Epstein-Barr Virus Serostatus Research Articles

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis

Background and Objective: Prior Epstein–Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother’s education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Human herpesvirus 6A and axonal injury before the clinical onset of multiple sclerosis.

Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.

Screening and Management of PTLD.

Posttransplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of lymphoproliferative diseases occurring in the setting of immunosuppression following hematopoietic stem cells transplant and solid organ transplantation. Despite its overall low incidence, PTLD is a serious complication following transplantation, with a mortality rate as high as 50% in transplant recipients. Therefore, it is important to establish for each transplant recipient a personalized risk evaluation for the development of PTLD based on the determination of Epstein-Barr virus serostatus and viral load following the initiation of immunosuppression. Due to the dynamic progression of PTLD, reflected in the diverse pathological features, different therapeutic approaches have been used to treat this disorder. Moreover, new therapeutic strategies based on the administration of virus-specific cytotoxic T cells have been developed. In this review, we summarize the available data on screening and treatment to suggest a strategy to identify transplant recipients at a higher risk for PTLD development and to review the current therapeutic options for PTLD.

Machine Learning Algorithm As a Prognostic Tool for Epstein-Barr Virus Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation

AbstractBackground: Epstein-Barr virus (EBV) reactivation is one of the most important infections after haploidentical related donor (HID) hematopoietic stem cell transplantation (HSCT). We aimed to establish a comprehensive model with machine learning, which could predict EBV reactivation after HID HSCT with antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis. Method: We enrolled 470 consecutive acute leukemia patients, 60% of them (n=282) were randomly selected as training cohort, and the remains 40% (n=188) were used as validation cohort. Results: The equation was as follows: Probability (EBV reactivation) = , where Y = 0.0250 × (age) - 0.3614 × (gender) + 0.0668 × (underlying disease) - 0.6297 × (disease status before HSCT) - 0.0726 × (DRI) - 0.0118 × (HCT-CI score) + 1.2037 × (HLA disparity) + 0.5347 × (EBV serostatus) + 0.1605 × (conditioning regimen) - 0.2270 × (donor/recipient gender matched) + 0.2304 × (donor/recipient relation) - 0.0170 × (mononuclear cell counts in graft) + 0.0395 × (CD34+ cells count in graft) - 2.4510. The threshold of probability was 0.4623, which separated patients into low- and high-risk groups. The 1-year cumulative incidence of EBV reactivation in the low- and high-risk groups was 11.0% versus 24.5% (P < 0.001), 10.7% versus 19.3% (P = 0.046), and 11.4% versus 31.6% (P = 0.001), respectively, in total, training, and validation cohorts. It also could predict relapse and survival after HID HSCT. Conclusion: We established a comprehensive model which could predict EBV reactivation in HID HSCT recipients using ATG for GVHD prophylaxis. Importance：We established a comprehensive model with machine learning in HID HSCT recipients using ATG for graft-versus-host disease prophylaxis, which separated patients into low- and high-risk groups. It could predict EBV reactivation in total, training, and validation cohort. It could predict EBV reactivation in patient with or without CMV infection, and it could also predict EBV reactivation in patients with or without acute GVHD. It could also predict relapse and survival after HID HSCT. This was the first predicted model for these patients who have a high risk of EBV reactivation and it can be popularized easily. It can also help to conduct risk stratification−directed EBV prophylaxis after HID HSCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

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. 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. 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). 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.

EBV-seronegative Status In Recipients Worsens Post Heart Transplant Survival

<h3>Background</h3> Although the incidence of Post-transplant lymphoproliferative disease which is associated with Epstein-Barr virus (EBV) is relatively high and its presence is associated with severe complications, impact of EBV serostatus on post heart transplantation (HT) survival is not clear. We sought to determine the impact of donor and recipient EBV serostatus on post HT survival. <h3>Methods</h3> We identified adult patients who underwent HT between 2000 and 2018 in the Scientific Registry of Transplant Recipients. These patients were categorized as per recipient and donor EBV serological status. We compared survival with the Kaplan-Meier method. We constructed Cox proportional hazards regression models to determine the risk-adjusted influence of EBV serostatus on post HT survival. <h3>Results</h3> Out of 20, 533 HT identified, 16,222 were +/+, 1081 were +/-, 2544 were -/+ and 186 were -/- EBV serological statuses. Compared to positive donor to negative recipient EBV serostatus, other donor and recipient EBV serostatuses were associated with decreased mortality (Figure and Table). <h3>Conclusion</h3> A primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pre-transplantation can lead to uninhibited growth of EBV-infected B cells which can impact post HT survival. In the absence of effective preventive strategies, such as vaccines and antiviral agents the role of EBV viral load monitoring and immunosuppression regimen modulation needs investigation.

Epstein-Barr virus status and immunosuppression use in paediatric autoimmune liver disease.

Since azathioprine is associated with lymphoproliferative disorders in Epstein-Barr virus (EBV)-naïve patients with inflammatory bowel disease, guidelines advise avoidance. No recommendations exist for autoimmune liver disease (AILD). To evaluate EBV status and EBV-related complications in paediatric AILD. Single-centre, retrospective, observational study of paediatric AILD. In 245 paediatric patients with AILD, azathioprine was used in 168 (68.6%) and mycophenolate mofetil in 69 (28.2%). EBV status was assessed in 18 (10.7%) prior to azathioprine and 6 (8.7%) MMF. Acute EBV infection was diagnosed in five patients while on immunosuppression, resulting in one transient hepatitis and one persistent hepatitis. There were no cases of lymphoproliferative disorder in native livers. Liver transplantation (LT) was performed in 39 (15.9%) patients, with 8 EBV IgG-negative at LT. Post-LT EBV viraemia developed in 29 (74.4%), first detected at median 26days (IQR, 13-86). EBV IgG-negative recipients had higher peak viraemia (266984IU/mL [IQR, 41108-2429050] v 5333 [IQR, 2036-38770], P=.004) and longer time to peak viraemia (375days [IQR, 251-884] v 70 [IQR, 21-604], P=.04). Early EBV-associated post-transplant lymphoproliferative disorder (PTLD) was diagnosed in two patients, both EBV-IgG negative with prior azathioprine. Real-world data demonstrate that EBV serostatus is not routinely checked before immunosuppression for paediatric AILD. Lymphoproliferative disorder was not diagnosed in those with native livers; however, EBV IgG-negative LT recipients receiving EBV IgG-positive donor organs are at risk of early PTLD. Large multicentre studies with longer follow-up are required to further evaluate the risk.

Donor EBV-Positive Serostatus Increases the Risk of Chronic GVHD in Patients with Myeloid and Lymphoid Malignancies Other Than Acute Leukemia: Infectious Diseases Working Party EBMT Study

BACKGROUND: In patients with acute leukemia (AL), donor EBV (Epstein-Barr Virus) seropositive status significantly increases the risk of development of acute and chronic GVHD after allo-HSCT, while it has no influence on other transplant outcomes (OS, RFS, RI, NRM) (Styczynski et al , J Clin Oncol, 2016). No data are available on the impact of EBV serostatus on transplant outcomes in patients with other hematological malignancies.OBJECTIVE: We analyzed the influence of the recipient's (R) and donor's (D) EBV serostatus on transplant outcomes (overall survival, OS; relapse-free survival, RFS; relapse incidence, RI; non-relapse mortality, NRM; acute graft-versus-host disease, aGVHD; chronic graft-versus-host disease, cGVHD) in patients with myeloid and lymphoid malignancies other than AL undergoing allo-HSCT.PATIENTS AND METHODS: 12,931 allo-HSCTs performed between 1997 and 2016 for myeloid (58.1%) or lymphoid malignancies (41.9%), other than AL, with PB (76%) or BM±PB (24%) as a stem cell source were included in this retrospective Registry megafile IDWP EBMT study.RESULTS:DEMOGRAPHICS : 48% had HSCT from a matched family donor, 4.2% from a mismatched family donor, and 47.8 from an unrelated donor. T-cell depletion was performed in vivo in 58.4%, and ex vivo in 7.9% patients. Conditioning regimen was myeloablative in 41.3%, RIC in 58.7%. Median follow-up was 4.7 years. TRANSPLANT OUTCOMES : EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+ transplants) had worse transplant outcomes in comparison to EBV-seronegative patients receiving grafts from EBV-seronegative donors (EBV R-/D-): lower OS (59.6% vs 65.9%), lower RFS (51.1% vs 57.5%), higher incidence of chronic GVHD (49.5% vs 41.8%), and higher incidence of de novo chronic GVHD (30.5% vs 24.0%). No significant differences were found for: RI, NRM, and acute GVHD (Table 1). MULTIVARIATE ANALYSIS : Allo-HSCT from EBV-seropositive donors had higher risk of development of cGVHD (HR=1.13; p=0.0096). When 4 subgroups (R-/D-, R-/D+, R+/D-, R+/D+ EBV serology) were analyzed, the risk of cGVHD was higher for EBV R-/D+ (HR=1.22; p=0.0395), R+/D- (HR=1.21; p=0.0375), and for R+/D+ (HR=1.28; p=0.0013) when compared to R-/D- transplants. On the other hand, R/D EBV serostatus had no significant impact on OS, RFS, RI, NRM and development of acute GVHD. Finally, since the R-/D- combination patients were more likely to be children than R+/D+, this could explain the effect in univariate analysis on OS and RFS while the chronic GVHD effect was independent of age.CONCLUSIONS: Allo-HSCT from EBV-seropositive donors are at 13% higher risk of chronic GVHD in patients with myeloid and lymphoid malignancies other than AL. [Display omitted] DisclosuresPetersen:Sanofi: Membership on an entity's Board of Directors or advisory committees. Leblond:SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Michallet:medac GmbH, Wedel, Germany: Honoraria, Other: Travel grants. Kröger:Janssen Global Services, LLC: Speakers Bureau; Amgen Inc.: Speakers Bureau; Novartis AG: Research Funding; RIEMSER Pharma: Research Funding; Neovii Pharmaceuticals AG: Speakers Bureau; Novartis AG: Speakers Bureau; Sanofi: Speakers Bureau.

Association between infectious event and de novo malignancy after heart transplantation.

The aim of the study was to investigate the incidence of and risk factors for de novo malignancy after heart transplantation (HTx) in a single center. We assessed 102 consecutive patients who received HTx and were followed-up in our center regularly for > 1year from June 2006 to May 2018. We investigated the incidence of and risk factors for de novo malignancy. The cumulative incidence of each malignancy type during the follow-up period was one (0.98%) for skin cancer, four (3.92%) for nonskin solid organ cancer, and six (5.88%) for posttransplant lymphoproliferative disorder (PTLD). The percentage of patients with more than one infectious event ≤ 1year after HTx was higher in the malignancy group than in the non-malignancy group. Furthermore, Kaplan-Meier analysis revealed that the incidence rate of infectious events was higher in patients with malignancies than in those without (log-rank P < 0.001). After dividing malignancies into a PTLD group and a solid organ malignancy group, we found that negative Epstein-Barr virus serostatus, cytomegalovirus-positive antigenemia, and the occurrence of any viral or gastrointestinal infectious event at ≤ 1year were more frequent in patients with PTLD than in patients without it. The survival rate was significantly lower for patients with solid organ malignancy than for patients without malignancy. In conclusion, there was a correlation between infectious events and de novo malignancy, particularly in patients with PTLD. We should confirm this finding by conducting a larger cohort study.

Incidence and outcome of post-transplant lymphoproliferative disorders in lung transplant patients: Analysis of ISHLT Registry

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication following lung transplant. We studied incidence and risk factors for PTLD in adult lung transplant recipients (LTRs) using the International Society for Heart and Lung Transplantation Registry. The International Society for Heart and Lung Transplantation Registry was used to identify adult, first-time, single and bilateral LTRs with at least 1 year of follow-up between 2006 and 2016. Kaplan-Meier method was used to describe the timing and distribution of PTLD. Univariable and multivariable Cox proportional hazards regression models were used to examine clinical characteristics associated with PTLD. Of 19,309 LTRs in the analysis cohort, we identified 454 cases of PTLD. Cumulative incidence of PTLD was 1.1% (95% CI = 1.0%-1.3%) at 1 year and 4.1%(95% CI = 3.6%-4.6%) at 10years. Of the PTLD cases, 47.4% occurred within the first year following lung transplantation. In the multivariable model, independent risk factors for PTLD included age, Epstein-Barr virus serostatus, restrictive lung diseases, and induction. Risk of PTLD during the first year after transplant increased with increasing age in patients between 45 and 62 years at time of transplantation; the inverse was true for ages <45 years or >62 years. Finally, receiving a donor organ with human leukocyte antigen types A1 and A24 was associated with an increased risk of PTLD, whereas the recipient human leukocyte antigen type DR11 was associated with a decreased risk. Our study indicates that PTLD is a relatively rare complication among adult LTRs. We identified clinical characteristics that are associated with an increased risk of PTLD.

Prognostic impact of Epstein-Barr virus serostatus in patients with nonmalignant hematological disorders undergoing allogeneic hematopoietic cell transplantation: the study of Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation

AbstractBackgroundIn patients with acute leukemia, lymphoma and chronic malignancies, donor and/or recipient Epstein-Barr virus (EBV) seropositive status increases the risk of development of chronic graft-versus-host disease (cGVHD) after allo-hematopoietic cell transplantation (allo-HCT), while it has no influence on other transplant outcomes. No data are available on the impact of EBV serostatus on transplant outcomes in patients with nonmalignant hematological disorders.ObjectiveWe analyzed the influence of the recipient's (R) and donor's (D) EBV serostatus on transplant outcomes (overall survival (OS); relapse-free survival (RFS); relapse incidence (RI); nonrelapse mortality (NRM); acute graft-versus-host disease (aGVHD); cGVHD) in patients with nonmalignant hematological disorders undergoing allo-HCT.Patients and MethodsA total of 2,355 allo-HCTs performed between 1997 and 2016 for acquired bone marrow failure or hemoglobinopathies were included in this retrospective Registry megafile Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (IDWP-EBMT) study.ResultsDemographics: The median age of recipient was 17.7 years (range: 0–77), and 50.8% were children. 79.0% of recipients and 75.4% of donors were EBV-seropositive. 67.8% had HCT from a matched family donor, 4.6% from a mismatched family donor, and 27.6% from an unrelated donor (UD). T-cell depletion was performed in vivo and ex vivo in 82.2% and 6.6% of patients, respectively. Conditioning regimen was myeloablative in 63.7% and reduced intensity conditioning (RIC) in 36.3% of patients. The median follow-up was 4.7 years. Transplant outcomes: EBV-seropositive recipients in comparison with EBV-seronegative recipients had lower OS (85.4% vs. 88.4%, p = 0.035) and higher NRM (10.0% vs. 6.4%, p = 0.018). No other significant differences were found for: RI, RFS, and aGVHD or cGVHD with respect to EBV pretransplant serostatus donor and/or recipient. Multivariate analysis: A trend toward higher risk of development of cGVHD (HR = 1.31; p = 0.081) and better survival (HR = 0.78; p = 0.087) in allo-HCT from EBV-seropositive donors was found. Allo-HCT in EBV-seropositive recipients had a trend toward lower risk of development of cGVHD (HR = 0.75; p = 0.065). When four subgroups (R−/D−, R−/D+, R+/D−, R+/D+ EBV serology) were analyzed, the EBV serostatus had no significant impact on OS, RFS, RI, NRM and development of aGVHD or cGVHD.ConclusionsAllo-HCT from EBV-seropositive versus EBV-seronegative donors are at 31% higher risk of cGVHD in patients with nonmalignant hematological disorders undergoing allo-HCT; however this difference is nonsignificant in multivariate analysis.

P1685POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD): SINGLE INSTITUTIONAL EXPERIENCE OF TWO DECADES

Abstract Background and Aims Post-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous lymphoid proliferations in chronic immunosuppressed recipients of solid organ and hematopoietic stem cell transplantation. Due to rarity of this disease, retrospective studies from transplant centers have been the main source to provide knowledge and treatment guidelines, which are still in evolution. This study examined the clinical outcomes and identified the predictors of mortality in adult renal transplant recipients who developed PTLD. Method We have studied the incidence of PTLD in adult renal transplant recipients who were transplanted in our hospital from 1996 to 2019. Data was collected for demographics, transplant and immunosuppression history, EBV and CMV serostatus, diagnosis, treatment and outcomes of PTLD. We performed univariate and multivariate analysis to identify prognostic factors. PTLD was classified according to 2018 WHO lymphoma classification. Results Twenty-four patients (12 males and 12 females) were eligible for the analysis. Mean age at time of the transplant was 43.1 ± 16.9 years, with a time between grafting and PTLD of 66 months (IQR 36-98 months). Mean follow-up time was 87 months (IQR 61-117 months). 25% of patients received a living donor renal transplant. 12,5% of patients received induction therapy with thymoglobulin. Mean age at time of PTLD diagnosis was 48,8 ± 17,9 years. Five cases were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and there was seroconversion at time of PTLD diagnosis. 25% of patients had central nervous system involvement. 19 patients have monomorphic PTLD and the most common histological diagnosis was diffuse large B cell lymphoma. We identified that age &amp;gt;30 years at time of the transplant was predictor of mortality (HR 33.01; 95% CI: 3.24-336.14; p=0.003). Surprisingly, presence of B symptoms at time of PTLD diagnosis confer a better prognosis (HR 0,143; 95% CI: 0,035-0,579; p=0.006). All cases were managed with reduction in immunosuppression and converted to everolimus. 8 patients were treated with rituximab and there was no significant difference in the survival of these patients. By the end of follow-up, 7 patients went into remission, 1 returned to chronic dialysis, and 16 patients died (15 of them due to the disease). Mean time between PTLD and death was 3 months (IQR 1-6 months). Conclusion PTLD is an infrequent disease with a poor prognosis in renal transplant patients. Some cases have a close relationship with EBV, but it can also develop in the absence of the classical risk factors. The factor affecting mortality in our population was age &amp;gt;30 years at time of the transplant. Presence of B symptoms at time of PTLD diagnosis seems to confer a better prognosis probably due to early investigation and diagnosis of the disease.

Predictors of Epstein-Barr virus serostatus and implications for vaccine policy: A systematic review of the literature.

BackgroundEpstein-Barr virus (EBV) is an important human pathogen; it infects >90% people globally and is linked to infectious mononucleosis and several types of cancer. Vaccines against EBV are in development. In this study we present the first systematic review of the literature on risk factors for EBV infection, and discuss how they differ between settings, in order to improve our understanding of EBV epidemiology and aid the design of effective vaccination strategies.MethodsMEDLINE, Embase, and Web of Science were searched on 6th March 2017 for observational studies of risk factors for EBV infection. Studies were excluded if they were published before 2008 to ensure relevance to the modern day, given the importance of influencing future vaccination policies. There were no language restrictions. After title, abstract and full text screening, followed by checking the reference lists of included studies to identify further studies, data were extracted into standardised spreadsheets and quality assessed. A narrative synthesis was undertaken.ResultsSeventy-seven papers met our inclusion criteria, including data from 31 countries. There was consistent evidence that EBV seroprevalence was associated with age, increasing throughout childhood and adolescence and remaining constant thereafter. EBV was generally acquired at younger ages in Asia than Europe/North America. There was also compelling evidence for an association between cytomegalovirus infection and EBV. Additional factors associated with EBV seroprevalence, albeit with less consistent evidence, included ethnicity, socioeconomic status, other chronic viral infections, and genetic variants of HLA and immune response genes.ConclusionsOur study is the first systematic review to draw together the global literature on the risk factors for EBV infection and includes an evaluation of the quality of the published evidence. Across the literature, the factors examined are diverse. In Asia, early vaccination of infants would be required to prevent EBV infection. In contrast, in Western countries a vaccine could be deployed later, particularly if it has only a short duration of protection and the intention was to protect against infectious mononucleosis. There is a lack of high-quality data on the prevalence and age of EBV infection outside of Europe, North America and South-East Asia, which are essential for informing effective vaccination policies in these settings.

Idiopathic Pulmonary Fibrosis Lung Transplant Recipients are at Increased Risk for Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorder

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorder (PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a seven-year period. All LTRs transplanted from 2010 to 2016 were included. LTRs who died within 3 months or were lost to follow-up were excluded. Sex, age, EBV serostatus, induction agent, indication agent, and survival were collected via chart review. The primary outcome was development of PTLD. Secondary endpoints were early and late PTLD and survival. Primary and secondary outcomes were assessed using Kaplan-Meier methods and Cox proportional hazards models. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed an increased rate of PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (p<0.02). Multivariable Cox proportional hazards modeling found IPF (HR 3.51, 95% CI 1.33-8.21, p=0.01), alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, p=0.03), and EBV mismatch (HR: 34.43, 95% CI: 15.57-76.09, p<0.0001) as risk factors for PTLD. Early PTLD (first-year) was associated with alemtuzumab use (p=0.04), whereas IPF was a predictor for late PTLD (after first-year) (p=0.002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF-LTRs compared to other LTRs (p=0.04). The use of alemtuzumab in EBV-mismatch was found to particularly increase PTLD risk. IPF-LTRs are at increased susceptibility for PTLD compared to non-IPF LTRs. LTRs who received alemtuzumab induction were at increased risk for PTLD, particularly those who were EBV mismatches. Ongoing studies are being conducted to understand the mechanisms driving PTLD in IPF-LTRs and develop strategies to mitigate risk.

Interpretation of EBV serology for human body material donors: Is there a need for early antigen IgG and heterophile antibodies testing?

In this report we evaluated a diagnostic algorithm, proposed by the Belgian Superior Health Council, to detect acute and past Epstein-Barr virus (EBV) infections by means of serology in donors of human body material for transplantation. The available EBV serology parameters were tested on eighty serum samples on three random access analysers: Architect i2000 SR, Liasion XL and BioPlex 2200. The EBV sero-status was determined according to the proposed algorithm and results were compared between the different analysers. Seventy one % of the samples gave concordant interpretations on the three analysers. Most of the discordant results were attributable to early antigen (EA) IgG. The knowledge of the EA IgG and heterophile antibodies (HA) IgM status provided only limited added value and was only useful to distinguish between a very early acute infection and false positivity of viral capsid antigen IgM. The diagnostic algorithm proposed by the Belgian Superior Health Council is merely directive and each individual lab remains responsible for the interpretation and implementation of test combinations for the detection of EBV infections. Our study shows the limited added value of testing for EA IgG and HA IgM, based both on clinical and technical performance.

Predictors of Epstein-Barr virus serostatus in young people in England

BackgroundEpstein-Barr virus (EBV) is an important human pathogen which causes lifelong infection of > 90% people globally and is linked to infectious mononucleosis (arising from infection in the later teenage years) and several types of cancer. Vaccines against EBV are in development. In order to determine the most cost-effective public health strategy for vaccine deployment, setting-specific data on the age at EBV acquisition and risk factors for early infection are required. Such data are also important to inform mathematical models of EBV transmission that can determine the required target product profile of vaccine characteristics. We thus aimed to examine risk factors for EBV infection in young people in England, in order to improve our understanding of EBV epidemiology and guide future vaccination strategies.MethodsThe Health Survey for England (HSE) is an annual, cross-sectional representative survey of households in England during which data are collected via questionnaires and blood samples. We randomly selected individuals who participated in the HSE 2002, aiming for 25 participants of each sex in each single year age group from 11 to 24 years. Stored samples were tested for EBV and cytomegalovirus (CMV) antibodies. We undertook descriptive and regression analyses of EBV seroprevalence and risk factors for infection.ResultsDemographic data and serostatus were available for 732 individuals. EBV seroprevalence was strongly associated with age, increasing from 60.4% in 11–14 year olds throughout adolescence (68.6% in 15–18 year olds) and stabilising by early adulthood (93.0% in those aged 22–24 years). In univariable and multivariable logistic regression models, ethnicity was associated with serostatus (adjusted odds ratio for seropositivity among individuals of other ethnicity versus white individuals 2.33 [95% confidence interval 1.13–4.78]). Smoking was less strongly associated with EBV seropositivity.ConclusionsBy the age of 11 years, EBV infection is present in over half the population, although age is not the only factor associated with serostatus. Knowledge of the distribution of infection in the UK population is critical for determining future vaccination policies, e.g. comparing general versus selectively targeted vaccination strategies.

Epidemiology of Post-Transplant Lymphoproliferative Disorders in Children with Solid Organ Transplant over 34 Years of a Single Center Experience

Background Post-Transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid neoplasms following solid organ transplantation (SOT) caused by uncontrolled lymphoproliferation often induced by Epstein Barr Virus (EBV) due to the lack of cytotoxic T cell response resulting from immunosuppression. A pre-emptive intervention strategy for PTLD prevention was implemented in our center in 2002 for all EBV-mismatched SOT recipients consisting in close monitoring of the viral load and consideration for early intervention (Ex; reduction of immunosuppression) in addition to universal antiviral prophylaxis (implemented in 1990). We aim to describe the incidence and risk factors for PTLD in children with SOT, including all transplant types, at a single center over 34 years. We also aim to analyze the impact of a pre-emptive PTLD prevention program. Material and methods All patients younger than 18 years of age who received SOT at the University of Alberta Hospital/Stollery Children's Hospital from January 1st, 1984 to December 31st, 2018 were included. Donor and recipient baseline data (age, sex, donor living status, date and type of transplant, EBV and cytomegalovirus serostatus) were extracted from a prospective database. Retrospective chart review was performed for PTLD cases along with expert pathology review (when tissue available). Local Ethics Board was obtained. Statistical analyses were performed using SPSS software version 25 and R version 3.3.3. Results Characteristics of the study population, immunosuppression regimen used by transplant program and specific immunosuppression for PTLD cases are summarized in table 1, 2 and 3 respectively. PTLD characteristics were compared based on the time of presentation of PTLD ≤1 year, 1 to 5 years and &amp;gt;5 years (table 4). Most of the cases with PTLD presented with primary involvement in multiple sites followed by lymph nodes, gastro-intestinal tract, allograft, tonsils/adenoids and other sites. Advance staging (III-IV) was present in 71% of cases. The incidence rate of PTLD for the whole group was 0.82/100 Person-year (Figure 1 A). The incidence rate peaked at 1-year post-transplant and had a decreasing trend in the following years post-transplant, with no cases beyond 12 years post-transplant (Figure 1 B). The cumulative incidence was the highest for the multi-visceral transplants followed by thoracic, liver and kidney transplants (Figure 1C). Univariate analysis showed children younger than 5 years at transplant had 5-fold higher risk of PTLD compared to children ≥ 10 years of age at transplant. Donors ≤ 5 years of age at transplant, showed 3-fold higher risk PTLD comparing to older donors. Liver transplant had 2.8-fold and thoracic transplants had 5-fold higher risk of PTLD comparing to kidney transplants, no significant risk was associated with multi-visceral group (only 1 case in the cohort). EBV seronegative recipient was associated with 2.6-fold higher risk of PTLD comparing to EBV seropositive recipient. Era prior to implementation of pre-emptive intervention had 3-fold risk of PTLD comparing to era post implementation. Patients transplanted at 1.1 - 5 years of age was an independent risk factor associated with PTLD in multivariate analysis (table 3) SOT recipients showed EBV seroconversion with age (Figure 3A). PTLD based on EBV Donor Recipient (DR) serostatus showed more cases D positive R negative (D+R-) in the first-year comparing to D negative Recipient negative (D-R-), D-R- cases increased between 1-5 years equivalent to D+R-, beyond 5 years D+R- decreased with no D-R- cases (Figure 3B). D-R- serostatus had the highest probability of PTLD followed by D+R- (Figure 3 C). Eleven (24%) out of 45 patients with PTLD presented with PTLD relapse. Seven (5.6%) out of 125 deaths of SOT were secondary to PTLD. PTLD was the most common cause of death in the PTLD group (50%) followed by graft failure/rejection. Conclusions Incidence of PTLD peaked in the first-year post-transplant and decreased overtime with increase incidence in thoracic and multi-visceral transplants. Risk factors for PTLD included patients transplanted at younger age, younger donors, thoracic and liver transplants and EBV seronegativity in the recipient. A pre-emptive intervention strategy for PTLD prevention implemented in 2002 decreased the risk of PTLD. Disclosures No relevant conflicts of interest to declare.

Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients After Cessation of Antiviral Prophylaxis.

Late cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted. We conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D + R-] and 51 CMV recipient seropositive [R+]) younger than 18 years who received a kidney transplant between January 2002 and June 2014 and were treated with antiviral prophylaxis for 3 months after transplantation. Incidence of CMV DNAemia and CMV disease was determined using Kaplan-Meier analyses and risk factors were assessed using Poisson regression. Of the 86 children, 61.6% were male and median age at transplant was 13.4 years (interquartile range [IQR], 8.9-15.6) with a median follow-up of 35.2 months (IQR, 18.0-54.5). Incidence of CMV DNAemia within the first 3 months after prophylaxis cessation in CMV D + R- and CMV R+ children was 22.9% and 23.5% and incidence of CMV disease was 11.4% and 0%, respectively. Cumulative incidence of CMV DNAemia in both groups was similar (31.4%). Children who received antithymocyte globulin were more likely to develop CMV DNAemia compared with those who received anti-IL-2 (IRR, 2.98; 95% confidence interval, 1.41-6.30) after controlling for age, sex, Epstein-Barr Virus serostatus and rejection. This study demonstrates a high incidence of CMV infection after cessation of antiviral prophylaxis. These results support extension of antiviral prophylaxis beyond 3 months and/or intensive viral load monitoring to reduce risk of CMV infection in D + R- and R+ children, especially those receiving antithymocyte globulin.

Prospective Assessment of Adenovirus Infection in Pediatric Kidney Transplant Recipients.

Adenovirus infection is associated with graft dysfunction and graft loss in pediatric cardiac, lung, and liver transplants in prior retrospective studies, but data in pediatric kidney transplant recipients is limited. We conducted a prospective single-center cohort study of 75 consecutive pediatric kidney transplant recipients who underwent monthly screening for adenovirus viremia and symptom assessment for 2 years posttransplant. Adenovirus viremia was detected in 11 (14.7%) patients at a median onset of 173 days (interquartile range, 109-310 days) posttransplant, 6 (8%) had asymptomatic viremia, and 5 (6.7%) had symptomatic disease (2 with hematuria and 3 with an acute febrile respiratory illness). Viremic patients did not differ from nonviremic patients in age, immunosuppression management, or cytomegalovirus or Epstein-Barr virus serostatus, but were more likely to develop cytomegalovirus viremia during the first 2 years posttransplant. No patient had an increase in creatinine from baseline during the time of adenovirus viremia. In a Cox proportional hazards regression, subclinical adenovirus viremia was not associated with a faster time to a 30% decline in estimated glomerular filtration rate. Adenovirus infection is common among pediatric kidney transplant recipients and frequently causes symptomatic disease; however, symptoms are often mild and are not associated with a decline in graft function. Routine monitoring for adenovirus viremia in pediatric kidney transplant recipients may not be warranted.

Epstein-Barr Virus–Related Post-Transplant Lymphoproliferative Disorders in Cystic Fibrosis Lung Transplant Recipients: A Case Series

BackgroundSolid organ transplantation is associated with a higher risk of Epstein-Barr virus (EBV)–related lymphoproliferative disease due to immunosuppressive regimen. Little evidence is currently available on post-transplant lymphoproliferative disorders (PTLDs) in the lung transplant (LuTx) setting, particularly in cystic fibrosis (CF) recipients. MethodsWe retrospectively analyzed all the cases of PTLDs that occurred in our LuTx center between January 2015 and December 2017. We reviewed clinical and radiologic data, donor and recipient EBV serostatus, immunosuppressive therapy, histologic data, and follow-up of these patients. ResultsA total of 77 LuTxs were performed at our center in the study period; 39 (50.6%) patients had CF; 4 developed EBV-related PTLDs. They were all young (17–26 years) CF patients with high serum EBV DNA load. Disease onset was within the first 3 months after LuTx. In 3 cases presentation was associated with fever and infection-like symptoms, whereas in 1 case radiologic suspicion arose unexpectedly from a CT scan performed for different clinical reasons. Diagnosis was reached through lung biopsy in all cases. All patients received rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone with variable response and complications. ConclusionIn our experience, the early development of EBV-related PTLD was a highly aggressive, life-threatening condition, which exclusively affected young CF patients in the early post-transplant period. The rate of this complication was relatively high in our population.Diagnosis with lung biopsy is crucial in all suspected cases and regular monitoring of EBV DNA levels is of utmost importance given the high correlation with PTLDs in patients at increased risk.