International prognostic index, type of transplant and response to rituximab are key parameters to tailor treatment in adults with CD20-positive B cell PTLD: clues from the PTLD-1 trial.

Tailoring treatment by patient strata based on the risk of disease progression and treatment toxicity might improve outcomes of patients with posttransplant lymphoproliferative disorder (PTLD). We analysed the cohort of 70 patients treated in the international, multicenter phase II PTLD-1 trial (NCT01458548) to identify such factors. Of the previously published scoring systems in PTLD, the international prognostic index (IPI), the PTLD prognostic index and the Ghobrial score were predictive for overall survival. None of the scoring systems had a considerable effect on the risk for disease progression. Age and ECOG performance status were the baseline variables with the highest prognostic impact in the different scoring systems. Baseline variables not included in the scoring systems that had an impact on overall survival and disease progression were the type of transplant and the response to rituximab at interim staging. Thoracic organ transplant recipients who did not respond to rituximab monotherapy were at particularly high risk for death from disease progression with subsequent CHOP-based chemotherapy. Patients in complete remission after four courses of rituximab and patients in partial remission with low-risk IPI had a low risk of disease progression. We speculate that chemotherapy might not be necessary in this patient cohort.

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.

Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation.

BACKGROUND: Cytomegalovirus (CMV) causes several complications following cardiac transplantation including cardiac allograft vasculopathy. Previous studies suggested that immunosuppressive treatment based on everolimus might reduce CMV infection. Aiming to better characterize the action of everolimus on CMV and its interplay with patient/recipient serology and anti-CMV prophylaxis, we analyzed data from 3 large randomized studies comparing various everolimus regimens with azathioprine (AZA)- and mycophenolate mofetil (MMF)-based regimens. METHODS: CMV data were analyzed from 1009 patients in 3 trials of de novo cardiac transplant recipients who were randomized to everolimus 1.5 mg/day, everolimus 3 mg/day, or AZA 1-3 mg/kg/day, plus standard-dose (SD) cyclosporine (CsA; study B253, n = 634); everolimus 1.5 mg/day plus SD- or reduced-dose (RD)-CsA (study A2403, n = 199); and everolimus 1.5 mg/day plus RD-CsA or MMF plus SD-CsA (study A2411, n = 176). RESULTS: In study B253, patients allocated to everolimus experienced almost a 70% reduction in odds of experiencing CMV infection compared with AZA (P < 0.001). In study A2403, CMV infection was low in both everolimus arms, irrespective of CsA dosing, and in study A2411, patients allocated to everolimus experienced an 80% reduction in odds of experiencing CMV infection, compared with MMF (P < 0.001). CMV syndrome/disease was rare and less frequent in everolimus-treated patients. Subgroup analyses showed that the benefit everolimus provides, in terms of CMV events, is retained in CMV-naïve recipients and is independent of anti-CMV prophylaxis or preemptive approaches. CONCLUSIONS: Everolimus is associated with a lower incidence of CMV infection compared with AZA and MMF, which combined with its immunosuppressive efficacy and antiproliferative effects may positively impact long-term outcomes.

Adoptive T-cell therapy of a lung transplanted patient with severe CMV disease and resistance to antiviral therapy.

Infections with cytomegalovirus (CMV) can induce severe complications after transplantation, particularly in patients resistant to virostatic therapy. Adoptive transfer of CMV-specific T-cell lines has demonstrated promising results in patients after hematopoietic stem cell transplantation. However, the generation of specific T-cell lines ex vivo and their function in vivo is complicated in solid organ transplant (SOT) recipients. Here, we present the successful adoptive transfer of autologous CMV-specific T cells to a lung transplant recipient with ganciclovir-resistant CMV-pneumonia requiring mechanical ventilation. Infused T cells rapidly expanded in vivo and efficiently inhibited viral replication as confirmed by extensive longitudinal immunological monitoring. After full recovery, the patient was released from the clinic. After 4 weeks, the infection reappeared and persisted at a low level even after a second T-cell infusion. Our experimental data indicate that this could be the consequence of the late differentiated phenotype of the infused T cells and therefore their insufficient longevity in vivo. In summary, our report signifies the high therapeutic potential of adoptive immunotherapy in the treatment of SOT recipients when all other measures show no effect. Further studies have to elucidate the most potent strategies to generate antigen-specific T cells with high functional capacity and robust long-term persistence.

Diagnosis and treatment of post-transplantation lymphoproliferative disorder in pediatric heart transplant patients.

PTLD is a severe complication in transplant recipients. Detection of increased EBV load in the peripheral blood acts as a surrogate marker for increased risk of PTLD development. We analyzed the time course of the disease, its severity, the organs involved, and mortality rates in our institutional experience of pediatric heart transplantation. This paper identifies risk factors for PTLD and describes the different ways of diagnosing and treating the disease. PTLD was screened for in 146 pediatric heart transplant patients using a retrospective analysis in patients who received transplantation before 1998. Prospective determination was performed in 72/146 patients transplanted after 1998 within the post-transplant follow-up. The occurrence of PTLD with all interventions, including tapering of immunosuppression, surgery, viral monitoring, and antiviral interventions, was recorded. PTLD was diagnosed in 12/147 (8.2%) children at a mean age of 7.2 +/- 3.3 yr after a mean post-transplant period of 3.2 +/- 2.2 yr. PTLD manifested in: lymph nodes (n = 4), intestine (n = 3), tonsils and adenoids (n = 2), eye (n = 2), and lung (n = 1). It was diagnosed in 7/12 as a monomorphic B-cell lymphoma and in four patients as a monomorphic Burkitt lymphoma, a polymorphic B-cell lymphoma, a T-cell rich or angiocentric lymphoma (Liebow) and as reactive plasmacytic hyperplasia (early lesion), respectively. Histology was not possible in one patient with ocular manifestation. EBV association was 83%. Risk factors in the comparison with patients without PTLD were age at time of Tx, primary EBV infection after Tx, use of Azathioprine and >or=3 doses of ATG. CMV mismatch and CMV infection, rejection episodes and steroids were not risk factors. Despite reduction of immunosuppression, treatment consisted of surgical procedures to remove tumor masses (n = 6), Rituximab (n = 5), polychemotherapy (n = 3), antiviral (n = 1) and autologous T-cell therapy (n = 1). All patients demonstrated full remission without death related to PTLD or treatment at 3.9 (1.3-6.2) yr median follow-up time. The manifestation of PTLD in pediatric heart transplant recipients is associated with EBV infection and is predominantly in the form of a B-cell lymphoma. A tight and specific follow-up including early assessment of immunity status and specific therapeutic intervention to improve cellular immunity is warranted and may contribute to a significant reduction of PTLD-related morbidity and mortality.

Prediction of short-term outcomes in patients with idiopathic dilated cardiomyopathy referred for transplantation using standard echocardiography and strain imaging.

OBJECTIVE: We sought to evaluate the short-term prognostic value of echocardiography including two-dimensional (2D) strain imaging in patients with end-stage idiopathic dilated cardiomyopathy (IDCM). METHODS: To evaluate the short-term (6-month) prognostic value of different parameters used for the assessment of IDCM patients referred for heart transplantation, we performed at the baseline transthoracic echocardiography including 2D strain imaging, N-terminal pro-BNP measurements, and exercise testing for all patients included in the study. After 6 months, all parameters, including endsystolic strain (ESS), peak systolic strain rate (SSR(max)), early and late diastolic strain rates, their ratio (diastolic strain rate E [DSR(E)], dialostolic strain rate A [DSR(A)], diastolic strain rate E and A wave ratio [DSR(E/A)]), and systolic intraventricular dyssynchrony indexes (IVDSI) were tested for their prognostic value to predict a patient's outcome. RESULTS: At the baseline stable patients had significantly lower transmitral E and A wave ratio (E/A), DSR(E/A), higher DSR(A) values, longer transmitral E wave deceleration time (DcT), higher longitudinal ESS and SSR(max) values, lower systolic circumferential and longitudinal IVDSI. CONCLUSION: The highest sensitivity for rapid heart failure progression was shown by DcT <100 ms, E/A > 1.5, DSR(A) < 0.3/s, circumferential IVDSI > 0.16, and longitudinal IVDSI > 0.22 (91%, 78%, 94%, 83%, and 75%, respectively).

Enteric-coated mycophenolate-sodium in heart transplantation: efficacy, safety, and pharmacokinetic compared with mycophenolate mofetil.

Mycophenolic acid (MPA) is an effective immunosuppressive treatment for renal transplant recipients, but its effective use and best practice are not established in cardiac transplantation. This multicenter, single-blind, randomized, parallel group clinical trial prospectively evaluated the therapeutic equivalence of enteric-coated mycophenolate-sodium (EC-MPS) versus mycophenolate mofetil (MMF) in combination with cyclosporine (CyA) and steroids as determined by the primary objective of treatment efficacy during the first 6 months of treatment in 154 de novo heart transplant recipients. Both groups received equivalent doses of MPA, either 720 mg b.i.d EC-MPS or 1000 mg b.i.d MMF. EC-MPS showed a comparable efficacy and safety profile compared with MMF with significantly less dose reduction. Treatment failure occurred in 57.7% and 60.5% with EC-MPS and MMF, respectively, EC-MPS was therapeutically equivalent to MMF in cardiac transplantation.

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.

Pseudoaneurysm after ICD battery replacement.

False aneurysms of the extracranial carotid arteries are rare and mainly of traumatic origin. We report on a patient who presented with a sudden onset mass in his right neck 2 weeks after routine replacement of his ICD battery. He had received systemic anticoagulation since an aortic valve replacement 5 years before. By color Doppler sonography the mass was identified as a partly thrombosed false aneurysm originating from the common carotid artery. As no spontaneous resolution occurred during the following days the aneurysm was removed surgically 5 days later without further complications. However no connection to the common carotid artery was found at surgery. Yet in the histopathological examination the specimen showed the morphological characteristics of a pseudoaneurysm. There was no history of neck-trauma and no attempted vascular access during the recent operation.

Everolimus (certican) in heart transplantation: optimizing renal function through minimizing cyclosporine exposure.

The proliferation signal inhibitor everolimus is efficacious for reducing the incidence of acute rejection and cardiac allograft vasculopathy (CAV) in heart transplantation; and it has the potential to facilitate cyclosporine (CsA) minimization in this setting. Reducing CsA dose in heart transplantation is dependent on everolimus trough blood levels of 3 to 8 ng/mL being achieved. Physicians experienced in the use of everolimus aim for CsA trough blood levels of 175 to 200 ng/mL in everolimus-treated patients during the initial 3 months following heart transplantation. Modeling data from the heart pivotal study suggest that CsA trough blood levels of 100 ng/mL at 6 months posttransplant could be targeted without loss of efficacy, and antibody induction therapy may assist with this approach. Target CsA trough blood levels for maintenance patients could possibly be reduced from the current 80 to 100 ng/mL to 50 to 80 ng/mL. Maintenance patients with renal dysfunction or CAV may benefit from conversion to everolimus and subsequent reduction in CsA trough blood levels (eg, by 50%). Initial experience of everolimus with reduced CsA trough blood levels in heart transplantation is favorable, but there is scope for further study.

Comparison of magnetic resonance real-time imaging of left ventricular function with conventional magnetic resonance imaging and echocardiography.

This study analyzes the accuracy of a new real-time magnetic resonance imaging (MRI) technique (acquisition duration, 62 ms/image) and echocardiography for the determination of left ventricular (LV) end-diastolic volume, end-systolic volume, ejection fraction, and muscle mass when compared with turbo gradient echo imaging as the reference standard. Thirty-four patients were examined with digital echocardiography, standard, and real-time MRI. A close correlation was found between the results of real-time imaging and the reference standard for end-diastolic volume, end-systolic volume, and ejection fraction (r >0.95), with a lower correlation for LV muscle mass (r = 0.81). Correlations between echocardiography and the reference standard were lower for all parameters. Real-time MRI enables the acquisition of high-quality cine loops of the entire heart in minimal time without electrocardiographic triggering or breath holding. Thus, patient setup and scan time can be reduced considerably. Results are similar to the reference standard and superior to echocardiography for determining LV volumes and ejection fraction. This technique is a valid alternative to current approaches and can form the basis of every cardiac MRI examination.

Experimental parainfluenza type 3 infection in young lambs: clinical, microbiological, and serological response.

Five, 1-week-old, colostrum-deprived lambs were inoculated transtracheally with a parainfluenza type-3 (PI-3) virus that had been isolated from a pneumonic lamb lung. A biphasic febrile response, cough, rapid breathing followed by forced expirations, listlessness, and anorexia were observed in the lambs. There were multifocal areas of consolidation in the lungs of all lambs and ulcerations in the nasal mucosa of three lambs. Serum antibody titers to PI-3 virus ranged from 2 to 16 in lambs necropsied Day 3 to Day 7 post-inoculation, respectively. Virus was isolated from nasal secretions, tracheal fluids, and lung tissues of all lambs.

Failure of experimental vaccines to protect against infection with ovine progressive pneumonia (maedi-visna) virus.

Cell culture medium was harvested from cells infected with ovine progressive pneumonia (OPP) virus and used to prepare killed virus vaccines. Virus was inactivated by either heat, formalin, or ethyleneimine and used either without adjuvant, with Freund incomplete adjuvant, or with aluminum hydroxide adjuvant to vaccinate sheep. The sheep produced precipitating antibody against the virus but were not protected against infection when challenged with live OPP virus.

Breed susceptibility to ovine progressive pneumonia (maedi/visna) virus.

In this retrospective study of breed differences in susceptibility to disease caused by ovine progressive pneumonia (OPP) virus, 29 Border Leicester sheep were compared with 46 Columbia sheep. As judged by frequency and severity of clinical signs and lesions attributable to the infection, Border Leicester sheep were markedly more susceptible than Columbia sheep and experimentally infected sheep were slightly more susceptible than naturally infected sheep. Differences in susceptibility to infection by the virus were not determined.

Ovine progressive pneumonia (maedi-visna) in sheep.

Ovine progressive pneumonia (OPP) is a multi-systemic disease of sheep caused by a nononcogenic exogenous retrovirus belonging to the Lentiviridae subfamily. Characteristics of the disease are chronic lymphocytic pneumonitis, encephalitis, arthritis, mastitis and vasculitis associated with progressive wasting, dyspnea, lameness, indurated udder and, rarely, paralysis. Any one or all of the characteristics may be manifest. Transmission of the virus is predominantly through the colostrum to newborn lambs, however, transmission can occur by contact and in utero. Treatment of the disease is only symptomatic and prevention of infection is only by avoiding the virus.

Characterization of ovine lentivirus envelope glycoprotein expressed in Escherichia coli cell and baculovirus systems.

The ovine lentivirus (OLV) envelope protein NH2- and COOH-terminal subunits gp70 and the NH2-terminal subunit gp40 were expressed in Escherichia coli cell. The entire gp70 envelope protein was also expressed in insect cells by the recombinant baculovirus. Guinea pigs were immunized with each bacterially expressed recombinant protein, and a serum neutralization assay was used to determine their capacity to neutralize OLV. These results showed that the major neutralization epitopes are located in the NH2-terminal half of the gp70. The baculovirus expressed gp70 was found on the surface of insect cells and was immunobiologically active. Virus neutralization activity was also produced in sheep immunized with the baculovirus expressed recombinant protein.

On-line evaluation of systolic performance by densitometry in digital left ventriculography.

The angiocardiographic evaluation of left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes and ejection fraction (EF) is routinely performed by the area-length method (ALM) but may lead to erroneous results. Digital imaging in real time allows densitometric procedures of determining left ventricular (LV) performance to be applied alternatively. In this study, we present densitometric algorithms for the analysis of LVEDV, LVESV, and EF from digital image data, establish accuracy and reproducibility, and determine value and limitations in comparison with ALM in single-plane 30 degrees right anterior oblique (RAO) projection. A linear relationship between iodine depth and measured densities is mainly burdened with scatter radiation and beam hardening which reduce primary radiation and suppress iodine depth. However, facilities such as deconvolution and correction algorithms are capable of reducing these sources of error. In the present study, computer-analyzed contrast images of iodine-filled wedges and spheres showed a near-linear relationship between iodine depth between 50-100 mg/cm2 and measured densities. Contrast images of heart casts and LV angio-grams of 54 patients were obtained with a digital image acquisition and processing system, and evaluated by two independent observers. The phantom study resulted in significantly (p < or = 0.01) better densitometric standard errors of estimate for volumes [3.3 ml densitometry (DENS) vs. 8.9 ml (ALM)] and simulated EF [4.3% (DENS) vs. 7.8% (ALM)] than ALM. The standard error of estimate for the comparison between both methods was 8.4 ml for volumes and 7.5% for EF. Densitometric volumes tended to underestimate volumes calculated by ALM. The angiographic study of patients demonstrated significant correlations between both methods (LVEDV r = 0.78, LVESV r = 0.83, total volumes: r = 0.89; EF r = 0.88). The standard errors of estimate can be ascribed to systematic, method-related errors of both DENS and ALM (LVEDV +/- 28.9 ml, LVESV +/- 23.4 ml, total volumes (EDV and ESV) +/- 27.1 ml; EF +/- 8.1%). The intra- and interobserver variability, respectively, exhibited significantly smaller (p < or = 0.01 and p < or = 0.05, respectively) standard errors of estimate for densitometric EF [4.6% (DENS) vs. 8.5% (ALM) and 7.1% (DENS) vs. 10.3% (ALM), respectively]. Inclined but not significant differences were found for LVEDV and LVESV. In conclusion, the data presented indicate that the calculation of LV volumes and EF in digital left ventriculography may be performed accurately by densitometric calculation in single-plane 30 degrees RAO projection. Minor underestimations in densitometric volume determination may be anticipated in the evaluation of LV geometry.

Fatal pulmonary edema in white-tailed deer (Odocoileus virginianus) associated with adenovirus infection.

Sporadic sudden deaths in adult white-tailed deer occurred from November 1997 through August 1998 on an Iowa game farm. Three of the 4 deer necropsied had severe pulmonary edema, widespread mild lymphocytic vasculitis, and amphophilic intranuclear inclusion bodies in scattered endothelial cells in blood vessels in the lung and abdominal viscera. Immunohistochemistry with bovine adenovirus 5 antisera and transmission electron microscopy demonstrated adenoviral antigen and nucleocapsids, respectively, within endothelial cells. Adenovirus was isolated in cell culture from 1 of the affected deer. The isolate was neutralized by California black-tailed deer adenovirus antiserum. These findings indicate that adenovirus should be considered in the differential diagnosis of both black-tailed and white-tailed deer with pulmonary edema and/or hemorrhagic enteropathy.

Isolation of a bovine adenovirus serotype 10 from a calf in the United States.

Virus isolated from the lung, liver, kidney, and small intestine of a 3-month-old Holstein heifer with a clinical history of pneumonia and lesions in multiple organs was identified as an adenovirus on the basis of morphological and physicochemical characteristics. The adenovirus was determined to be a serotype 10 bovine adenovirus and represents the first reported isolation of this serotype in the United States. Inoculation of calves with this isolate resulted in mild to moderate clinical response consisting of fever, inappetence, increased respiratory rate, cough, and listlessness. Gross lesions were minimal in the respiratory tract and consisted of fibrin in the airways and small areas of consolidation in the cranial lobes of the lung. Mucofibrinous foci were present on the mucosa of the upper small intestine.

A new serotype adenovirus isolated from a goat in the United States.

A virus (T94-0353) isolated from the small intestine of a 3-week-old kid with diarrhea and serous ocular and nasal discharge was identified as an adenovirus based on morphologic and physicochemical characteristics. Neutralization tests and restriction endonuclease analysis comparing the caprine adenovirus with the prototype bovine and ovine adenovirus serotypes and a previously isolated caprine adenovirus showed that the caprine isolate was antigenically distinct, produced a unique restriction pattern compared with currently recognized bovine, caprine, and ovine adenoviruses, and represents a new adenovirus type. The role and significance of naturally acquired adenovirus infection in respiratory and enteric disease in goats has not been established. Isolation of adenovirus from goats with disease coupled with seroepidemiologic and pathogenicity studies will help define the role of the adenoviruses in disease production.