histologic rejection and donor-specific antibodies were not.

Conclusions: Molecular TCMR can be detected in TBBs regardless of surfactant and in mucosal biopsies, which show less variability in the sampled tissue than TBBs. On the basis of these findings, molecular TCMR appears to be an important predictor of the risk of future graft failure.

Trial Registration: ClinicalTrials.gov NCT02812290.
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http://dx.doi.org/10.1016/j.healun.2020.08.013DOI Listing
December 2020

Sterile inflammation in thoracic transplantation.

Cell Mol Life Sci 2021 Jan 17;78(2):581-601. Epub 2020 Aug 17.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St. Louis, MO, 63110, USA.

The life-saving benefits of organ transplantation can be thwarted by allograft dysfunction due to both infectious and sterile inflammation post-surgery. Sterile inflammation can occur after necrotic cell death due to the release of endogenous ligands [such as damage-associated molecular patterns (DAMPs) and alarmins], which perpetuate inflammation and ongoing cellular injury via various signaling cascades. Ischemia-reperfusion injury (IRI) is a significant contributor to sterile inflammation after organ transplantation and is associated with detrimental short- and long-term outcomes. While the vicious cycle of sterile inflammation and cellular injury is remarkably consistent amongst different organs and even species, we have begun understanding its mechanistic basis only over the last few decades. This understanding has resulted in the developments of novel, yet non-specific therapies for mitigating IRI-induced graft damage, albeit with moderate results. Thus, further understanding of the mechanisms underlying sterile inflammation after transplantation is critical for identifying personalized therapies to prevent or interrupt this vicious cycle and mitigating allograft dysfunction. In this review, we identify common and distinct pathways of post-transplant sterile inflammation across both heart and lung transplantation that can potentially be targeted.
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http://dx.doi.org/10.1007/s00018-020-03615-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878195PMC
January 2021

Bacterial products in donor airways prevent the induction of lung transplant tolerance.

Am J Transplant 2021 01 5;21(1):353-361. Epub 2020 Sep 5.

Department of Surgery, Washington University, Saint Louis, Missouri.

Although postoperative bacterial infections can trigger rejection of pulmonary allografts, the impact of bacterial colonization of donor grafts on alloimmune responses to transplanted lungs remains unknown. Here, we tested the hypothesis that bacterial products present within donor grafts at the time of implantation promote lung allograft rejection. Administration of the toll-like receptor 2 (TLR2) agonist Pam Cys to Balb/c wild-type grafts triggered acute cellular rejection after transplantation into B6 wild-type recipients that received perioperative costimulatory blockade. Pam Cys -triggered rejection was associated with an expansion of CD8 T lymphocytes and CD11c CD11b MHC (major histocompatibility complex) class II antigen-presenting cells within the transplanted lungs. Rejection was prevented when lungs were transplanted into TLR2-deficient recipients but not when MyD88-deficient donors were used. Adoptive transfer of B6 wild-type monocytes, but not T cells, following transplantation into B6 TLR2-deficient recipients restored the ability of Pam Cys to trigger acute cellular rejection. Thus, we have demonstrated that activation of TLR2 by a bacterial lipopeptide within the donor airways prevents the induction of lung allograft tolerance through a process mediated by recipient-derived monocytes. Our work suggests that donor lungs harboring bacteria may precipitate an inflammatory response that can facilitate allograft rejection.
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http://dx.doi.org/10.1111/ajt.16256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775268PMC
January 2021

Circulating Mitochondrial DNA is an Early Indicator of Severe Illness and Mortality from COVID-19.

bioRxiv 2020 Jul 30. Epub 2020 Jul 30.

Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether the appearance of cell-free MT-DNA is linked to poor COVID-19 outcomes remains undetermined. Here, we quantified circulating MT-DNA in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at the time of hospital presentation. Circulating MT-DNA were sharply elevated in patients who eventually died, required ICU admission or intubation. Multivariate regression analysis revealed that high circulating MT-DNA levels is an independent risk factor for all of these outcomes after adjusting for age, sex and comorbidities. Additionally, we found that circulating MT-DNA has a similar or superior area-under-the curve when compared to clinically established measures of systemic inflammation, as well as emerging markers currently of interest as investigational targets for COVID-19 therapy. These results show that high circulating MT-DNA levels is a potential indicator for poor COVID-19 outcomes.
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http://dx.doi.org/10.1101/2020.07.30.227553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402031PMC
July 2020

Local complement activation is associated with primary graft dysfunction after lung transplantation.

JCI Insight 2020 09 3;5(17). Epub 2020 Sep 3.

Department of Medicine, Perlman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

BACKGROUNDThe complement system plays a key role in host defense but is activated by ischemia/reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared with systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD after LTx. We also aimed to identify which complement activation pathways are associated with PGD.METHODSWe performed a multicenter cohort study at the University of Pennsylvania and Washington University School of Medicine. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA.RESULTSIn both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma.CONCLUSIONComplement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.FUNDINGThis research was supported by the NIH, American Lung Association, Children's Discovery Institute, Robert Wood Johnson Foundation, Cystic Fibrosis Foundation, Barnes-Jewish Hospital Foundation, Danish Heart Foundation, Danish Research Foundation of Independent Research, Svend Andersen Research Foundation, and Novo Nordisk Research Foundation.
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http://dx.doi.org/10.1172/jci.insight.138358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526453PMC
September 2020

Residual endotoxin induces primary graft dysfunction through ischemia/reperfusion-primed alveolar macrophages.

J Clin Invest 2020 08;130(8):4456-4469

Division of Thoracic Surgery.

Despite the widespread use of antibiotics, bacterial pneumonias in donors strongly predispose to the fatal syndrome of primary graft dysfunction (PGD) following lung transplantation. We report that bacterial endotoxin persists in human donor lungs after pathogen is cleared with antibiotics and is associated with neutrophil infiltration and PGD. In mouse models, depletion of tissue-resident alveolar macrophages (TRAMs) attenuated neutrophil recruitment in response to endotoxin as shown by compartmental staining and intravital imaging. Bone marrow chimeric mice revealed that neutrophils were recruited by TRAM through activation of TLR4 in a MyD88-dependent manner. Intriguingly, low levels of endotoxin, insufficient to cause donor lung injury, promoted TRAM-dependent production of CXCL2, increased neutrophil recruitment, and led to PGD, which was independent of donor NCMs. Reactive oxygen species (ROS) increased in human donor lungs starting from the warm-ischemia phase and were associated with increased transcription and translocation to the plasma membrane of TLR4 in donor TRAMs. Consistently, scavenging ROS or inhibiting their production to prevent TLR4 transcription/translocation or blockade of TLR4 or coreceptor CD14 on donor TRAMs prevented neutrophil recruitment in response to endotoxin and ameliorated PGD. Our studies demonstrate that residual endotoxin after successful treatment of donor bacterial pneumonia promotes PGD through ischemia/reperfusion-primed donor TRAMs.
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http://dx.doi.org/10.1172/JCI135838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410086PMC
August 2020

Chemokine Receptor 2-targeted Molecular Imaging in Pulmonary Fibrosis. A Clinical Trial.

Am J Respir Crit Care Med 2021 01;203(1):78-89

Department of Radiology.

Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. To phenotype patients with IPF for potential targeted therapy, we developed Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2 monocytes and macrophages using positron emission tomography (PET). CCR2 cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2 cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and RNA hybridization and then correlated with parallel quantitation of lung uptake by Cu-DOTA-ECL1i PET. Mouse models established that increased Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2 cell infiltration associated with fibrosis ( = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade ( = 19) or antifibrotic pirfenidone ( = 18) reduced CCR2 macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2 cells concentrated in perifibrotic regions and correlated with radiotracer localization ( = 21). Human imaging revealed little lung uptake in healthy volunteers ( = 7), whereas subjects with IPF ( = 4) exhibited intensive signals in fibrotic zones. These findings support a role for imaging CCR2 cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).
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http://dx.doi.org/10.1164/rccm.202004-1132OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781144PMC
January 2021

Developmental changes in myocardial B cells mirror changes in B cells associated with different organs.

JCI Insight 2020 08 20;5(16). Epub 2020 Aug 20.

Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine.

The naive heart harbors a population of intravascular B cells that make close contact with the cardiac microvasculature. However, the timing of their appearance and their organ specificity remain unknown. To address this knowledge gap, we performed a systematic analysis of B cells isolated from the myocardium and other organs, from embryonic life to adulthood. We found that the phenotype of myocardial B cells changed dynamically during development. While neonatal heart B cells were mostly CD11b+ and CD11b- CD21-CD23-, adult B cells were predominantly CD11b-CD21+CD23+. Histological analysis and intravital microscopy of lung and liver showed that organ-associated B cells in contact with the microvascular endothelium were not specific to the heart. Flow cytometric analysis of perfused hearts, livers, lungs, and spleen showed that the dynamic changes in B cell subpopulations observed in the heart during development mirrored changes observed in the other organs. Single cell RNA sequencing (scRNAseq) analysis of B cells showed that myocardial B cells were part of a larger population of organ-associated B cells that had a distinct transcriptional profile. These findings broaden our understanding of the biology of myocardial-associated B cells and suggest that current models of the dynamics of naive B cells during development are incomplete.
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http://dx.doi.org/10.1172/jci.insight.139377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455131PMC
August 2020

Shipping Lungs Greater Distances Increases Costs Without Cutting Waitlist Mortality.

Ann Thorac Surg 2020 11 6;110(5):1691-1697. Epub 2020 Jun 6.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University, St Louis, Missouri. Electronic address:

Background: On November 24, 2017, a change in lung allocation policy was initiated to replace the donor service area with a 250-nautical-mile radius circle around the donor hospital. We aim to analyze the consequences of this change, including organ acquisition cost and transplant outcomes, at the national level.

Methods: Data on adult patients undergoing lung transplantation between April 27, 2017, and June 22, 2018 (30 weeks before to 30 weeks after allocation policy change) were extracted from the Scientific Registry of Transplant Recipients database. Patients were classified into pre-change and post-change subgroups. Six-month overall survival was evaluated by Kaplan-Meier analysis. Organ acquisition costs were compared between the pre-change and post-change groups.

Results: Of the 3317 adult patients removed from the waiting list during the study period (pre-change 1637 vs post-change 1680), 2734 underwent transplantation (pre-change 1371 of 1637 [83.8%] vs post-change 1363 of 1680 [81.1%]), and 382 died or became too sick to be transplanted (pre-change 168 of 1637 [10.3%] vs post-change 214 of 1680 [12.7%], P = .077). Six-month survival rates of transplanted patients were similar between the two groups. However, average organ acquisition costs increased after policy change (pre-change $50,735 ± $10,858 vs post-change $53,440 ± $10,247, P < .001) with an increase in nonlocal donors (pre-change 44.3% vs post-change 68.9%, P < .001).

Conclusions: Organ acquisition costs and resource utilization increased with the new lung allocation policy, whereas deaths on the waiting list or after transplantation did not decrease. Further optimization of the allocation policy is necessary to balance access to transplant and proper stewardship of human and financial resources.
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http://dx.doi.org/10.1016/j.athoracsur.2020.04.086DOI Listing
November 2020

Extended post-ex vivo lung perfusion cold preservation predicts primary graft dysfunction and mortality: Results from a multicentric study.

J Heart Lung Transplant 2020 Sep 16;39(9):954-961. Epub 2020 May 16.

Section of General Thoracic Surgery, Lung Transplant Program, Columbia University Medical Center, New York, New York. Electronic address:

Background: Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic-cold preservations affect outcomes.

Methods: A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics.

Results: Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88-20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56-161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36-95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes.

Conclusions: Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP.
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http://dx.doi.org/10.1016/j.healun.2020.05.002DOI Listing
September 2020

Targeted PET Imaging of Chemokine Receptor 2-Positive Monocytes and Macrophages in the Injured Heart.

J Nucl Med 2021 Jan 22;62(1):111-114. Epub 2020 May 22.

Department of Radiology, Washington University School of Medicine, St. Louis, Missouri

Proinflammatory macrophages are important mediators of inflammation after myocardial infarction and of allograft injury after heart transplantation. The aim of this study was to image the recruitment of proinflammatory chemokine receptor 2-positive (CCR2+) cells in multiple heart injury models. Cu-DOTA-extracellular loop 1 inverso (ECL1i) PET was used to image CCR2+ monocytes and macrophages in a heart transplantation mouse model. Flow cytometry was performed to characterize CCR2+ cells. Autoradiography on a human heart specimen was conducted to confirm binding specificity. Cu- and Ga-DOTA-ECL1i were compared in an ischemia-reperfusion injury mouse model. Cu-DOTA-ECL1i showed sensitive and specific detection of CCR2+ cells in all tested mouse models, with efficacy comparable to that of Ga-DOTA-ECL1i. Flow cytometry demonstrated specific expression of CCR2 on monocytes and macrophages. The tracer binds to human CCR2. This work establishes the utility of Cu-DOTA-ECL1i to image CCR2+ monocytes and macrophages in mouse models and provides the requisite preclinical information to translate the targeted clinical-grade CCR2 imaging probe for clinical investigation of heart diseases.
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http://dx.doi.org/10.2967/jnumed.120.244673DOI Listing
January 2021

Double lung transplantation for end-stage Kartagener syndrome: a case report and literature review.

J Thorac Dis 2020 Apr;12(4):1588-1594

Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.

Kartagener syndrome (KS) is an autosomal recessive disorder characterized by situs inversus, paranasal sinusitis and bronchiectasis. We report the successful use of double lung transplant (DLTx) to treat end-stage KS. A 49-year-old Han woman was admitted to Renmin Hospital (Wuhan University, China) in September 2017 with a ≥15 year history of chronic productive cough that had worsened during the past year. Clinical examination and imaging investigations revealed respiratory failure and situs inversus consistent with KS. The patient was successfully treated with DLTx involving bilateral bronchial anastomoses. DLTx is a feasible treatment option for end-stage KS.
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http://dx.doi.org/10.21037/jtd.2020.02.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212169PMC
April 2020

Anellovirus Dynamics Are Associated With Primary Graft Dysfunction in Lung Transplantation.

Transplant Direct 2020 Feb 13;6(2):e521. Epub 2020 Jan 13.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.

Primary graft dysfunction (PGD) is the leading cause of early death in lung transplant. Anelloviruses are small circular DNA viruses that have been noted to be present at elevated levels in immunosuppressed patients. They have been associated with both short- and long-term outcomes in lung transplant, and we hypothesized that anellovirus dynamics might be associated with the development of PGD.

Methods: We analyzed alphatorquevirus (ie, an anellovirus genus) levels in whole blood samples from 64 adult lung transplant recipients.

Results: Patients with a relatively rapid rise in alphatorquevirus levels in the week following transplant were less likely to develop higher-grade PGD over the first 3 days following transplant ( = 0.031).

Conclusions: This study is the first to establish an association between the development of PGD and a component of the blood virome. While it is not known whether anelloviruses directly affect outcomes in lung transplant, they may serve as a biomarker of immune status in lung transplant recipients.
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http://dx.doi.org/10.1097/TXD.0000000000000969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004632PMC
February 2020

Myocardial B cells are a subset of circulating lymphocytes with delayed transit through the heart.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

Cardiovascular Division, Department of Medicine, and.

Current models of B lymphocyte biology posit that B cells continuously recirculate between lymphoid organs, without accumulating in peripheral healthy tissues. Nevertheless, B lymphocytes are one of the most prevalent leukocyte populations in the naive murine heart. To investigate this apparent inconsistency in the literature, we conducted a systematic analysis of myocardial B cell ontogeny, trafficking dynamics, histology, and gene expression patterns. We found that myocardial B cells represent a subpopulation of circulating B cells that make close contact with the microvascular endothelium of the heart and arrest their transit as they pass through the heart. The vast majority (>95%) of myocardial B cells remain intravascular, whereas few (<5%) myocardial B cells cross the endothelium into myocardial tissue. Analyses of mice with B cell deficiency or depletion indicated that B cells modulate the myocardial leukocyte pool composition. Analysis of B cell-deficient animals suggested that B cells modulate myocardial growth and contractility. These results transform our current understanding of B cell recirculation in the naive state and reveal a previously unknown relationship between B cells and myocardial physiology. Further work will be needed to assess the relevance of these findings to other organs.
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http://dx.doi.org/10.1172/jci.insight.134700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098796PMC
February 2020

Role of donor macrophages after heart and lung transplantation.

Am J Transplant 2020 05 29;20(5):1225-1235. Epub 2020 Jan 29.

Department of Medicine, Washington University, Saint Louis, Missouri, USA.

Since the 1960s, heart and lung transplantation has remained the optimal therapy for patients with end-stage disease, extending and improving quality of life for thousands of individuals annually. Expanding donor organ availability and immunologic compatibility is a priority to help meet the clinical demand for organ transplant. While effective, current immunosuppression is imperfect as it lacks specificity and imposes unintended adverse effects such as opportunistic infections and malignancy that limit the health and longevity of transplant recipients. In this review, we focus on donor macrophages as a new target to achieve allograft tolerance. Donor organ-directed therapies have the potential to improve allograft survival while minimizing patient harm related to global suppression of recipient immune responses. Topics highlighted include the role of ontogenically distinct donor macrophage populations in ischemia-reperfusion injury and rejection, including their interaction with allograft-infiltrating recipient immune cells and potential therapeutic approaches. Ultimately, a better understanding of how donor intrinsic immunity influences allograft acceptance and survival will provide new opportunities to improve the outcomes of transplant recipients.
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http://dx.doi.org/10.1111/ajt.15751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202685PMC
May 2020

Comparison of outcomes in lung and heart transplant recipients from the same multiorgan donor.

Clin Transplant 2020 01 30;34(1):e13768. Epub 2019 Dec 30.

Division of Pulmonary & Critical Care, Washington University School of Medicine, St. Louis, MO, USA.

Background: Primary graft dysfunction (PGD) and acute cellular rejection (ACR) are important causes of early morbidity and mortality following lung and heart transplantation. While many studies have elucidated donor-related risk factors of PGD and ACR, these complications often occur even with "ideal" donors. Therefore, we investigated potential associations of PGD and ACR between bilateral lung and heart transplant recipients from the same multiorgan donor, respectively.

Methods: Between 2011 and 2017, 100 donors contributed 100 bilateral lung transplants and 100 heart transplants performed. Logistic regression analysis for PGD and Cox proportional hazards regression analysis for ACR were used to estimate the relationship of heart and lung transplants.

Results: The incidence of PGD was 33% among lung and 17% among heart transplant recipients. Similarly, the incidence of ACR grade ≥ A2 for lung recipients was 38% (30/80), and the incidence of ACR grade ≥ 2R for heart recipients was 19% (15/80). There was no association between the development of PGD and ACR in lung and heart transplant recipients from the same donor, respectively.

Conclusions: These findings suggest that inherent donor factors are not critical to the development of PGD and ACR after lung and heart transplantation.
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http://dx.doi.org/10.1111/ctr.13768DOI Listing
January 2020

Donation after circulatory death in lung transplantation-five-year follow-up from ISHLT Registry.

J Heart Lung Transplant 2019 12;38(12):1235-1245

University of Toronto, Toronto, Ontario, Canada.

Background: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD).

Methods: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model.

Results: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61).

Conclusion: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.
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http://dx.doi.org/10.1016/j.healun.2019.09.007DOI Listing
December 2019