Epstein–Barr virus‐associated pneumonia in patients with post‐transplant lymphoproliferative disease after hematopoietic stem cell transplantation

Q.‐F. Liu, Z.‐P. Fan, X.‐D. Luo, J. Sun, Y. Zhang, Y.‐Q. Ding. Epstein–Barr virus‐associated pneumonia in patients with post‐transplant lymphoproliferative disease after hematopoietic stem cell transplantation.
Transpl Infect Dis 2010: 12: 284–291. All rights reserved. Abstract: Epstein–Barr virus (EBV) reactivation or infection after hematopoietic stem cell transplantation (HSCT) most often induces post‐transplant lymphoproliferative disease (PTLD), but it also may be associated with clinical symptoms such as pneumonia. Our aim was to investigate and describe the clinical manifestations of PTLD and PTLD accompanied by EBV‐associated pneumonia in 323 patients after HSCT. PTLD within extravisceral lymphoid tissue was identified in 7 cases (5 with CD20⁺ diffuse large B‐cell lymphoma, 1 with CD20⁺ polymorphic B‐cell hyperplasia, and 1 with CD3⁺CD45RO⁺ peripheral T‐cell lymphoma unspecified). Six of the patients with PTLD were EBV positive. Three patients had EBV‐associated pneumonia, and chest computed tomography revealed multifocal patchy and diffuse ground‐glass attenuation in both lungs. EBV‐DNA was positive in bronchoalveolar lavage (BAL) fluid, which contained mainly CD3⁺ T cells but no CD19⁺ or CD20⁺ B cells. Lung biopsy showed interstitial intra‐alveolar infiltrates of mainly CD3⁺ T cells and some CD68⁺ macrophages without CD19⁺ and CD20⁺ B cells. The patients with PTLD accompanied by EBV‐associated pneumonia developed hyperpyrexia and dyspnea, which progressed rapidly, and eventually all died within 2 weeks of the onset of PTLD. EBV‐associated PTLD accompanied by EBV‐associated pneumonia after HSCT is rare. Cytology of BAL fluid and lung biopsy may help establish the diagnosis.     

The value of prospective monitoring of Epstein–Barr virus DNA in blood samples of pediatric liver transplant recipients

Post-transplant lymphoproliferative disease (PTLD) is one of the major causes of morbidity and mortality in transplantation patients. A primary Epstein-Barr virus (EBV) infection is a major risk factor for developing PTLD. The aim of this study was to determine circulating EBV DNA after liver transplantation in pediatric patients in relation to primary EBV infection and development of PTLD. EBV serology was performed before transplantation. Every 4 weeks after transplantation a competitive quantitative polymerase chain reaction (PCR) assay for EBV nuclear antigen-1 was performed in 13 patients. Patients were followed for development of a PTLD. Before transplantation four patients were EBV seropositive and nine patients were EBV seronegative. In one of the four patients who were EBV seropositive before transplantation, EBV DNA became detectable after transplantation, with a peak load of 3600 copies/mL. None of these four patients developed a PTLD. Eight of the nine patients who were EBV seronegative before transplantation developed positive EBV DNA samples. EBV DNA was first detected at a mean of 64 days after transplantation (range 38-89). The mean peak EBV DNA load was 79,700 copies/mL (3600-446,000). Two of these patients developed PTLD, but they could not be identified based on prior or concomitant EBV PCR results. Conclusions: In pediatric liver transplantation EBV DNA load is higher in patients with a primary infection than in patients who were EBV seropositive before transplantation. The EBV PCR cannot be used to identify individual patients who develop PTLD. However, elevated EBV DNA load can be used to detect a group of patients at increased risk for PTLD.     

Subacute immune response to primary EBV infection leading to post‐transplant lymphoproliferative disease in a renal transplant patient

A 23‐year‐old man sero‐negative for Epstein–Barr virus (EBV) developed recurrent sore throats 3 and 6 months after a renal transplant from an EBV sero‐positive donor. Tonsillar biopsy at 9 months post‐transplant showed post‐transplant lymphoproliferative disease (PTLD) caused by EBV. Following reduction of immunosuppressive treatment, he developed further signs and symptoms, and serological evidence of infectious mononucleosis followed by resolution of lymphadenopathy. This case emphasizes the difficulty in interpreting EBV serology in immunosuppressed patients and the importance of pre‐transplant EBV serology.     

Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges

N.A. Kittan, F. Beier, K. Kurz, H.H. Niller, L. Egger, W. Jilg, R. Andreesen, E. Holler, G.C. Hildebrandt. Isolated cerebral manifestation of Epstein–Barr virus‐associated post‐transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges.
Transpl Infect Dis 2011: 13: 524–530. All rights reserved Abstract: We present the case of a 49‐year‐old male patient with Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorder (PTLD) limited to the brain that occurred 6 months after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical symptoms included mental confusion, ataxia, and diplopia. Magnetic resonance imaging (MRI) revealed cerebellar and periventricular lesions consistent with an inflammatory process. Cerebrospinal fluid (CSF) analysis, but not peripheral blood, was positive for EBV‐DNA, but no malignant cells were found. Brain biopsy was not feasible because of low platelet counts. As we considered a diagnosis of either EBV‐associated encephalitis or PTLD, the patient was treated with rituximab combined with antiviral therapy. However, the cerebral lesions progressed and follow‐up CSF testing revealed immunoglobulin H clonality as evidence of a malignant process. Subsequent treatment attempts included 2 donor lymphocyte infusions (DLI). Despite treatment, the patient died from autopsy‐proven PTLD within 8 weeks of the onset of symptoms. This case demonstrates the clinical and diagnostic challenges of primary cerebral PTLD in a patient following allogeneic HSCT.     

Recurrent Epstein–Barr virus associated disease in a cardiac transplant patient: evolution from plasmacytic hyperplasia to diffuse large cell lymphoma

Abstract: An Epstein–Barr virus (EBV)-seronegative 31-year-old male underwent cardiac transplantation in 1991 for congenital cardiomyopathy. He presented with a protracted course of waxing and waning lymphadenopathy beginning four years after transplantation with eventual progression to a fulminant EBV-positive large cell lymphoma eight years after transplantation. Risk factors for the development of post-transplant lymphoproliferative disease in this patient, the importance of a standardized approach to pathology in assessing therapeutic options, and the management strategies used are discussed.     

Epstein–Barr virus‐associated smooth muscle tumors in a composite tissue allograft and a pediatric liver transplant recipient

Epstein–Barr virus (EBV) is known to establish latent infections in B‐lymphocytes that can cause lymphoproliferative disorders particularly in immunocompromised patients. More recently, the development of rare EBV‐associated smooth muscle tumors has been reported in transplant recipients. We herein describe 2 new cases of EBV‐associated post‐transplant smooth muscle tumors (EBV‐PTSMT), including the first in a facial composite tissue graft recipient. Among the striking features shared by these 2 patients were their young ages, the fact that they were naïve for EBV before the transplantation, that they developed a post‐transplant lymphoproliferative disorder before the diagnosis of EBV‐PTSMT, and that they responded favorably to reduction of immunosuppression. Radiological and histologic features of EBV‐PTSMT are shown. Finally, pathophysiology and therapeutic management of EBV‐PTSMT are discussed based on a comprehensive review of the literature.     

Umbilical cord blood transplantation in adults with advanced hodgkin's disease: high incidence of post‐transplant lymphoproliferative disease

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single‐unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74–98%] with a median of 18 d (range, 10–48). CI of acute graft‐versus‐host disease (GvHD) grades II–IV was 30% (95% C.I., 17–44%), while the incidence of chronic GVHD was 42% (95% C.I., 23–77%). The non‐relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13–46%) and 47% (95% C.I., 29–65%), respectively. EBV‐related post‐transplant lymphoproliferative disease (EBV‐PTLD) accounted for more than one‐third of transplant‐related death, with an estimate incidence of 26% (95% C.I., 9–44). The incidence of relapse at 4 yr was 25% (95% C.I., 9–42%). Four‐year event‐free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV‐PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.     

Programmed death‐1 receptor and interleukin‐10 in liver transplant recipients at high risk for late cytomegalovirus disease

A. Krishnan, W. Zhou, S.F. Lacey, A.P. Limaye, D.J. Diamond, C. La Rosa. Programmed death‐1 receptor and interleukin‐10 in liver transplant recipients at high risk for late cytomegalovirus disease.
Transpl Infect Dis 2010: 12: 363–370. All rights reserved Abstract: Despite significant advances in antiviral treatment, solid organ transplant (SOT) recipients remain at heightened risk for developing late cytomegalovirus (CMV) disease. Elevated inhibitory immune signaling suggests a state of immune impairment in SOT recipients, who do not control CMV infection and develop severe clinical symptoms after discontinuation of antiviral prophylaxis. We longitudinally monitored the negative immune modulator programmed death (PD)‐1 receptor on both CD4 and CD8 T cells, co‐expressing the CD137 surface marker of recent activation, in a liver transplant cohort. Liver recipients who progressed to CMV disease expressed elevated levels of PD‐1 on CD137⁺ CD4 and CD8 T cells, following stimulation with either full‐length peptide libraries or CMV lysate. This novel approach, applicable to a multitude of human leukocyte antigen types, enhances the usefulness of the PD‐1 measurements as a clinical strategy to predict late CMV disease. In parallel, we detected an increased level of the immunosuppressive cytokine interleukin (IL)‐10, in plasma of liver recipients diagnosed with CMV disease. CMV‐specific T cells were still functional when both PD‐1 and IL‐10 were upregulated; however they showed a marked proliferation deficit, which may limit their ability to contain viremia and lead to CMV disease. Our preliminary observations support further investigation of dual monitoring of PD‐1 and IL‐10, as potential immune markers of CMV disease.     

Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection

T. Hori, F. Oike, K. Hata, M. Nishikiori, Y. Ogura, K. Ogawa, Y. Takada, H. Egawa, J.H. Nguyen, S. Uemoto. Hashimoto's encephalopathy after interferon therapy for hepatitis C virus in adult liver transplant recipient accompanied by post‐transplant lymphoproliferative disorder related to Epstein–Barr virus infection
Transpl Infect Dis 2010: 12: 347–352. All rights reserved Abstract: A 55‐year‐old woman underwent living‐donor liver transplantation (LDLT). She had no history of autoimmune diseases. Spleen was preserved. Steroids were withdrawn at 3 months after LDLT. Epstein–Barr virus (EBV) infection occurred at 3.5 years after LDLT. Recurrent hepatitis C virus infection was confirmed at 4.5 years after LDLT, and pegylated interferon was introduced. Diagnosis of EBV‐positive post‐transplant lymphoproliferative disorder (PTLD) was made at 4.8 years after LDLT, and tacrolimus (Tac) was stopped completely. Then, unconsciousness, convulsion, and cervical stiffness appeared suddenly. Electroencephalography, cerebrospinal fluid analysis, and image studies revealed normal or only nonspecific findings. The patient was in a state of exhaustion; therefore, steroid pulse therapy (SPT) was attempted. Surprisingly, her general condition, including consciousness disturbance, was improved markedly, and Hashimoto's encephalopathy (HE) was suspected, based on this reaction to SPT. Elevations of anti‐thyroglobulin antibody and anti‐thyroid peroxidase antibody were confirmed. After withdrawal of Tac, and treatment with acyclovir and steroids, EBV‐positive PTLD and HE improved, although they recurred at 5.1 years after LDLT. SPT improved only neurological symptoms. Molecular‐targeted therapy was given for recurrent PTLD, based on analysis of sampling specimens. This therapy was effective, but tumor lysis syndrome occurred, and the patient died at 5.3 years after LDLT.     

Epstein–Barr virus (EBV) genotypes among human immunodeficiency virus (HIV)‐related B‐cell Lymphomas and B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) – late‐onset lymphomas,especially in the HIV setting,are associated with type‐B‐EBV

We investigated 26 B‐cell post‐transplant lymphoproliferative disorders (B‐PTLD) and 15 human immunodeficiency virus‐related aggressive B‐cell lymphomas (HIV‐BCL) from England that were associated with Epstein–Barr virus (EBV) for the polymorphic sequences of the EBV‐encoded nuclear antigen 3C (EBNA3C) gene to distinguish the two different EBV strains. Type‐A‐EBV was identified in 92% of B‐PTLDS and in 53% of HIV‐BCL (P = 0.003). Among HIV‐BCL, patients associated with type‐B‐EBV had been HIV positive for significantly longer when compared to those associated with type‐A (P = 0.037) although there were no correlations with ethnicity, CD4 cell counts or plasma HIV viral load.     

Hepatitis C cure improved patient‐reported outcomes in patients with and without liver fibrosis in a prospective study at a large urban medical center

Patient‐reported outcomes (PROs) are important measures of quality of life. Direct‐acting antiviral (DAA) drugs for hepatitis C virus (HCV) improved PROs in clinical trials. We prospectively evaluated the impact of DAA‐based HCV cure on PROs and liver‐related outcomes in real‐world patients at a large urban medical center. The short form (SF)‐36 and three additional validated instruments were used. F3‐4 fibrosis was defined as > 9.6 kPa by transient elastography (TE); S2‐3 steatosis was defined as > 270 dB/m by TE‐controlled attenuation parameter (CAP). Data were analysed by paired and unpaired t tests. Patients (n = 16) who did not achieve a sustained virologic response at 12 weeks (SVR12) were excluded. The study achieved its primary endpoint and showed a significant 30% improvement in the SF‐36 vitality score, measured baseline to SVR12: 63 versus 82, P < .001 (n = 111). Scores in 24 of 25 PRO domains improved at SVR12 (P < .05). Nearly all gains exceeded 5%, indicating their clinical significance. Transaminase values and liver stiffness improved (decreased) significantly, baseline to SVR12 (P < .005), but steatosis was unchanged (P = .58). Patients with baseline F0‐2 fibrosis and those with F3‐F4 fibrosis both improved in 22 domains. Patients with baseline S0‐S1 steatosis improved in more domains (23) than patients with S2‐S3 steatosis (19). At baseline, patients with F3‐F4 fibrosis and patients with S2‐3 steatosis had worse scores in certain PRO domains than patients with F0‐2 fibrosis or S0‐S1 steatosis, but this difference resolved by SVR12. HCV cure led to meaningful gains in PROs, and these findings may encourage patients to seek treatment.