Post-transplant lymphoproliferative disorders(PTLD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are a group of rare, but are grievous complications. The occurrence of these diseases are most associated with EBV infection. The clinical manifestations usually include recurrent fever, lymph node enlargement, progressive decline of three lineage cells of hemogram, EB viremia and response failure to formal broad-spectrum antibiotics therapy, then the disease rapidly deteriorated in the short term, which result in high mortality. Therefore, early diagnosis and timely effective treatment such as rituximab, donor lymphocyte infusion and/or EB virus-specific cytotoxic T lymphocytes are needed to improve the prognosis. This review briefly summarized the diagnosis and therapy advance on the lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation.
Epstein-Barr Virus Infections ; diagnosis ; therapy ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Herpesvirus 4, Human ; Humans ; Lymphoproliferative Disorders ; diagnosis ; etiology ; therapy ; Transplantation, Homologous

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, affecting >90% of the adult population. EBV targets B-lymphocytes and achieves latent infection in a circular episomal form. Different latency patterns are recognized based on latent gene expression pattern. Latent membrane protein-1 (LMP-1) mimics CD40 and, when self-aggregated, provides a proliferation signal via activating the nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, phosphoinositide 3-kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase pathways to promote cellular proliferation. LMP-1 also induces BCL-2 to escape from apoptosis and gives a signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of retinoblastoma (Rb) protein and by inhibiting p16 and p27. LMP-2A blocks the surface immunoglobulin-mediated lytic cycle reactivation. It also activates the Ras/PI3K/Akt pathway and induces Bcl-xL expression to promote B-cell survival. Recent studies have shown that ebv-microRNAs can provide extra signals for cellular proliferation, cell cycle progression and anti-apoptosis. EBV is well known for association with various types of B-lymphocyte, T-lymphocyte, epithelial cell and mesenchymal cell neoplasms. B-cell lymphoproliferative disorders encompass a broad spectrum of diseases, from benign to malignant. Here we review our current understanding of EBV-induced lymphomagenesis and focus on biology, diagnosis and management of EBV-associated B-cell lymphoproliferative disorders.
B-Lymphocytes/*pathology/*virology ; Diagnosis, Differential ; Disease Management ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Lymphoproliferative Disorders/*diagnosis/*etiology/therapy

Adolescent ; Adult ; Child ; Female ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Lymphoproliferative Disorders ; diagnosis ; etiology ; therapy ; Male ; Middle Aged ; Retrospective Studies ; Transplantation, Homologous ; Young Adult

Adult ; Antiviral Agents ; therapeutic use ; Colonic Neoplasms ; diagnosis ; etiology ; therapy ; Cyclosporine ; adverse effects ; Esophageal Neoplasms ; diagnosis ; etiology ; therapy ; Female ; Ganciclovir ; therapeutic use ; Humans ; Immunosuppression ; adverse effects ; Immunosuppressive Agents ; adverse effects ; Liver Neoplasms ; diagnosis ; etiology ; therapy ; Liver Transplantation ; adverse effects ; Lymphoproliferative Disorders ; diagnosis ; etiology ; therapy ; Middle Aged ; Pharyngeal Neoplasms ; diagnosis ; etiology ; therapy ; Survival Analysis ; Tacrolimus ; adverse effects ; Time Factors

Epstein-Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein-Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein-Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein-Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein-Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases.
Cell Transformation, Viral ; Epstein-Barr Virus Infections/*complications ; Herpesvirus 4, Human/*physiology ; Humans ; Killer Cells, Natural/immunology/metabolism/*pathology/*virology ; Lymphoproliferative Disorders/diagnosis/*etiology/therapy ; T-Lymphocytes/immunology/metabolism/*pathology/*virology

OBJECTIVETo summarize the clinical characteristics, early diagnosis, comprehensive treatment and prognosis of 6 cases of children with post-transplantation lymphoproliferative disorder (PTLD) after liver transplantation.

METHODData of 6 cases with PTLD seen between January 2011 and December 2013 were retrospectively analyzed. The anti-rejection drug dose adjustments, the effect of rituximab, antiviral therapy and comprehensive treatment program after surgery were explored.

RESULT(1) The diagnosis of PTLD was confirmed by histologic findings. Six cases of PTLD including 3 males and 3 females were diagnosed as congenital biliary atresia and underwent split liver transplantation. The occurrence rate of PTLD was 2.9%. (2) The median time to the development of PTLD was less than 6 months. The initial symptom of PTLD in all patients was fever and clinical manifestations of PTLD were non-specific, depending on the involving organs. Five cases of PTLD developed gastrointestinal symptoms, including diarrhea, abdominal pain, and abdominal distension. One case developed respiratory symptoms, including cough and tachypnea. Three cases had lymph node involvement. In 2 cases pathophysiology involved polymorphic lymphocyte proliferation and in 4 cases B lymphocyte proliferation. (3) Two cases died, in whom EBV DNA was not detected and were diagnosed as PTLD by surgical pathology before death. Four survived cases had high EBV-DNA load and then were diagnosed as PTLD by biopsy pathology. (4) Of the 6 cases of PTLD, 2 cases died and 4 cases survived. The overall mortality was 33%. The dead cases were only treated with laparotomy because of intestinal obstruction or perforation and the survived cases were treated with tacrolimus at reduced doses or discontinuation and rituximab. In 2 cases antiviral therapy (acyclovir) was continued, including 1 cases of intestinal obstruction treated with surgical repair. All the survived patients were followed up for 4 months to 1 year and no evidence has been found.

CONCLUSIONEBV infection is the high risk factor for PTLD after liver transplantation. Close clinical surveillance of EBV DNA for pediatric liver transplantation was important for the early diagnosis of PTLD. Reducing doses of immunosuppressive agents and rituximab is the initial therapy for PTLD. A reduction in the dose of tacrolimus is suggested. Operation therapy can also play a role in the management of local complications.

Antiviral Agents ; administration & dosage ; Biliary Atresia ; therapy ; DNA, Viral ; analysis ; Drug Therapy, Combination ; Early Diagnosis ; Epstein-Barr Virus Infections ; diagnosis ; therapy ; Female ; Humans ; Immunosuppressive Agents ; administration & dosage ; adverse effects ; Infant ; Liver Transplantation ; adverse effects ; Lymphoproliferative Disorders ; diagnosis ; etiology ; mortality ; therapy ; Male ; Pediatrics ; Postoperative Complications ; Retrospective Studies ; Survival Rate ; Tacrolimus ; administration & dosage

Epstein Barr virus (EBV)-associated lymphoproliferative diseases (LPDs) express all EBV latent antigens (type III latency) in immunodeficient patients and limited antigens (type I and II latencies) in immunocompetent patients. Post-transplantation lymphoproliferative disease (PTLD) is the prototype exhibiting type III EBV latency. Although EBV antigens are highly immunogenic, PTLD cell proliferation remains unchecked because of the underlying immunosuppression. The restoration of anti-EBV immunity by EBV-specific T cells of either autologous or allogeneic origin has been shown to be safe and effective in PTLDs. Cellular therapy can be improved by establishing a bank of human leukocyte antigen-characterized allogeneic EBV-specific T cells. In EBV+ LPDs exhibiting type I and II latencies, the use of EBV-specific T cells is more limited, although the safety and efficacy of this therapy have also been demonstrated. The therapeutic role of EBV-specific T cells in EBV+ LPDs needs to be critically reappraised with the advent of monoclonal antibodies and other targeted therapy. Another strategy involves the use of epigenetic approaches to induce EBV to undergo lytic proliferation when expression of the viral thymidine kinase renders host tumor cells susceptible to the cytotoxic effects of ganciclovir. Finally, the prophylactic use of antiviral drugs to prevent EBV reactivation may decrease the occurrence of EBV+ LPDs.
Antiviral Agents/therapeutic use ; Cell- and Tissue-Based Therapy ; DNA Methylation ; Epstein-Barr Virus Infections/*complications ; Genome, Viral ; Hematopoietic Stem Cell Transplantation ; Herpesvirus 4, Human/*physiology ; Humans ; Immunotherapy, Adoptive ; Lymphoproliferative Disorders/diagnosis/*etiology/*therapy ; Organ Transplantation/adverse effects ; T-Lymphocytes/immunology ; Transplantation, Homologous ; Virus Latency

INTRODUCTIONThe objective of this study was to determine the necessity of further evaluation of patients presented with herpes zoster (HZ) to the Emergency Department for the underlying decreased cell-mediated immunity.

MATERIALS AND METHODSThe data of 132 adult patients presenting with HZ to the Emergency Department were collected from the computerised database of Akdeniz University Hospital. The following data were recorded: demographic data and underlying diseases during onset of HZ and laboratory results (white blood cell counts, blood glucose levels).

RESULTSThere were 132 patients with HZ in the study period. The mean age of patients was 52.98 +/- 18.91 years (range, 14 to 96) and 53% (70 patients) were male. Of the study patients, 70.5% (93 patients) were over 45 years old. Eight (6.1%) patients had been diagnosed to have a malignancy, 18 (13.6%) had diabetes mellitus and 3 (2.3%) patients had undergone organ transplantation during their admission. Malignancy, diabetes mellitus and organ transplantation prevalence in the HZ group was significantly higher than the whole Emergency Department population.

CONCLUSIONSOur results indicate a relationship between the presence of HZ and increasing age and cell-mediated immunosuppressive disorders in Emergency Department patients over the age of 45 years. HZ should be considered as a clinical marker of cell-mediated immunosuppressive disorders, particularly in elderly patients.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Herpes Zoster ; epidemiology ; etiology ; immunology ; Humans ; Immune Tolerance ; immunology ; Immunity, Cellular ; immunology ; Immunosuppressive Agents ; adverse effects ; therapeutic use ; Incidence ; Lymphoproliferative Disorders ; complications ; drug therapy ; immunology ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Singapore ; epidemiology ; T-Lymphocyte Subsets ; immunology ; Young Adult