EBV PCR in the Diagnosis and Monitoring of Posttransplant Lymphoproliferative Disorder: Results of a Two-Arm Prospective Trial

While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remains unclear. We performed a prospective 2-arm trial utilizing an EBV PCR panel measuring LMP-1, EBER-1 and EBNA-1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV-positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV-positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnosing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.     

Primary Cutaneous Posttransplant Lymphoproliferative Disorders in Solid Organ Transplant Recipients: A Multicenter European Case Series

Primary cutaneous posttransplant lymphoproliferative disorders (PTLD) are rare. This retrospective, multicenter study of 35 cases aimed to better describe this entity. Cases were (re)‐classified according to the WHO‐EORTC or the WHO 2008 classifications of lymphomas. Median interval between first transplantation and diagnosis was 85 months. Fifty‐seven percent of patients had a kidney transplant. Twenty‐four cases (68.6%) were classified as primary cutaneous T cell lymphoma (CTCL) and 11 (31.4%) as primary cutaneous B cell PTLD. Mycosis fungoides (MF) was the most common (50%) CTCL subtype. Ten (90.9%) cutaneous B cell PTLD cases were classified as EBV‐associated B cell lymphoproliferations (including one plasmablastic lymphoma and one lymphomatoid granulomatosis) and one as diffuse large B cell lymphoma, other, that was EBV‐negative. Sixteen (45.7%) patients died after a median follow‐up of 19.5 months (11 [68.8%] with CTCL [6 of whom had CD30⁺ lymphoproliferative disorders (LPD)] and 5 [31.2%] with cutaneous B cell PTLD. Median survival times for all patients, CTCL and cutaneous B cell PTLD subgroups were 93, 93, and 112 months, respectively. Survival rates for MF were higher than those for CD30⁺ LPD. The spectrum of primary CTCL in organ transplant recipients (OTR) is similar to that in the general population. The prognosis of posttransplant primary cutaneous CD30⁺ LPD is worse than posttransplant MF and than its counterpart in the immunocompetent population. EBV‐associated cutaneous B cell LPD predominates in OTR.     

Posttransplant Lymphoproliferative Disorder After Clinical Islet Transplantation: Report of the First Two Cases

We report the first two cases of posttransplant lymphoproliferative disorder (PTLD) in recipients of islet transplants worldwide. First, a 44‐year‐old recipient of three islet infusions developed PTLD 80 months after his initial transplantation, presenting with abdominal pain and diffuse terminal ileum thickening on imaging. He was treated with surgical excision, reduction of immunosuppression, and rituximab. Seven months later, he developed central nervous system PTLD, presenting with vertigo and diplopia; immunosuppression was discontinued, resulting in graft loss, and he was given high‐dose methotrexate and underwent consolidative autologous stem cell transplantation. He remains in remission 37 months after the initial diagnosis. Second, a 58‐year‐old female recipient of two islet infusions developed PTLD 24 months after initial islet infusion, presenting with pancytopenia secondary to extensive bone marrow involvement. Immunosuppression was discontinued, resulting in graft loss, and she received rituximab and chemotherapy, achieving complete remission. Both patients were monomorphic B cell PTLD subtype by histology and negative for Epstein–Barr virus in tissue or blood. These cases document the first occurrences of this rare complication in islet transplantation, likely secondary to prolonged, intensive immunosuppression, and highlight the varying clinical manifestations of PTLD. Further studies are needed to determine incidence rate and risk factors in islet transplantation.     

Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas

A registry of posttransplant lymphoproliferative disorders (PTLD) was set up for the entire population of adult kidney transplant recipients in France. Cases of PTLD were prospectively enrolled between January 1, 1998, and December 31, 2007. Ten-year cumulative incidence was analyzed in patients transplanted after January 1, 1989. PTLD risk factors were analyzed in patients transplanted after January 1, 1998 by Cox analysis. Cumulative incidence was 1% after 5 years, 2.1% after 10 years. Multivariate analysis showed that PTLD was significantly associated with: older age of the recipient 47-60 years and >60 years (vs. 33-46 years, adjusted hazard ratio (AHR) = 1.87, CI = 1.22-2.86 and AHR = 2.80, CI = 1.73-4.55, respectively, p < 0.0001), simultaneous kidney-pancreas transplantation (AHR = 2.52, CI = 1.27-5.01 p = 0.008), year of transplant 1998-1999 and 2000-2001 (vs. 2006-2007, AHR = 3.36, CI = 1.64-6.87 and AHR = 3.08, CI = 1.55-6.15, respectively, p = 0.003), EBV mismatch (HR = 5.31, CI = 3.36-8.39, p < 0.001), 5 or 6 HLA mismatches (vs. 0-4, AHR = 1.54, CI = 1.12-2.12, p = 0.008), and induction therapy (AHR = 1.42, CI = 1-2.02, p = 0.05). Analyses of subgroups of PTLD provided new information about PTLD risk factors for early, late, EBV positive and negative, polymorphic, monomorphic, graft and cerebral lymphomas. This nationwide study highlights the increased risk of PTLD as long as 10 years after transplantation and the role of cofactors in modifying PTLD risk, particularly in specific PTLD subgroups.     

The Role of Antiviral Prophylaxis for the Prevention of Epstein–Barr Virus–Associated Posttransplant Lymphoproliferative Disease in Solid Organ Transplant Recipients: A Systematic Review

The role of antiviral prophylaxis for the prevention of posttransplant lymphoproliferative disease (PTLD) remains controversial for solid organ transplantation (SOT) recipients who are seronegative for Epstein–Barr virus (EBV) but who received organs from seropositive donors. We performed a systematic review and meta‐analysis to address this issue. Two independent assessors extracted data from studies after determining patient eligibility and completing quality assessments. Overall, 31 studies were identified and included in the quantitative synthesis. Nine studies were included in the direct comparisons (total 2366 participants), and 22 were included in the indirect analysis. There was no significant difference in the rate of EBV‐associated PTLD in SOT recipients among those who received prophylaxis (acyclovir, valacyclovir, ganciclovir, valganciclovir) compared with those who did not receive prophylaxis (nine studies; risk ratio 0.95, 95% confidence interval 0.58–1.54). No significant differences were noted across all types of organ transplants, age groups, or antiviral use as prophylaxis or preemptive therapy. There was no significant heterogeneity in the effect of antiviral prophylaxis on the incidence of PTLD. In conclusion, the use of antiviral prophylaxis in high‐risk EBV‐naive patients has no effect on the incidence of PTLD in SOT recipients.     

Posttransplant lymphoproliferative disorder in pediatric patients: Survival rates according to primary sites of occurrence and a proposed clinical categorization

Posttransplant lymphoproliferative disorder (PTLD) is a devastating complication of organ transplant. In a hospital‐based registry, we identified biopsy‐proven cases of PTLD among children during a 15‐year period and reviewed trends in PTLD rates, the sites of involvement, and the associated survival rates. Cases that were included had at least 1 year of follow‐up after the diagnosis of PTLD. We studied 82 patients with first‐episode PTLD. Median age at diagnosis was 6.4 years (IQR 3.2‐12.3 years). The most frequent PTLD sites were tonsillar/adenoidal (T/A [34%]) and gastrointestinal (32%), followed by miscellaneous (defined as less common sites including central nervous system, kidney, lung, and soft tissue [12%]), lymph node (11%), and multisite (11%). Kaplan‐Meier survival curves showed that T/A PTLD was associated with decreased all‐cause mortality compared with PTLD at other sites (log‐rank 0.004), even after adjustment for histological subtype (P = .047). PTLD‐related mortality was also decreased among T/A PTLD (log‐rank 0.012) but showed a trend toward significance only after adjustment for histological subtype (P = .09). Among first episodes of PTLD, T/A PTLD was associated with a survival advantage compared with PTLD at other sites, even after adjustment for potential confounders. Based on our observations, we propose a clinical categorization of PTLD according to anatomical site of occurrence.     

Outcomes Following De Novo CNI-Free Immunosuppression After Heart Transplantation: A Single-Center Experience

Renal impairment at the time of heart transplantation complicates the choice of subsequent immunosuppressive therapy. Calcineurin (CNI)-free regimens utilizing proliferation signal inhibitors (PSI) may mitigate against nephrotoxicity in this group; however, their effectiveness remains unclear.
We present our 7-year experience with de novo CNI-free, PSI-based immunosuppression after heart transplantation. Of the 152 patients transplanted between July 1999 and July 2006, de novo immunosuppression regimens were 49 CNI-free, PSI-based, 88 CNI, 15 combination of CNI+PSI.
Pretransplant creatinine clearance improved within 6 months in the PSI group (0.69 ± 0.34 mL/s vs. 1.00 ± 0.54 mL/s, p < 0.05) but not the CNI (1.32 ± 0.54 mL/s vs. 1.36 ± 0.53 mL/s, p = ns) or CNI+PSI (1.20 ± 0.24 mL/s vs. 1.20 ± 0.41 mL/s, p = ns) groups. The PSI group had more episodes of early (≤6 months) acute rejection, bacterial or fungal infections and pleural effusions but less CMV infection (p < 0.05 for all comparisons). Early CNI addition occurred in 37% of the PSI group for acute rejection. 33% of the entire cohort changed immunosuppression regimens over 3.6 ± 2.2 years follow-up.
De novo CNI-free, PSI-based immunosuppression in patients with significant renal dysfunction allowed significant posttransplantation renal recovery but with increased early acute rejection, bacterial and fungal infections and pleural effusions.     

Association of antiviral prophylaxis and rituximab use with posttransplant lymphoproliferative disorders (PTLDs): A nationwide cohort study

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation (SOT). Most PTLD cases are associated with Epstein–Barr virus (EBV) infection. The role of antiviral prophylaxis or rituximab therapy for prevention of PTLD in SOT recipients is controversial. In a nationwide cohort, we assessed the incidence, presentation, and outcome of histologically proven PTLD. We included 4765 patients with a follow-up duration of 23 807 person-years (py). Fifty-seven PTLD cases were identified; 39 (68%) were EBV positive (EBV+ PTLD). Incidence rates for EBV+ PTLD at 1, 2, and 3 years posttransplant were 3.51, 2.24, and 1.75/1000 py and 0.44, 0.25, and 0.29/1000 py for EBV− PTLD. We did not find an effect of antiviral prophylaxis on early and late EBV+ PTLD occurrence (early EBV+ PTLD: SHR 0.535 [95% CI 0.199–1.436], p = .264; late EBV+ PTLD: SHR 2.213, [95% CI 0.751–6.521], p = .150). However, none of the patients (0/191) who received a rituximab-containing induction treatment experienced PTLD, but 57 of 4574 patients without rituximab induction developed PTLD. In an adjusted restricted mean survival time model, PTLD-free survival was significantly longer (0.104 years [95% CI 0.077–0.131]) in patients receiving rituximab as induction treatment. This study provides novel data on the association of rituximab induction and reduced risk for PTLD.     

Transplant Infectious Diseases: A Review of the Scientific Registry of Transplant Recipients Published Data

The Scientific Registry of Transplant Recipients (SRTR) serves to collect data on organ transplants performed in the United States. Although the infectious diseases data are limited and include mostly pretransplant serologies and other nonspecific infection‐related outcomes, this multicenter data collection allows for insightful national data and the ability to monitor trends over time. We reviewed the published concise reports for each organ type in SRTR reports containing data from 2005 to 2014, and summarized our findings with respect to cytomegalovirus (CMV), Epstein‐Barr virus, posttransplant lymphoproliferative disorder (PTLD), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, general infection, and prophylaxis. Our review highlights a few developments. While rates of donor–recipient CMV serology combinations remain fairly constant over time, there are generally more seronegative donors and recipients among living donor transplants. There has been a reduction in PTLD for pediatric transplant recipients. There has also been a slight reduction in anti‐HBV core antibody–positive donor organs and stable reporting of HCV‐positive donor organs and HIV‐positive recipients.     

Toxic epidermal necrolysis data from the CELESTE multinational registry. Part II: Specific systemic and local risk factors for the development of infectious complications

The aim of the study was to identify the most important systemic and local risk factors for the development of infectious complications in patients with toxic epidermal necrolysis (TEN).

Pneumocystis jiroveci in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of Pneumocystis jiroveci fungal infection transplant recipients. Pneumonia (PJP) may develop via airborne transmission or reactivation of prior infection. Nosocomial clusters of infection have been described among transplant recipients. PJP should not occur during prophylaxis with trimethoprim‐sulfamethoxazole (TMP‐SMX). Without prophylaxis, PJP risk is greatest in the first 6 months after organ transplantation but may develop later. Risk factors include low lymphocyte counts, cytomegalovirus infection (CMV), hypogammaglobulinemia, treated graft rejection or corticosteroids, and advancing patient age (>65). Presentation typically includes fever, dyspnea with hypoxemia, and cough. Chest radiographic patterns generally reveal diffuse interstitial processes best seen by CT scans. Patients generally have PO₂ < 60 mm Hg, elevated serum lactic dehydrogenase (LDH), and elevated serum (1 → 3) β‐d ‐glucan assay. Specific diagnosis uses respiratory specimens with direct immunofluorescent staining; invasive procedures may be required. Quantitative PCR is a useful adjunct to diagnosis. TMP‐SMX is the drug of choice for therapy; drug allergy should be documented before resorting to alternative therapies. Adjunctive corticosteroids may be useful early. Routine PJP prophylaxis is recommended for at least 6‐12 months post–transplant, preferably with TMP‐SMX.     

Association of electroencephalogram trajectories during emergence from anaesthesia with delirium in the postanaesthesia care unit: an early sign of postoperative complications

Background

Postoperative delirium is associated with an increased risk of morbidity and mortality, especially in the elderly. Delirium in the postanaesthesia care unit (PACU) could predict adverse clinical outcomes.

Perioperative Prostaglandin E1 Treatment for the Prevention of Postoperative Complications After Esophagectomy: A Randomized Clinical Trial

Purpose We conducted a prospective randomized clinical study to examine whether perioperative prostaglandin E1 (PGE1) could help in the prevention of postoperative complications after esophagectomy for esophageal cancer.Methods Forty patients with esophageal cancer eligible for radical esophagectomy were randomly assigned to an experimental group (n = 20), given perioperative PGE1, or to a control group (n = 20), given standard postoperative treatment. The main clinical endpoints examined were the incidence of postoperative complications, hospitalization, duration of systemic inflammatory response syndrome (SIRS), portal vein blood flow, and serum bilirubin levels.Results Severe postoperative complications developed in five patients in the control group and two in the PGE1 group. There was one surgery-related death in the control group. The duration of SIRS was significantly shorter in the PGE1 group than in the control group (5.74 days vs 7.50 days; P = 0.047). Portal vein flow was also significantly lower on postoperative day (POD) 1 in the control group than in the PGE1 group (P = 0.042). Maximum postoperative serum bilirubin levels were significantly lower in patients treated with PGE1, at 2.91 vs 4.38mg/dl in the control group (P = 0.040).Conclusions The perioperative administration of PGE1 helps maintain adequate portal blood flow, improves hyperbilirubinemia, and attenuates the duration of SIRS, thereby reducing the risk of postoperative complications after esophagectomy and lymphadenectomy for esophageal cancer.     

Fibrosing cholestatic hepatitis after kidney transplantation from HCV‐viremic donors to HCV‐negative recipients: A unique complication in the DAA era

Fibrosing cholestatic hepatitis (FCH) posttransplantation can lead to graft failure and death. In the era of direct acting antiviral therapy (DAA), several studies have demonstrated the efficacy and safety of transplanting hepatitis C virus (HCV)–positive allografts into HCV‐negative recipients. In this case series, we present two cases of HCV‐negative recipients who underwent kidney transplantation from viremic donors and developed FCH. Both patients presented after transplant with abnormal liver function tests and HCV viral loads of greater than 100 000 000 IU/mL. FCH was diagnosed by histology and/or clinical data. Both patients were started on DAA therapy within 24 hours of admission with improvement in LFTs. One patient has undetectable HCV 12 weeks after completing treatment and the other patient has undetectable HCV after completing DAA treatment. The introduction of DAAs has changed the landscape of solid organ transplantation with the potential to expand the donor pool and increase access to organs. While HCV viremic organs have tremendous potential to increase access to a scarce resource, FCH is a potentially fatal complication and therefore clinicians must maintain a high index of suspicion for this unique complication.     

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression, graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially on the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research.     

Antiphospholipase A2 receptor antibody-positive membranous nephropathy in the kidney donor: Lessons from a serendipitous transplantation

Primary membranous nephropathy (PMN) is an autoimmune disease limited to the kidney that is characterized by the presence of circulating PLAR2 antibodies in 70% of the cases and usually positivity for PLA2R and IgG4 by immunohistochemistry (IHC) staining. We report the first documented case of PMN (PLA2R positive) in a deceased kidney donor, transplanted to two different recipients and their clinical and immunological evolution through serial biopsies. Recipient A's first allograft biopsy (Day 26) was compatible with a MN with both positive PLA2R and IgG4 subepithelial deposits in IHC. The donor's preimplantation kidney biopsies were retrieved and reexamined, revealing MN, with high intensity for PLA2R and IgG4 in IHC. Recipient B's protocol allograft biopsy, performed later at 3 months, also revealed histology compatible with MN but without the presence of PLA2R nor IgG4 in IHC. At 1-year follow-up, both recipients maintain graft function. Serial protocol biopsies were performed in both patients showing disappearance of IgG4 in recipient A but the persistence of PLA2R in IHC. We can conclude that, given the reversal of PMN changes in the grafts, it could be considered to transplant a patient from an asymptomatic deceased donor with PMN as long as he maintains unaltered renal function.