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Impact of Pretransplant Malignancy on Heart Transplantation Outcomes: Contemporary United Network for Organ Sharing Analysis Amidst Evolving Cancer Therapies

Batra, Jaya; DeFilippis, Ersilia M; Golob, Stephanie; Clerkin, Kevin; Topkara, Veli K; Habal, Marlena V; Restaino, Susan; Griffin, Jan; Hi Lee, Sun; Latif, Farhana; Farr, Maryjane A; Sayer, Gabriel; Raikelkar, Jayant; Uriel, Nir
BACKGROUND:An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression. METHODS:Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated. RESULTS:<0.001). CONCLUSIONS:Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.
PMID: 35094567
ISSN: 1941-3297
CID: 5241202

De Novo Human Leukocyte Antigen Allosensitization in Heartmate 3 Versus Heartmate II Left Ventricular Assist Device Recipients

Jain, Rashmi; Habal, Marlena V; Clerkin, Kevin J; Latif, Farhana; Restaino, Susan W; Zorn, Emmanuel; Takeda, Koji; Naka, Yoshifumi; Yuzefpolskaya, Melana; Farr, Maryjane A; Colombo, Paolo C; Sayer, Gabriel T; Uriel, Nir; Topkara, Veli K
Left ventricular assist devices (LVADs) are associated with the development of antihuman leukocyte antigen (HLA) antibodies, which can create a challenge for future transplantation in these patients. The differential effects of Heartmate 3 (HM3) versus Heartmate II (HMII) on de novo HLA allosensitization remain unknown. Patients who underwent HMII or HM3 implantation and had no prior HLA antibodies by solid-phase assay (Luminex) testing were included in this study. Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) levels and Luminex antibody profiles were followed until cardiac transplantation, device explantation, or death. Electronic medical records were reviewed to examine posttransplant outcomes. Thirty-eight HM3 and 34 HMII patients with complete data were followed for 1.5 ± 1.1 years on device support. HM3 and HMII groups had similar age at implant, female gender, ischemic heart failure etiology, bridge strategy at implant, as well as intraoperative and postoperative transfusion requirements. 39.5% of HM3 and 47.1% of HMII patients developed detectable HLA antibodies by Luminex testing (p = 0.516). Development of high-level (mean fluorescence intensity >10,000) antibodies was significantly lower in HM3 than HMII patients (5.3 vs. 20.6%, p = 0.049). CDC PRA testing showed fewer HM3 patients with a positive result (PRA > 0%) than HMII patients (39.4 vs. 70.0%, p = 0.015). Among transplanted patients, those who had developed de novo sensitization on LVAD support showed a trend toward incidence of moderate to severe grade rejection compared with unsensitized patients (23.8 vs. 4.8%, p = 0.078). HM3 is associated with lower risk of de novo HLA sensitization compared with HMII.
PMID: 33883507
ISSN: 1538-943x
CID: 5238682

Prolonged severe acute respiratory syndrome coronavirus 2 persistence, attenuated immunologic response, and viral evolution in a solid organ transplant patient [Case Report]

Purpura, Lawrence J; Chang, Michelle; Annavajhala, Medini K; Mohri, Hiroshi; Liu, Lihong; Shah, Jayesh; Cantos, Anyelina; Medrano, Nicola; Laracy, Justin; Scully, Brian; Miko, Benjamin A; Habal, Marlena; Pereira, Marcus R; Tsuji, Moriya; Ho, David D; Uhlemann, Anne-Catrin; Yin, Michael T
Unlike immunocompetent hosts, the duration of viral persistence after infection with severe acute respiratory syndrome coronavirus 2 can be prolonged in immunosuppressed patients. Here, we present a case of viral persistence for over 19 weeks in a patient with a history of solid organ transplant and explore the clinical, virologic, and immunologic course. Our patient still demonstrated viral persistence at 138 days with low polymerase chain reaction cycle threshold values and evidence of continuing viral sequence evolution indicative of ongoing virus replication. These findings have important implications for infection prevention and control recommendations in immunosuppressed patients. Immune response, including neutralizing antibody titers, T cell activity, and cytokine levels, peaked around days 44-72 after diagnosis. Anti-S trimer antibodies were low at all time points, and T cell response was attenuated by day 119. As immune response waned and viral load increased, increased genetic diversity emerged, suggesting a mechanism for the development of viral variants.
PMID: 34510730
ISSN: 1600-6143
CID: 5238692

Chronic intermittent intravenous immunoglobulin in heart transplant recipients with elevated donor-specific antibody levels

Yopes, Margot; Fanek, Tala; Fuselier, Byron; Gaine, Maureen; Jackson, Ruslana; Mabasa, Angelo; Kim, Andrea; Jennings, Douglas L; Clerkin, Kevin; Yuzefpolskaya, Melana; Habal, Marlena; Latif, Farhana; Restaino, Susan; Lee, Sun Hi; Farr, Maryjane; Colombo, Paolo; Sayer, Gabriel; Uriel, Nir
Donor-specific antibodies (DSA) are associated with antibody-mediated rejection (AMR) and poor patient survival. In heart transplant, the efficacy of intermittent intravenous immunoglobulin (IVIg) in reducing de novo DSA levels and treating AMR has not been characterized. We retrospectively studied a cohort of 19 patients receiving intermittent IVIg for elevated DSA and examined changes in DSA levels and graft function. Intermittent IVIg infusions were generally safe and well tolerated. Overall, 23 of 62 total DSA (37%) were undetectable after treatment, 21 DSA (34%) had MFI decrease by more than 25%, and 18 (29%) had MFI decrease by less than 25% or increase. The average change in MFI was -51% ± 71% (P < .001). Despite reductions in DSA, among the six patients (32%) with biopsy-confirmed AMR, left ventricular ejection fraction (LVEF) decreased in five (83%) and cardiac index (CI) decreased in three (50%). Conversely, LVEF increased in 91% and CI increased in 70% of biopsy-negative patients. All six AMR patients were readmitted during treatment, four for confirmed or suspected rejection. IVIg infusions may stabilize the allograft in patients with elevated DSA and negative biopsies, but once AMR has developed does not appear to improve allograft function despite decreasing DSA levels.
PMID: 34705286
ISSN: 1399-0012
CID: 5387802

How can we better inform our patients about post-heart transplantation survival? A conditional survival analysis

Clerkin, Kevin J; Griffin, Jan M; Fried, Justin A; Raikhelkar, Jayant; Jain, Rashmi; Topkara, Veli K; Habal, Marlena V; Latif, Farhana; Restaino, Susan; Colombo, Paolo C; Takeda, Koji; Naka, Yoshifumi; Farr, Maryjane A; Sayer, Gabriel; Uriel, Nir
BACKGROUND:Conditional survival (CS) is a dynamic method of survival analysis that provides an estimate of how an individual's future survival probability changes based on time post-transplant, individual characteristics, and post-transplant events. This study sought to provide post-transplant CS probabilities for heart transplant recipients based on different prognostic variables and provide a discussion tool for the providers and the patients. METHODS:Adult heart transplant recipients from January 1, 2004, through October 18, 2018, were identified in the UNOS registry. CS probabilities were calculated using data from Kaplan-Meier survival estimates. RESULTS:CS probability exceeded actuarial survival probability at all times post-transplant. Women had similar short-term, but greater long-term CS than men at all times post-transplant (10-year CS 1.8-11.5% greater [95% CI 1.2-12.9]). Patients with ECMO or a surgical BiVAD had decreased survival at the time of transplant, but their CS was indistinguishable from all others by 1-year post-transplant. Rejection and infection requiring hospitalization during the first year were associated with a persistently decreased CS probability. CONCLUSIONS:In this study, we report differential conditional survival outcomes based on time, patient characteristics, and clinical events post-transplant, providing a dynamic assessment of survival. The survival probabilities will better inform patients and clinicians of future outcomes.
PMID: 34363421
ISSN: 1399-0012
CID: 5241192

Extracorporeal photopheresis and its role in heart transplant rejection: prophylaxis and treatment

Slomovich, Sharon; Bell, Jennifer; Clerkin, Kevin J; Habal, Marlena V; Griffin, Jan M; Raikhelkar, Jayant K; Fried, Justin A; Vossoughi, Sarah R; Finnigan, Katie; Latif, Farhana; Farr, Maryjane A; Sayer, Gabriel T; Uriel, Nir
Heart transplantation is the gold standard therapeutic option for select patients with end-stage heart failure. Unfortunately, successful long-term outcomes of heart transplantation can be hindered by immune-mediated rejection of the cardiac allograft, specifically acute cellular rejection, antibody-mediated rejection, and cardiac allograft vasculopathy. Extracorporeal photopheresis is a cellular immunotherapy that involves the collection and treatment of white blood cells contained in the buffy coat with a photoactive psoralen compound, 8-methoxy psoralen, and subsequent irradiation with ultraviolet A light. This process is thought to cause DNA and RNA crosslinking, ultimately leading to cell destruction. The true mechanism of therapeutic action remains unknown. In the last three decades, extracorporeal photopheresis has shown promising results and is indicated for a variety of conditions. The American Society for Apheresis currently recommends the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma, scleroderma, psoriasis, pemphigus vulgaris, atopic dermatitis, graft-versus-host disease, Crohn's disease, nephrogenic systemic fibrosis, and solid organ rejection in heart, lung, and liver transplantation. In this review, we aim to explore the proposed effects of extracorporeal photopheresis and to summarize published data on its use as a prophylactic and therapy in heart transplant rejection.
PMID: 33914369
ISSN: 1399-0012
CID: 5238512

Exception Status Listing in the New Adult Heart Allocation System: A New Solution to an Old Problem?

Topkara, Veli K; Clerkin, Kevin J; Fried, Justin A; Griffin, Jan; Raikhelkar, Jayant; Hi Lee, Sun; Latif, Farhana; Habal, Marlena; Horn, Evelyn; Farr, Maryjane A; Takada, Koji; Naka, Yoshifumi; Jorde, Ulrich P; Sayer, Gabriel; Uriel, Nir
BACKGROUND:One of the goals of the revised 6-tiered US adult heart allocation policy was to improve risk stratification of patients to lower exception status utilization for transplant listing. We sought to define the characteristics and outcomes of waitlisted patients using exception status and to examine region- and center-level differences in utilization of exception status in the new heart allocation system. METHODS:This retrospective cohort analysis of the United Network for Organ Sharing database included adult waitlisted patients for heart transplant between October 18, 2018, and June 30, 2020, in the United States, stratified by use of exception status versus standard criteria. RESULTS:=0.12) after multivariable adjustment. CONCLUSIONS:The status tiers of the new heart allocation system may not fully capture medical urgency and complexity of waitlisted patients as assessed by transplant physicians and review committees and may limit the ability to develop a heart allocation score.
PMID: 34044577
ISSN: 1941-3297
CID: 4888262

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy

Habal, Marlena V; Miller, April M I; Rao, Samhita; Lin, Sijie; Obradovic, Aleksandar; Khosravi-Maharlooei, Mohsen; See, Sarah B; Roy, Poulomi; Shihab, Ronzon; Ho, Siu-Hong; Marboe, Charles C; Naka, Yoshifumi; Takeda, Koji; Restaino, Susan; Han, Arnold; Mancini, Donna; Givertz, Michael; Madsen, Joren C; Sykes, Megan; Addonizio, Linda J; Farr, Maryjane A; Zorn, Emmanuel
T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor β chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.
PMID: 33021057
ISSN: 1600-6143
CID: 5238502

Current Desensitization Strategies in Heart Transplantation

Habal, Marlena V
Heart transplant candidates sensitized to HLA antigens wait longer for transplant, are at increased risk of dying while waiting, and may not be listed at all. The increasing prevalence of HLA sensitization and limitations of current desensitization strategies underscore the urgent need for a more effective approach. In addition to pregnancy, prior transplant, and transfusions, patients with end-stage heart failure are burdened with unique factors placing them at risk for HLA sensitization. These include homograft material used for congenital heart disease repair and left ventricular assist devices (LVADs). Moreover, these risks are often stacked, forming a seemingly insurmountable barrier in some cases. While desensitization protocols are typically implemented uniformly, irrespective of the mode of sensitization, the heterogeneity in success and post-transplant outcomes argues for a more tailored approach. Achieving this will require progress in our understanding of the immunobiology underlying the innate and adaptive immune response to these varied allosensitizing exposures. Further attention to B cell activation, memory, and plasma cell differentiation is required to establish methods that durably abrogate the anti-HLA antibody response before and after transplant. The contribution of non-HLA antibodies to the net state of sensitization and the potential implications for graft longevity also remain to be comprehensively defined. The aim of this review is to first bring forth select issues unique to the sensitized heart transplant candidate. The current literature on desensitization in heart transplantation will then be summarized providing context within the immune response. Building on this, newer approaches with therapeutic potential will be discussed emphasizing the importance of not only addressing the short-term pathogenic consequences of circulating HLA antibodies, but also the need to modulate alloimmune memory.
PMID: 34504489
ISSN: 1664-3224
CID: 5238522

Allosensitization in Heart Transplantation: The Importance of a Comprehensive Approach [Meeting Abstract]

Bell, J.; Yuzefpolskaya, M.; Latif, F.; Restaino, S.; Uriel, N.; Sayer, G.; Dadhania, D.; Farr, M.; Sharma, V.; Habal, M.
ISSN: 1053-2498
CID: 5241332