Bio

Dr. Deborah Jo Levine is a board-certified pulmonologist and lung transplantation and pulmonary hypertension specialist. She is a clinical professor of medicine in the Department of Pulmonary, Allergy, and Critical Care Medicine. Dr. Levine also serves as director of lung transplant outreach for Stanford Health Care.

Dr. Levine is internationally recognized for her work in lung transplantation and pulmonary hypertension (PH). She has been instrumental in developing international guidelines for defining, diagnosing, and managing antibody-mediated rejection (AMR) after lung transplantation. She has served as chair of pulmonary AMR guidelines for the International Society of Heart and Lung Transplantation.

Dr. Levine’s research interests include lung allograft monitoring and risk assessment. Her research has also included monitoring lung allograft health using donor-derived cell-free DNA (dd-cfDNA)—a technique pioneered at Stanford Medicine. She has received National Institutes of Health (NIH) funding as a clinical investigator. Dr. Levine is a co-chair of the ALAMO (AlloSure Lung Assessment and Metagenomics Outcomes) Study national registry. She has been involved in many clinical trials in lung transplantation and pulmonary hypertension.

As a respected educator and researcher, Dr. Levine has led and contributed to dozens of abstracts, presentations, and peer-reviewed articles. She has also written several books and book chapters on pulmonary hypertension, interstitial lung disease, pulmonary vascular disorders, and lung transplantation.

Dr. Levine is editor-in-chief for Advances in Pulmonary Hypertension, the quarterly journal of the Pulmonary Hypertension Association. She is an editorial board member of The Journal of Heart and Lung Transplantation and an ad hoc reviewer for several other industry journals. Dr. Levine also serves as a grant reviewer and section study reviewer for the American College of Chest Physicians and the American Society of Transplantation.

Dr . Levine is a fellow of the American College of Chest Physicians and the American Society of Transplantation. She is also the chair of the Diffuse Lung Disease and Lung Transplant Network and the incoming vice chair of the Council of Networks for the American College of Chest Physicians (CHEST).

Clinical Focus

  • Pulmonary Disease

Academic Appointments

Honors & Awards

  • Chairperson, Thoracic Community of Practice, American Society of Transplantation
  • Co-Chair, Lung Transplantation Master Class, International Society for Heart and Lung Transplantation (2023)
  • Co-Chair, Reiteration of the Pulmonary Antibody-Mediation Rejection Guidelines, International Society of Heart and Lung Transplantation (2023)
  • President and Chair, International Paris Lung Transplant Congress (2022)
  • Guidelines Committee Chair, Pulmonary Hypertension-Interstitial Lung Disease, American College of Chest Physicians (2022)
  • Course Chair, Pulmonary Hypertension-Interstitial Lung Disease, American College of Chest Physicians (2022)
  • Chair, Advanced Lung Disease Course, American College of Chest Physicians
  • Transplant Grant Chair, American College of Chest Physicians (2022)
  • Donor Management Course Chair, Gift of Hope, American College of Chest Physicians (2022)

Professional Education

  • Board Certification: American Board of Internal Medicine, Critical Care Medicine (2002)
  • Board Certification: American Board of Internal Medicine, Pulmonary Disease (2001)
  • Fellowship: UT Health San Antonio Pulmonary Medicine Fellowship (2003) TX
  • Fellowship: UT Health San Antonio Critical Care Fellowship (2002) TX
  • Fellowship: Banner Good Samaritan Medical Center (2001) AZ
  • Residency: Banner Good Samaritan Regional Medical Center AZ
  • Medical Education: University of Arizona College of Medicine (1996) AZ

Contact

  • Academic
    levinedj@stanford.edu
    University - Academic staff Department: Medicine - Med/Pulmonary and Critical Care Medicine Position: Clinical Professor
  • Clinical (Primary)  Stanford Lung Transplant Program 300 Pasteur Dr Stanford, CA 94305 (650) 725-7523 (fax)

Additional Clinical Info

Additional Info

  • Mail Code: 5236

All Publications

  • Chronic Lung Allograft Dysfunction is Associated with an Increased Number of Non-HLA Antibodies. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Xu, Q., Elrefaei, M., Taupin, J. L., Hitchman, K. M., Hiho, S., Gareau, A., Iasella, C., Marrari, M., Belousova, N., Bettinotti, M., Narula, T., Alvarez, F., Sanchez, P. G., Levvey, B., Westall, G., Snell, G., Levine, D. J., Zeevi, A., Roux, A. 2023

    Abstract

    Chronic Lung Allograft Dysfunction (CLAD) is the major cause of adverse outcomes in lung transplant recipients. Multiple factors, such as infection, alloimmunity, and autoimmunity, may lead to CLAD. Here, we aim to examine the role of non-HLA antibodies in CLAD in a large retrospective cohort.We analyzed non-HLA antibodies in the pre-and post-transplant sera of 226 (100 CLAD, 126 stable) lung transplant recipients from 5 centers, and we used a separate cohort to confirm our findings.A panel of 18 non-HLA antibodies was selected for analysis based on their significantly higher positive rates in CLAD vs. stable groups. The panel-18 non-HLA antibodies (n>3) may be positive pre- or post-transplant; the risk for CLAD is higher in the latter. The presence of both non-HLA antibody and HLA donor-specific antibody (DSA) was associated with an augmented risk of CLAD (HR=25.09 [5.52-14.04], p <0.001), which was higher than that for single-positive patients. In the independent confirmatory cohort of 61 (20 CLAD, 41 stable) lung transplant recipients, the risk for CLAD remained elevated in double-positive patients (HR=10.67 [0.98-115.68], p=0.052). After adjusting for non-standard immunosuppression, patients with double-positive DSA/Non-HLA antibodies had an elevated risk for graft loss (HR=2.53 [1.29-4.96], p=0.007).Circulating non-HLA antibodies (n>3) were independently associated with a higher risk for CLAD. Furthermore, when non-HLA antibodies and DSA were detected concomitantly, the risk for CLAD and graft loss was significantly increased. These results show that humoral immunity to HLA and non-HLA antigens may contribute to CLAD development.

    View details for DOI 10.1016/j.healun.2023.12.007

    View details for PubMedID 38141896

  • The 2022 Banff Meeting Lung Report. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Pavlisko, E. N., Adam, B. A., Berry, G. J., Calabrese, F., Cortes-Santiago, N., Glass, C. H., Goddard, M., Greenland, J. R., Kreisel, D., Levine, D. J., Martinu, T., Verleden, S. E., Sam, W. S., Roux, A. 2023

    Abstract

    The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference - held in Banff, Alberta - focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and impact on lung transplant outcomes were discussed. Key conclusions from discussion were 1) recognition of limitations in current standard of care assessment of lung allograft dysfunction 2) agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathological data, inclusive of all lesions associated with graft outcome (e.g., non-rejection pathology), and 3) optimism regarding promising novel diagnostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes.

    View details for DOI 10.1016/j.ajt.2023.10.022

    View details for PubMedID 37931751

  • Lung Transplantation Training in North America: Bridging the Gap. Chest Azfar Ali, H., Levine, D. J. 2023; 164 (3): 580-582

    View details for DOI 10.1016/j.chest.2023.04.026

    View details for PubMedID 37689471

  • Defining a NK cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Gauthier, P. T., Mackova, M., Hirji, A., Weinkauf, J., Timofte, I. L., Snell, G. I., Westall, G. P., Havlin, J., Lischke, R., Zajacova, A., Simonek, J., Hachem, R., Kreisel, D., Levine, D., Kubisa, B., Piotrowska, M., Juvet, S., Keshavjee, S., Jaksch, P., Klepetko, W., Halloran, K., Halloran, P. F. 2023

    Abstract

    In lung transplantation, antibody-mediated rejection (AMR) diagnosed by ISHLT criteria is uncommon compared to other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often DSA-negative and associated with NK cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies (TBBs) using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets (RSTS) in a training set (n = 488), the resulting algorithms separated an NK cell-enriched rejection-like state (NKRL) from TCMR/Mixed in a test set (n = 488). Applying this approach to all 896 TBBs distinguished three groups - No rejection; TCMR/Mixed; and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with CLAD, reduced FEV1, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

    View details for DOI 10.1016/j.ajt.2023.06.003

    View details for PubMedID 37295720

  • Guidelines and principles for the care of the cardiothoracic transplant patient in the intensive care unit. Clinical transplantation Nurok, M., Nunnally, M. E., O'Connor, M., Pierson, R. N., Baran, D. A., Harper, M. D., Malinoski, D., El Banayosy, A., Orija, A., Hall, S., Edelman, J. D., Sundt, T. M., Levine, D., Kobashigawa, J., Nelson, D. 2023: e14978

    Abstract

    Heart and lung transplant recipients require care provided by clinicians from multiple different specialties, each contributing unique expertise and perspective. The period the patient spends in the intensive care unit is one of the most critical times in the perioperative trajectory. Various organizational models of intensive care exist, including those led by intensivists, surgeons, transplant cardiologists, and pulmonologists. Coordinating timely efficient intensive care is an essential and logistically difficult goal. The present work product of the American Society of Transplantation's Thoracic and Critical Care Community of Practice, Critical Care Task Force outlines operational guidelines and principles that may be applied in different organizational models to optimize the delivery of intensive care for the cardiothoracic organ recipient.

    View details for DOI 10.1111/ctr.14978

    View details for PubMedID 36964943

  • OPTN required SARS-CoV-2 lower respiratory testing for lung donors: Striking the balance. Transplant infectious disease : an official journal of the Transplantation Society Booker, S. E., Jett, C., Fox, C., Anesi, J. A., Berry, G. J., Dunn, K. E., Fisher, C. E., Goldman, J. D., Ho, C., Kittleson, M., Lee, D. H., Levine, D. J., Marboe, C. C., Marklin, G., Martinez, C., Razonable, R. R., Sellers, M. T., Taimur, S., Te, H. S., Trindade, A. J., Wood, R. P., Woolley, A. E., Zaffiri, L., Klassen, D. K., Michaels, M. G., Pouch, S. M., Danziger-Isakov, L., La Hoz, R. M. 2023: e14048

    View details for DOI 10.1111/tid.14048

    View details for PubMedID 36864666

  • Transplant of organs from donors with positive SARS-CoV-2 nucleic acid testing: A report from the organ procurement and transplantation network ad hoc disease transmission advisory committee. Transplant infectious disease : an official journal of the Transplantation Society Goldman, J. D., Pouch, S. M., Woolley, A. E., Booker, S. E., Jett, C. T., Fox, C., Berry, G. J., Dunn, K. E., Ho, C. S., Kittleson, M., Lee, D. H., Levine, D. J., Marboe, C. C., Marklin, G., Razonable, R. R., Taimur, S., Te, H. S., Anesi, J. A., Fisher, C. E., Sellers, M. T., Trindade, A. J., Wood, R. P., Zaffiri, L., Levi, M. E., Klassen, D., Michaels, M. G., La Hoz, R. M., Danziger-Isakov, L. 2023: e14013

    Abstract

    Decisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test-positive (NAT+) donors must balance risk of donor-derived transmission events (DDTE) with the scarcity of available organs.Organ Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS-CoV-2 NAT+ and NAT- donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee.From May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT- donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT- donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30-day mortality, and 30-day graft loss were similar for all organ types. No SARS-CoV-2 DDTE occurred in this interval.Transplantation of SARS-CoV-2 NAT+ donor organs appears safe for short-term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes.

    View details for DOI 10.1111/tid.14013

    View details for PubMedID 36694448

  • A survey of intensive care unit models in cardiothoracic transplantation at high-volume centers. Clinical transplantation Nurok, M., Nunnally, M. E., Gill, G., O'Connor, M., Harper, M., Edelman, J., Orija, A., Banayosy, A. E., Malinoski, D., Sundt, T., Baran, D. A., Levine, D., Hall, S., Kobashigawa, J., Nelson, D. 2023: e14911

    View details for DOI 10.1111/ctr.14911

    View details for PubMedID 36630254

  • Immunosuppression in Lung Transplantation. Handbook of experimental pharmacology Nelson, J., Kincaide, E., Schulte, J., Hall, R., Levine, D. J. 2022; 272: 139-164

    Abstract

    Immunosuppression in lung transplantation is an area devoid of robust clinical data. This chapter will review the history of immunosuppression in lung transplantation. Additionally, it will evaluate the three classes of induction, maintenance, and rescue immunosuppression in detail. Induction immunosuppression in lung transplantation aims to decrease incidence of lung allograft rejection, however infectious risk must be considered when determining if induction is appropriate and which agent is most favorable. Similar to other solid organ transplant patient populations, a multi-drug approach is commonly prescribed for maintenance immunosuppression to minimize single agent drug toxicities. Emphasis of this review is placed on key medication considerations including dosing, adverse effects, and drug interactions. Clinical considerations will be reviewed per drug class given available literature. Finally, acute cellular, antibody mediated, and chronic rejection are reviewed.

    View details for DOI 10.1007/164_2021_548

    View details for PubMedID 34796380

    View details for PubMedCentralID 2955417

  • Clinical features and allograft failure rates of pulmonary antibody-mediated rejection categories. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Charya, A. V., Ponor, I. L., Cochrane, A., Levine, D., Philogene, M., Fu, Y. P., Jang, M. K., Kong, H., Shah, P., Bon, A. M., Krishnan, A., Mathew, J., Luikart, H., Khush, K. K., Berry, G., Marboe, C., Iacono, A., Orens, J. B., Nathan, S. D., Agbor-Enoh, S. 2022

    Abstract

    Pulmonary antibody-mediated rejection (AMR) consensus criteria categorize AMR by diagnostic certainty. This study aims to define the clinical features and associated outcomes of these recently defined AMR categories.Adjudication committees reviewed clinical data of 335 lung transplant recipients to define clinical or subclinical AMR based on the presence of allograft dysfunction, and the primary endpoints, time from transplant to allograft failure, a composite endpoint of chronic lung allograft dysfunction and/or death. Clinical AMR was subcategorized based on diagnostic certainty as definite, probable or possible AMR if 4, 3, or 2 characteristic features were present, respectively. Allograft injury was assessed via plasma donor-derived cell-free DNA (ddcfDNA). Risk of allograft failure and allograft injury was compared for AMR categories using regression models.Over the 38.5 months follow-up, 28.7% of subjects developed clinical AMR (n = 96), 18.5% developed subclinical AMR (n = 62) or 58.3% were no AMR (n = 177). Clinical AMR showed higher risk of allograft failure and ddcfDNA levels compared to subclinical or no AMR. Clinical AMR included definite/probable (n = 21) or possible AMR (n = 75). These subcategories showed similar clinical characteristics, ddcfDNA levels, and risk of allograft failure. However, definite/probable AMR showed greater measures of AMR severity, including degree of allograft dysfunction and risk of death compared to possible AMR.Clinical AMR showed greater risk of allograft failure than subclinical AMR or no AMR. Subcategorization of clinical AMR based on diagnostic certainty correlated with AMR severity and risk of death, but not with the risk of allograft failure.

    View details for DOI 10.1016/j.healun.2022.09.012

    View details for PubMedID 36319530

  • Lung allograft standardized histological analysis (LASHA) template: A research consensus proposal. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Calabrese, F., Roden, A. C., Pavlisko, E., Lunardi, F., Neil, D., Adam, B., Hwang, D., Goddard, M., Berry, G. J., Ivanovic, M., Thusen, J. v., Gibault, L., Lin, C., Wassilew, K., Glass, C., Westall, G., Zeevi, A., Levine, D. J., Roux, A. 2022

    Abstract

    BACKGROUND: Routine monitoring of lung-transplanted patients is crucial for the identification of immunological and non-immunological complications. Determining the etiology of acute allograft dysfunction, particularly in alloimmune-mediated disorders, relies heavily on the lung biopsy with histopathologic analysis. Standardization of the pathologic diagnosis of rejection (e.g., cellular and antibody-mediated) is based on consensus statements and guidelines, indicating the importance of a multidisciplinary approach to achieve a definitive etiological diagnosis. In addition to these statements and guidelines, refinements and standardizations are feasible through systematic analysis morphological, immunophenotypic and molecular alterations observed in transbronchial biopsies. This study is to identify key morphologic features to be assessed, select consistent and reproducible terminology for each histological feature, and provide standardized definitions for pathological assessment and grading.METHODS: A template was created by experts in lung transplantation including pathologists, pulmonologists, immunologists. An initial draft was circulated, followed by discussions and multiple revisions by email and conference calls.RESULTS: The "lung allograft standardized histological analysis - LASHA" template was created and structured as multiple-choice questions with number of fields to be filled in to allow for standardization of results and easy transfer into a future electronic spreadsheet.CONCLUSION: This template will help facilitate multicenter studies through a uniform protocol and correlations with new diagnostic modalities. After validation in large-scale studies, an optimized template could be included in routine clinical practice to enhance graft assessment and medical decision-making.

    View details for DOI 10.1016/j.healun.2022.06.021

    View details for PubMedID 35931644

  • Screening Strategies for Pulmonary Hypertension in Patients With Interstitial Lung Disease: A Multidisciplinary Delphi Study. Chest Rahaghi, F. F., Kolaitis, N. A., Adegunsoye, A., de Andrade, J. A., Flaherty, K. R., Lancaster, L. H., Lee, J. S., Levine, D. J., Preston, I. R., Safdar, Z., Saggar, R., Sahay, S., Scholand, M. B., Shlobin, O. A., Zisman, D. A., Nathan, S. D. 2022; 162 (1): 145-155

    Abstract

    Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD) and is associated with worse outcomes and increased mortality. Evaluation of PH is recommended in lung transplant candidates, but there are currently no standardized screening approaches. Trials have identified therapies that are effective in this setting, providing another rationale to routinely screen patients with ILD for PH.What screening strategies for identifying PH in patients with ILD are supported by expert consensus?The study convened a panel of 16 pulmonologists with expertise in PH and ILD, and used a modified Delphi consensus process with three surveys to identify PH screening strategies. Survey 1 consisted primarily of open-ended questions. Surveys 2 and 3 were developed from responses to survey 1 and contained statements about PH screening that panelists rated from -5 (strongly disagree) to 5 (strongly agree).Panelists reached consensus on several triggers for suspicion of PH including the following: symptoms, clinical signs, findings on chest CT scan or other imaging, abnormalities in pulse oximetry, elevations in brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP), and unexplained worsening in pulmonary function tests or 6-min walk distance. Echocardiography and BNP/NT-proBNP were identified as screening tools for PH. Right heart catheterization was deemed essential for confirming PH.Many patients with ILD may benefit from early evaluation of PH now that an approved therapy is available. Protocols to evaluate patients with ILD often overlap with evaluations for pulmonary hypertension-interstitial lung disease and can be used to assess the risk of PH. Because standardized approaches are lacking, this consensus statement is intended to aid physicians in the identification of patients with ILD and possible PH, and provide guidance for timely right heart catheterization.

    View details for DOI 10.1016/j.chest.2022.02.012

    View details for PubMedID 35176276

    View details for PubMedCentralID PMC9993339

  • Biological Variation of Donor-Derived Cell-Free DNA in Stable Lung Transplant Recipients. The journal of applied laboratory medicine Keller, M., Mutebi, C., Shah, P., Levine, D., Aryal, S., Iacono, A., Timofte, I., Mathew, J., Varghese, A., Giner, C., Agbor-Enoh, S. 2022; 7 (4): 901-909

    Abstract

    Prior studies demonstrate that donor-derived cell-free DNA (dd-cfDNA) in lung transplant recipients may serve as a marker of allograft injury for detecting allograft rejection and infection. Clinical interpretation of dd-cfDNA requires understanding its biological variation in stable lung transplant patients in order to identify abnormal results suggesting underlying allograft dysfunction. This study establishes the biological variation and reference change values (RCV) of dd-cfDNA in stable lung transplant recipients using an analytically validated assay with an established analytic coefficient of variation (CVA).The AlloSure® assay, a targeted, sequencing-based approach, was used to measure plasma dd-cfDNA in a cohort of lung transplant patients at 4 centers that used dd-cfDNA to monitor for allograft dysfunction in preference to surveillance transbronchial biopsy. Patients with stable allograft function and ≥3 dd-cfDNA samples were included. Intraindividual coefficient of variation (CVI), interindividual CV (CVG), index of individuality (II) and the RCV were calculated.Thirty-five patients with a combined 124 dd-cfDNA samples were included in the final analysis. The median dd-cfDNA was 0.31% (interquartile range 0.18%-0.68%), the 97.5th percentile and 95th percentile were 1.3% and 1.0%, respectively. In 30 stable patients with an average of 3.7 tests, the CVI was 25%, CVG 19%, II 1.33, and RCV 70%.In stable lung transplant patients, fluctuations in dd-cfDNA levels of up to 70% or levels less than 1% are within normal biological variation. With further validation, these thresholds may be incorporated into surveillance monitoring algorithms to identify potentially abnormal results indicating allograft dysfunction.

    View details for DOI 10.1093/jalm/jfab171

    View details for PubMedID 35024828

  • Donor-derived cell-free DNA as a composite marker of acute lung allograft dysfunction in clinical care. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Keller, M., Sun, J., Mutebi, C., Shah, P., Levine, D., Aryal, S., Iacono, A., Timofte, I., Mathew, J., Varghese, A., Giner, C., Agbor-Enoh, S. 2022; 41 (4): 458-466

    Abstract

    As a marker of underlying lung allograft injury, donor-derived cell-free DNA (dd-cfDNA) may be used to identify episodes of acute allograft injury in lung transplant recipients. We investigated the utility of dd-cfDNA to monitor subjects at risk of acute rejection or infection in routine clinical practice.This multicenter, retrospective cohort study collected data from lung transplant recipients within 3 years of transplant at 4 centers between March 24, 2020 and September 1, 2020. During this period, as part of routine care during the COVID-19 pandemic, these centers implemented a home-based surveillance program using plasma dd-cfDNA in preference to surveillance bronchoscopy. Dd-cfDNA was used to detect acute lung allograft dysfunction (ALAD) - a composite endpoint of acute rejection and infection. dd-cfDNA levels in patients with ALAD were compared to stable patients. The performance characteristics of dd-cfDNA ≥ 1.0% to detect ALAD were estimated.A total of 175 patients underwent 380 dd-cfDNA measurements, of which 290 were for routine surveillance purposes. dd-cfDNA was higher in patients with ALAD than stable patients (Median (IQR) 1.7% (0.63, 3.1) vs 0.35% (0.22, 0.79), p < 0.001). As an indication of underlying ALAD during surveillance testing, the estimated sensitivity of dd-cfDNA ≥1% was 73.9%, specificity of 87.7%, positive predictive value of 43.4% and negative predictive value of 96.5%.dd-cfDNA identified acute lung allograft dysfunction in asymptomatic lung transplant patients that may not have been identified by using a clinically indicated biopsy strategy alone. dd-cfDNA <1.0% may be useful in ruling out acute rejection and infection, supporting its use as a potential noninvasive marker for surveillance monitoring.

    View details for DOI 10.1016/j.healun.2021.12.009

    View details for PubMedID 35063338

  • Utilization of risk assessment tools in management of PAH: A PAH provider survey. Pulmonary circulation Sahay, S., Balasubramanian, V., Memon, H., Poms, A., Bossone, E., Highland, K., Kay, D., Levine, D. J., Mullin, C. J., Melendres-Groves, L., Mathai, S. C., Soto, F. J., Shlobin, O., Elwing, J. M. 2022; 12 (2): e12057

    Abstract

    Pulmonary arterial hypertension (PAH) is a chronically progressive fatal disease. A goal-oriented approach to achieve low risk status has been associated with improved survival. A variety of risk stratification tools are available, but use is low. We conducted a survey to assess potential reasons for under-utilization. We conducted a survey-based study of global PAH disease specialists with a goal of assessing risk assessment utilization and identifying modifiable barriers to use. The survey was designed by the American College of Chest Physicians' Pulmonary Vascular Diseases (PVD) NetWork. Respondents were global members of the PVD NetWork and Pulmonary Hypertension Association. Survey invitations were sent electronically to all members. Participation was anonymous and no provider or patient level data was collected. Participants from four countries responded with the majority (84%) being from the United States. Our survey found suboptimal use of any risk stratification tool with 71/112 (63%) reporting use. A total of 85% of the respondents had more than 5 years of experience in managing PAH. REVEAL 2.0 and European Society of Cardiology/European Respiratory Society risk tools were the most commonly used. A total of 44 (65%) surveyed felt that use of risk tools led to change in PAH therapies. Only 6 (9%) felt they prompted additional testing or changed the frequency of follow-up. A total of 5 (7%) reported they prompted goals of care/palliative care discussions and 2 (3%) that they triggered lung transplant referral. The vast majority indicated that incorporation of risk tools into electronic medical records (EMR) would improve utilization. PAH risk assessment tools remain under-utilized. Most respondents were experienced PAH clinicians. More than one-third were not routinely using risk tools. Most felt that risk tools led to PAH therapy changes but few reported impacts on other aspects of care. The most commonly identified barriers to use were time constraints and lack of integration with EMR.

    View details for DOI 10.1002/pul2.12057

    View details for PubMedID 35514787

    View details for PubMedCentralID PMC9063963

  • Incidence, Clinical Correlates, and Outcomes of Pulmonary Hypertension After Kidney Transplantation: Analysis of Linked US Registry and Medicare Billing Claims. Transplantation Lentine, K. L., Lam, N. N., Caliskan, Y., Xiao, H., Axelrod, D. A., Costa, S. P., Levine, D. J., Runo, J. R., Te, H. S., Rangaswami, J., Dadhania, D. M., Schnitzler, M. A., Kasiske, B. L., Villines, T. C. 2022; 106 (3): 666-675

    Abstract

    The incidence, risks, and outcomes associated with pulmonary hypertension (P-HTN) in the kidney transplant (KTx) population are not well described.We linked US transplant registry data with Medicare claims (2006-2016) to investigate P-HTN diagnoses among Medicare-insured KTx recipients (N = 35 512) using billing claims. Cox regression was applied to identify independent correlates and outcomes of P-HTN (adjusted hazard ratio [aHR] 95%LCLaHR95%UCL) and to examine P-HTN diagnoses as time-dependent mortality predictors.Overall, 8.2% of recipients had a diagnostic code for P-HTN within 2 y preceding transplant. By 3 y posttransplant, P-HTN was diagnosed in 10.310.6%11.0 of the study cohort. After adjustment, posttransplant P-HTN was more likely in KTx recipients who were older (age ≥60 versus 18-30 y a HR, 1.912.403.01) or female (aHR, 1.151.241.34), who had pretransplant P-HTN (aHR, 4.384.795.24), coronary artery disease (aHR, 1.051.151.27), valvular heart disease (aHR, 1.221.321.43), peripheral vascular disease (aHR, 1.051.181.33), chronic pulmonary disease (aHR, 1.201.311.43), obstructive sleep apnea (aHR, 1.151.281.43), longer dialysis duration, pretransplant hemodialysis (aHR, 1.171.371.59), or who underwent transplant in the more recent era (2012-2016 versus 2006-2011: aHR, 1.291.391.51). Posttransplant P-HTN was associated with >2.5-fold increased risk of mortality (aHR, 2.572.843.14) and all-cause graft failure (aHR, 2.422.642.88) within 3 y posttransplant. Outcome associations of newly diagnosed posttransplant P-HTN were similar.Posttransplant P-HTN is diagnosed in 1 in 10 KTx recipients and is associated with an increased risk of death and graft failure. Future research is needed to refine diagnostic, classification, and management strategies to improve outcomes in KTx recipients who develop P-HTN.

    View details for DOI 10.1097/TP.0000000000003783

    View details for PubMedID 33859148

  • White paper on antimicrobial stewardship in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons So, M., Hand, J., Forrest, G., Pouch, S. M., Te, H., Ardura, M. I., Bartash, R. M., Dadhania, D. M., Edelman, J., Ince, D., Jorgenson, M. R., Kabbani, S., Lease, E. D., Levine, D., Ohler, L., Patel, G., Pisano, J., Spinner, M. L., Abbo, L., Verna, E. C., Husain, S. 2022; 22 (1): 96-112

    Abstract

    Antimicrobial stewardship programs (ASPs) have made immense strides in optimizing antibiotic, antifungal, and antiviral use in clinical settings. However, although ASPs are required institutionally by regulatory agencies in the United States and Canada, they are not mandated for transplant centers or programs specifically. Despite the fact that solid organ transplant recipients in particular are at increased risk of infections from multidrug-resistant organisms, due to host and donor factors and immunosuppressive therapy, there currently are little rigorous data regarding stewardship practices in solid organ transplant populations, and thus, no transplant-specific requirements currently exist. Further complicating matters, transplant patients have a wide range of variability regarding their susceptibility to infection, as factors such as surgery of transplant, intensity of immunosuppression, and presence of drains or catheters in situ may modify the risk of infection. As such, it is not feasible to have a "one-size-fits-all" style of stewardship for this patient population. The objective of this white paper is to identify opportunities, risk factors, and ASP strategies that should be assessed with solid organ transplant recipients to optimize antimicrobial use, while producing an overall improvement in patient outcomes. We hope it may serve as a springboard for development of future guidance and identification of research opportunities.

    View details for DOI 10.1111/ajt.16743

    View details for PubMedID 34212491

    View details for PubMedCentralID PMC9695237

  • Acute respiratory distress syndrome in the cardiothoracic patient: State of the art and use of veno-venous extracorporeal membrane oxygenation. JTCVS open Copeland, H., Levine, D., Morton, J., Hayanga, J. W. 2021; 8: 97-103

    View details for DOI 10.1016/j.xjon.2021.10.003

    View details for PubMedID 34723221

    View details for PubMedCentralID PMC8541831

  • ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Bermudez, C. A., Crespo, M. M., Shlobin, O. A., Cantu, E., Mazurek, J. A., Levine, D., Gutsche, J., Kanwar, M., Dellgren, G., Bush, E. L., Heresi, G. A., Cypel, M., Hadler, R., Kolatis, N., Franco, V., Benvenuto, L., Mooney, J., Pipeling, M., King, C., Mannem, H., Raman, S., Knoop, C., Douglas, A., Mercier, O. 2021

    Abstract

    Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

    View details for DOI 10.1016/j.healun.2021.07.016

    View details for PubMedID 34404570

  • Single Center "Snapshot" Experience With Donor-Derived Cell-Free DNA After Lung Transplantation. Biomarker insights Levine, D. J., Ross, D. J., Sako, E. 2020; 15: 1177271920958704

    View details for DOI 10.1177/1177271920958704

    View details for PubMedID 32982146

    View details for PubMedCentralID PMC7498978

  • Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Glanville, A. R., Verleden, G. M., Todd, J. L., Benden, C., Calabrese, F., Gottlieb, J., Hachem, R. R., Levine, D., Meloni, F., Palmer, S. M., Roman, A., Sato, M., Singer, L. G., Tokman, S., Verleden, S. E., von der Thüsen, J., Vos, R., Snell, G. 2019; 38 (5): 483-492

    View details for DOI 10.1016/j.healun.2019.03.008

    View details for PubMedID 31027539

  • Banff Lung Report: Current knowledge and future research perspectives for diagnosis and treatment of pulmonary antibody-mediated rejection (AMR). American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Roux, A., Levine, D. J., Zeevi, A., Hachem, R., Halloran, K., Halloran, P. F., Gibault, L., Taupin, J. L., Neil, D. A., Loupy, A., Adam, B. A., Mengel, M., Hwang, D. M., Calabrese, F., Berry, G., Pavlisko, E. N. 2019; 19 (1): 21-31

    Abstract

    The Lung session of the 2017 14th Banff Foundation for Allograft Pathology Conference, Barcelona focused on the multiple aspects of antibody-mediated rejection (AMR) in lung transplantation. Multidimensional approaches for AMR diagnosis, including classification, histological and immunohistochemical analysis, and donor- specific antibody (DSA) characterization with their current strengths and limitations were reviewed in view of recent research. The group also discussed the role of tissue gene expression analysis in the context of unmet needs in lung transplantation. The current best practice for monitoring of AMR and the therapeutic approach are summarized and highlighted in this report. The working group reached consensus of the major gaps in current knowledge and focused on the unanswered questions regarding pulmonary AMR. An important outcome of the meeting was agreement on the need for future collaborative research projects to address these gaps in the field of lung transplantation.

    View details for DOI 10.1111/ajt.14990

    View details for PubMedID 29956477

  • Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Aguilar, C. A., Hamandi, B., Fegbeutel, C., Silveira, F. P., Verschuuren, E. A., Ussetti, P., Chin-Hong, P. V., Sole, A., Holmes-Liew, C., Billaud, E. M., Grossi, P. A., Manuel, O., Levine, D. J., Barbers, R. G., Hadjiliadis, D., Singer, L. G., Husain, S. 2018; 37 (10): 1226-1234

    Abstract

    Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA.We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models.Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates.Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

    View details for DOI 10.1016/j.healun.2018.06.008

    View details for PubMedID 30139546

  • Human leukocyte antigens antibodies after lung transplantation: Primary results of the HALT study AMERICAN JOURNAL OF TRANSPLANTATION Hachem, R. R., Kamoun, M., Budev, M. M., Askar, M., Ahya, V. N., Lee, J. C., Levine, D. J., Pollack, M. S., Dhillon, G. S., Weill, D., Schechtman, K. B., Leard, L. E., Golden, J. A., Baxter-Lowe, L., Mohanakumar, T., Tyan, D. B., Yusen, R. D. 2018; 18 (9): 2285–94

    Abstract

    Donor-specific antibodies (DSA) to mismatched human leukocyte antigens (HLA) are associated with worse outcomes after lung transplantation. To determine the incidence and characteristics of DSA early after lung transplantation, we conducted a prospective multicenter observational study that used standardized treatment and testing protocols. Among 119 transplant recipients, 43 (36%) developed DSA: 6 (14%) developed DSA only to class I HLA, 23 (53%) developed DSA only to class II HLA, and 14 (33%) developed DSA to both class I and class II HLA. The median DSA mean fluorescence intensity (MFI) was 3197. We identified a significant association between the Lung Allocation Score and the development of DSA (HR = 1.02, 95% CI: 1.001-1.03, P = .047) and a significant association between DSA with an MFI ≥ 3000 and acute cellular rejection (ACR) grade ≥ A2 (HR = 2.11, 95% CI: 1.04-4.27, P = .039). However, we did not detect an association between DSA and survival. We conclude that DSA occur frequently early after lung transplantation, and most target class II HLA. DSA with an MFI ≥ 3000 have a significant association with ACR. Extended follow-up is necessary to determine the impact of DSA on other important outcomes.

    View details for PubMedID 29687961

  • Lung autoantibodies: Ready for prime time? The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Milross, L., Hachem, R., Levine, D., Glanville, A. R. 2017

    Abstract

    Despite advances in our understanding of the immunology of lung allograft tolerance and a reduction in the rate of acute allograft rejection using contemporary immunosuppressive protocols, the rate of chronic lung allograft dysfunction (CLAD), both obstructive and restrictive, remains unacceptably high. CLAD, particularly the restrictive phenotype, is a harbinger of a foreshortened survival. The development of a consensus approach to the diagnosis of antibody-mediated rejection by the International Society for Heart and Lung Transplantation has highlighted the need for a uniform approach toward the investigation, diagnosis, implications and management of both human leukocyte antigen (HLA) and non-HLA-related antibody formation. This Perspective summarizes the current information that underpins the way forward in recognizing the potential importance of non-HLA-related antibody formation with respect to allograft injury and outcomes.

    View details for DOI 10.1016/j.healun.2017.10.026

    View details for PubMedID 29198928

  • Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. journal of heart and lung transplantation Levine, D. J., Glanville, A. R., Aboyoun, C., Belperio, J., Benden, C., Berry, G. J., Hachem, R., Hayes, D., Neil, D., Reinsmoen, N. L., Snyder, L. D., Sweet, S., Tyan, D., Verleden, G., Westall, G., Yusen, R. D., Zamora, M., Zeevi, A. 2016; 35 (4): 397-406

    Abstract

    Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications.

    View details for DOI 10.1016/j.healun.2016.01.1223

    View details for PubMedID 27044531