Comparison of feasibility and results of frailty assessment methods prior to left ventricular assist device implantation.

AIMS: Assessing frailty and sarcopenia is considered a valuable cornerstone of perioperative risk stratification in advanced heart failure patients. The lack of an international consensus on a diagnostic standard impedes its implementation in the clinical routine. This study aimed to compare the feasibility and prognostic impact of different assessment tools in patients undergoing continuous-flow left ventricular assist device (cf-LVAD) implantation. METHODS AND RESULTS: We prospectively compared feasibility and prognostic values of six frailty/sarcopenia assessment methods in 94 patients prior to cf-LVAD implantation: bioelectrical impedance analysis (BIA), computed tomography (CT)-based measurement of two muscle areas/body surface area [erector spinae muscle (TMESA/BSA) and iliopsoas muscle (TPA/BSA)], physical performance tests [grip strength, 6 min walk test (6MWT)] and Rockwood Clinical Frailty Scale (RCFS). Six-month mortality and/or prolonged ventilation time >95 h was defined as the primary endpoint. BIA and CT showed full feasibility (100%); physical performance and RCFS was limited due to patients' clinical status (feasibility: 87% grip strength, 62% 6MWT, 88% RCFS). Phase angle derived by BIA showed the best results regarding the prognostic value for 6 month mortality and/or prolonged ventilation time >95 h (odds ratio (OR) 0.66 [95% confidence interval (CI): 0.46-0.92], P = 0.019; area under the curve (AUC) 0.65). It provided incremental value to the clinical risk assessment of EuroSCORE II: C-index of the combined model was 0.75 [95% CI; 0.651-0.848] compared with C-index of EuroSCORE II alone, which was 0.73 (95% CI: 0.633-0.835). Six-month survival was decreased in patients with reduced body cell mass derived by BIA or reduced muscle area in the CT scan compared with patients with normal values: body cell mass 65% (95% CI: 51.8-81.6%) vs. 83% (95% CI: 74.0-93.9%); P = 0.03, TMESA/BSA 65% (95% CI: 51.2-82.2%) vs. 82% (95% CI: 73.2-93.0%); P = 0.032 and TPA/BSA 66% (95% CI: 53.7-81.0%) vs. 85% (95% CI: 75.0-95.8%); P = 0.035. CONCLUSIONS: Bioelectrical impedance analysis parameters and CT measurements were shown to be suitable to predict 6-month mortality and/or prolonged ventilation time >95 h in patients with advanced heart failure prior to cf-LVAD implantation. Phase angle had the best predictive capacity and sarcopenia diagnosed by reduced body cell mass in BIA or muscle area in CT was associated with a decreased 6 month survival.

Impact of Muscle Mass as a Prognostic Factor for Failed Waiting Time Prior to Heart Transplantation.

Objectives: Clinical deterioration during the waiting time impairs the prognosis of patients listed for heart transplantation. Reduced muscle mass increases the risk for mortality after cardiac surgery, but its impact on resilience against deterioration during the waiting time remains unclear. Methods: We retrospectively analyzed data from 93 patients without a VAD who were listed in Eurotransplant status "high urgent (HU)" for heart transplantation between January 2015 and October 2020. The axial muscle area of the erector spinae muscles at the level of thoracic vertebra 12 indexed to body surface area (TMESA/BSA) measured in the preoperative thoracic computed tomography scan was used to measure muscle mass. Results: Forty patients (43%) underwent emergency VAD implantation during the waiting time and four patients (4%) died during the waiting time. The risk of emergency VAD implantation/death during the waiting time decreased by 10% for every cm2/m2 increase in muscle area [OR 0.901 (95% CI: 0.808-0.996); p = 0.049]. After adjusting for gender [OR 0.318 (95% CI: 0.087-1.073); p = 0.072], mean pulmonary artery pressure [OR 1.061 (95% CI: 0.999-1.131); p = 0.060], C-reactive protein [OR 1.352 (95% CI: 0.986-2.027); p = 0.096], and hemoglobin [OR 0.862 (95% CI: 0.618-1.177); p = 0.360], TMESA/BSA [OR 0.815 (95% CI: 0.698-0.936); p = 0.006] remained an independent risk factor for emergency VAD implantation/death during the HU waiting time. Conclusion: Muscle area of the erector spinae muscle appears to be a potential, easily identifiable risk factor for emergency VAD implantation or death in patients on the HU waiting list for heart transplantation. Identifying patients at risk could help optimize the outcome and the timing of VAD support.

Safety of bioelectrical impedance analysis in advanced heart failure patients.

BACKGROUND: Cardiac cachexia and frailty are major complications of advanced heart failure (AHF). Bioelectrical impedance analysis (BIA) may provide valuable information regarding fluid balance, muscle mass and prognosis. The main concerns regarding the use of BIA in AHF patients remain arrhythmias and electromagnetic interferences with cardiac implantable electronic devices (CIEDs). Reliable data regarding patients on continuous-flow ventricular assist device (cf-VAD) remain scarce. The aim of this study is to evaluate the safety of BIA in AHF patients on pro-arrhythmogenic therapy with an implanted CIED and/or with a cf-VAD. METHODS: We prospectively performed 217 BIA measurements in 143 AHF patients at risk of severe arrhythmias due to inotropic support/a history of ventricular arrhythmias and/or treated with CIED, including 104 patients with an ICD, CRT or pacemaker and 95 patients with a cf-VAD. All patients were under continuous Electrocardiogram (ECG) monitoring and clinical surveillance for 24 hours. RESULTS: No adverse events were observed during the 217 BIA measurements: No rhythm disturbances were documented in the telemetric monitoring during or within 30 minutes after the measurement. CIEDs showed no malfunction, regardless of the location measured or the device manufacturer. In particular, no inappropriate shocks were observed. No alarms, flow disturbances, or malfunctions of the cf-VAD occurred during or after the measurements. CONCLUSION: We consider BIA a safe measurement with major clinical relevance in our cohort of AHF patients, despite an increased arrhythmic potential on inotropic support or the presence of implanted electronic devices (ICD, CRT, pacemaker and cf-VAD).

Plasmid-Mediated Transmission of KPC-2 Carbapenemase in Enterobacteriaceae in Critically Ill Patients.

Carbapenem-resistant Enterobacteriaceae (CRE) cause health care-associated infections worldwide, and they are of severe concern due to limited treatment options. We report an outbreak of KPC-2-producing CRE that was caused by horizontal transmission of a promiscuous plasmid across different genera of bacteria and hospitals in Germany. Eleven isolates (8 Citrobacter freundii, 2 Klebsiella oxytoca, and 1 Escherichia coli) were obtained from seven critically ill patients during the six months of the outbreak in 2016. One patient developed a CRE infection while the other six patients were CRE-colonized. Three patients died in the course of the hospital stay. Six of the seven patients carried the same C. freundii clone; one K. oxytoca clone was found in two patients, and one patient carried E. coli and C. freundii. Molecular analysis confirmed the presence of a conjugative, bla KPC-2-carrying 70 kb-IncN plasmid in C. freundii and E. coli and an 80 kb-IncN plasmid in K. oxytoca. All transconjugants harbored either the 70 or 80 kb plasmid with bla KPC-2, embedded within transposon variant Tn4401g. Whole genome sequencing and downstream bioinformatics analyses of all plasmid sequences showed an almost perfect match when compared to a bla KPC-2-carrying plasmid of a large outbreak in another German hospital two years earlier. Differences in plasmid sizes and open reading frames point to the presence of inserted mobile genetic elements. There are few outbreak reports worldwide on the transmission of bla KPC-2-carrying plasmids across different bacterial genera. Our data suggest a regional and supraregional spread of bla KPC-2-carrying IncN-plasmids harboring the Tn4401g isoform in Germany.

Adjusting preoperative risk models of post heart transplant survival to a European cohort in the age of a new cardiac allocation score in Europe.

Background Several risk models target the issue of posttransplant survival, but none of them have been validated in a large European cohort. This aspect is important, in a time of the planned change of the Eurotransplant allocation system to a scoring system. Material and Methods Data of 761 heart transplant recipients from the Eurotransplant region with a total follow up of 5027 patient-years were analyzed. We assessed 30-day to 10-year freedom from graft failure. Existing post-transplant mortality risk models, IMPACT, Meld-XI and Columbia Risk Stratification Score were (RSS) were evaluated. A new risk model was created and the predictive accuracy was compared with the existing risk scores, with a focus on LVAD patients. Results Thirty-day, 1-year, 5-year and 10-year rates of freedom from graft failure were 78.3±1.5%, 68.8±1.71%, 59.1±1.8% and 44.1±1.9. The 1-year incidence of graft failure varied from 14.1% to 50% (RSS), from 22.9% to 57.1 (IMPACT) and from 24.9% to 42.6% using MELD-XI. Our newly adjusted risk score showed an improved area under the curve (AUC) of 0.69 (95% CI 0.64-0.72) with better discrimination in the intermediate to moderate risk cohort (CABDES Score). Conclusion IMPACT, Meld-XI and RSS were suitable to predict posttransplant graft failure only in a high and low risk cohort. CABDES Score, might be an alternative scoring system, with donor age and eGFR beeing the strongest predictors. Implementation of the IMPACT score within the new Eurotransplant Cardiac Allocation Score for patient prioritization for heart transplantation, should be reevaluated.

Effect of surgical incision management on wound infections in a poststernotomy patient population.

Skin breakdown and infiltration of skin flora are key causative elements in poststernotomy wound infections. We hypothesised that surgical incision management (SIM) using negative pressure wound therapy over closed surgical incisions for 6-7 days would reduce wound infections in a comprehensive poststernotomy patient population. 'All comers' undergoing median sternotomy at our institution were analysed prospectively from 1 September to 15 October 2013 (study group, n = 237) and retrospectively from January 2008 to December 2009 (historical control group, n = 3508). The study group had SIM (Prevena™ Therapy) placed immediately after skin suturing and applied at -125 mmHg for 6-7 days, whereas control group received conventional sterile wound tape dressings. Primary endpoint was wound infection within 30 days. Study group had a significantly lower infection rate than control group: 1·3% (3 patients) versus 3·4% (119 patients), respectively (P < 0·05; odds ratio 2·74). In the study group, when the foam dressing was removed after 6-7 days, the incision was primarily closed in 234 of 237 patients (98·7%). SIM over clean, closed incisions for the first 6-7 postoperative days significantly reduced the incidence of wound infection after median sternotomy. Based on these data SIM may be cost-effective in patients undergoing cardiac surgery.

The effects of bilateral lung transplantation on ventilatory efficiency, oxygen uptake and the right heart: a two-yr follow-up.

BACKGROUND: This study was to examine the course of ventilation/perfusion mismatch (VE/VCO(2)-slope) before and during two-yr follow-up after bilateral lung transplantation (BLTx) and to relate exercise parameters with the reverse right ventricular remodeling. METHODS: We prospectively examined 20 patients (nine women; age 46.0 ± 13.0 yr) by cardiopulmonary exercise testing (before and at 3, 6, 12, and 24 months after BLTx), and by echocardiography and blood gas analysis. Etiology of pulmonary failure was chronic obstructive pulmonary disease as well (n = 8), pulmonary hypertension (n = 7), idiopathic fibrosis (n = 3), others (n = 2). RESULTS: The VE/VCO(2)-slope before BLTx was 47.5 (interquartile range 24.5) and declined at 3 months -25.9%, 6 months -30.9%, 12 months -33.9%, and 24 months -35.1% (all p ≤ 0.003) and was then not different from normal. The right ventricular end diastolic diameter RVEDd narrowed from 35.0 (22.5) before to 31.0 (9.0) mm at 3 months after LTx. Similarly, right ventricular systolic pressure (RV(sys)) decreased from 53.6 ± 28.3 to 26.2 ± 5.2 mmHg (all p < 0.01). RVEDd correlated with VE/VCO(2)-slope before (p < 0.0001) but not after BLTx. PeakVO(2) increased from 10.0 ± 2.3 mL/min per kg before BLTx by 86.5% at 24 months (p < 0.01). CONCLUSIONS: The functional status (VE/VCO(2)-slope, peakVO(2)) improves quickly after lung transplantation and is accompanied by reverse remodeling of the right heart. A correlation between exercise parameters and right heart function was found before BLTx only.

Cyanoacrylate-sealed Donati suture for wound closure after cardiac surgery in obese patients.

The majority of wound infections after median sternotomy in obese patients are triggered by the breakdown of skin suture and subsequent seepage of skin flora into the deeper tissue layers. In a prospective study, 90 patients (body mass index ≥30) who had cardiac surgery via median sternotomy were enrolled. In 45 patients, skin closure was performed according to the Donati technique (vertical interrupted mattress suture) and sealed with octylcyanoacrylate (group A). In 45 patients, intracutaneous running technique without sealed was performed (group B). The endpoint was wound infection within 90 days. Degree of obesity and other risk factors for wound infection were equally distributed between groups A and B (all P>0.05). In group A only two superficial infections occurred, whereas in group B there were nine wound infections including two deep infections (P=0.026). In 10 of 11 infections (both groups) coagulase-negative staphylococci were isolated. In eight of 11 wound infections the caudal third of the incision was affected. Intertrigo in inframammary skin folds was found in 20.0% (18/90) of all patients but in 63.6% (seven of 11) of cases with infection. We conclude, that cyanoacrylate-sealed Donati suture is superior to intracutaneous suture technique since it offers tension-resistant closure with immediate microbial barrier properties.

A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus.

BACKGROUND: Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed. METHODS: Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed. RESULTS: CMV-positive donors (D+) and CMV-negative recipients (R-) were evenly distributed across groups 1-3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R- subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA. CONCLUSIONS: Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

Observational study with everolimus (Certican) in combination with low-dose cyclosporine in de novo heart transplant recipients.

BACKGROUND/METHODS: This observational study reports on immunosuppression with cyclosporine (CsA) in 38 de novo heart transplant recipients receiving everolimus compared with 14 patients receiving mycophenolate mofetil (MMF). RESULTS: Mean (+/- SD) everolimus C0 blood levels remained stable within 5 to 7 ng/ml. Mean CsA C0 blood levels were reduced by 47%, from 240 +/- 57 ng/ml at 2 weeks post-transplant to 128 +/- 38 ng/ml at Month 6 and by 58% to 101 +/- 26 ng/ml at Month 12 in the everolimus group, compared to 18% from 246 +/- 54 ng/ml at 2 weeks post-transplant to 201 +/- 48 ng/ml at Month 6 and by 35% to 160 +/- 41 ng/ml in MMF patients. Efficacy was high with a rejection rate of 23.6% (everolimus) vs 28.5% (MMF) by Month 12. Mean pre-transplant serum creatinine levels of 1.67 +/- 0.59 mg/dl decreased to 1.53 +/- 0.57 mg/dl under everolimus and increased from 1.22 +/- 0.36 to 1.99 +/- 0.75 mg/dl in the MMF group by Month 12 post-transplant. However, calculated GFR declined in both groups by Month 12 (everolimus: from 71 +/- 29 to 57 +/- 27 ml/min/1.73 m2; MMF: from 73 +/- 22 to 44 +/- 24 ml/min/1.73 m2), with stabilization after 3 to 6 months in everolimus-treated patients and after 6 to 9 months in MMF-treated patients. CONCLUSIONS: Everolimus allows marked reduction of CsA exposure without significant loss of efficacy and also provides early protection of renal function.

Salvage chemotherapy for refractory and relapsed posttransplant lymphoproliferative disorders (PTLD) after treatment with single-agent rituximab.

BACKGROUND: Single-agent rituximab has demonstrated encouraging efficacy and tolerability in posttransplant lymphoproliferative disorders (PTLDs) failing to respond to immunosuppression reduction (IR). This retrospective analysis was undertaken to determine the efficacy and safety of salvage therapy in recipients of solid organ transplants with progression of PTLD after rituximab first-line therapy. METHODS: Eleven patients who had received IR and single-agent rituximab were analyzed. Of these, 10 had received CHOP salvage chemotherapy. One patient with limited disease received tumor irradiation and further IR. Most patients (73%) had late PTLD (median onset of disease 145 months posttransplant), and most (83%) had monomorphic histology; 36% had EBV-association. RESULTS: IR and irradiation therapy re-induced complete remission (CR) and allowed long-term disease control in a patient with polymorphic PTLD relapse. CHOP therapy achieved CR in five (50%) and partial remission (PR) in two (20%) patients. Four of five (80%) patients achieving CR remained in CR at a median follow-up of 44.2 months. Of the patients achieving PR, one is currently alive, and the second died from transplant rejection after converting to CR after consolidative chemotherapy. Patients with stable disease (two) and progressive disease (one) have died from PTLD. There was one possible CHOP-associated death (acute cardiac event) and two patients had to be switched to less-toxic monotherapies. Median overall survival was 46.5 months (95% confidence interval: 23.6-49.1 months). CONCLUSIONS: CHOP salvage therapy achieved a favorable overall response rate of 70% in this setting, indicating that PTLD generally remains chemotherapy-sensitive after progression following first-line rituximab.

Recommendations for the use of everolimus (Certican) in heart transplantation: results from the second German-Austrian Certican Consensus Conference.

Everolimus (Certican; Novartis Pharma AG, Basel, Switzerland) represents the latest generation of proliferation signal inhibitors (PSIs). Everolimus is indicated for use as an immunosuppressive drug in renal and heart transplantation. This report reflects the recommendations of the second German-Austrian Certican Consensus Conference, held in January 2006, for the clinical use of everolimus.

Prevalence of CCR5Delta32 polymorphism in long-term survivors of heart transplantation.

BACKGROUND: CC chemokine receptor 5 (CCR5) contributes to the alloimmune response following solid organ transplantation. In individuals homozygous for the CCR5Delta32 mutation, the receptor is inactive and lymphocyte recruitment and leukocyte trafficking during rejection are inhibited. A significant improvement in graft survival following renal transplantation has been observed in homozygous CCR5Delta32 patients, although conflicting data exist. To determine whether CCR5Delta32 homozygous heart transplant recipients may also benefit compared to those with a normally functioning CCR receptor, the proportion of patients with CCR5Delta32 mutation was examined in a large cohort of patients surviving for a long period after heart transplantation. METHODS: The prevalence of CCR5 genotype was identified in patients who had survived >or=7 years after heart transplantation. Genotyping was performed centrally by polymerase chain reaction (PCR). RESULTS: A total of 555 patients were recruited at three heart transplant centers in Germany. Of these, 442 patients (79.6%) were homozygous for the wild-type allele, 106 (19.1%) were heterozygous for CCR5Delta32 and 7 (1.3%) were homozygous for CCR5Delta32. No statistically significantly differences were observed between the incidence of CCR5Delta32 homozygosity in the study population and the estimated incidence in the normal population. CONCLUSIONS: In the absence of a control arm, it cannot be established if homozygous carriers of the CCR5Delta32 allele experience a long-term survival benefit following heart transplantation that may be masked by underrepresentation of the CCR5Delta32 allele in recipients of a heart transplant. To answer this question, the prevalence of CCR5Delta32 homozygosity needs to be established in patients awaiting heart transplantation.

Pharmacokinetics and variability of mycophenolic acid from enteric-coated mycophenolate sodium compared with mycophenolate mofetil in de novo heart transplant recipients.

Sequential pharmacokinetic assessments were performed at five centers within the context of a multicenter, single-blind, randomized clinical trial comparing the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS, myfortic) and mycophenolate mofetil (MMF, CellCept) in de novo heart transplant recipients. Patients were randomized to either EC-MPS 1080 mg bid or MMF 1500 mg bid, as part of a triple immunosuppressive therapy including cyclosporine microemulsion. Steady-state pharmacokinetic profiles of mycophenolic acid (MPA) and its inactive phenolic glucuronide (MPAG) were assessed at weeks 2, 12, and 52. Pharmacokinetic parameters were evaluated in 32 patients (17 on EC-MPS and 15 on MMF). Dose-normalized peak (C(max,ss)) and area under the curve (AUC(tau,ss)) of MPA and MPAG increased between week 2 and week 12 assessments for both treatments. Comparisons between EC-MPS and MMF showed no statistically significant differences in MPA and MPAG AUC(tau,ss), C(max,ss), and trough (C(min,ss)) values (p-values ranged from 0.225 to 0.990). Consistent with the delayed release characteristics of EC-MPS, C(max,ss) occurred approximately one hour later compared with MMF. Inter-subject coefficients of variation (%CV) for MPA pharmacokinetic parameters of both EC-MPS and MMF were high (37-72% for AUC(tau,ss) at weeks 2 and 12). Also within patients, the pharmacokinetics of MPA varied considerably. Specifically, intra-subject %CVs for MPA AUC(tau,ss), C(max,ss), and C(min,ss) were 28%, 63%, and 34% with EC-MPS and 54%, 139%, and 41% with MMF respectively. These results indicate that a dose of EC-MPS 1080 mg bid in combination with cyclosporine provides adequate systemic MPA exposure in de novo heart transplant patients, comparable with MMF 1500 mg bid. Overall, there is a large inter- and intra-subject variability in MPA pharmacokinetic parameters with both treatments.

Changes in exercise capacity, ventilation, and body weight following heart transplantation.

AIMS: Peak oxygen uptake adjusted to body weight (peak VO(2)) and ventilatory efficiency (VE/VCO(2)-slope) are important prognostic parameters in chronic heart failure. Our study prospectively examined changes in these parameters over 24 months following heart transplantation (HTx) and evaluated the potentially confounding effects of weight gain. METHODS AND RESULTS: One hundred patients with chronic heart failure (16 female, mean age at HTx 53.9+/-9.6 years) underwent cardiopulmonary exercise testing before and 3, 6, 12 and/or 24 months after HTx. Twenty-five healthy individuals served as matched normals. VE/VCO(2)-slope during exercise improved significantly at 6 (-23.7%), 12 (-21.3%), and 24 months (-32.3%; all p<0.002 vs. baseline). At 6 months, VE/VCO(2)-slopes were similar to the matched normals (31.8+/-4.3), 46 of 78 patients achieved values within the 95% confidence interval of normal. Peak VO(2) increased significantly after HTx at 6 (+31.8%), 12 (+36.2%), and 24 months (+42.2%; all p<0.005). None of the patients reached values within the 95% CI of normal. Although VE/VCO(2)-slope and peak VO(2) were correlated inversely at every time point (p<0.03), reduction in VE/VCO(2)-slope did not correlate with increase in peak VO(2). Symptoms that limited exercise changed from dyspnoea before HTx to leg fatigue after HTx. CONCLUSION: Following HTX, VE/VCO(2)-slope returns to normal values in the majority of patients; however, despite improvement, peak VO(2) remains abnormal in all patients. Symptoms causing patients to stop exercising change from dyspnoea to leg fatigue.

Epstein-Barr viral load in whole blood of adults with posttransplant lymphoproliferative disorder after solid organ transplantation does not correlate with clinical course.

Posttransplant lymphoproliferative disease (PTLD) is closely linked to primary Epstein-Barr virus (EBV) infection. A defect of EBV specific cellular immunity is postulated to play a pivotal role in the etiology of PTLD, but there is some debate as to whether EBV load in the peripheral blood of transplant patients predicts onset of PTLD or relapse after treatment. The current prospective, single-center study was undertaken to investigate the impact of therapy on EBV load in adult patients with PTLD. Fifteen patients with PTLD after solid organ transplantation were included and of these, seven had EBV-associated PTLD. All 15 patients received Rituximab as primary therapy. In cases of treatment failure or relapse after Rituximab treatment, patients received polychemotherapy according to the cyclophosphamide, vincristine, doxorubicin, and prednisone regimen. At onset of PTLD, the median EBV load in the peripheral blood of patients was higher in EBV-associated PTLD than PTLD with no associated EBV infection. After Rituximab therapy, four of seven patients with EBV-associated PTLD achieved long-lasting complete remissions. However, in two of these patients, EBV load increased to reach levels as high as those recorded at onset of PTLD. Another patient showed a dramatic decline of EBV load after the first dose of Rituximab while suffering from progressive disease. The other patient relapsed after Rituximab monotherapy, but his viral load stayed low. In total, discordance in EBV load and clinical course was observed in five of the seven patients with EBV-associated PTLD. We conclude that in adult patients with PTLD, EBV load does not correlate with treatment response and is not suitable as a predictive marker for PTLD relapse.

Reversibility of cardiac cachexia after heart transplantation.

BACKGROUND: Cachexia is an independent risk factor for mortality in patients with chronic heart failure and increases mortality even after heart transplantation (HTx). We aimed to determine whether cardiac cachexia is reversible after HTx, and investigated differences specific to gender. METHODS: We prospectively examined 106 patients before and serially 3, 6, 12 and 24 months after HTx (18 women, 88 men; median age at transplantation 53.7 +/- 9.7 years; n = 68 dilative cardiomyopathy, n = 33 coronary heart disease, n = 5 other origin of heart failure). Patients were sub-grouped as underweight (body mass index [BMI] < or =21 kg/m2, n = 15), normal weight (BMI 21 to 27 kg/m2, n = 64) and obese (BMI > or =27 kg/m2, n = 27). RESULTS: Body weight increase was restricted to underweight patients: at 3 months (+6.8% vs pre-transplant weight); at 6 months (+11.3%), at 12 months (+15.6%); and at 24 months (+17.7%, all p < or = 0.03). The entire population had weight loss at 3 months (-2.9%), but had weight gain at 6 (+2.5%), 12 (+6.1%, all p < or = 0.02) and 24 months (+1.3%, p = 0.44). A lower BMI before HTx correlated significantly with greater weight increase after HTx at every follow-up time-point (r = 0.55; p < 0.001). There were no gender-specific differences for BMI or weight change. Weight loss within 3 months after HTx was associated with higher mortality during 4 years of follow-up. CONCLUSIONS: Weight gain after HTx is particularly strong in underweight patients, and the increased cardiac function causes the cessation of cachexia. The weight increase of the entire heart transplant population is partially an effect of reversibility of cachexia and not affected by gender.

Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients.

BACKGROUND: This study reports the 36-month results of a randomized, double-blind, active-controlled trial of mycophenolate mofetil (MMF) vs azathioprine (AZA) in heart transplant patients. METHODS: Patients were randomized at the time of transplant to receive MMF (1,500 mg twice a day, N = 327) or AZA (1.5 to 3 mg/kg in 4 daily doses, N = 323) in addition to cyclosporine and corticosteroids; 289 patients in each group received study drug. Data were analyzed in all randomized patients (enrolled) and in patients who received study medications (treated). Clinical and graft assessments continued for 36 months. RESULTS: For the co-primary end-point, 53 of 289 (18.3%) AZA-treated patients either died or received another transplant compared with 34 of 289 (11.8%) MMF-treated patients (p < 0.01). Time to re-transplantation or patient death was significantly shorter for AZA- than MMF-treated patients (p = 0.029). In patients undergoing intravascular ultrasound, the change in mean maximal intimal thickness was less for the MMF group than for the AZA group (0.06 +/- 0.03 mm vs 0.13 +/- 0.03 mm, respectively; p = 0.056). No significant differences between treatments were observed in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia and leukopenia were more common in the AZA group, whereas diarrhea, esophagitis, Herpes simplex, Herpes zoster and cytomegalovirus (CMV) tissue invasion were more common in MMF-treated patients. CONCLUSION: MMF reduces mortality and graft loss up to 36 months after transplantation.

Recommendations for use of Certican (everolimus) after heart transplantation: results from a German and Austrian Consensus Conference.

The Certican Consensus Conference has produced guidelines to help physicians apply Certican (everolimus) clinical trial data in clinical practice. Everolimus is indicated in combination with cyclosporine microemulsion (CsA; Neoral) and corticosteroids for prophylaxis of acute rejection after heart transplantation. It has also shown efficacy for prevention of cardiac allograft vasculopathy. Further indications for use pertain to patients with chronic renal failure, to allow reduced calcineurin inhibitor (CNI) exposure; reduce the risk of cytomegalovirus to disease; second transplantation; heart/lung transplantation after occurrence of bronchiolitis obliterans; and in patients with malignancies under immunosuppression. Contraindications include intolerance, severe leukocytopenia and severe thrombocytopenia. The everolimus dose is 0.75 or 1.5 mg twice daily, adjusted according to trough blood levels. Target blood levels are 3 to 8 ng/ml, with 6 to 8 ng/ml considered the optimal range for most patients. Recommended CsA trough blood levels in patients receiving everolimus are 150 to 175 ng/ml for Months 1 to 3 post-transplant, around 135 ng/ml for Months 3 to 6, and <100 ng/ml after Month 6. It may be possible to discontinue steroids in patients receiving long-term everolimus and CsA. Early cytomegalovirus prophylaxis is recommended for patients with a high-risk mismatch, and trimethoprim-sulfamethoxazole should be given to prevent Pneumocystis carinii. Everolimus dose should be reduced by about 50% if administered in conjunction with azoles or erythromycin, and increased 100% to 200% if given with rifampicin. All heart transplant recipients should receive statins unless contraindicated.