The International Consortium on Primary Graft Dysfunction: Redefining Clinical Risk Factors in the Contemporary Era of Heart Transplantation.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT. METHODS: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability. RESULTS: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD. CONCLUSIONS: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices.

European dermatology forum: Updated guidelines on the use of extracorporeal photopheresis 2020 - Part 2.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multidisciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-vs.-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines were divided into two parts: PART I covers Cutaneous T-cell lymphoma, chronic graft-vs.-host disease and acute graft-vs.-host disease, while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatric patients, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

European dermatology forum - updated guidelines on the use of extracorporeal photopheresis 2020 - part 1.

BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-versus-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T-cell lymphoma, chronic graft-versus-host disease and acute graft-versus-host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.

Dual-source cardiac computed tomography angiography (CCTA) in the follow-up of cardiac transplant: comparison of image quality and radiation dose using three different imaging protocols.

OBJECTIVES: To prospectively evaluate image quality (IQ) and radiation dose of dual-source cardiac computed tomography (CCTA) using different imaging protocols. METHODS: CCTA was performed in 150 patients using the retrospective ECG-gated spiral technique (rECG) the prospective ECG-gated technique (pECG), or the prospective ECG-gated technique with systolic imaging and automated tube voltage selection (pECGsys). IQ was rated using a 16-segment coronary artery model. Techniques were compared for overall IQ, IQ of the large and the small coronary artery segments. Effective dose was used for comparison of radiation dose. RESULTS: Overall IQ and IQ of the large segments showed no differences between the groups. IQ analysis of the small segments showed lowered IQ in pECGsys compared to rECG (p = 0.02), but not to pECG (p = 0.6). Effective dose did not differ significantly between rECG and pECG (p = 0.13), but was significantly lower for pECGsys (p < 0.001 vs. rECG and pECG). CONCLUSION: Radiation dose of dual-source CCTA in heart transplant recipients is significantly reduced by using prospective systolic scanning and automated tube voltage selection, while overall IQ and IQ of the large coronary segments are maintained. IQ appears to be lower compared to retrospective techniques with regard to small coronary segments. KEY POINTS: • Cardiac computed tomography angiography is useful for cardiac allograft vasculopathy assessment. • Despite elevated heart rate, dose reduction in cardiac computed tomography is possible. • Prospective systolic gating and automated tube voltage selection enable 50 % dose reduction.

A pilot study on reparixin, a CXCR1/2 antagonist, to assess safety and efficacy in attenuating ischaemia-reperfusion injury and inflammation after on-pump coronary artery bypass graft surgery.

Reparixin, a CXCR 1/2 antagonist, has been shown to mitigate ischaemia-reperfusion injury (IRI) in various organ systems in animals, but data in humans are scarce. The aim of this double-blinded, placebo-controlled pilot study was to evaluate the safety and efficacy of reparixin to suppress IRI and inflammation in patients undergoing on-pump coronary artery bypass grafting (CABG). Patients received either reparixin or placebo (n = 16 in each group) after induction of anaesthesia until 8 h after cardiopulmonary bypass (CPB). We compared markers of systemic and pulmonary inflammation, surrogates of myocardial IRI and clinical outcomes using Mann-Whitney U- and Fisher's exact tests. Thirty- and 90-day mortality was 0% in both groups. No side effects were observed in the treatment group. Surgical revision, pleural and pericardial effusion, infection and atrial fibrillation rates were not different between groups. Reparixin significantly reduced the proportion of neutrophil granulocytes in blood at the beginning [49%, interquartile range (IQR) = 45-57 versus 58%, IQR = 53-66, P = 0·035], end (71%, IQR = 67-76 versus 79%, IQR = 71-83, P = 0·023) and 1 h after CPB (73%, IQR = 71-75 versus 77%, IQR = 72-80, P = 0·035). Reparixin patients required a lesser positive fluid balance during surgery (2575 ml, IQR = 2027-3080 versus 3200 ml, IQR = 2928-3778, P = 0·029) and during ICU stay (2603 ml, IQR = 1023-4288 versus 4200 ml, IQR = 2313-8160, P = 0·021). Numerically, more control patients required noradrenaline ≥ 0·11 µg/kg/min (50 versus 19%, P = 0·063) and dobutamine (50 versus 25%, P = 0·14). Therefore, administration of reparixin in CABG patients appears to be feasible and safe. It concurrently attenuated postoperative granulocytosis in peripheral blood.

Sirolimus conversion after heart transplant: risk factors for acute rejection and predictors of renal function response.

In a randomized, comparative study of cardiac transplant patients with mild-to-moderate renal insufficiency, conversion from calcineurin inhibitors (CNIs) to sirolimus improved renal function at 1 year versus continuing CNIs, with an attendant risk of biopsy-confirmed acute rejection (BCAR). Post hoc analyses were conducted to identify predictors of BCAR and GFR improvement associated with conversion. Patients with proteinuria >500 mg/day were excluded. Univariate and multivariate regression analyses tested 13 parameters for BCAR and six for GFR improvement. In 57 sirolimus-treated patients, mean daily mycophenolate mofetil (MMF) dose was lower in those with versus without BCAR (1000 vs. 1420 mg; p = 0.014). Receiver operating characteristic analysis identified MMF dose ≤1000 mg/day as the optimal cutoff to predict BCAR. Multivariate analysis confirmed low MMF dose (odds ratio: 9.94; p = 0.007) and non-white race (odds ratio: 15.3; p = 0.06) were independently associated with BCAR. GFR improvement was evaluated in intent-to-treat patients (n = 116). Significant interaction was detected between treatment effect and preexisting diabetes status (univariate p = 0.077; multivariate p = 0.022), indicating greater beneficial effect of sirolimus in those without preexisting diabetes. These findings suggest that sirolimus is more effective in improving GFR in patients without preexisting diabetes, and adequate MMF doses are needed for sirolimus conversion.

Everolimus in heart transplantation: does it finally have a home?

This editorial approves the use of everolimus to wean calcineurin inhibitors (by 7­11 weeks postoperative) as safe and effective with improved first-year renal function and reduced intimal thickness by intravascular ultrasound. See article by Andreassen et al on page 1828.

Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial.

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: -7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency.

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

Influenza A-induced cardiogenic shock requiring temporary ECMO support and urgent heart transplantation.

We report a case of a child with familial cardiomyopathy who contracted H1N1 influenza followed by cardiovascular collapse requiring immediate arteriovenous ECMO support. Despite the lack of experience with heart transplantation (HTx) soon after H1N1 infection, HTx was considered as an exit strategy since restoration of cardiac function was considered unlikely. In contrast to the most common indication for ECMO use in patients with H1N1 infection, early ECMO support in cases with infection-induced myocardial decompensation may be lifesaving. Additionally, this report shows that urgent heart transplantation in a patient on ECMO support can be performed safely after recent H1N1 infection and simultaneous heparin-induced thrombocytopenia, which has not been reported before. This case also indicates that H1N1 vaccination should be considered for potential transplantation candidates to prevent severe infection.

Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions.

Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.

Introducing a mouse model of brain death.

Experimental animal models of brain death increasing intracranial pressure (ICP) by inflating an intracranial placed balloon-catheter are well established and used in transplant-associated studies. Our aim was to develop an experimental mouse model of brain death (BD) and to compare explosive and gradual brain death induction under ICP monitoring. We therefore induced BD in female OF-1 mice by injecting 40 microl saline every 5 min into an intracranial placed balloon increasing ICP rapidly [BD ex, n=7], or gradually [BD grad, n=7] with 20 microl volume every 5 min under electroencephalogram (EEG) and ICP monitoring until BD occurred. The major criterion for BD was a flat-line-EEG, confirmed by cessation of spontaneous respiration and maximally dilated and fixed pupils. ICP, central activity and heart rate were continuously monitored during the entire 6h follow-up. In sham-operated controls [control, n=7] a burr hole was drilled but no balloon inserted. The BD groups showed equal ICP levels at the time of BD. Both groups had increased heart rates (HR) 15 min after BD, HR decreased to 402+/-29.39 bpm (beats per minute) [BD ex] and 409.33+/-26.46 bpm [BD grad] (n.s. vs. control) by 30 min after the inflation of the balloon, but only BD ex showed a significant decrease in HR compared to control, progressively decreasing thereafter. On the basis of these results, we conclude that the mouse model of brain death can be performed in a standardized, reproducible and successful way.

Serum matrix metalloprotease-1 and vascular endothelial growth factor--a predict cardiac allograft rejection.

Cardiac allograft rejection is currently diagnosed from endomyocardial biopsies (EMB) that are invasive and impractical to repeat. A serological marker could facilitate rejection monitoring and minimize EMB-associated risks. We investigated the relation of serum matrix metalloprotease (MMP)-1 and vascular endothelial growth factor (VEGF)-A concentrations to cardiac allograft rejection, using 1176 EMBs and serum samples obtained from 208 recipients. Acute cellular rejection was diagnosed in 186 EMBs. Mean week 1 and week 2 serum MMP-1 concentrations predicted rejection (p = 0.001, AUC = 0.80). At the optimal cut-off level of >or=7.5 ng/mL, MMP-1 predicted rejection with 82% sensitivity and 72% specificity. Initial serum MMP-1 <5.3 ng/mL (lowest quartile) was associated with rejection-free outcome in 80% of patients. Both MMP-1 (p < 0.001, AUC = 0.67-0.75) and VEGF-A (p < 0.01, AUC = 0.62-0.67) predicted rejection on the next EMB, while rejection at EMB was identified only by VEGF-A (p < 0.02, AUC = 0.70-0.77). Patients receiving combined cyclosporine-A and everolimus had the lowest serum MMP-1 concentrations. While serum MMP-1 predicts rejection-free outcome and VEGF-A identifies rejection on EMB, both markers predict rejection in follow-up of cardiac transplant recipients. Combination of serum MMP-1 and VEGF-A concentration may be a noninvasive prognostic marker of cardiac allograft rejection, and could have important implications for choice of surveillance and immunosuppression protocols.

Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients.

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil +/- steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0-5.7) preswitch to 0.23 g/day (0-9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.

Proliferation signal inhibitors in transplantation: questions at the cutting edge of everolimus therapy.

While advances in immunosuppressive therapy have allowed dramatic improvements in the control of acute allograft rejection, there is still a need to improve long-term graft and patient survival rates following renal and heart transplantation. Among the recognized threats to long-term organ survival are chronic allograft dysfunction in the form of chronic allograft nephropathy and cardiac allograft vasculopathy, with long-term patient morbidity and mortality further compromised by higher than normal rates of posttransplant cardiovascular disease, infection, and malignancy. A growing body of evidence finds that the selection and dosing of immunosuppressive therapies can have great influence on long-term transplantation outcomes. Early evidence suggests that the proliferation signal inhibitors (PSIs), everolimus and sirolimus, might offer effective immunosuppressive activity together with antiproliferative effects that may address some of the unmet needs in the long-term therapeutic management of the posttransplant patient. This review summarizes the emerging evidence for employing PSI-based immunosuppression to seek a balance between the goals of maximizing graft and patient survival, while minimizing the risks of adverse events and long-term complications. Based on the proceedings of an international gathering of nephrologists, cardiologists and surgeons at the inaugural PSI Forum meeting "Proliferation signal inhibitors in transplantation: questions at the cutting edge," this paper aims to provide both an evidence base and practical guidance for transplant physicians seeking to optimize their use of PSI treatment and highlights avenues of ongoing research into the clinical potential of this class of immunosuppressive therapy.

Donor myocardial HIF-1alpha is an independent predictor of cardiac allograft dysfunction: a 7-year prospective, exploratory study.

Knowledge on interplay between the cardiac molecular response to transplantation-induced stress and primary graft dysfunction (PGD) is limited. A cDNA array identified HIF-1, EGR-1, NAB-2, VEGF-A and uPA as mediators of cardiac tissue response to transplantation-induced stress. mRNA expression of these molecules was measured in left ventricular biopsies from 200 donors before and after aortic cross-clamping and at 10-, 30- and 60-min reperfusion by real-time RT-PCR. HIF-1alpha expression at two time points was significantly associated with PGD, as shown by univariate analysis, receiver operating characteristic curve and multivariate logistic regression. At a cut-off level of 200 arbitrary units, HIF-1alpha after aortic cross-clamping in donors (78% sensitivity, 83% specificity) and at 10-min reperfusion (85% sensitivity, 83% specificity) identified PGD. HIF-1alpha demonstrates the potential to be a predictive marker for PGD; however, as multiple factors were tested at different time points, prospective evaluation is clearly necessary to confirm this observation.

[Vacuum assisted closure therapy for the treatment of sternal wound infections after heart transplantation: preliminary results]. / VAC-Therapie zur Behandlung von sternalen Wundinfektionen nach Herztransplantation: Erste Ergebnisse.

Sternal wound infection after heart transplantation is a feared and potentially life threatening complication with reported incidences between 2.5 % and 3.6 %. However, optimal therapy of sternal wound infections in heart transplant recipients remains a matter of controversy, particularly the effect of immunosuppression in those patients is still unclear. We examined 5 heart transplanted patients (4 men and 1 woman with a median age of 46 +/- 21.4 years (ranging from 14 to 59 years) in terms of inflammation and treatment response during VAC therapy. Infection begin was median 18.2 days (+/- 10 days, ranging from 5 to 28 days) after transplantation. VAC therapy lasted on average 12.2 +/- 2 days, ranging from 10 to 19 days. A median of 3 changes (range from 3 to 5) were necessary until the definitive closure. We examined C-reactive protein, leucocyte count and fibrinogen 2 days pre VAC, during VAC treatment and 2 days after definitive closure. All five patients showed an increase of leucocytes at every VAC change. Furthermore, we saw an adequate reaction to the VAC in terms of granulation tissue growth and resolution of infection. Transplanted patients had an increase of leucocytes at every VAC change. Furthermore all patients showed an adequate response of VAC treatment in terms of granulation tissue in growth and infection decline. Therefore a reduction of immunosuppressive therapy is not necessary, which in turn would increase the risk of rejection.

Recovery from giant cell myocarditis with ECMO support and utilisation of polyclonal antithymocyte globulin: a case report.

Giant cell myocarditis (GCM) is a rare and frequently fatal disorder. Patients suffer of ventricular arrhythmias or congestive heart failure. Here we describe a patient with cardiogenic shock and histological verified GCM. The patient was saved by implantation of extracorporeal membrane oxygeneation (ECMO) device and concomitant application of Rabbit antithymocyte globuline (rATG, Thymoglobulin, Sangstat), cyclosporine, and steroids in the acute event. 12 months after the crisis the patient evidences NYHA class I heart function and only a moderate impairment of heart function (EF 55%). The novel utilisation of ECMO in GCM related cardiogenic shock and application of rATG have prooven life-saving in this patient. Studies utilizing rATG in the treatment of GCM are warrented.