T. Khuu

Extended spectrum β-lactamase-producing Enterobacteriaceae infection in heart and lung transplant recipients and in mechanical circulatory support recipients.

Background Extended spectrum &bgr;-lactamase (ESBL)–producing gram-negative bacilli are increasingly reported in patients with a variety of risk factors including prior cephalosporin and antibiotic usage, prolonged hospitalizations, existence of comorbid conditions, and critical illness. Methods Retrospective review of infections caused by ESBL-producing Enterobacteriaceae was performed in heart transplant (HTx), lung transplant (LTx), and mechanical circulatory support (MCS) device recipients at a large transplant center. Results Among 1065 patients transplanted/implanted, the incidence of ESBL-related infections (bacteremia, urinary tract infections, pneumonia, central venous catheter–associated infection, and wound infections) in HTx, LTx, and MCS device recipients was reported at 2.2%, 5.5%, and 10.7%, respectively, caused by ESBL-producing Klebsiella pneumoniae, Escherichia coli, Klebsiella oxytoca, and Citrobacter freundii. Conclusions Early detection and adequate duration of therapy for ESBL-producing Enterobacteriaceae in solid organ transplants and MCS device recipients are essential in successful patient outcomes including prevention of recurrent infection.

Reduced HLA Class II antibody response to proteasome inhibition in heart transplantation

Antibody-mediated rejection (AMR) has become an increasingly recognized entity in heart transplantation linked to poor outcomes. Treatment algorithms for AMR vary from institution to institution, and therapeutic options remain limited. Responses to standard therapies, such as plasmapheresis, intravenous immunoglobulin, corticosteroids, and rituximab, are not always apparent. Bortezomib, a first-in-class 26S proteasome inhibitor that was approved by the U.S. Food and Drug Administration for multiple myeloma, is emerging as an alternative therapy option for AMR. Proteasome inhibition results in depletion of plasma cells, a primary source of antibody production. Additionally, a major function of the 26S proteasome is antigen processing for HLA Class I presentation. We postulated that compared with Class II responses, bortezomib would be more effective in preventing de novo Class I antibody production. To date, there have not been published reports of the variable immunologic responses of specific HLA antibody types to bortezomib in heart transplantation. Here we report the first case series, to our knowledge, of the differential effect on donor-specific and third-party antibodies in heart transplant recipients treated with bortezomib. Institutional review board approval was obtained. A retrospective review was conducted of all adult patients receiving bortezomib for biopsy-proven or clinically suspected AMR from August 2010 to January 2012. Diagnosis of AMR consisted of positive endomyocardial biopsy by histology and immunohistochemistry, hemodynamic changes, or significant changes in donor-specific antibody (DSA) mean fluorescence intensity (MFI). An antibody MFI cutoff of Z5,000 was used, and a Z50% change in MFI was considered significant. Treatment consisted of plasmapheresis followed by bortezomib (0.7–1 mg/m intravenous push) on Day 1, 4, 7, and 10 followed by a 3-day course of plasmapheresis beginning 72 hours after the last bortezomib dose. Treatment efficacy was determined by clinical or histologic improvement or a significant change in DSA. Antibody MFI was determined via single-antigen Luminex assay (Luminex (R), One Lambda Inc., Canoga, Park, CA). Antibody samples were obtained on Day 5, 11, 14, and 30 and at each clinical follow-up. To study the antibody response to treatment, we constructed a matrix of data of all tested antibodies and used hierarchical clustering based on the Pearson correlation to generate a clustered heat map. The Pearson correlation is a standardized measure of linear dependency between 2 variables and was used because of its independence of scale, allowing for the identification of variables undergoing similar relative changes without dependence on absolute magnitudes or units. Wilcoxon signed rank test was used to calculate statistical significance of MFI changes. Statistical analysis was done using R (R Foundation for Statistical Computing, Vienna, Austria).

INFLUENCE OF PRE-TRANSPLANT CHRONIC KIDNEY DISEASE ON OUTCOMES OF ADULT HEART TRANSPLANT-ONLY RECIPIENTS: UNOS REGISTRY ANALYSIS

Renal dysfunction severity is considered for heart transplant (HT) candidacy. However, acceptable level of dysfunction is not well defined. The influence of Chronic Kidney Disease (CKD) stage on post-HT outcomes is unknown. 30437 HT patients (pts) were identified from UNOS (1987-2011) & stratified

Clinical phenomapping and outcomes after heart transplantation

BACKGROUND Survival after heart transplantation (HTx) is limited by complications related to alloreactivity, immune suppression, and adverse effects of pharmacologic therapies. We hypothesize that time-dependent phenomapping of clinical and molecular data sets is a valuable approach to clinical assessments and guiding medical management to improve outcomes. METHODS We analyzed clinical, therapeutic, biomarker, and outcome data from 94 adult HTx patients and 1,557 clinical encounters performed between January 2010 and April 2013. Multivariate analyses were used to evaluate the association between immunosuppression therapy, biomarkers, and the combined clinical end point of death, allograft loss, retransplantation, and rejection. Data were analyzed by K-means clustering (K = 2) to identify patterns of similar combined immunosuppression management, and percentile slopes were computed to examine the changes in dosages over time. Findings were correlated with clinical parameters, human leucocyte antigen antibody titers, and peripheral blood mononuclear cell gene expression of the AlloMap (CareDx, Inc., Brisbane, CA) test genes. An intragraft, heart tissue gene coexpression network analysis was performed. RESULTS Unsupervised cluster analysis of immunosuppressive therapies identified 2 groups, 1 characterized by a steeper immunosuppression minimization, associated with a higher likelihood for the combined end point, and the other by a less pronounced change. A time-dependent phenomap suggested that patients in the group with higher event rates had increased human leukocyte antigen class I and II antibody titers, higher expression of the FLT3 AlloMap gene, and lower expression of the MARCH8 and WDR40A AlloMap genes. Intramyocardial biomarker-related coexpression network analysis of the FLT3 gene showed an immune system-related network underlying this biomarker. CONCLUSIONS Time-dependent precision phenotyping is a mechanistically insightful, data-driven approach to characterize patterns of clinical care and identify ways to improve clinical management and outcomes.

Fungi as Eukaryotes: Understanding the Antifungal Effects of Immunosuppressive Drugs

The immunosuppressive agents cyclosporine, tacrolimus, and sirolimus are naturally occurring products of environmental fungi or bacteria, so the fact that they possess intrinsic antifungal activity is not surprising. Both calcineurin and the target of rapamycin (TOR) are conserved across eukaryotes and share a common function, regulating the organism’s ability to react to environmental changes and response to stress. In the medically important fungi Candida, Cryptococcus, and Aspergillus, mutations in the calcineurin gene affect in vitro patterns of growth and serum sensitivity, and attenuate virulence in animal models. Notably, cyclosporine, tacrolimus, and sirolimus exhibit strong synergy with many classes of antifungal drugs including azoles, amphotericin B, and the echinocandins, with potentiation of fungicidal effects even against drug-resistant strains. Hopefully, future studies will realize the promise of exploiting the antifungal properties of the immunosuppressive drugs to help decrease the burden of these clinically important infections on patient survival.

SURVIVAL OF HEART TRANSPLANT RECIPIENTS BRIDGED WITH LVAD SUPPORT BY GENDER

Gender differences in heart transplant (HT) outcomes are well known. However, differences among those bridged with LVAD (BTT) have not been well studied. We sought to examine the mortality differences in this population. 3020 BTT HT patients (exclusions:< 18y, multiorgan, follow up loss) were