The use of extracorporeal photopheresis in solid organ transplantation-current status and future directions.

Prevention and management of allograft rejection urgently require more effective therapeutic solutions. Current immunosuppressive therapies used in solid organ transplantation, while effective in reducing the risk of acute rejection, are associated with substantial adverse effects. There is, therefore, a need for agents that can provide immunomodulation, supporting graft tolerance, while minimizing the need for immunosuppression. Extracorporeal photopheresis (ECP) is an immunomodulatory therapy currently recommended in international guidelines as an adjunctive treatment for the prevention and management of organ rejection in heart and lung transplantations. This article reviews clinical experience and ongoing research with ECP for organ rejection in heart and lung transplantations, as well as emerging findings in kidney and liver transplantation. ECP, due to its immunomodulatory and immunosuppressive-sparing effects, offers a potential therapeutic option in these settings, particularly in high-risk patients with comorbidities, infectious complications, or malignancies.

Preliminary Experience of Extracorporeal Cytokine Hemoadsorption during Left Ventricular Assist Device Implantation in Cardiogenic Shock Patients.

BACKGROUND: Systemic inflammation due to cardiogenic shock is associated with vasoplegia leading to organ hypoperfusion, right heart failure, and poor clinical outcome. Extracorporeal cytokine hemoadsorption emerged to attenuate excessive levels of inflammatory cytokines, potentially improving patient outcomes. Nevertheless, its prognostic impact during high-risk left ventricular assist device (LVAD) implantation remains unknown. METHODS: In total, 40 consecutive patients with advanced heart failure underwent continuous-flow LVAD implantation at our institution between 2018 and 2020. Out of 25 high-risk patients in cardiogenic shock (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 and 2), 9 patients (CytoSorb group) underwent LVAD implantation with and 16 patients (control group) without simultaneous cytokine hemoadsorption during cardiopulmonary bypass. Besides preoperative patient characteristics, postoperative lactate clearance, vasopressor administration and mean arterial pressure, perioperative complication, and 30-day mortality rates were retrospectively analyzed. RESULTS: Apart from an increased rate of reoperations within the CytoSorb group, baseline characteristics including the severity of ventricular dysfunction and consecutive signs of end-organ failure were similar in both groups. Preoperative short-term mechanical circulatory support bridging was comparable (66.7 vs. 75%; p = 0.66) prior to LVAD implantation. Procedural characteristics including intraoperative volume management and postoperative vasopressor administration were similar in both groups. There was no difference regarding postoperative lactate clearance, although postoperative mean arterial pressure was significantly higher in the control group (71.3 vs. 57.4 mm Hg; p < 0.01). Furthermore, the 30-day mortality rate was significantly higher in the CytoSorb group (33.3 vs. 0.0%; p = 0.01). CONCLUSION: Extracorporeal cytokine hemoadsorption during high-risk LVAD implantation was not associated with a decrease of postoperative vasopressor support, improved hemodynamics, or an accelerated lactate clearance.

Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

ABSTRACT: When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.

Transvenous lead extraction after heart transplantation: How to avoid abandoned lead fragments.

BACKGROUND: Many patients awaiting heart transplantation (HTX) have a cardiac implantable electronic device (CIED). Lead removal is often still a part of the HTX procedure. Abandoned lead fragments carry a risk for infections and prohibit magnetic resonance imaging (MRI) imaging. This study evaluated the concept of an elective lead management algorithm after HTX. METHODS AND RESULTS: Between 2009 and 2018, 102 consecutive patients with previously implanted CIED underwent HTX. Lead removal by manual traction during HTX was performed in 74 patients until December 2014. Afterward, treatment strategy was changed and 28 patients received elective lead extraction procedures in a hybrid operating room (OR) using specialized extraction tools. Total of 74 patients with 157 leads underwent lead extraction by manual traction during HTX. The mean lead age was 32.3 ± 38.7 months. Postoperative X-ray revealed abandoned intravascular lead fragments in 31(41.9%) patients, resulting in a complete lead extraction rate of only 58.1%. The high rate of unsuccessful lead extractions led to the change in the extraction strategy in 2015. Since then, HTX was performed in 28 CIED patients. In those patients, 64 leads with a mean lead age of 53.8 ± 42.8 months were treated in an elective lead extraction procedure. No major or minor complications occurred during lead extraction. All leads could be removed completely, resulting in a procedural success rate of 100%. CONCLUSION: Our results demonstrate that chronically implanted leads should be removed in an elective procedure, using appropriate extraction tools. This enables complete lead extraction, which reduces the infection risk in this patient population with the necessity for permanent immunosuppressive therapy and allows further MRI surveillance.

Comparing everolimus-based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from six months after heart transplantation: the randomized MANDELA study.

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (i) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n=71), or to (ii) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n=74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at radomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 post-transplant post-randomization) with superiority of the CNI-free group versus EVR/redCNI : mean 64.1mL/min/1.73m2 versus 52.9mL/min/1.73m2 ; difference +11.3mL/min/1.73m2 (p<0.001). By month 18, estimated GFR had increased by ≥10mL/min/1.732 in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by ≥25 mL/min/1.73m2 in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI versus the CNI-free regimen (p=0.015); 6/15 episodes in CNI-free patients occurred with EVR concentration <5ng/mL. Rates of adverse events and associated discontinuations were comparable EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. This article is protected by copyright. All rights reserved.

Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report.

Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

The meaning of donor-specific antibodies after heart transplant.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) is a major contributor of impaired long-term survival after heart transplantation (HTx). The presence of circulating donor-specific antihuman leukocyte antigen (HLA) antibodies (DSAs) is considered as a mandatory criterion for AMR after HTx. DSA are known prognostic biomarkers of outcome, for example, recipients with de-novo DSA have a three-fold increased risk of mortality. RECENT FINDINGS: Although the awareness of the impact and prognosis of DSA on the survival has been increased in the HTx community over the last decade, the management of DSA pre and posttransplant varies among centers and is mainly based on the experience of transplant physicians. Thus, firm consensus strategies for each HTx recipient should be established by a center advisory board of experts in the field of HLA genetics, transplantation immunology, and HTx to evaluate the immunological risk preoperatively and also continuously during the posttransplant course. Consequently, the recent advances of invasive and noninvasive diagnostic tools should be applied, according to the risk, laboratory findings, and clinical events of the recipient. Such individual strategy will result in tailored therapeutic options. SUMMARY: Novel standards for the management of DSA in HTx recipients on the basis of an interdisciplinary approach of experts will improve diagnostics for personalized medicine.

Indication-specific immunomodulatory effects of extracorporeal photopheresis: A pilot study in heart transplanted patients.

BACKGROUND: The clinical use of extracorporeal photopheresis (ECP) is based on its ability to induce cell-mediated immune tolerance towards foreign and self-antigens. Up-to-date, no clear consensus consists on how to use ECP after heart transplantation (HTx). In this pilot study, we evaluated the stimulatory effects of ECP on immune cells in HTx patients. METHODS: HTx patients received ECP therapy as prophylaxis of rejection (PRX, n = 15), to treat acute cellular rejection (ACR, n = 13) or cardiac allograft vasculopathy (CAV, n = 5). Three ECP cycles with monthly frequency were performed. Blood samples were taken before every ECP cycle and 2 months after the last ECP cycle and were analyzed for cytokines and the tolerance-inducing cell subsets regulatory T cells (Tregs ), myeloid (mDCs), and plasmacytoid dendritic cells (pDCs). RESULTS: While ECP treatment induced first an increase of pDCs in the CAV group (baseline: 22.0% ± 9.6%, prior third ECP cycle: 8.6% ± 3.2%, follow-up: 31.5% ± 8.4%, P = .009), no significant changes of DC subsets and Tregs were observed in the ACR- and in the PRX group. Furthermore, analysis of the immune balance showed different response profiles of pro- and anti-inflammatory cytokines among prophylactically ECP-treated patients and ECP-treated patients suffering from CAV or ACR. CONCLUSIONS: In our pilot study, we showed different stimulatory effects of ECP on pDCs and cytokines among prophylactic and therapeutic ECP therapy after HTx. Immunological monitoring should be included in a larger clinical study of ECP treatment following HTx and to identify predictable parameters for ECP efficacy.

Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients.

CONTEXT: Several assays of monitoring immune cell function have been developed to enhance therapeutic drug monitoring. OBJECTIVE: An in vitro-validated whole-blood assay of phosphorylated ribosomal protein S6 (pS6RP) was evaluated for confounders to monitor the mTOR-inhibitor everolimus (ERL). MATERIALS AND METHODS: Whole blood samples from 87 heart transplant recipients were analyzed for pS6RP-expression in CD3-positive T-cells by phospho-flow analysis. RESULTS: ERL blood concentration, laboratory parameters, co-medications, demographic and clinical data were reviewed. CONCLUSION: Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.

Target Enzyme Activity and Phosphorylation of Pathway Molecules As Specific Biomarkers in Transplantation.

Therapeutic drug monitoring of immunosuppressants in the clinic is based on the measurement of blood concentration (pharmacokinetics). However, pharmacokinetic monitoring of immunosuppressants does not allow prediction of individual differences in pharmacological effects on immune cells. Pharmacodynamic (PD) monitoring via direct determination of target enzyme activity and phosphorylation of pathway molecules may enhance therapeutic drug monitoring and allow prediction of individual responses to immunosuppressants. This review discusses the clinical relevance of monitoring the activity of inosine-5'-monophosphate dehydrogenase (IMPDH), the target enzyme of mycophenolic acid, and of the phosphorylation of mechanistic target of rapamycin (mTOR) molecules. Significant progress regarding a robust and practicable assay for the determination of IMPDH activity as a specific PD parameter of mycophenolic acid activity has been achieved. The development of a rapid and reliable IMPDH assay system suitable for use in clinical practice was an important step that allowed thorough pharmacokinetics-PD investigations in large numbers of mycophenolic acid-treated patients. A reproducible and validated IMPDH assay was used in a few clinical trials by different research groups and is based on the chromatographic determination of newly generated xanthine monophosphate in mononuclear cell lysates. This assay requires only small volumes of blood and can be reliably used in multicenter trials; however, more clinical data from larger cohorts are needed to determine its clinical utility. Regarding monitoring of mTOR inhibitors (mTORis), the results of the first study that provided data on measurement of mTOR pathway molecules [p70 ribosomal protein S6 kinase (p70S6 kinase) and phosphorylated ribosomal protein S6] suggest that they are suitable targets for individualized PD monitoring of sirolimus and everolimus after organ transplantation. At present, only the phospho-flow phosphorylated ribosomal protein S6 assay has been validated in vitro and evaluated for confounding factors in vivo. The reported specific biomarkers for IMPDH activity and phosphorylation of mTOR molecules must be validated in clinical settings and multicenter studies to prove their clinical validity.

Therapeutic Drug Monitoring of Everolimus: A Consensus Report.

In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.

Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation.

With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.

Thymoglobulin induction in heart transplantation: patient selection and implications for maintenance immunosuppression.

Clinical data relating to rabbit antithymocyte globulin (rATG) induction in heart transplantation are far less extensive than for other immunosuppressants, or indeed for rATG in other indications. This was highlighted by the low grade of evidence and the lack of detailed recommendations for prescribing rATG in the International Society for Heart and Lung Transplantation (ISHLT) guidelines. The heart transplant population includes an increasing frequency of patients on mechanical circulatory support (MCS), often with ongoing infection and/or presensitization, who are at high immunological risk but also vulnerable to infectious complications. The number of patients with renal impairment is also growing due to lengthening waiting times, intensifying the need for strategies that minimize calcineurin inhibitor (CNI) toxicity. Additionally, the importance of donor-specific antibodies (DSA) in predicting graft failure is influencing immunosuppressive regimens. In light of these developments, and in view of the lack of evidence-based prescribing criteria, experts from Germany, Austria, and Switzerland convened to identify indications for rATG induction in heart transplantation and to develop an algorithm for its use based on patient characteristics.

Assessment of sub-clinical acute cellular rejection after heart transplantation: comparison of cardiac magnetic resonance imaging and endomyocardial biopsy.

OBJECTIVE: Comparing the diagnostic value of multi-sequential cardiac magnetic resonance imaging (CMR) with endomyocardial biopsy (EMB) for sub-clinical cardiac allograft rejection. METHODS: One hundred and forty-six examinations in 73 patients (mean age 53 ± 12 years, 58 men) were performed using a 1.5 Tesla system and compared to EMB. Examinations included a STIR (short tau inversion recovery) sequence for calculation of edema ratio (ER), a T1-weighted spin-echo sequence for assessment of global relative enhancement (gRE), and inversion-recovery sequences to visualize late gadolinium enhancement (LGE). Histological grade ≥1B was considered relevant rejection. RESULTS: One hundred and twenty-seven (127/146 = 87 %) EMBs demonstrated no or mild signs of rejection (grades ≤1A) and 19/146 (13 %) a relevant rejection (grade ≥1B). Sensitivity, specificity, positive predictive, and negative predictive values were as follows: ER: 63 %, 78 %, 30 %, and 93 %; gRE: 63 %, 70 %, 24 %, and 93 %; LGE: 68 %, 36 %, 13 %, and 87 %; with the combination of ER and gRE with at least one out of two positive: 84 %, 57 %, 23 %, and 96 %. ROC analysis revealed an area under the curve of 0.724 for ER and 0.659 for gRE. CONCLUSION: CMR parameters for myocarditis are useful to detect sub-clinical acute cellular rejection after heart transplantation. Comparable results to myocarditis can be achieved with a combination of parameters. KEY POINTS: • Magnetic resonance imaging is useful for the assessment of cardiac allograft rejection. • CMR has a high negative predictive value for exclusion of allograft rejection. • Diagnostic performance is not yet good enough to replace endomyocardial biopsy.

Prognostic impact of implantable cardioverter defibrillators and associated adverse events in patients with continuous flow left ventricular assist devices.

Objectives: Implantation of implantable cardioverter defibrillators (ICD) reduces the risk of all-cause mortality in symptomatic heart failure (HF) patients with severe left ventricular (LV) dysfunction. Nevertheless, the prognostic impact of ICD therapy in continuous flow left ventricular assist device (LVAD) recipients remains controversial. Methods: 162 consecutive HF patients, who underwent LVAD implantation at our institution between 2010 and 2019, were categorized according to the presence (n = 94, ICD-group) or absence (n = 68, Control-group) of ICDs. Apart from clinical baseline and follow-up parameters, adverse events (AEs) related to ICD therapy and overall survival rates were retrospectively analyzed. Results: Out of 162 consecutive LVAD recipients 79 patients (48.8%) were preoperatively categorized as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile ≤2. The prevalence of severe HF symptoms and preoperative use of short-term circulatory support devices (54.4% vs. 13.8%, p < 0.001) was higher within the Control-group, although baseline severity of LV and RV dysfunction was similar. Apart from an increased prevalence of perioperative right heart failure (RHF) within the Control-group (45.6% vs. 17.0%; p < 0.001), procedural characteristics and perioperative outcome were similar. Overall-survival during a median follow-up of 14 (3.0-36.5) months was similar within both groups (p = 0.46). During the first 2 years after LVAD implantation 53 ICD-related AEs occurred within the ICD-group. Thereof, lead-dysfunction occurred in 19 patients and unplanned ICD-reintervention in 11 patients. Furthermore, in 18 patients appropriate shocks without loss of consciousness occurred, whereas inappropriate shocks occurred in 5 patients. Conclusion: ICD therapy in LVAD recipients was not associated with a survival benefit or reduced morbidity after LVAD implantation. Conservative ICD-programming seems to be justified to avoid ICD-related complications and "awake shocks" after LVAD implantation.

Unloading, ablation, bridging and transplant: different indications and treatments using the Impella 5.5 as longer-term circulatory support in one patient-an interdisciplinary case report.

Background: In patients with cardiogenic shock the clinical treatment often involves temporary mechanical circulatory support for initial haemodynamic stabilization to enable further assessment of therapeutic strategies. The surgically implanted Impella 5.5 can be used for several indications like ventricular unloading, haemodynamic support during high-risk interventions, and as a bridge-to-transplant strategy.We present an interdisciplinary managed case of using Impella 5.5 for multiple indications and treatment strategies in one patient. Case summary: A 66-year-old patient with known dilated cardiomyopathy was admitted with non-ST-elevation myocardial infarction and underwent urgent coronary bypass grafting. His native heart function did not recover and he experienced recurrent episodes of sustained ventricular tachycardia (VT) and electrical storm. He was evaluated for heart transplantation (OHT) and received a VT-ablation. However, he suffered an in-hospital cardiac arrest (IHCA) with subsequent implantation of an extracorporeal life support system (ECLS). After surgical placement of an Impella 5.5 due to left ventricular distension and pulmonary congestion, the ECLS was successfully weaned. He showed good neurological outcomes and underwent another high-risk VT-ablation. The patient was further stabilized under Impella 5.5 support in a bridge-to-transplant strategy. After 34 days he underwent a successful OHT. Discussion: In this interdisciplinary case report the surgically implanted Impella 5.5 as temporary mechanical circulatory support was used for multiple different indications and treatment strategies like ventricular unloading, haemodynamic support during high-risk interventions, and as bridge-to-transplant strategy in one patient.

European multicenter study on the real-world use and clinical impact of extracorporeal photopheresis after heart transplantation.

BACKGROUND: Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. METHODS: Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. RESULTS: Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. CONCLUSIONS: This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors.

Effectiveness of Prophylactic Human Cytomegalovirus Hyperimmunoglobulin in Preventing Cytomegalovirus Infection following Transplantation: A Systematic Review and Meta-Analysis.

Cytomegalovirus (CMV) is a common infection occurring in patients undergoing solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). CMV-specific hyperimmunoglobulin (CMVIG) has been used for the past four decades and is typically administered either prophylactically or pre-emptively. The present meta-analysis evaluated CMV infection rates in SOT patients who received prophylactic CMVIG. PubMed and the Cochrane Library were searched for studies published up to October 2021. The primary endpoint was CMV infection rate. Thirty-two SOT studies were identified (n = 1521 CMVIG-treated and n = 1196 controls). Prophylactic CMVIG treatment was often associated with a lower risk of CMV infection in transplant recipients. The average CMV infection rate was 35.8% (95% confidence interval [CI]: 33.4−38.2%) in patients treated prophylactically with CMVIG and 41.4% (95% CI: 38.6−44.2%) in the control group not receiving CMVIG (p = 0.003). Similar results were observed in analyses limited to publications evaluating currently available CMVIG products (Cytotect CP and Cytogam; p < 0.001). In combination with the established safety profile for CMVIG, these results suggest that prophylactic CMVIG treatment in patients undergoing solid organ transplantation may be beneficial, particularly in those at high risk of CMV infection or disease.

Prognostic impact of functional mitral regurgitation prior to left ventricular assist device implantation.

BACKGROUND: Functional mitral regurgitation (FMR) is a common finding of advanced heart failure with detrimental effects. The prognostic impact of uncorrected FMR prior to left ventricular assist device (LVAD) implantation remains controversial. METHODS: Between 2016 and 2019 77 patients underwent continuous-flow LVAD implantation at our institution. 34 patients showed FMR ≥ 2 (MR-group), whereas 43 patients showed FMR < 2 (Control-group). Data was retrospectively analyzed. Primary composite endpoint comprised freedom from death, stroke, pump-thrombosis, major bleeding and right heart failure (RHF) after 1 year. RESULTS: Baseline characteristics, including the severity of left and right ventricular dysfunction, and periprocedural results were comparable. The overall survival during a mean follow up of 24.9 months was 55.9% in the MR-group versus 58.1% in the Control-group (p = 0.963), whereas 1-year event-free survival was 35.3% in the MR-group compared to 44.2% in the Control-group (p = 0.404). RHF within the first postoperative year occurred more frequently in the MR-group (35.3% vs. 11.6%; p = 0.017). Furthermore, RV function was significantly reduced in comparison to baseline values in the MR-group. 12 months after surgery, 74% of patients in the MR-group were classified as NYHA III in comparison to 24% of patients in the Control-group (p < 0.001). CONCLUSIONS: Preoperative uncorrected FMR prior to LVAD implantation did not affect overall survival, nevertheless it was associated with an impaired RV function and increased incidence of right heart failure during follow-up. Furthermore, preoperative FMR ≥ 2 was associated with persistent symptoms of heart failure.

An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients.

As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.