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Background: Epstein–Barr virus (EBV) reactivation represents a frequent condition after allogeneic hematopoietic stem cell transplantation (allo-HCT) and can cause the development of a severe complication: post-transplant lymphoproliferative disease (PTLD). This retrospective study aims at investigating the incidence of EBV reactivations and analyzing the potential impact of recipient/donor-related transplant-related factors in pediatric patients. The secondary objective was to study the consequences of the approach used at our center regarding the initiation of pre-emptive therapy. Methods: This study used a retrospective evaluation of patients aged ≤25 years who received an allo-HCT at IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Giannina Gaslini, between 2012 and 2022, with follow-up censored in July 2023. Criteria to start rituximab were as follows: a viral load ≥20,000 copies/105 PBMCs or ≥10,000/105 PBMCs associated with a rise in the proportion of CD 20+ lymphocytes. Results: Overall, 214 allo-HCTs were performed in 189 patients. A total of 127 (59.3%) procedures were complicated by at least one EBV reactivation, but in only one rituximab was administered. All other reactivations were characterized by viremia below reference ranges and no increase in CD20+ lymphocytes, without clinical consequences. Risk factors for EBV reactivation identified were associated with delayed immune reconstitution. Conclusion: These results could suggest the effectiveness of the approach used in providing pre-emptive therapy. The strategy adopted differs from that highlighted by other studies and allowed the reduction of the number of children who received rituximab. It has proven effective considering the low incidence rate of PTLD and reduces the risk of rituximab-related adverse events. [ABSTRACT FROM AUTHOR]

Posttransplantation primary cutaneous T‐cell lymphomas (PT‐CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT‐CTCLs are typically EBV− and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75‐year‐old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T‐cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one‐copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T‐cell lymphoma of gamma/delta T‐cell lineage in the posttransplantation setting. [ABSTRACT FROM AUTHOR]

Background: Posttransplant lymphoproliferative disorder (PTLD), a term that encompasses a wide array of malignancies that occur after transplant, can be one of the most devastating transplant complications. While there have been major advancements in care, especially after the landmark PTLD-1 trial in 2012, there is a paucity of information on hospitalizations for PTLD and the changes in hospitalizations over time. Methods: This retrospective cohort study used the National Inpatient Sample to identify hospitalizations for PTLD that occurred between 2009 and 2018. We extracted data for hospitalizations with a primary or secondary diagnosis of PTLD and examined a range of variables, including age, gender, race, hospital type, hospital location, and disposition status. We also collected data on hospital region, median household income, insurance status, and bed size. Results: There was a statistically significant increase in the number of hospitalizations from 2009 to 2019 and an increasing rate of hospitalizations over the study period. Hypertension, electrolyte imbalances, renal failure, and anemia were among the most common comorbidities. We found an increased mortality rate, but this was not statistically significant. Conclusion: Our study provides insight into the changes in hospitalizations for PTLD over nearly a decade, showing an increase in hospitalizations and reports of comorbidities. [ABSTRACT FROM AUTHOR]

Abstract Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that occurs in immunocompromised patients. It can manifest months or years after transplantation, presenting with various neurological symptoms. A 64-year-old woman, who had received a liver transplant due to autoimmune hepatitis, presented with generalized weakness, headache, and confusion. Further investigation revealed multiple ring-enhancing lesions in the right frontal and temporoparietal regions on brain MRI. A brain biopsy confirmed the diagnosis of PT-PCNSL. This case underscores the importance of considering PT-PCNSL in the differential diagnosis of contrast-enhancing brain lesions in post-transplant patients. Timely recognition of PT-PCNSL is crucial for appropriate management and improved outcomes. To the best of our knowledge, this report describes the first instance of isolated CNS lymphoma in a liver transplant recipient, due to autoimmune hepatitis, successfully brought to complete remission with a rituximab-methotrexate regimen.

Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that occurs in immunocompromised patients. It can manifest months or years after transplantation, presenting with various neurological symptoms. A 64-year-old woman, who had received a liver transplant due to autoimmune hepatitis, presented with generalized weakness, headache, and confusion. Further investigation revealed multiple ring-enhancing lesions in the right frontal and temporoparietal regions on brain MRI. A brain biopsy confirmed the diagnosis of PT-PCNSL. This case underscores the importance of considering PT-PCNSL in the differential diagnosis of contrast-enhancing brain lesions in post-transplant patients. Timely recognition of PT-PCNSL is crucial for appropriate management and improved outcomes. To the best of our knowledge, this report describes the first instance of isolated CNS lymphoma in a liver transplant recipient, due to autoimmune hepatitis, successfully brought to complete remission with a rituximab-methotrexate regimen. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders (PTLD) after pediatric solid organ transplantation. This report addresses the outcomes of deliberations by the PTLD Management Working Group. A strong recommendation was made for reduction in immunosuppression as the first step in management. Similarly, strong recommendations were made for the use of the anti‐CD20 monoclonal antibody (rituximab) as was the case for chemotherapy in selected scenarios. In some scenarios, there is uncoupling of the strength of the recommendations from the available evidence in situations where such evidence is lacking but collective clinical experiences drive decision‐making. Of note, there are no large, randomized phase III trials of any treatment for PTLD in the pediatric age group. Current gaps and future research priorities are highlighted. [ABSTRACT FROM AUTHOR]

Background: Children undergoing allo-HCT are at high risk of EBV-related complications. The objective of the study was to analyze the impact of prophylactic post-transplant rituximab on EBV infection and EBV-PTLD in children after allo-HCT, to determine the risk factors for the development of EBV infection and EBV-PTLD and to determine their outcomes. Additionally, the impact of EBV-driven complications on transplant outcomes was analyzed. Methods: Single center retrospective analysis of EBV-related complications in pediatric population undergoing allo-HCT, based on strategy of prophylaxis with rituximab. Overall 276 consecutive children, including 122 on prophylaxis, were analyzed for EBV-driven complications and transplant outcomes. Results: Prophylaxis with rituximab resulted in significant reduction of EBV infection (from 35.1% to 20.5%; HR=2.7; p<0.0001), and EBV-PTLD (from 13.0% to 3.3%; HR=0.23; p=0.0045). A trend for improved survival was also observed (HR=0.66; p=0.068), while non-relapse mortality was comparable in both cohorts. The peak value of viral load was a risk factor in the development of EBV-PTLD: 10-fold higher peak viral load in comparison to the baseline 104 copies/mL, caused a 3-fold (HR=3.36; p<0.001) increase in the risk of EBV-PTLD. Rituximab treatment was effective as a preemptive therapy in 91.1%, and in 70.9% in EBV-PTLD. Patients who developed PTLD had dismal 5-year overall survival (29% vs 60%; p<0.001), and an increased risk of relapse (72% vs 35%; p=0.024). Conclusions: Rituximab for prophylaxis of EBV infection and EBV-PTLD was highly effective in pediatric population. Treatment of EBV-PTLD was successful in 70%, however the occurrence of EBV-PTLD was associated with an increased risk of relapse of primary malignant disease. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV)‐associated post‐transplant lymphoproliferative disorders (PTLD) is the most common malignancy in children after transplant; however, difficulties for early detection may worsen the prognosis. Methods: The prospective, multicenter, study enrolled 944 children (≤21 years of age). Of these, 872 received liver, heart, kidney, intestinal, or multivisceral transplants in seven US centers between 2014 and 2019 (NCT02182986). In total, 34 pediatric EBV+ PTLD (3.9%) were identified by biopsy. Variables included sex, age, race, ethnicity, transplanted organ, EBV viral load, pre‐transplant EBV serology, immunosuppression, response to chemotherapy and rituximab, and histopathological diagnosis. Results: The uni−/multivariable competing risk analyses revealed the combination of EBV‐seropositive donor and EBV‐naïve recipient (D+R−) was a significant risk factor for PTLD development (sub‐hazard ratio: 2.79 [1.34–5.78], p =.006) and EBV DNAemia (2.65 [1.72–4.09], p <.001). Patients with D+R− were significantly more associated with monomorphic/polymorphic PTLD than those with the other combinations (p =.02). Patients with monomorphic/polymorphic PTLD (n = 21) had significantly more EBV DNAemia than non‐PTLD patients (p <.001) and an earlier clinical presentation of PTLD than patients with hyperplasias (p <.001), within 6‐month post‐transplant. Among non‐liver transplant recipients, monomorphic/polymorphic PTLD were significantly more frequent than hyperplasias in patients ≥5 years of age at transplant (p =.01). Conclusions: D+R− is a risk factor for PTLD and EBV DNAemia and associated with the incidence of monomorphic/polymorphic PTLD. Intensive follow‐up of EBV viral load within 6‐month post‐transplant, especially for patients with D+R− and/or non‐liver transplant recipients ≥5 years of age at transplant, may help detect monomorphic/polymorphic PTLD early in pediatric transplant. [ABSTRACT FROM AUTHOR]

BackgroundEpstein–Barr virus (EBV) reactivation represents a frequent condition after allogeneic hematopoietic stem cell transplantation (allo-HCT) and can cause the development of a severe complication: post-transplant lymphoproliferative disease (PTLD). This retrospective study aims at investigating the incidence of EBV reactivations and analyzing the potential impact of recipient/donor-related transplant-related factors in pediatric patients. The secondary objective was to study the consequences of the approach used at our center regarding the initiation of pre-emptive therapy.MethodsThis study used a retrospective evaluation of patients aged ≤25 years who received an allo-HCT at IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Giannina Gaslini, between 2012 and 2022, with follow-up censored in July 2023. Criteria to start rituximab were as follows: a viral load ≥20,000 copies/105 PBMCs or ≥10,000/105 PBMCs associated with a rise in the proportion of CD 20+ lymphocytes.ResultsOverall, 214 allo-HCTs were performed in 189 patients. A total of 127 (59.3%) procedures were complicated by at least one EBV reactivation, but in only one rituximab was administered. All other reactivations were characterized by viremia below reference ranges and no increase in CD20+ lymphocytes, without clinical consequences. Risk factors for EBV reactivation identified were associated with delayed immune reconstitution.ConclusionThese results could suggest the effectiveness of the approach used in providing pre-emptive therapy. The strategy adopted differs from that highlighted by other studies and allowed the reduction of the number of children who received rituximab. It has proven effective considering the low incidence rate of PTLD and reduces the risk of rituximab-related adverse events.

Epstein–Barr Virus (EBV) is a ubiquitous herpes type virus that is associated with post‐transplant lymphoproliferative disorder (PTLD). Usual management includes reduction or cessation of immunosuppression and in some cases chemotherapy including rituximab. However, limited therapies are available if PTLD is refractory to rituximab. Several clinical trials have investigated the use of EBV‐directed T cells in rituximab‐refractory patients; however, data regarding response is scarce and inconclusive. Herein, we describe a patient with EBV‐PTLD refractory to rituximab after orthotopic heart transplantation (OHT) requiring EBV‐directed T‐cell therapy. This article aims to highlight the unique and aggressive clinical presentation and progression of PTLD with utilization of EBV‐directed T‐cell therapy for management and associated pitfalls. [ABSTRACT FROM AUTHOR]

BackgroundChildren undergoing allo-HCT are at high risk of EBV-related complications. The objective of the study was to analyze the impact of prophylactic post-transplant rituximab on EBV infection and EBV-PTLD in children after allo-HCT, to determine the risk factors for the development of EBV infection and EBV-PTLD and to determine their outcomes. Additionally, the impact of EBV-driven complications on transplant outcomes was analyzed.MethodsSingle center retrospective analysis of EBV-related complications in pediatric population undergoing allo-HCT, based on strategy of prophylaxis with rituximab. Overall 276 consecutive children, including 122 on prophylaxis, were analyzed for EBV-driven complications and transplant outcomes.ResultsProphylaxis with rituximab resulted in significant reduction of EBV infection (from 35.1% to 20.5%; HR=2.7; p

Summary: Epstein–Barr virus (EBV)‐associated lymphomas cover a range of histological B‐ and T‐cell non‐Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B‐cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO‐HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association convened an expert consensus conference to assess current evidence and develop recommendations for various aspects of care relating to post‐transplant lymphoproliferative disorders after solid organ transplantation in children. In this report from the Viral Load and Biomarker Monitoring Working Group, we reviewed the existing literature regarding the role of Epstein‐Barr viral load and other biomarkers in peripheral blood for predicting the development of PTLD, for PTLD diagnosis, and for monitoring of response to treatment. Key recommendations from the group highlighted the strong recommendation for use of the term EBV DNAemia instead of "viremia" to describe EBV DNA levels in peripheral blood as well as concerns with comparison of EBV DNAemia measurement results performed at different institutions even when tests are calibrated using the WHO international standard. The working group concluded that either whole blood or plasma could be used as matrices for EBV DNA measurement; optimal specimen type may be clinical context dependent. Whole blood testing has some advantages for surveillance to inform pre‐emptive interventions while plasma testing may be preferred in the setting of clinical symptoms and treatment monitoring. However, EBV DNAemia testing alone was not recommended for PTLD diagnosis. Quantitative EBV DNAemia surveillance to identify patients at risk for PTLD and to inform pre‐emptive interventions in patients who are EBV seronegative pre‐transplant was recommended. In contrast, with the exception of intestinal transplant recipients or those with recent primary EBV infection prior to SOT, surveillance was not recommended in pediatric SOT recipients EBV seropositive pre‐transplant. Implications of viral load kinetic parameters including peak load and viral set point on pre‐emptive PTLD prevention monitoring algorithms were discussed. Use of additional markers, including measurements of EBV specific cell mediated immunity was discussed but not recommended though the importance of obtaining additional data from prospective multicenter studies was highlighted as a key research priority. [ABSTRACT FROM AUTHOR]

The International Pediatric Transplant Association (IPTA) Consensus Conference on Practice Guidelines for the Diagnosis, Prevention, and Management of Post‐Transplant Lymphoproliferative Disorders after Solid Organ Transplantation in Children took place on March 12–13, 2019, and the work of conference members continued until the end of December 2021. The goal was to produce evidence‐based consensus guidelines on the definitions, diagnosis, prevention, and management of PTLD and related disorders based on the critical review of the literature and consensus of experts. This report describes the goals, organization, and methodology of the consensus conference and follow‐up activities. The results of each working group (Definitions, Prevention, Management, and Epstein–Barr viral [EBV] load/Biomarker Monitoring) are presented in separate manuscripts within this volume of Pediatric Transplantation. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death ligand 1 (PD‐L1) expression on tumor cells engages the PD‐1 receptor on T cells, inhibiting anti‐tumor responses. PD‐L1 has been detected in cases of post‐transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD‐L1 expression and evaluate for clinical correlations. Methods: Twenty‐one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin‐embedded tissue biopsies, we examined 21 primary tumors for expression using PD‐L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD‐L1 on lesional B‐cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. Results: Applying revised 2017 WHO PTLD classification showed five non‐destructive, nine polymorphic, and seven monomorphic cases. Average PD‐L1 expression based upon PTLD subtype was: non‐destructive 11%, polymorphic 43%, and monomorphic 73% (p =.01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B‐cells expressed PD‐L1. Conclusion: In this case series, significant differences in PD‐L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD‐L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis. [ABSTRACT FROM AUTHOR]

Here, we describe a rare case of malignant lymphoma after liver transplantation for liver cirrhosis caused by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) co-infection. A male patient was diagnosed with hemophilia A at 8 months of age. Since then, he had been receiving blood products, which led to HIV and HCV co‐infection. His HIV viral load was suppressed with antiretroviral therapy, and a sustained virologic response was achieved for HCV using direct-acting antivirals. However, his decompensated liver cirrhosis progressed, and deceased donor liver transplantation was performed. A post-transplant lymphoproliferative disorder (PTLD) developed 105 days after liver transplantation, with enlarged para-aortic and hilar lymph nodes, a right renal mass, and masses in the small and large intestines. Histopathological examination confirmed monomorphic PTLD (diffuse large B-cell lymphoma). Against the treatment (reduction of immunosuppression, rituximab, and chemotherapy), the response was poor, and the patient died 94 days after the outbreak of PTLD. Both transplantation and HIV infection are risk factors for lymphoproliferative diseases. To the best of our knowledge, this is one of the very few reports of PTLD in a patient with HIV/HCV co-infection. [ABSTRACT FROM AUTHOR]

Post-transplant lymphoproliferative disorders (PTLD) are diseases occurring in immunocompromised patients after hematopoietic stem cell transplantation (HCT) or solid organ transplantation (SOT). Although PTLD occurs rarely, it may be associated with poor outcomes. In most cases, PTLD is driven by Epstein-Barr virus (EBV) infection. Few studies have investigated the mutational landscape and gene expression profile of PTLD. In our study, we performed targeted deep sequencing and RNA-sequencing (RNA-Seq) on 16 cases of florid follicular hyperplasia (FFH) type PTLD and 15 cases of other PTLD types that include: ten monomorphic (M-PTLD), three polymorphic (P-PTLD), and two classic Hodgkin lymphoma type PTLDs (CHL-PTLD). Our study identified recurrent mutations in JAK3 in five of 15 PTLD cases and one of 16 FFH-PTLD cases, as well as 16 other genes that were mutated in M-PTLD, P-PTLD, CHL-PTLD and FFH-PTLD. Digital image analysis demonstrated significant differences in single cell area, major axis, and diameter when comparing cases of M-PTLD and P-PTLD to FFH-PTLD. No morphometric relationship was identified with regards to a specific genetic mutation. Our findings suggest that immune regulatory pathways play an essential role in PTLD, with the JAK/STAT pathway affected in many PTLDs.

Epstein-Barr virus (EBV) infection and EBV-associated post-transplant lymphoproliferative disorder (EBV/PTLD) is one of the most devastating complications occurring in pediatric solid organ transplant (SOT) recipients. Observations of SOT recipients undergoing serial EBV monitoring to inform reduction of immune suppression to prevent EBV-/PTLD has identified patients who maintain chronic high EBV load (CHL) in their blood. The CHL carrier state has been seen more commonly in pediatric compared to adult transplant recipients. Some but not all CHL may progress to EBV/PTLD. However, little is known regarding the biology of this CHL carrier state and the optimal clinical approach to CHL has not been established. This review summarizes the current knowledge and evidence of chronic high EBV load and introduces commonly adopted approaches from experts in this field.

Background: Post-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT). Methods: In this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022. Results: Median age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P<0.001). Treatment regimens were heterogeneous, with reduction of immunosuppression in combination with rituximab being the most common first-line treatment strategy in both cohorts (allo-HSCT: 66%; SOT: 80%). The overall response rate was lower in the allo-HSCT (67%) as compared to the SOT group (100%). Consequently, the overall survival (OS) trended towards a worse outcome for the allo-HSCT group (1-year OS: 54% vs. 78%; P=0.58). We identified PTLD onset ≤150 days in the allo-HSCT (P=0.046) and ECOG >2 in the SOT group (P=0.03) as prognostic factors for lower OS. Conclusion: PTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation. [ABSTRACT FROM AUTHOR]

Background: Pneumocystis jirovecii pneumonia (PJP) is a potentially fatal infection afflicting the immunocompromised population, including solid organ transplant (SOT) recipients. Several risk factors have been described; however, little is known regarding the risk of PJP in SOT recipients with posttransplant lymphoproliferative disorder (PTLD). Methods: We performed a nested case‐control study of SOT recipients diagnosed with PJP from 2000 to 2020. PJP was defined as positive microscopy or polymerase chain reaction testing with compatible symptoms and radiographic findings. Control patients were matched 2:1 by year of first transplant, first transplanted organ, transplant center, and sex. Multivariable conditional logistic regression was performed to test associations with PJP and Cox regression analyzed post‐PJP outcomes. Results: Sixty‐seven PJP cases were matched to 134 controls. The most common transplant was kidney (55.2%). Fourteen patients had a history of PTLD, 12 of whom developed PJP. After adjusting for age, acute rejection, cytomegalovirus infection, PJP prophylaxis, and lymphopenia (lymphocyte count <.5 × 109/L), PTLD was independently associated with PJP (OR 14.0, 95% CI 1.7–114.5; p =.014). Lymphopenia was also a significant association (OR 8.2, 95% CI 3.2–20.7; p <.001). PJP was associated with mortality within 90 days of diagnosis (p <.001), but not after 90 days (p =.317). PJP was also associated with 90‐day death‐censored renal allograft loss (p =.026). Conclusions: PTLD is independently associated with PJP after adjustment for recognized risk factors. This is likely influenced by PTLD‐directed chemotherapy, particularly rituximab‐containing regimens. PJP is associated with early mortality, but this effect is not persistent after 90 days. PJP prophylaxis should be considered in SOT recipients with PTLD. [ABSTRACT FROM AUTHOR]

Background: Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off‐target reads incidentally obtained during targeted hematolymphoid next‐generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens. Methods: Alignment of off‐target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus‐Clip. Results: Four cases of post‐cardiac‐transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T‐cell lymphoma (PTCL) were positive in off‐target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes. Conclusions: Our findings raise the question of whether MCPyV may play a role in rare cases of T‐lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting. [ABSTRACT FROM AUTHOR]

Lyme disease (also known as Lyme borreliosis) is the most common vector-borne disease in the United States with an estimated 476,000 cases per year. While historically, the long-term impact of Lyme disease on patients has been controversial, mounting evidence supports the idea that a substantial number of patients experience persistent symptoms following treatment. The research community has largely lacked the necessary funding to properly advance the scientific and clinical understanding of the disease, or to develop and evaluate innovative approaches for prevention, diagnosis, and treatment. Given the many outstanding questions raised into the diagnosis, clinical presentation and treatment of Lyme disease, and the underlying molecular mechanisms that trigger persistent disease, there is an urgent need for more support. This review article summarizes progress over the past 5 years in our understanding of Lyme and tick-borne diseases in the United States and highlights remaining challenges.

Background: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein‐losing enteropathy (PLE, P). The post‐HTx effects of this altered immune phenotype are not well studied. Methods: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post‐HTx. Results: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L−P, n = 23; −L+P, n = 10; and −L−P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L−P: 86%, −L+P: 87%, −L−P: 89%, p =.9). Freedom from first infection post‐HTx was greatest among −L−P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the −L−P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L−P: 1, −L+P: 1.3, −L−P: 0.3 infections/year, p <.001) and were similar to a non‐single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post‐HTx, differed among the groups. Conclusions: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post‐HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients. [ABSTRACT FROM AUTHOR]

Summary: The use of CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy for relapsed/refractory solid organ transplantation (SOT)‐related post‐transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT‐associated PTLD. Among 22 relapsed/refractory SOT‐PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre‐CAR‐T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR‐T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell‐associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR‐T. The two‐year progression‐free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post‐CAR‐T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR‐T therapy in relapsed/refractory SOT‐related PTLD appeared similar to pivotal CAR‐T data, including approximately one‐third of patients achieving sustained remission. [ABSTRACT FROM AUTHOR]

Post Transplant Lymphoproliferative Disorder (PTLD) is a heterogeneous group of Lymphoid proliferative disorders that occur in patients post Hematogenous or Solid organ transplants. They are closely associated with Ebstein-Barr Virus and can range from polyclonal lesions to frank lymphomas. PTLD is usually a rare post-transplant complication, with the incidence being higher post Lung or Heart Transplantation and less commonly seen post-renal transplantation. The incidence post renal transplantation is less than 1%, with most of the cases being limited to the Gastro-Intestinal Tract and Lymph nodes, and incidence in the lungs being extremely rare. Here we present a case report of PTLD of the lung in a post-renal transplant recipient.

Background: Pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(−)M‐PTLD] comprises approximately 10% of M‐PTLD. No large multi‐institutional pediatric‐specific reports on treatment and outcome are available. Methods: A multi‐institutional retrospective review of solid organ recipients diagnosed with EBV(−)M‐PTLD aged ≤21 years between 2001 and 2020 in 12 centers in the United States and United Kingdom was performed, including demographics, staging, treatment, and outcomes data. Results: Thirty‐six patients were identified with EBV(−)M‐PTLD. Twenty‐three (63.9%) were male. Median age (range) at transplantation, diagnosis of EBV(−)M‐PTLD, and interval from transplant to PTLD were 2.2 years (0.1–17), 14 years (3.0–20), and 8.5 years (0.6–18.3), respectively. Kidney (n = 17 [47.2%]) and heart (n = 13 [36.1%]) were the most commonly transplanted organs. Most were Murphy stage III (n = 25 [69.4%]). Lactate dehydrogenase was elevated in 22/34 (64.7%) and ≥2 times upper limit of normal in 11/34 (32.4%). Pathological diagnoses included diffuse large B‐cell lymphoma (n = 31 [86.1%]) and B–non‐Hodgkin lymphoma (B‐NHL) not otherwise specified (NOS) (n = 5 [13.9%]). Of nine different regimens used, the most common were: pediatric mature B–NHL‐specific regimen (n = 13 [36.1%]) and low‐dose cyclophosphamide, prednisone, and rituximab (n = 9 [25%]). Median follow‐up from diagnosis was 3.0 years (0.3–11.0 years). Three‐year event‐free survival (EFS) and overall survival (OS) were 64.8% and 79.9%, respectively. Of the seven deaths, six were from progressive disease. Conclusions: EFS and OS were comparable to pediatric EBV(+) PTLD, but inferior to mature B‐NHL in immunocompetent pediatric patients. The wide range of therapeutic regimens used directs our work toward developing an active multi‐institutional registry to design prospective studies. Plain Language Summary: Pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorders (EBV(−)M‐PTLD) have comparable outcomes to EBV(+) PTLD, but are inferior to diffuse large B‐cell lymphoma in immunocompetent pediatric patients.The variety of treatment regimens used highlights the need to develop a pediatric PTLD registry to prospectively evaluate outcomes.The impact of treatment regimen on relapse risk could not be assessed because of small numbers.In the intensive pediatric B–non‐Hodgkin lymphoma chemoimmunotherapy group, 11 of 13 patients remain alive in complete remission after 0.6 to 11 years. No consensus exists about treatment and outcomes of pediatric Epstein‐Barr virus–negative monomorphic post solid organ transplant lymphoproliferative disorder [EBV(−)M‐PTLD]. Retrospective evidence suggests that EBV(−)M‐PTLD has comparable outcomes to published results in EBV(+) PTLD, but inferior to diffuse large B‐cell lymphoma in immunocompetent pediatric patients. [ABSTRACT FROM AUTHOR]

BackgroundPost-transplant lymphoproliferative disorders (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that can arise after solid organ transplantation (SOT) and allogeneic hematopoietic transplantation (allo-HSCT).MethodsIn this multi-center retrospective study, we compare patient characteristics, therapies, and outcomes of PTLD after allo-HSCT and SOT. Twenty-five patients (15 after allo-HSCT and 10 after SOT) were identified who developed PTLD between 2008 and 2022.ResultsMedian age (57 years; range, 29-74 years) and baseline characteristics were comparable between the two groups (allo-HSCT vs SOT), but median onset of PTLD was markedly shorter after allo-HSCT (2 months vs. 99 months, P2 in the SOT group (P=0.03) as prognostic factors for lower OS.ConclusionPTLD cases present heterogeneously and pose unique challenges after both types of allogeneic transplantation.

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne illness in the United States. Many aspects of the disease are still topics of controversy within the scientific and medical communities. One particular point of debate is the etiology behind antibiotic treatment failure of a significant portion (10–30%) of Lyme disease patients. The condition in which patients with Lyme disease continue to experience a variety of symptoms months to years after the recommended antibiotic treatment is most recently referred to in the literature as post treatment Lyme disease syndrome (PTLDS) or just simply post treatment Lyme disease (PTLD). The most commonly proposed mechanisms behind treatment failure include host autoimmune responses, long-term sequelae from the initial Borrelia infection, and persistence of the spirochete. The aims of this review will focus on the in vitro, in vivo, and clinical evidence that either validates or challenges these mechanisms, particularly with regard to the role of the immune response in disease and resolution of the infection. Next generation treatments and research into identifying biomarkers to predict treatment responses and outcomes for Lyme disease patients are also discussed. It is essential that definitions and guidelines for Lyme disease evolve with the research to translate diagnostic and therapeutic advances to patient care.

Posttransplant lymphoproliferative disorder (PTLD) is a serious complication of kidney transplantation, and whole-body 18F- FDG PET/CT imaging plays a key role in patients with PTLD. This article reports three cases of 18F-FDG PET/CT manifestations of gastric, prostate, and pulmonary lymphomas after kidney transplantation, all of which showed local lesions without involvement of adjacent or distant lymph nodes and lymphoid node organs. All patients were treated with a reduced dose of R–CHOP and were generally in a good condition after discharge. Early diagnosis and reasonable treatment are key factors in achieving a better prognosis in patients with PTLD, and whole-body 18F-FDG PET/CT imaging plays an important role in the diagnosis and monitoring of PTLD.

Post-transplant lymphoproliferative disorder (PTLD) is a malignancy that occurs in 2-20% of solid organ transplant recipients. Isolated, primary central nervous system (PCNS) PTLD is exceedingly rare, with existing data limited to case reports and case series. The diagnosis of PCNS PTLD is difficult to diagnose given 1) non-specific clinical presentation and 2) burden of immunosuppression broadens diagnostic possibilities, often requiring extensive testing to reach a definitive diagnosis. We present the first known case of isolated PCNS PTLD after liver transplantation safely treated with methotrexate. Our case highlights the complex diagnostic and treatment considerations in the setting of immunosuppression and maintenance of adequate graft function. [ABSTRACT FROM AUTHOR]

EBV-associated lymphoproliferative disorders (LPD) include conditions of B, T, and NK cell derivation with a wide clinicopathological spectrum ranging from indolent, self-limiting, and localized conditions to highly aggressive lymphomas. Since the 2016 World Health Organization (WHO) lymphoma classification, progress has been made in understanding the biology of the EBV-associated LPDs. The diagnostic criteria of EBV+ mucocutaneous ulcer and lymphomatoid granulomatosis have been refined, and a new category of EBV-positive polymorphic B cell LPD was introduced to encompass the full spectrum of EBV-driven B cell disorders. The differential diagnosis of these conditions is challenging. This report will present criteria to assist the pathologist in diagnosis. Within the group of EBV-associated T and NK cell lymphomas, a new provisional entity is recognized, namely, primary nodal EBV+ T or NK cell lymphoma. The EBV + T and NK cell LPDs in children have undergone major revisions. In contrast to the 2016 WHO classification, now four major distinct groups are recognized: hydroa vacciniforme (HV) LPD, severe mosquito bite allergy, chronic active EBV (CAEBV) disease, and systemic EBV-positive T cell lymphoma of childhood. Two forms of HV LPD are recognized: the classic and the systemic forms with different epidemiology, clinical presentation, and prognosis. The subclassification of PTLD, not all of which are EBV-positive, remains unaltered from the 2016 WHO classification. This review article summarizes the conclusions and the recommendations of the Clinical Advisory Committee (CAC), which are summarized in the International Consensus Classification of Mature Lymphoid Neoplasms. [ABSTRACT FROM AUTHOR]

Background: Epstein–Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post‐transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein–Barr nuclear antigen‐1 (EBNA‐1), but PTLD risk among SOT recipients with discordant VCA and EBNA‐1 results is unknown. Methods: We performed a retrospective, single‐center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre‐transplant VCA and EBNA‐1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox‐proportional hazards models. Results: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04–6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10–0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04–12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06–0.82, p =.02). Conclusions: Risk of PTLD among SOTRs with discordant VCA and EBNA‐1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification. [ABSTRACT FROM AUTHOR]

Commercial immunoassays that detect IgG and IgM directed toward VCA and IgG EBNA are used in combination to assess EBV immune status. However, this strategy does not always confirm/exclude recent/past EBV infection or absence of immunity. The aim of our study was to perform complementary investigations on samples with atypical EBV serological profiles, in order to identify the clinical situation they correspond to. EBV serology was performed using EBV VCA IgM/IgG and EBNA IgG LXL® DiaSorin assay. Complementary investigations included ELISA IgM VCA, immunoblots, CMV IgM/IgG and CMV IgG avidity, and EBV PCR. In our study, 12810 EBV serological results were analyzed, and 3580 atypical profiles were detected (28 %). Among these latter, isolated VCA IgG represented 42.9 %, the three positive markers accounted for 29.1 %, isolated EBNA IgG represented 18.5 %, isolated VCA IgM accounted for 6.4 % and positive VCA IgM & positive EBNA IgG represented 3.1 %. VCA IgG detected alone were specific in 100 % cases and EBNA IgG detected alone were specific in 91.7 % cases. VCA IgM detected alone were false positive or due to a cross reaction with CMV in 52.8 % cases. The pattern positive VCA IgM and positive EBNA IgG correspond to a false positive in VCA IgM, EBNA IgG or both in 83.4 % cases. Positive EBV VCA IgM/IgG and EBNA IgG were unreliable to detect active EBV infection in 66.7 % cases. Atypical EBV serological profiles may correspond to several clinical situations and complementary investigations allow to determine the immune status in more than 98.5 % cases. • Among 12,810 EBV serological results, 3,580 (28%) were atypical profiles. • Isolated VCA IgG were specific in 100% cases; Isolated EBNA IgG in 91.7% cases. • Isolated VCA IgM were a false positive or cross-reacted with CMV in 52.8% cases. • Positive VCA IgM/IgG and EBNA IgG failed to detect active infection in 66.7% of cases. • Complementary investigations confirmed immune status in over 98.5% of cases. [ABSTRACT FROM AUTHOR]

IntroductionPrimary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial.Patients and methodsAll pediatric kidney transplant recipients aged 4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P−).ResultsA total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P− group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group (n = 13, 22.8%) and the P− group (n = 5, 22.7%) (p = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P−). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P− group (33.4%) (p