Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients

INTRODUCTION: Posttransplant lymphoproliferative disorder (PTLD) is a relatively infrequent but devastating complication that occurs after solid-organ transplantation. Although the optimal treatment for this condition is unknown, rituximab, a murine/human chimeric monoclonal antibody, has shown promise in the treatment of PTLD. In this report, we define the incidence, clinical features at presentation, and response to treatment of all cases of PTLD observed at our institution over a 10-year period, including four patients who received treatment with rituximab. METHODS: A review of all patients who underwent lung or heart-lung transplant at Duke University from 1992 to 2002 was performed (n = 400), and demographic and clinical outcome data were extracted. RESULTS: PTLD was observed in 10 of 400 patients (2.5%). Patients who acquired PTLD were predominantly > 55 years old (8 of 10 patients) and with a native disease of COPD (7 of 10 patients). Diagnosis of PTLD was made a median of 343 days after transplant. The type of transplant and Epstein-Barr virus (EBV) status prior to transplant did not appear to influence the risk for PTLD. Patients presented with thoracic organ involvement (7 of 10 patients), extrapulmonary disease (2 of 10 patients), or both (1 of 10 patients). Histologic subtypes included polymorphic B cell (n = 4), monomorphic B cell (n = 3), B cell without further classification (n = 2), and anaplastic T cell (n = 1). Only one patient responded to reduced immunosuppression alone. Patients treated with surgery or radiation (n = 2) or rituximab (n = 4) had favorable responses to therapy. Both patients treated with chemotherapy died related to complications of treatment and PTLD. CONCLUSIONS: Presentation and histologic appearance of PTLD varies considerably among lung transplant recipients. PTLD was more frequent among older patients with COPD, regardless of pretransplant EBV serology. Rituximab appears effective as a first-line therapy for PTLD, but additional studies are needed in order to define its efficacy and side effect profile in this population of patients.     

Posttransplant lymphoproliferative disorder in a lung transplant recipient

The authors describe a case of posttransplant lymphoproliferative disorder (PTLD) in a 38-year-old Japanese male patient who had undergone bilateral lung transplantation. Chest CT performed on day 109 revealed multiple lung nodules measuring approximately 1cm in the left lower lobe. Despite administration of anti-fungal agents, follow-up CT performed on day 138 showed bilateral lung nodules increased in size and number. Transcutaneous lung biopsy was performed, yielding a diagnosis of polymorphic PTLD positive for Epstein-Barr virus (EBV)-encoded RNA (EBER) and CD20. Treatment with rituximab was successful, resulting in decreased size and number of lung nodules. FDG-PET showed no increased metabolic activity in the residual nodules. In this case, CT and FDG-PET were useful for initial diagnosis and evaluation of treatment response. To the best of our knowledge, this is the first report of PTLD in a lung transplant recipient in Japan documented in the English literature.     

Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) in the staging of post transplant lymphoproliferative disorder in lung transplant recipients

Posttransplantation lymphoproliferative disorder (PTLD) is a histologic heterogeneous disease that complicates 4 to 8% of lung transplant recipients. Disease extent is an important prognostic factor and may affect therapy. Positron emission tomography with fluoro-2-deoxy-D-glucose (FDG-PET) has proven useful for staging high-grade lymphomas but is less accurate for staging low-grade and extranodal lymphoma. This study examined our initial experience using FDG-PET imaging to stage lung transplant recipients with posttransplantation lymphoproliferative disorder. FDG can show foci of uptake, particularly in extrathoracic sites, not seen by conventional imaging, which allows more accurate staging of disease thereby yielding useful prognostic information and guiding therapy.     

Successful treatment of post-transplant lymphoproliferative disorder in autologous blood stem cell transplant recipients

We report three cases of post-transplant lymphoproliferative disorder (PTLD) in the context of autologous stem cell transplantation (ASCT) for multiple myeloma (MM) and non-Hodgkin's lymphoma. The first two cases received ASCT for MM, one with a CD34-selected autograft and the other with an unmanipulated autograft. Both these cases of PTLD achieved a complete response following treatment with IVIG, gancyclovir, solumedrol and interferon (IFN). The third case received ASCT with an unmanipulated autograft for relapsed angioimmunoblastic lymphoma. He also achieved a complete response but only after rituximab was added to IVIG, gancyclovir, solumedrol and IFN. None of these patients experienced a relapse of their PTLD with follow-up ranging from 1.5 to 5 years. These cases highlight the importance of considering PTLD in the differential diagnosis of lymphadenopathy and fever post ASCT. They also demonstrate the possibility of durable complete remission of post-ASCT PTLD following antiviral and immune modulating therapy.     

The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients

Background/Aims: Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60–80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options.Methods: CD20/CF45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in situ hybridisation for Epstein-Barr virus genome detection; κ/λ immunostaining and gene rearrangement analysis for clonality.Results: There were six females and four males (age range 24–56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), bone marrow (n=2), lungs (n=2), kidneys (n=2), brain, ovaries, : and pancreas (n = 1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months.Conclusions: Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.     

Hepatitis C virus infection and risk of posttransplantation lymphoproliferative disorder among solid organ transplant recipients

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of solid organ transplantation. Hepatitis C virus (HCV) infection has been linked to increased risk of lymphoma among immunocompetent individuals. We therefore investigated the association between HCV infection and PTLD in a retrospective cohort study of all individuals in the United States who received their first solid organ transplant from 1994 to 2005 (N = 210 763) using Scientific Registry of Transplant Recipients data. During follow-up, 1630 patients with PTLD were diagnosed. HCV prevalence at transplantation was 11.3%. HCV infection did not increase PTLD risk in the total cohort (Cox regression model, hazard ratio [HR] = 0.84; 95% confidence interval [CI] 0.68-1.05), even after adjustment for type of organ transplanted, indication for transplantation, degree of HLA mismatch, donor type, or use of immunosuppression medications. Additional analyses also revealed no association by PTLD subtype (defined by site, pathology, cell type, and tumor Epstein-Barr virus [EBV] status). HCV infection did increase PTLD risk among the 2.8% of patients (N = 5959) who were not reported to have received immunosuppression maintenance medications prior to hospital discharge (HR = 3.09; 95% CI, 1.14-8.42; P interaction = .007). Our findings suggest that HCV is not a major risk factor for PTLD, which is consistent with the model in which an intact immune system is necessary for development of HCV-related lymphoproliferation.     

Diagnosis of post‐transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS Guidelines

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post‐transplant lymphoproliferative disorder (PTLD) in adult recipients of solid organ transplants. This review details the risk factors predisposing to development, initial features and diagnosis. It is important that the risk of developing PTLD is considered when using post transplant immunosuppression and that the appropriate investigations are carried out when there are suspicions of the diagnosis. These must include tissue for histology and computed tomography scan to assess the extent of disease. These recommendations have been made primarily for adult patients, there have been some comments made with regard to paediatric practice.     

Quantitative oropharyngeal Epstein-Barr virus shedding in renal and cardiac transplant recipients: relationship to immunosuppressive therapy, serologic responses, and the risk of posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV) infection plays a major role in the pathogenesis of posttransplant lymphoproliferative disorder (PTLD). Quantitative oropharyngeal EBV shedding measured by a DNA-DNA dot blot assay and the genotype of isolates determined by a polymerase chain reaction assay were studied in 23 renal and 23 cardiac transplant recipients followed over the first posttransplant year. Five patients developed PTLD and two additional PTLD renal transplant recipients were studied from the time of diagnosis. Significantly higher levels of EBV were observed in primary versus reactivation infection (P < .04) when sequential courses of antilymphocyte globulins or > 4 g of methylprednisolone were used in the first 6 months after transplant and in patients with versus those without PTLD (P < .04), although the former group had a high incidence of primary infection. Patients with the highest EBV shedding had the poorest serologic responses. All PTLD patients shed EBV-1, which was also shed by patients without PTLD.     

Management of post‐transplant lymphoproliferative disorder in adult solid organ transplant recipients – BCSH and BTS Guidelines

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Transplantation Society (BTS) has reviewed the available literature and made recommendations for the diagnosis and management of post‐transplant lymphoproliferative disorder in adult recipients of solid organ transplants. This review details the therapeutic options recommended including reduction in immunosuppression (RIS), transplant organ resection, radiotherapy and chemotherapy. Effective therapy should be instituted before progressive disease results in declining performance status and multi‐organ dysfunction. The goal of treatment should be a durable complete remission with retention of transplanted organ function with minimal toxicity.     

Longitudinal dynamics of Epstein-Barr virus-specific cytotoxic T lymphocytes during posttransplant lymphoproliferative disorder

Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD) is a serious complication after allogeneic bone marrow transplantation (BMT). Dynamics of EBV-specific cytotoxic T lymphocytes (CTL), which are important in controlling EBV during the LPD, have not been fully elucidated. A patient with Wiskot-Aldrich's syndrome was diagnosed as suffering from LPD on day 47 after BMT. Fluorescence-activated cell sorter (FACS) analysis for interferon-gamma production revealed that >70% of the patient's CD8(+) T cells were EBV specific. The patient's lymphocytes were directly cytotoxic to donor-derived EBV-positive lymphoblastoid cells, which was blocked by an anti-class I antibody. EBV-specific CD8(+) T cell counts declined in parallel with EBV genome load, and full recovery of LPD was obtained with relaxation of immunosuppressive drugs. The results illustrate longitudinal dynamics of EBV-specific CTL during the posttransplant LPD; they also illustrate the advantages of using FACS analysis for EBV-specific CTL to make decisions about treatment.     

Multifocal cranial plasmablastic lymphoma as a rare manifestation of posttransplant lymphoproliferative disorder

We present an unusual case of a young woman who developed multiple cranial masses and unilateral facial palsy 10 years after a successful living-unrelated kidney transplant. She was diagnosed with diffuse large B-cell plasmablastic differentiated lymphoma, a rare form of posttransplant lymphoproliferative disorder. She responded to 5 cycles of cyclophosphamide, doxorubicin, vincristine and prednisone chemotherapy with resolution of all cranial masses. However, her facial palsy did not resolve, and she died 6 months after diagnosis with pneumonia and sepsis.     

Fungal infections in lung transplant recipients

PURPOSE OF REVIEW: Despite numerous advances in lung transplantation, survival is still significantly compromised by a higher rate of infections. This review intends to provide an overview of the most common fungal infections afflicting lung transplant recipients, focusing on the most recent developments in diagnosis, therapy and prophylaxis. RECENT FINDINGS: Although detection of galactomannan in serum has poor sensitivity for the diagnosis of invasive aspergillosis in lung transplant recipients, detection of galactomannan in the bronchoalveolar lavage of a lung transplant recipient, with a compatible clinical illness, is highly suggestive of invasive disease. New antifungal agents, with a broader spectrum of activity and a more tolerable side effect profile, have become available for the treatment and prophylaxis of fungal infections. Evidence suggests that, at least for voriconazole, monitoring of drug concentrations may be advisable to prevent clinical failure due to underdosing and toxicity due to excessive dosing. SUMMARY: Fungal infections remain a significant cause of morbidity and mortality in lung transplant recipients; however, advances have been made in the recent years, which will allow earlier diagnosis and more effective and tolerated treatment.     

Mycobacterial infections in lung transplant recipients

BACKGROUND: Immunosuppression and chronic lung disease are known risk factors for mycobacterial infection and might be expected to develop with an increased frequency in lung transplant recipients. We therefore sought to document the incidence and type of mycobacterial infections in a large lung transplant program. METHODS: A retrospective review of 219 transplant procedures (60 single lung transplants and 159 double lung transplants) in 210 patients was conducted. All patients had scheduled surveillance bronchoscopies at 3, 6, 9, 12, 18, and 24 months, and yearly thereafter. BAL samples were processed routinely for mycobacterium. RESULTS: Eight patients (3.8%) had evidence of infection (5 men, 3 women; age range, 26 to 63 years). The reasons for transplant were obstructive lung disease (six), cystic fibrosis (one), and pulmonary fibrosis (one). Five recipients had infection in their native lungs; two of five cultured mycobacterium from BAL following transplantation. At least four of five patients had nontuberculous mycobacterium (one showed acid fast bacilli and granuloma on a biopsy specimen that was not sent for culture). None of the five developed disease (mean follow-up = 22 months; range, 3 to 30 months). The organisms were Mycobacterium avium complex (three), Mycobacterium xenopi (one), and unidentified (one). Of the three remaining patients who developed infection after transplantation, one grew Mycobacterium chelonae and the others grew Mycobacterium tuberculosis (both received double lung transplants and had no evidence of mycobacterium in their native lungs). The only definite symptomatic disease occurred in the patients with M tuberculosis, one of whom had evidence of dissemination. The patients with M tuberculosis responded to standard treatment. There have been no deaths due to mycobacterium. CONCLUSION: Mycobacterial disease rarely occurs following lung transplantation. Cultures for mycobacterium in surveillance BALs in the absence of symptoms are likely unnecessary.     

High incidence of ganciclovir-resistant cytomegalovirus infection among lung transplant recipients receiving preemptive therapy.

Preemptive antiviral therapy in transplant patients is thought to be less likely to lead to antiviral resistance than is routine prophylaxis. Cytomegalovirus (CMV)-seropositive lung transplant patients (R+) were assigned to receive pp65 antigen-guided ganciclovir therapy, and seronegative recipients of organs from seropositive donors (D+/R-) were assigned to receive initially preemptive and then routine ganciclovir prophylaxis. The incidence of infection with ganciclovir-resistant (ganR) CMV was assessed retrospectively. GanR CMV infection developed in 4 (9%) of 45 patients, at a median of 4.4 months (range, 3.1-6.6 months) after transplantation, and was more common among D+/R- patients than among R+ patients (3 of 11 vs. 1 of 34; P =.04). The incidence among patients who received preemptive therapy was similar to that among patients who received routine prophylaxis. All ganR isolates contained a UL97 mutation. GanR CMV infection occurs in nearly 10% of lung transplant recipients, despite preemptive antiviral therapy, and is more common among D+/R- patients.