Post-transplant lymphoproliferative disorders (PTLD) may significantly impair outcomes in children after solid organ transplantation (SOT). Diagnosis and treatment may be challenging. We analyze a representative pediatric liver transplant (LT) cohort in light of these challenges.

Pediatric LT recipients monitored by the Swiss Pediatric Liver Center from 2009 to 2021 with a suspicion of Epstein-Barr virus (EBV) driven PTLD were included. All cases were retrospectively reviewed using the World Health Organization (WHO) 2022 classification criteria for Pediatric Tumors. Two groups were defined: (1) histologically confirmed PTLD, and (2) 'indeterminate PTLD' if criteria were not entirely met.

During the inclusion period, 111 patients underwent LT. Histology review confirmed PTLD in 13 patients (11.7%) while 3 patients were included in the 'indeterminate' group. The most common subtype was non-destructive PTLD (6/13), followed by monomorphic (4/13) and polymorphic PTLD (3/13). Hypermetabolism on whole body (18F) fluorodeoxyglucose PET/CT helped define adequate biopsy location in 11/13 patients. Three patients with monomorphic PTLD also showed low-grade PTLD subtypes in other biopsy sites. Nine patients received mTOR inhibitors after diagnosis, either as monotherapy or in combination with calcineurin inhibitors, without major side effects.

The detailed analysis of our series of pediatric LT patients with PTLD allowed for the development of a diagnostic and management algorithm, now applied at our institution. Spatial and temporal heterogeneity argues in favor of multiple and, if necessary, repeated biopsies at different sites.

Epstein-Barr virus (EBV) is a highly prevalent virus among adults worldwide. In an immunocompetent individual, EBV infection generally results in lifelong latency of the virus and no sequelae. However, in the setting of immune dysfunction, EBV can induce the development of autoimmune disorders, hyperplastic proliferations, and cancers, including lymphoma. Here, we explore the pathogenic and oncogenic role of EBV in Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorders and lymphoproliferative disorders associated with immune deficiency and dysregulation. In addition to describing general mechanisms of EBV-associated oncogenesis, we also discuss EBV-associated oncogenesis in the context of each disorder, as well as their microscopic, phenotypic, and clinical presentations.

Epstein-Barr virus (EBV) viral load (VL) monitoring is recommended post-transplant for EBV-mismatched (donor EBV seropositive/recipient EBV seronegative) solid organ transplant (SOT) recipients as a component of post-transplant lymphoproliferative disorder (PTLD) prevention, but the optimal frequency and timing of EBV VL monitoring remains unknown.

In this retrospective cohort study, we investigated the incidence and timing of whole blood EBV DNAemia in EBV-mismatched adult and pediatric SOT recipients, who had EBV VL monitoring as part of a pre-emptive approach to PTLD prevention to optimize monitoring algorithms. We explored associations between donor-acquired EBV DNAemia (DA-EBV), defined as EBV DNAemia within 1 year post-transplant, and donor and recipient characteristics, and determined the proportion who developed PTLD.

We analyzed 257 D+/R- recipients (kidney n = 64, heart n = 75, liver n = 93, lung n = 25); 126/257 (49.0%) developed DA-EBV at a median of 83 days (Q1-Q3: 50-130 days) post-transplant. Incidence of DA-EBV varied by organ and was highest in liver (62.4%) and lowest in heart recipients (28.0%). PTLD was diagnosed in 38/257 (14.8%) EBV-mismatched recipients, 25/162 (15.4%) children, and 13/95 (13.7%) adults. DA-EBV was uncommon in recipients less than 6 months old (3/29, 10.3%) and among recipients less than 12 months with donors less than 12 months (2/29, 6.9%); possible mechanisms of protection other than recipient passive maternal antibody and false-positive donor serostatus are discussed.

Monitoring for DA-EBV should be focused on months 2-6 post-transplant. Less frequent whole blood EBV VL monitoring is likely a safe option in recipients less than 6 months old and recipients 6-12 months old with donors less than 12 months old.

Post-transplant lymphoproliferative disorder (PTLD) is a severe complication following liver transplantation, particularly in pediatric patients, with a high incidence rate associated with Epstein-Barr virus (EBV) infection. The immunological microenvironment of PTLD, particularly the cellular and molecular changes associated with EBV infection, remains unclear. Using scRNA-seq, we examined changes in the immune microenvironment of PBMC from pediatric liver transplant recipients across four groups: PTLD patients with EBV infection, EBV-positive non-PTLD transplant recipients, EBV-negative transplant recipients, and healthy children. PTLD patients exhibited profound immune dysregulation, marked by weakened cytotoxicity in NK cells, reduced B cell differentiation and activation, and an inflammatory shift in myeloid cells. EBV infection primarily targeted memory B cells and plasma cells in PTLD patients, with uninfected memory B cells showing impaired functional potential. Furthermore, CD8+ T cells in PTLD were characterized by increased exhaustion and low cytotoxic activity. In addition, regulatory T cells in PTLD displayed enhanced suppressive functions. Our findings present an in-depth view of the immune landscape in PTLD, identifying key immune cell alterations associated with EBV infection and PTLD development. These insights could inform the development of targeted therapies aimed at restoring immune function and controlling EBV-driven lymphoproliferation in pediatric liver transplant recipients.

Post-transplant lymphoproliferative disease (PTLD) represents the second most frequent malignancy in cardiac allograft recipients and constitutes up to 10% of de novo cancers. This study attempts to determine risk factors in adult heart transplant patients to develop a risk prediction model using the Scientific Registry of Transplant Recipients database and the lasso regression model. Data on 55,150 adult heart transplant patients (1987-2021) were extracted. The χ 2 /Wilcoxon tests were performed to identify significant variables ( p < 0.05). The dataset was divided into two. One set was used for model development/validation, and the other for simulating external validation. Lasso logistic regression models were developed to predict disease at 1, 3, and 5 years post-transplant. Cyclosporine, positive donor Epstein-Barr Virus (EBV) IgG, induction with OKT3, and the donor's human leukocyte antigen (HLA) B38 antigen had a higher risk at 3 and 5 years post-transplant. African American recipients have a lower risk of developing PTLD as compared with other ethnic groups. This is the first report of a lasso regression model with good discriminatory power ( c statistic of >0.7) in testing and validation cohorts. Future studies need to explore advanced modeling technologies and artificial intelligence systems capable of capturing patient diversity.

Kidney transplantation is the preferred treatment for patients with advanced chronic kidney disease and end-stage kidney disease, offering superior quality of life and survival compared to dialysis. This manuscript provides an updated overview of post-transplant care, highlighting recent advancements and current practices to assist generalists in managing these patients. It covers key areas such as immunosuppression strategies, drug interactions, and the management of transplant-specific acute kidney injury. The focus includes the use of sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring for evaluating allograft health and immune-mediated injury. The manuscript reviews the fundamentals of immunosuppression, including both induction and maintenance therapies, and underscores the importance of monitoring kidney function, as well as addressing hypertension, diabetes, and infections. It also provides recommendations for vaccinations and cancer screening tailored to kidney transplant recipients and emphasizes lifestyle management strategies, such as exercise and sodium intake, to reduce post-transplant complications.

Hepatitis B virus (HBV) infection remains a global health challenge, affecting over 254 million individuals chronically and contributing significantly to cirrhosis, liver failure, and hepatocellular carcinoma. Despite advancements in antiviral therapy, HBV reactivation remains a critical concern, particularly in immunosuppressed individuals, including non-transplant patients undergoing immunosuppressive therapy and solid organ transplant recipients. This review provides screening and management strategies for HBV reactivation in these populations.

Epstein-Barr virus (EBV) causes different clinical presentations in immunocompetent and immunocompromised persons, and thus indications for testing vary between these populations. We reviewed our institution's EBV DNA testing across these populations to understand its clinical utility and appropriateness.

We conducted a retrospective chart review of adult patients with positive EBV nucleic acid amplification (NAAT) testing from November 2022 to 2023. We recorded demographics, indications for testing, EBV-related diagnosis, laboratory results, and whether testing influenced patient treatment.

Of 3560 EBV NAAT tests, 187 (5.3%) were positive, representing 124 unique adult patients (51 immunocompetent and 73 immunocompromised). Reactivation of EBV was the most common diagnosis in both populations, followed by acute EBV infection in the immunocompetent and non-posttransplant lymphoproliferative disorder malignancies in the immunocompromised. In immunocompromised patients, positive tests led to treatment changes more frequently than in immunocompetent patients (27.4% vs 11.7%, P = .06). Testing affected clinical management in 0% to 2% of cases when sent for sepsis/shock and nonspecific viral syndromes compared to 37% to 49% of cases when sent for posttransplant and malignancy screening/monitoring.

EBV NAAT testing infrequently influenced clinical management in immunocompetent individuals but had a notable impact in immunocompromised patients, particularly those undergoing posttransplant or malignancy screening. This underscores the need for targeted testing to optimize resource utilization and cost-effectiveness.

Liver transplantation (LT) is a well-established therapy for patients with decompensated cirrhosis and early-stage hepatocellular carcinoma. Liver transplantation activity varies sharply across Latin American (LATAM) countries due to differences in resources, expertise, and funding and local attitudes toward organ donation and transplantation. This current guidance of postoperative care after LT is the first position paper of the Latin American Association for the Study of the Liver (ALEH) Special Interest Group (SIG), drawing evidence-based recommendations regarding immediate and long-term postoperative care of LT recipients, taking into consideration their applicability in Latin America.

One strategy to minimize the risk of posttransplant lymphoproliferative disorder (PTLD) is to avoid an Epstein-Barr Virus (EBV) mismatch through kidney paired donation. We aimed to estimate the incidence of PTLD in EBV-negative kidney transplant recipients with EBV-positive donors (D+/R-) and evaluate the excess risk of death following the occurrence of PTLD.

We included adult patients in OPTN database who underwent kidney transplants between 2012 and 2022. Cox regression analysis was employed to evaluate the impact of EBV serostatus on the development of PTLD, and to assess mortality following PTLD diagnosis in D+/R- individuals.

A total of 179 068 patients were included, with 92.8% in the R+, 6.4% in the D+/R-, and 0.8% in the D-/R- group. D+/R- exhibited a significantly higher risk of PTLD compared to R+ and D-/R- groups. D+/R- had a greater risk of PTLD when compared to D-/R- recipients (aHR: 3.82; p < 0.001). Among D+/R- recipients, those who developed PTLD had a significantly higher risk of mortality (aHR: 2.28; p < 0.001 in deceased donor kidney transplant [DDKT] and aHR: 5.22; p < 0.001 in living donor kidney transplant [LDKT]).

D+/R- recipients have nearly a fourfold higher risk of PTLD compared to D-/R- recipients, suggesting that choosing an EBV D-/R- transplant could reduce the PTLD risk by about 73%. This data is crucial for counseling EBV-negative patients considering kidney paired donation to avoid an EBV serostatus mismatch.

Posttransplant lymphoproliferative disorder (PTLD) is a complication of solid organ transplantation (SOT) due to immunosuppression. In 2023, a pediatric PTLD register was established in Norway because of a perceived increase in the incidence of pediatric PTLD. This study aimed to analyze population-based data on the incidence and management of pediatric PTLD after SOT using the pediatric PTLD registry in Norway.

This retrospective quality assurance study collected the data of pediatric patients with PTLD after SOT in Norway from January 1, 1995, to December 31, 2023. For comparison and calculation of incidence rates, SOT patients without PTLD required a minimum of 1 year posttransplant follow-up to be included.

A total of 457 patients underwent SOT (57% males) and 22 (4.8%) developed PTLD (73% males). The median age at transplant in the SOT and PTLD groups were 9.5 (interquartile range, 2.4-14.5) and 4.3 (1.1-12.5) years, respectively. Twenty patients with PTLD (91%) were Epstein-Barr virus naive at the time of transplantation. Eighteen (82%) and four (18%) patients developed early and late PTLD, respectively. Ten patients had monomorphic PTLD (45%). All patients received a reduction in immunosuppression, 15 received rituximab, and six required chemotherapy. Six patients (27%) died after PTLD, five of whom had active PTLD disease at the time of death. None of the patients experienced graft loss.

Our findings regarding the incidence, EBV status, sex, and age at transplantation align with those of previous studies.

Post-transplant lymphoproliferative disorder (PTLD) is a devastating complication of immunosuppressive treatment in both solid organ transplantations (SOT) and hematopoietic stem cell transplantations (HSCT). Epstein-Barr virus (EBV) infection precedes PTLD in 90% of patients. Rituximab, a monoclonal anti-CD20 antibody, depletes B-lymphocytes, which are the ultimate reservoir for EBV. Although rituximab therapy is commonly used as a preventive measure for PTLD in high-risk HSCT, it is not established in SOT.

Pediatric kidney transplant recipients (PKTR) underwent routine EBV-PCR surveillance. Patients with increasing viral loads, despite immunosuppressive dose reduction, were managed with preventive rituximab therapy.

Between 2012 and 2023, we identified eight episodes of asymptomatic EBV-PCR-positive blood tests in seven out of 65 PKTR (11%) under our care. EBV DNAemia emerged 120-720 days post-transplantation. Five of seven patients with EBV DNAemia (71%) were EBV-seronegative prior to transplantation. All five patients did not respond to MMF dose reduction and were therefore treated with preventive rituximab therapy. Following this treatment, EBV PCR clearance was observed in all patients with only minimal complications.

PKTR who are EBV-naïve prior to transplantation are expected to have a higher prevalence of EBV DNAemia. We found that PKTR who were EBV seronegative prior to transplantation were less likely to achieve EBV clearance in response to immunosuppression dose reduction. We suggest that rituximab therapy in PKTR may be safe and effective in EBV clearance and PTLD prevention.

Epstein-Barr virus (EBV) is strongly associated with the development of post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients. PTLD is one of the most common malignancies following liver transplantation and is associated with significant morbidity and mortality. Factors such as EBV-serostatus mismatch and prolonged or high levels of immunosuppression impact a patient's risk of developing PTLD. While pre-transplant EBV serological screening and post-transplant monitoring of EBV-DNA levels are strongly recommended, universal guidelines for its prevention and management are lacking. Due to a lack of robust prospective studies, current clinical practices vary widely. The treatment of PTLD typically involves reducing immunosuppression and using targeted therapies such as rituximab, or chemotherapy for refractory cases. This review aims to address our current understanding of EBV's relationship with PTLD, evaluate the available treatment modalities, and highlight evolving strategies for using EBV as a biomarker for PTLD screening and prevention.

EBV DNAemia surveillance, with reduction of immunosuppression at certain viral load (VL) thresholds, is a common practice for mitigating progression from EBV DNAemia to post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTRs). The utility of EBV surveillance in adult EBV seropositive LTRs is unknown.

We performed a retrospective cohort study of EBV seropositive adult LTRs who underwent lung transplant between 1/1/19 and 12/31/20 and received whole blood (WB) EBV PCR surveillance. We compared peak WB EBV VLs among 3 groups: 1) asymptomatic LTRs who developed PTLD, before PTLD was clinically suspected, 2) LTRs who developed PTLD, after PTLD was clinically suspected, and 3) LTRs who did not develop PTLD. We calculated the positive predictive value (PPV) of moderate-grade DNAemia (2840 to 11,360 IU/mL) and high-grade DNAemia (≥ 11,360 IU/mL) for identifying active or future PTLD.

Six (2.6 %) of 229 LTRs developed PTLD. Among LTRs who developed PTLD, median peak EBV VL was significantly higher after PTLD was suspected than before clinical signs of PTLD were present (16,004 IU/mL vs. ≤568 IU/mL, p = 0.016). Median peak EBV VLs were similar between asymptomatic LTRs who later developed PTLD and LTRs who did not develop PTLD (median peak EBV VL ≤568 IU/mL vs. ≤568 IU/mL, p = 0.62). The PPVs for moderate- and high-grade DNAemia were 14.7 % and 33.3 %, respectively.

EBV surveillance did not accurately identify EBV seropositive LTRs at risk for progressing to PTLD. EBV PCR testing in asymptomatic EBV seropositive transplant recipients may represent an opportunity for diagnostic stewardship.

This review explores four Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders (LPD) and lymphomas with significant diagnostic overlap: EBV(+) mucocutaneous ulcer (EBVMCU), EBV(+) polymorphic LPD, EBV(+) classic Hodgkin lymphoma (CHL), and EBV(+) diffuse large B-cell lymphoma (DLBCL). Each entity is compared for both overlapping and defining features of clinical presentation, morphology, immunohistochemical profile and EBV expression pattern and latency. Our aims for this review are to provide useful guidance to the practicing pathologist in the diagnosis of these EBV-associated entities.

Prior studies indicate that 1% to 4% of Epstein-Barr virus (EBV)-seronegative recipients of EBV-seropositive donor (EBV D+/R-) kidneys develop posttransplant lymphoproliferative disorder (PTLD). However, these estimates are based on limited data that lack granularity.

To determine the associations between pretransplant EBV D+/R- and recipient EBV-seropositive status (R+) and the outcomes of PTLD and graft and patient survival among adult kidney transplant recipients.

Retrospective cohort study.

Two large U.S. transplant centers.

Epstein-Barr virus D+/R- and EBV R+ recipients matched 1:3 on donor, recipient, and transplant characteristics between 1 January 2010 and 30 June 2022.

Exposure was pretransplant donor and recipient EBV serostatus. The primary outcome was biopsy-proven PTLD. Secondary outcomes were all-cause graft loss (death, retransplant, or graft failure) and death. Follow-up was truncated to 3 years after transplant.

The final cohort comprised 104 EBV D+/R- recipients matched to 312 EBV R+ recipients. The mean age was 42 years (SD, 17.1), 59% were living donor transplants, and 95% received thymoglobulin induction. Among EBV D+/R- recipients, 50 (48.1%) developed EBV DNAemia, with a median time of 198 days (IQR, 110 to 282 days) after transplantation. Posttransplant lymphoproliferative disorder occurred in 23 (22.1%) EBV D+/R- recipients at a median of 202 days (IQR, 118 to 317 days) after transplantation. Epstein-Barr virus D+/R- recipients had higher all-cause graft failure (hazard ratio, 2.21 [95% CI, 1.06 to 4.63]); mortality was higher but not statistically significant (hazard ratio, 2.19 [CI, 0.94 to 5.13]).

Two-center study.

Compared with previous studies, this study showed that EBV D+/R- kidney recipients face a 5- to 10-fold higher cumulative incidence of PTLD. Strategies to mitigate the PTLD risk are urgently needed.

National Institutes of Health.

Posttransplant lymphoproliferative disorder (PTLD) poses a serious challenge in kidney transplant recipients. Epstein-Barr virus (EBV)-seronegative recipients have a significantly increased risk of PTLD, but few studies have investigated risk factors for PTLD in EBV-seronegative recipients in the current era of immunosuppression. This cohort study from Norway and western Denmark included first-time kidney transplant recipients between 2007 and 2021 and estimated the cumulative incidence, risk, and prognosis of PTLD. In total, 80 of 5084 recipients developed biopsy-proven PTLD (median follow-up of 6.8 years). Two-year cumulative incidence of PTLD was 7.3% in EBV-seronegative adults and 14.1% in EBV-seronegative children. The age-adjusted hazard ratio (HR) for PTLD was 30.7 (95% CI, 13.9-67.9) in EBV-seronegative vs EBV-seropositive adults and 5.4 (95% CI, 1.1-26.9) in children. Recipients receiving induction therapy with antithymocyte globulin had an increased risk of PTLD (HR, 4.4; 95% CI, 1.8-10.6), while rituximab induction was associated with a lower risk of PTLD (HR, 0.20; 95% CI, 0.03-1.49). The age-adjusted mortality rate was higher in EBV-seronegative recipients with vs without PTLD (HR, 3.3; 95% CI, 1.3-8.3). In conclusion, the risk of PTLD in EBV-seronegative kidney transplant recipients is high in the contemporary era of immunosuppression. Induction therapy should be carefully considered in this high-risk population.

Organ transplant recipients face a substantial risk of developing posttransplant lymphoproliferative disorders (PTLD). In over 90% of cases with B-cell PTLD following solid organ transplantation, the Epstein-Barr virus (EBV) genome is promptly identified, usually within the initial year. A continuing discussion revolves around the efficacy of antiviral prophylaxis in mitigating the incidence of PTLD in solid organ transplant (SOT) patients. This study aimed to conduct a systematic review and meta-analysis to investigate this issue.

A comprehensive search was conducted up to December 31, 2023, in databases including PubMed, Embase, and the Cochrane Library for retrospective and prospective studies comparing antiviral prophylaxis effects on EVB viremia and PTLD incidence in SOT recipients. Fixed or random effect models were applied based on the heterogeneity assessed via the I2 statistic, using Stata 16.0 software for data analysis.

In total, 22 eligible studies involving 13,498 patients were analyzed. Antiviral prophylaxis was associated with a significant reduction in EBV viremia incidence in SOT recipients, as demonstrated in 10 studies (relative risk (RR) 0.69, 95% CI 0.54 to 0.88). The rate of PTLD was significantly lower among those who received antiviral prophylaxis compared to those who did not, as reported in 18 studies (RR 0.77, 95% CI 0.63 to 0.94). No significant difference was observed in the subgroup of high-risk recipients based on EBV serology (RR 1.13, 95% CI 0.72 to 1.78). Additionally, a notable reduction in PTLD incidence was seen in the pediatric subgroup (RR 0.58, 95% CI 0.43 to 0.79) using antiviral prophylaxis, while no significant differences were observed in the subgroup of adults (RR 0.88, 95% CI 0.64 to 1.21). Administration of antiviral prophylaxis can significantly reduce the incidence of PTLD among kidney (RR 0.63, 95% CI 0.46 to 0.87) and heart transplant patients (RR 0.61, 95% CI 0.39 to 0.96). PTLD incidence was significantly reduced among recipients of T-cell depletion or steroid-based immunosuppression using antiviral prophylaxis (RR 0.54, 95% CI 0.39-0.74 and RR 0.55, 95% CI 0.41-0.73, respectively).

This meta-analysis revealed that administering antiviral prophylaxis to patients after solid organ transplantation reduces PTLD and EBV viremia occurrences, especially among pediatric recipients, individuals undergoing kidney or heart transplantation, and those receiving high-intensity immunosuppression regimens. Post-transplant lymphoproliferative disorders (PTLD) and other EBV syndromes are among the most serious complications following solid organ transplantation (SOT), primarily due to the necessity for prolonged immunosuppressive therapy. Among the strategies for preventing EBV-related complications, the use of antiviral prophylaxis is a subject of ongoing debate. This systematic review and meta-analysis found that antiviral prophylaxis significantly reduced EBV viremia incidence (risk ratio (RR) 0.69, 95% confidence interval (CI) 0.54 to 0.88) compared to those without prophylaxis. In the sub-analysis related to high-risk EBV serologically mismatched SOT recipients (EBV D+/R-), the result did not show a significant difference in terms of PTLD incidence (RR 1.13, 95% CI 0.72 to 1.78). Antiviral prophylaxis significantly impacted the occurrence of PTLD events among pediatric SOT patients (RR 0.58, 95% CI 0.43 to 0.79), but not among adult patients (RR 0.88, 95% CI 0.64 to 1.21). Antiviral prophylaxis significantly impacted the occurrence of PTLD events among kidney/simultaneous pancreas and kidney (RR 0.63, 95% CI 0.46 to 0.87) and heart (RR 0.61, 95% CI 0.39 to 0.96) transplant patients but not liver  (RR 0.5, 95% CI 0.23 to 1.08) transplant recipients.

Molecular testing for Epstein-Barr virus (EBV) infection is a cornerstone of care to prevent adverse outcomes in immunocompromised patients, including transplant recipients. We evaluated the analytical and clinical performance of the quantitative Alinity m EBV assay for plasma sample testing on the fully automated Alinity m platform. Assay lower limit of detection and precision were determined using commercially available panels in plasma. Alinity m EBV detected 100% of panels at 1.3 Log IU/mL, and precision ranged from 1.9% to 5.2% coefficients of variance (SD ≤ 0.14 Log IU/mL). Remnant-de-identified specimens initially tested with the Eurofins Viracor EBV Laboratory Developed Test (LDT) (n = 357), ELITech EBV LDT (n = 113), University of Washington (UW) LDT (n = 151), or Roche cobas EBV assay (n = 148) were subsequently tested with the Alinity m EBV assay. Comparison of the Alinity m EBV assay and Eurofins Viracor EBV assay demonstrated a correlation coefficient of 0.762 and mean bias of -0.48 Log IU/mL, comparison of the Alinity m EBV assay with UW LDT demonstrated a correlation coefficient of 0.970 and mean bias of -0.24 Log IU/mL, and comparison of the Alinity m EBV assay with cobas EBV demonstrated a correlation coefficient of 0.964 and mean bias of 0.35 Log IU/mL. The Alinity m EBV assay demonstrated high precision across the analytical measurement range and produced comparable results to the EBV test of record assays. These findings support the utility of the fully automated Alinity m EBV assay in transplant patient management.

Epstein-Barr virus (EBV) infection and reactivation are associated with increased risk for post-transplant lymphoproliferative disorders (PTLD) in transplant recipients with the development of PTLD occurring predominantly within a year of transplant. Quantitative PCR for EBV is used to monitor the viral load of EBV with a negative result as a good negative predictor of PTLD. Nucleic acid amplification tests (NAATs) with high sensitivity and specificity are available on fully automated high-throughput instruments to provide accurate quantitation and improve test result turn-around time. This study evaluates the analytical and clinical performance of one such NAAT, the Alinity m EBV assay.

Improved diagnostic testing (DT) of infections may optimize outcomes for solid organ transplant recipients (SOTR), but a comprehensive analysis is lacking.

We conducted a systematic literature review across multiple databases, including EMBASE and MEDLINE(R), of studies published between 1 January 2012-11 June 2022, to examine the evidence behind DT in SOTR. Eligibility criteria included the use of conventional diagnostic methods (culture, biomarkers, directed-polymerase chain reaction [PCR]) or advanced molecular diagnostics (broad-range PCR, metagenomics) to diagnose infections in hospitalized SOTR. Bias was assessed using tools such as the Cochrane Handbook and PRISMA 2020.

Of 2362 studies, 72 were eligible and evaluated heterogeneous SOT populations, infections, biospecimens, DT, and outcomes. All studies exhibited bias, mainly in reporting quality. Median study sample size was 102 (range, 11-1307). Culture was the most common DT studied (N = 45 studies, 62.5%), with positive results in a median of 27.7% (range, 0%-88.3%). Biomarkers, PCR, and metagenomics were evaluated in 7, 19, and 3 studies, respectively; only 6 reported sensitivity, specificity, and positive/negative predictive values. Directed-PCR performed well for targeted pathogens, but only 1 study evaluated broad-range PCR. Metagenomics approaches detected numerous organisms but required clinical adjudication, with too few studies (N = 3) to draw conclusions. Turnaround time was shorter for PCR/metagenomics than conventional diagnostic methods (N = 4 studies, 5.6%). Only 6 studies reported the impact of DT on outcomes like antimicrobial use and length of stay.

We identified considerable evidence gaps in infection-related DT among SOT, particularly molecular DT, highlighting the need for further research.

Though antimicrobial stewardship programs (ASPs) are required for hospitals, the involvement of transplant recipients in programmatic interventions, protocols, and metrics has historically been limited. Though there is a growing interest in studying stewardship practices in transplant patients, optimal practices have not been clearly established. A component of ASPs, antiviral stewardship (AVS), specifically targeting cytomegalovirus (CMV), has been more recently described. Understanding AVS opportunities and interventions is particularly important for transplant recipients, given the morbidity and mortality associated with viral infections, challenging clinical syndromes, ultrasensitive molecular diagnostic assays, antiviral resistance, and costs of viral disease and medications, as well as antiviral drug toxicities. This review highlights opportunities for AVS for CMV, EBV, HSV, VZV, SARS-CoV-2, respiratory syncytial virus, and BK polyomavirus in transplant patients.

Solid organ transplantation (SOT) recipients have a heightened risk for infection due to prolonged immunosuppressive drug use following transplant procedures. The occurrence of post-transplant infections is influenced not only by the transplanted organ type but also by varied factors. The kidney is the most common organ in SOT, followed by the liver, heart, and lung. This review aims to provide a comprehensive overview of the current epidemiological characteristics of infections after kidney, liver, heart, and lung transplantation, focusing on bacterial, fungal, and viral infections. The incidence and infection types demonstrated significant variability across different SOTs. Furthermore, this review attempts to elucidate the clinical characteristics of infections across patients following different SOTs and contribute to the development of individualized prevention strategies according to infection incidence, ultimately enhancing the quality of life of transplant recipients.

Epstein-Barr virus (EBV) is a herpesvirus capable of establishing lifelong latent infections, leading to a wide spectrum of diseases. It can affect multiple organs, including the gastrointestinal tract, typically through lymphoproliferative syndromes or gastric cancer, while acute gastrointestinal disease is rare and poorly understood. Two cases of EBV-induced acute colitis in kidney transplant recipients were described. Additionally, a scoping review of the literature was conducted to identify all reported cases of EBV infection presenting with acute gastrointestinal involvement. A total of 11 174 articles from PubMed and Embase were analyzed, from which 30 articles were ultimately selected, encompassing 33 cases. Two distinct patient profiles emerged. Patients with gastric-limited disease were typically healthy women and exhibited a benign course, characterized by a more acute presentation and complete recovery in all cases. In contrast, patients with intestinal disease were often immunocompromised, presenting with deep colonic ulcers frequently associated with rectal bleeding, high rates of perforation, frequent need for surgical intervention, and significant mortality. Antiviral therapy and reduction of immunosuppression were commonly employed, although no specific treatment approach demonstrated a clear benefit in reducing mortality or complications. In conclusion, EBV-related gastrointestinal disease varies by patient immunocompetence and the site of involvement. Gastric-limited disease usually has a favorable prognosis, while intestinal involvement in immunocompromised patients is linked to severe complications and higher mortality. Individualized treatment strategies and vigilant long-term follow-up are needed due to the lack of standardized treatment protocols and the risk of relapse or development of EBV-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disease (PTLD) is a rare but life-threatening disease that occurs after organ transplantation. Histopathology is the gold standard for the diagnosis of PTLD. Because of its rarity and atypical symptoms, many patients are misdiagnosed with liver abscess, liver cancer, or missed diagnosis long before pathological diagnosis is obtained, thus delaying treatment. Early and accurate diagnosis, in addition to histopathological examination, is difficult. Contrast-enhanced ultrasound (CEUS) imaging techniques have overwhelming advantages of being safe (noninvasive, radiation-free) and sensitive for evaluating the microcirculation of lesions, thus making them widely used in the diagnosis of hepatic lesions. Unfortunately, there are few reports of CEUS data on hepatic PTLD (HPTLD). This study reported and analyzed four cases of HPTLD in detail, all of which underwent pre-biopsy CEUS examinations and had a complete diagnosis and treatment process. By offering readers comprehensive knowledge of CEUS in the diagnosis of HPTLD, our study aims to help reduce misdiagnoses and missed diagnoses, thereby improving patient treatment and prognosis.

Immunosuppressive medications play a crucial role in determining both organ and patient survival following liver transplantation (LT). Typically, immunosuppressive protocols for pediatric LT patients rely on calcineurin inhibitors (CNIs). While inhibitors of mammalian target of rapamycin (mTOR) have demonstrated beneficial outcomes in adult recipients of liver allografts, such as improved renal function post-LT, their application in pediatric liver transplant recipients is a subject of debate due to uncertain efficacy and potential adverse effects.

This review evaluates the potential roles of mTOR inhibitors in the context of pediatric LT patients.

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for conduct and reporting. Databases until 31 August 2023 were searched using specific terms and keywords. All clinical studies focusing on mTOR inhibitors in pediatric LT were included.

Out of 888 identified articles, 30 studies, involving 386 children who had undergone liver transplantation and received mTOR-inhibitor-based immunosuppressive regimens, met the inclusion criteria. The beneficial impacts of switching from a CNI to an mTOR inhibitor or adding an mTOR inhibitor to CNI-reduced immunosuppression in LT pediatric patients with impaired kidney function are controversial, and high-powered clinical studies are need. It appears that enhancing immunosuppression by adding an mTOR inhibitor to CNI is helpful for pediatric LT recipients who are experiencing refractory acute rejection or chronic rejection. mTOR-inhibitor-containing regimens failed to reduce the occurrence of post-transplant lymphoproliferative disorders (PTLD) among children with LT that may be due to concomitant high CNI concentration among studied patients. The effectiveness of mTOR inhibitors in treating PTLD remains uncertain; however, in patients with PTLD who are at high risk of rejection, mTOR inhibitors may be administered. Conversion to or the addition of mTOR inhibitors to maintenance immunosuppression seems to be suitable for pediatric patients who received a transplant due to hepatic malignancies such as hepatoblastoma or hepatocellular carcinoma or for those with post-transplant primary or recurrent malignancies. Switching to an mTOR inhibitor may improve some CNI-related adverse effects such as gingival hyperplasia, neurotoxicity, nephropathy, hypertrophic cardiomyopathy, or thrombotic microangiopathy.

Although the exact role of mTOR inhibitors among pediatric patients who have received a liver transplant needs further study, two algorithms are presented in this review to guide conversion from CNIs to mTOR inhibitors or the addition of mTOR inhibitor to a CNI-minimization immunosuppressive regimen for pediatric patients who may benefit from this class of drugs. This review mainly consisted of retrospective studies with inadequate sample sizes and lacked a control group, which represents the main limitation of this study.

We present a challenging case of Epstein-Barr virus-related isolated small bowel post-transplant lymphoproliferative disorder (PTLD) in a pediatric heart transplant recipient presenting as recurrent gastrointestinal (GI) bleeding and subsequently a GI fistulous tract with associated intra-abdominal abscess. Diagnosis was not confirmed until exploratory laparoscopy was performed, with excision of the fistulous tract revealing evidence of PTLD on pathology. Early diagnosis of GI-PTLD remains a challenge, especially if isolated in the small intestine. Diagnosis may rely on positron emission tomography/ computed tomography scan (PET/CT) or invasive intervention to obtain appropriate tissue samples for pathology diagnosis.

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%-80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies.

Transplant recipients have an increased risk of complications, including graft dysfunction and infections, which can be life-threatening if not recognized early. Pneumonia ranks as one of the most frequent complications in both solid organ and hematopoietic stem cell transplants. Clinical symptoms manifest late during infections in immunocompromised patients. An aggressive approach centered on early confirmatory diagnosis and a low threshold for empiric therapy is often the most effective strategy. The isolation of a pathogen in an upper airway sample does not necessarily mean the same organism is responsible for pneumonia. Viruses such as CMV (cytomegalovirus virus) may function as co-pathogens for opportunistic infections in transplant recipients in addition to causing their own primary infectious syndrome. Furthermore, some viruses exhibit immunomodulatory effects that can affect the graft function. Given the exhaustive list of causative pathogens responsible for pneumonia, the best approach to the diagnosis is to have a conceptual framework that includes a detailed history, such as the type of transplant, degree of immunosuppression, antimicrobial prophylaxis, risk factors, time of presentation since transplantation and the radiographic pattern on the CT chest (computer tomography of the chest). Management depends predominantly on the degree of antimicrobial resistance, drug-to-drug interaction, and adjustments to the immunosuppression.

Post-transplant lymphoproliferative disorders (PTLD) are complications that arise from post-transplantation immunosuppressive therapy. Although Epstein-Barr virus (EBV) viremia is often seen in PTLD, it is not a definitive feature for diagnosis. We report a rare case of recurrent PTLD in a 26-year-old heart transplant recipient on high-dose tacrolimus who presented with emesis, fatigue, and bloody diarrhea. Although substantial EBV viremia was seen in the first PTLD episode, the current episode was a gastrointestinal manifestation with barely detectable circulating EBV. The patient's history of gastrointestinal disease delayed definitive diagnosis, which was later established through endoscopy and biopsy sample analysis.

Epstein-Barr virus (EBV) specific T-cell response measurement can help adjust immunosuppression in transplant patients with persistent infections. We aim to define T-cell responses against EBV in a cohort of pediatric liver-transplant patients.

Thirty-eight immunosuppressed pediatric liver-transplant patients (IP) and 25 EBV-seropositive healthy-adult controls (HC) were included in our cross-sectional study. Based on their EBV serological (S) and viral load (VL) status, patients were categorized into IP-SNEG, IP-SPOSVLNEG and IP-SPOSVLPOS groups. T-cell response was assessed at two timepoints by stimulating cells with EBV peptides (PepTivator®) and performing intracellular-cytokine and activation-induced marker staining. Background subtraction was used to determine EBV-specific T-lymphocyte frequency.

Polyfunctional CD8+ T cells indicated previous EBV contact (IP-SNEG 0.00% vs IP-SPOS 0.04% and HC 0.02%; p=0.001 and p=0.01, respectively). Polyfunctional CD8+CD107a+IFNɣ+IL2-TNFα- profile was increased in serology-positive (IP-SNEG 0.01% vs IP-SPOS 0.13% and HC 0.03%; p=0.01 and p=0.50, respectively) and viral-load positive (IP-SPOSVLPOS 0.43% vs IP-SPOSVLNEG 0.07% and HC 0.03%; p=0.03 and p=0.001, respectively) patients. Central-memory cells were increased among serology-positive adults (IP-SNEG 0.00% vs IP-SPOS 0.13% and HC 4.33%; p=0.58 and p=0.002, respectively). At the second timepoint, IP-SNEG patients remained negative (first visit 0.01% vs second visit 0.00%, p=0.44). On the other hand, IP-SPOSVLPOS patients had cleared viral loads and, subsequently, decreased polyfunctional CD8+CD107a+IFNɣ+IL2-TNFα- cells (first visit 0.43% vs second visit 0.10%, p=0.81).

Polyfunctional CD8+ EBV-specific T-cell response allows detecting EBV previous contact in liver-transplant children. %CD8+CD107a+IFNɣ+IL2-TNFα- is increased in patients with positive viral loads. Central memory CD4+ T-cell population more effectively determines prior EBV-exposure in adults.

Epstein-Barr Virus (EBV) is associated with lung disease in immunocompromised patients, particularly transplant recipients. EBV DNA testing of lower respiratory tract specimens may have diagnostic utility.

This was a retrospective, observational study of all patients with bronchoalveolar lavage (BAL) fluids submitted for EBV qPCR testing from February 2016 to June 2022 at the Stanford Clinical Virology Laboratory.

There were 140 patients that underwent 251 EBV qPCR BAL tests (median 1; range 1 - 10). These patients had a mean age of 15.9 years (standard deviation, 15.1 years) and 50 % were female. Transplant recipients accounted for 67.1 % (94/140) of patients, including 67.0 % (63/94) solid organ transplant (SOT) and 33.0 % (31/94) hematopoietic cell transplant. Diagnostic testing was performed more commonly than surveillance testing [57.0 % (143/251) v. 43.0 % (108/251)]; 96.2 % (104/108) of surveillance samples were from lung transplant recipients. Excluding internal control failures, 34.7 % (83/239) of BAL had detectable EBV DNA, encompassing a wide range of viral loads (median=3.03 log10 IU/mL, range 1.44 to 6.06). Overall agreement of EBV DNA in BAL compared to plasma was 74.1 % [117/158; 95 % confidence interval (CI): 66.5 % to 80.7 %], with a kappa coefficient of 0.44 (95 % CI: 0.30 to 0.57). Only 20.1 % (48/239) of results were discussed in a subsequent clinical note, and one result (0.4 %; 1/239) changed clinical management.

EBV qPCR testing on BAL offers limited clinical impact. Additional biomarkers are required to improve the diagnosis of EBV-associated lung diseases.

Post-transplant lymphoproliferative disorders (PTLD) are rare but severe complications that occur after solid organ or allogeneic hematopoietic stem cell transplantations (allo-HSCT), with rapid progression and high mortality. Primary central nervous system (CNS)-PTLD are rarely recognized histo-pathologically. In addition, the diagnostic value of the Epstein-Barr virus (EBV) DNA copies in CNS-PTLD remains poorly understood.

We herein report a case of monomorphic EBV-associated CNS-PTLD (diffuse large B-cell lymphoma, DLBCL) after allo-HSCT and perform a meta-analysis to assess the efficacy of PTLD treatment strategies in recent years.

We present the case report covering clinical manifestations, diagnosis, treatment, and outcomes of a patient with primary CNS-PTLD. Additionally, we include a systematic review and meta-analysis of the clinical characteristics of 431 patients with PTLD after allo-HSCT. We evaluate the main treatment options and outcomes of PTLD management, including rituximab, chemotherapies, and autologous or human leukocyte antigen (HLA)-matched EBV-specific cytotoxic T lymphocyte infusion (EBV-CTLs)/donor lymphocyte infusion (DLI).

The meta-analysis revealed an overall response rate of 69.0% for rituximab alone (95% CI: 0.47-0.84), 45.0% for rituximab plus chemotherapies (95% CI: 0.15-0.80), and 91.0% for rituximab plus EBV-CTLs/DLI (95% CI: 0.83-0.96). The complete response (CR) rate after treatments for PTLD was 67.0% (95% CI: 0.56-0.77). Moreover, the 6-month and 1-year overall survival (OS) rate was 64.0% (95% CI: 0.31-0.87) and 49.0% (95% CI: 0.31-0.68), respectively.

This case highlighted the urgent need for effective, low-toxic treatment regimens for CNS-PTLD. Our meta-analysis suggested that rituximab combined with EBV-CTLs/DLI could be a favorable strategy for the management of PTLD after allo-HSCT.

The donor-derived cell-free DNA (ddcfDNA) is found in the plasma and urine of kidney transplant recipients and displays notable potential in diagnosing rejection, specifically antibody-mediated rejection (ABMR). Nonetheless, the quantitative methods of ddcfDNA lacking standardization and diverse detection techniques can impact the test outcomes. Besides, both the fraction and absolute values of ddcfDNA have been reported as valuable markers for rejection diagnosis, but they carry distinct meanings and are special in various pathological conditions. Additionally, ddcfDNA is highly sensitive to kidney transplant injury. The various sampling times and combination with other diseases can indeed impact ddcfDNA detection values. This review comprehensively analyses the various factors affecting ddcfDNA detection in kidney transplantation, including the number of SNPs and sequencing depths. Furthermore, different pathological conditions, distinct sampling time points, and the presence of complex heterologous signals can influence ddcfDNA testing results in kidney transplantation. The review also provides insights into ddcfDNA testing on different platforms along with key considerations.

Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.