Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Performance of the cobas EBV and cobas BKV assays: multi-site comparison of standardized quantitation.

Guidelines recommend monitoring of Epstein-Barr virus (EBV) and BK virus (BKV) in solid organ and hematopoietic stem cell transplant patients. The majority of quantitative DNA testing for EBV and BKV employs unstandardized individual laboratory-developed testing solutions (LDTs), with implications for accuracy, reproducibility, and comparability between laboratories. The performance of the cobas EBV and cobas BKV assays was assessed across five laboratories, using the World Health Organization International Standards (WHO IS) for EBV and BKV, and the National Institute of Standards and Technology Quantitative Standard for BKV, and results were compared with the LDTs in use at the time. Methods were also compared using locally sourced clinical specimens. Variation was high when laboratories reported EBV or BKV DNA values using LDTs, where quantitative values were observed to differ by up to 1.5 log10 unit/mL between sites. Conversely, results from the cobas EBV and cobas BKV assays were accurate and reproducible across sites and on different testing days. Adjustment of LDTs using the international standards led to closer alignment between the assays; however, day-to-day reproducibility of LDTs remained high. In addition, BKV continued to show bias, indicating challenges with the commutability of the BKV International Standard. The cobas EBV and cobas BKV assays are automated, aligned to the WHO IS, and have the potential to reduce the variability in viral load testing introduced by differences in LDTs. Standardization of reporting values may eventually allow different centers to compare data to allow clinical decision thresholds to be established supporting improvements in patient management.IMPORTANCEThe application of center-specific cut-offs for clinical decisions and the variability of LDTs often hinder interpretation; thus, the findings reported here support the need for standardization in the field of post-transplant monitoring of EBV and BKV to improve patient management. Alongside the choice of assay, it is also important to consider which standard to use when deciding upon a testing methodology. This is a call to action for standardization, as treatment for EBV and BKV is driven by viral load test results, and the more accurate and comparable the test results are across institutions, the more informed and better the treatment decisions can be.

Combined Flow-Fluorescence in situ hybridization to HHV-8 and EBV reveals the viral heterogeneity of primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma associated with Kaposi Sarcoma-associated herpesvirus (KSHV/HHV8) infection. Lymphoma cells are coinfected with Epstein-Barr virus (EBV) in 60-80% of cases. Tools allowing a reliable PEL diagnosis are lacking. This study reports PEL diagnosis in 4 patients using a Flow-Fluorescence in situ hybridization (FlowFISH) technique that allowed detection of differentially expressed EBV and HHV8 transcripts within the same sample, revealing viral heterogeneity of the disease. Moreover, infected cells exhibited variable expressions of CD19, CD38, CD40, and CD138. Therefore, FlowFISH is a promising tool to diagnose and characterize complex viral lymphoproliferations.

Analysis of the epidemiology and clinical characteristics of Epstein-Barr virus infection.

The Epstein-Barr virus (EBV) is responsible for a spectrum of human diseases and demonstrates a considerable prevalence among various populations. Advances in molecular epidemiological research have enhanced our comprehension of EBV-related pathologies. In this study, our objective was to examine the epidemiological profile and clinical features of EBV infection in Chongqing, China. We enrolled patients suspected of EBV-related diseases who were admitted to the First Affiliated Hospital of Chongqing Medical University between May 2013 and November 2022. Inclusion criteria were based on those who underwent EBV-specific immunofluorescence or plasma EBV-DNA testing. Among 13 584 inpatients, the overall seropositivity rates for EBNA-1-IgG, EBV-VCA-IgM, EBV-EA-IgG, EBV-EA-IgA, EBV-VCA-IgA, and EBV-DNA were 91.89%, 7.22%, 18.00%, 16.19%, 30.78%, and 18.00%, respectively. The seropositivity rate for EBNA-1-IgG steadily increased with age. The seropositivity rate for VCA-IgM, an indicator of acute EBV infection, was highest in patients aged 11-20 years at 26.41%, decreasing to 2%-6% in older patients. Additionally, among 205 outpatients, the EBV-DNA positivity rate was 14.15%. In 3670 individuals from health check-up centers, the seropositivity rates for EBV-EA-IgA and EBV-VCA-IgA were 11.96% and 28.09%, respectively, and the EBV-DNA positivity rate was 11.92%, all of which were lower than those in inpatients. Among the 762 EBV-DNA positive inpatients, adults aged 31-40 years were the least affected, with a seropositivity rate of 12.00%, which increased with age. The most common diseases associated with primary EBV infection were infectious mononucleosis (IM) (35.49%), followed by EBV infection (14.15%) and pneumonia (7.19%). The most common diseases associated with EBV reactivation were pneumonia (16.80%), nasopharyngeal carcinoma (NPC) (11.02%), and autoimmune diseases (7.04%). Patients with hemophagocytic lymphohistiocytosis (HLH) had the highest viral load, significantly higher than those with NPC, pneumonia, and liver cirrhosis. This large-scale retrospective study explores the epidemiological characteristics and disease spectrum of EBV infection across all age groups. The findings contribute to the improvement of diagnostic and management strategies for EBV infection.

Enhanced prognostic evaluation of diffuse large B-cell lymphoma: A comprehensive surveillance study incorporating Epstein-Barr virus infection status and immunohistochemical markers.

Emerging biologic subsets and new prognostic markers are significantly important for aggressive diffuse large B-cell lymphoma (DLBCL). Nevertheless, the high cost of testing limits the availability of these tests in most hospitals, thus making prognostic judgment based on basic immunohistochemical testing, whole blood Epstein-Barr virus DNA (WBEBV) surveillance and clinical features advantageous for hospitals and patients with poor medical conditions. We included 647 DLBCL patients treated in our hospital from January 2009 to March 2023. Non-germinal center B-cell like, Ki-67, and International Prognostic Index (IPI) scores were related to cMYC/B-cell lymphoma 2 (Bcl-2)-double expression. Age, Epstein-Barr virus-encoded small RNA (EBER) positivity, and IPI scores were associated with mortality. The cutoffs for differential overall survival (OS) of age, WBEBV, Bcl-2, and cMYC were 57 years, 1514 copies/mL (baseline), 5.89 × 104 copies/mL (treatment), 40%, and 55%, respectively. EBER positivity was significantly associated with a worse OS. Patients with newly defined DE (Bcl-2 ≥ 40 and cMYC > 55) had a worse prognosis than controls (p = 0.04). We found that cMYC with an optimal cutoff of 47.5 could effectively predict high-grade DLBCL with an area under the curve of 0.912, and the specificity and sensitivity were 70.7% and 100%, respectively. Our study provides valuable insights into the prognostic factors and biomarker cutoffs that influence OS in DLBCL patients, which may guide clinicians in tailoring treatment strategies and improving patient outcomes.

EBV+ lymphoproliferative diseases: opportunities for leveraging EBV as a therapeutic target.

Epstein-Barr virus (EBV) is a ubiquitous human tumor virus, which contributes to the development of lymphoproliferative disease, most notably in patients with impaired immunity. EBV-associated lymphoproliferation is characterized by expression of latent EBV proteins and ranges in severity from a relatively benign proliferative response to aggressive malignant lymphomas. The presence of EBV can also serve as a unique target for directed therapies for the treatment of EBV lymphoproliferative diseases, including T cell-based immune therapies. In this review, we describe the EBV-associated lymphoproliferative diseases and particularly focus on the therapies that target EBV.

KSHV/HHV8-mediated hematologic diseases.

Kaposi sarcoma (KS) herpesvirus (KSHV), also known as human herpesvirus 8, is the causal agent of KS but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extracavitary (EC) PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV+ diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. These different KSHV-associated diseases may co-occur and may have overlapping features. KSHV, similar to Epstein-Barr virus (EBV), is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immunecompromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in KSHV+ EBV+ PEL/EC-PEL. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the 2 most common KSHV-associated lymphoid proliferations, including viral associations, patterns of viral gene expression, and cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding of KSHV biology, clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

A nomogram based on nutritional and inflammatory parameters to predict DMFS and identify beneficiaries of adjuvant chemotherapy in IVA-stage nasopharyngeal carcinoma.

OBJECTIVE: This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment and prediction for stage IVA NPC. Furthermore, it endeavors to pinpoint specific subgroups that may derive significant benefits from S-1 adjuvant chemotherapy. METHODS: A total of 834 patients diagnosed with stage IVA NPC were enrolled in this study and randomly allocated into training and validation cohorts. Multivariate Cox analyses were conducted to identify independent prognostic factors for constructing the nomogram. The predictive and clinical utility of the nomogram was assessed through measures including the AUC, calibration curve, DCA, and C-indexes. IPTW was employed to balance baseline characteristics across the population. Kaplan-Meier analysis and log-rank tests were utilized to evaluate the prognostic value. RESULTS: In our study, we examined the clinical features of 557 individuals from the training cohort and 277 from the validation cohort. The median follow-up period was 50.1 and 49.7 months, respectively. For the overall cohort, the median follow-up duration was 53.8 months. The training and validation sets showed 3-year OS rates of 87.7% and 82.5%, respectively. Meanwhile, the 3-year DMFS rates were 95.9% and 84.3%, respectively. We created a nomogram that combined PNI, NRI, and EBV DNA, resulting in high prediction accuracy. Risk stratification demonstrated substantial variations in DMFS and OS between the high and low risk groups. Patients in the high-risk group benefited significantly from the IC + CCRT + S-1 treatment. In contrast, IC + CCRT demonstrated non-inferior 3-year DMFS and OS compared to IC + CCRT + S-1 in the low-risk population, indicating the possibility of reducing treatment intensity. CONCLUSIONS: In conclusion, our nomogram integrating NLR, PNI, and EBV DNA offers precise prognostication for stage IVA NPC. S-1 adjuvant chemotherapy provides notable benefits for high-risk patients, while treatment intensity reduction may be feasible for low-risk individuals.

Early predictors of Epstein-Barr virus infection in patients with severe fever with thrombocytopenia syndrome.

BACKGROUND: Epstein-Barr virus (EBV) can be reactivated and proliferated with fatal outcome in immuno-compromised people, but the clinical consequences of EBV infection in patients with severe fever with thrombocytopenia syndrome (SFTS) remain uncertain. In this study, we investigated the infection rate, the influence and the early predictors of EBV infection in SFTS patients. METHODS: In this retrospective study, SFTS patients who were treated in the First Affiliated Hospital of Nanjing Medical University from May 2011 to August 2021 were enrolled and divided into infected and non-infected groups. We compared the demographic characteristics, clinical manifestations and signs, laboratory tests and prognosis, and explored the risk factors of EBV infection by receiver operating characteristic (ROC) curve and logistic regression. RESULTS: A total of 120 hospitalized SFTS patients with EBV-DNA testing were enrolled in this study. Patients with EBV infection had statistically significant higher mortality rate (32.0% vs. 11.43%, P = 0.005). Compared with the non-infected group, the EBV-infected group had higher levels of C-reactive protein (CRP), creatine-kinase (CK), fasting blood glucose (FBG), blood urea nitrogen (BUN), D-dimer, and CD56+ cell counts, lower levels of immunoglobulin G (IgG), IgM, complement 3 (C3), and C4. The proportion of patients with age ≥ 60 years and ferritin > 1500.0 ng/ml in the EBV-infected group was significantly higher than that in the non-infected group. The results of ROC analysis showed that the cut-off values of CRP, IgG, C3, C4, and CD56+ cell counts to predict EBV infection were 13.2 mg/l, 12.5 g/l, 1.1 g/l, 0.6 g/l, 0.3 g/l, and 94.0 cells/µl. Multivariable logistic analysis showed that age ≥ 60 years old, CRP > 13.2 mg/l, BUN > 5.4 mmol/l, ferritin > 1500.0 ng/ml, IgG < 12.5 g/l, IgM < 1.1 g/l, C4 < 0.3 g/l, and CD56+ cell counts > 94.0 cells/µl were the independent risk factors of EBV infection in SFTS patients. CONCLUSIONS: SFTS combined with EBV infection is associated with high morbidity and mortality. It is necessary to strengthen screening for EBV infection and its early predictive markers after admission in SFTS patients.

Epstein-Barr Virus-Associated Smooth Muscle Tumor After Kidney Transplantation: A French Multicenter Retrospective Study.

BACKGROUND: Epstein-Barr virus (EBV) is a herpesvirus linked to nine different human tumors and lymphoproliferative disorders. Immunosuppression promotes EBV-driven malignancies. The most frequent EBV-induced malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (EBV-SMT). EBV-SMT is a rare oncological entity for which no current guideline for diagnosis or management exists. Data on posttransplant EBV-SMT (PT-SMT) are scarce in kidney transplant recipients. METHODS: We conducted a national multicentric retrospective study and collected cases among transplantation centers in France. Kidney transplant recipients experiencing histologically proven PT-SMT were included. We collected data on demographic characteristics of patient, history of kidney transplantation, history of PT-SMT, evolution of graft function, and patient survival. RESULTS: Eight patients were included. The median age at PT-SMT diagnosis was 31 years (range 6.5-40). PT-SMT occurred after a median delay of 37.8 months after transplantation (range 6-175). PT-SMT management consisted in immunosuppressive regimen minimization in all patients. Introduction of mTOR inhibitors was performed in two patients. Four patients (50%) needed chemotherapy. Surgical resection was performed in four patients. At last follow-up after PT-SMT diagnosis (median 33 months (range 17-132)), five patients were considered in complete remission, and two patients had died. Two patients experienced graft rejection; two resumed dialysis (25%). All patients with available data presented with impaired graft function at last follow-up. CONCLUSION: PT-SMT is a subacute and progressive disease during kidney transplantation. Even if the risk of developing PT-SMT is low in kidney transplant recipients (0.07% in our cohort), PT-SMT is associated with significant graft loss, possibly due to reduced immunosuppression. Developing guidelines could help transplantation teams better manage these patients.

Presence of Epstein-Barr virus in cerebrospinal fluid is associated with increased mortality in HIV-negative cryptococcal meningitis.

Cryptococcus neoformans is the most common cause of fungal meningitis and is associated with a high mortality. The clinical significance of concurrent Epstein-Barr virus (EBV) in the cerebrospinal fluid (CSF) of human immunodeficiency virus (HIV)-negative patients with cryptococcal meningitis (CM) remains unclear. A retrospective cohort study was performed by analyzing CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA in these patients by metagenomic next-generation sequencing (mNGS) and compared 10-week survival rates among those with and without EBV DNA in CSF. Of the 79 CSF samples tested, 44.3% (35/79) had detectable viral DNA in CSF, while 55.7% (44/79) were virus-negative. The most frequent viral pathogen was EBV, which was detected in 22.8% (18/79) patients. The median number of CSF-EBV DNA reads was 4 reads with a range from 1 to 149 reads. The 10-week mortality rates were 22.2% (4/18) in those with positive CSF-EBV and 2.3% (1/44) in those with negative CSF-virus (hazard ratio 8.20, 95% confidence interval [CI] 1.52-81.80; P = 0.014), which remained significant after a multivariate adjustment for the known risk factors of mortality (adjusted hazard ratio 8.15, 95% CI 1.14-92.87; P = 0.037). mNGS can identify viruses that coexist in CSF of HIV-negative patients with CM. EBV DNA is most commonly found together with C. neoformans in CSF and its presence is associated with increased mortality in HIV-negative CM patients.

We retrospectively analyzed CSF samples from 79 HIV-negative Chinese Han patients with confirmed CM. We identified CSF viral DNA by mNGS and compared 10-week survival rates among those with and without EBV DNA. Positive CSF-EBV DNA is associated with the increased mortality in HIV-negative CM patients.

Head and neck squamous cell carcinomas of unknown primary: Can ancillary studies help identify more primary tumor sites?

A subset of head and neck squamous cell carcinomas present solely as metastatic disease in the neck and are of unknown primary origin (SCCUP). Most primary tumors will ultimately be identified, usually in the oropharynx. In a minority of cases, the primary site remains elusive. Here, we examine the role of ancillary testing, including mutational signature analysis (MSA), to help identify likely primary sites in such cases. Twenty-two cases of SCCUP in the neck, collected over a 10-year period, were classified by morphology and viral status; including human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) and RT-qPCR, as well as Epstein-Barr virus (EBV) testing by EBER-ISH. CD5 and c-KIT (CD117) IHC was done to evaluate for possible thymic origin in all virus-negative cases. Whole exome sequencing, followed by MSA, was used to identify UV signature mutations indicative of cutaneous origin. HPV was identified in 12 of 22 tumors (54.5%), favoring an oropharyngeal origin, and closely associated with nonkeratinizing tumor morphology (Fisher's exact test; p = 0.0002). One tumor with indeterminant morphology had discordant HPV and p16 status (p16+/HPV-). All tumors were EBV-negative. Diffuse expression of CD5 and c-KIT was identified in 1 of 10 virus-negative SCCUPs (10%), suggesting a possible ectopic thymic origin rather than a metastasis. A UV mutational signature, indicating cutaneous origin, was identified in 1 of 10 (10%) virus-negative SCCUPs. A cutaneous auricular primary emerged 3 months after treatment in this patient. Primary tumors became clinically apparent in 2 others (1 hypopharynx, 1 hypopharynx/larynx). Thus, after follow-up, 6 tumors remained unclassifiable as to the possible site of origin (27%). Most SCCUPs of the neck in our series were HPV-associated and thus likely of oropharyngeal origin. UV signature mutation analysis and additional IHC for CD5 and c-KIT for possible thymic origin may aid in further classifying virus-negative unknown primaries. Close clinical inspection of hypopharyngeal mucosa may also be helpful, as a subset of primary tumors later emerged at this site.

The Prevalence of Epstein-Barr Virus in Normal, Premalignant, and Malignant Uterine Cervical Samples in Iran.

INTRODUCTION: It is suggested that Epstein-Barr virus (EBV) may play an important role in cervical cancer development. Most studies found a higher rate of EBV in cervical cancer samples in comparison to premalignant and normal groups. In this regard, this study aimed to investigate the prevalence of EBV in cervical samples. METHODS: In total, 364 samples from 179 healthy subjects, 124 women with premalignant lesions, and 61 patients with cervical cancer were investigated using nested-PCR. RESULTS: The mean age ± SE was 54.1 ± 13.4 in women with cervical cancer, 36.1 ± 9.4 among women with premalignant lesions, and 36.6 ± 11.5 in healthy individuals. In total, 290 out of 364 samples were human papillomavirus (HPV) positive and the following HPV genotypes were detected among them: HPV 16/18 was found in 43.1%, 23.9%, and 65.5% of normal, premalignant, and malignant samples, respectively, and other high-risk types were detected in 56.9% of normal, 76.1% of premalignant, and 34.5% of malignant samples. The prevalence of EBV was found to be 9.8%, 2.4%, and 2.8% in cervical cancer, premalignant lesions, and normal specimens, respectively, and the difference was statistically significant (p = 0.028). The overall frequency of coinfection between EBV and HPV was shown to be 3.6%. The coinfection was more prevalent among HPV 16/18-infected samples than other high-risk HPVs (6.6 vs. 2.9%) although the difference was not reached a statistically significant difference (p = 0.23). CONCLUSION: Our findings indicated that EBV could play an important role as a cofactor in the progression of cervical cancer. However, future studies with larger sample sizes and the expression analysis of EBV transcripts or proteins are mandatory.

Treatment of pediatric refractory or relapsed Epstein-Barr virus-associated hemophagocytic syndrome with PD-1 inhibitors.

PURPOSE: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a type of pediatric HLH that occurs frequently in Asia. Although immunochemotherapy based on etoposide and hormone has improved survival rates, there are still about 30% of HLH patients that do not respond. The objective of the article is to examine the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors for children with relapsed/refractory (r/r) EBV-HLH. METHODS: A retrospective case note review of four pediatric patients with r/r EBV-HLH who were treated with PD-1 inhibitors at Sun Yat-sen Memorial Hospital, Sun Yat-sen University. RESULTS: All four patients responded to PD-1 inhibitors and achieved partial response after their first infusion. Plasma EBV DNA copy number and HLH-related monitoring indicators decreased in all of these patients. All patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), and two were still alive at the last follow-up on December 30, 2022. Two patients died because of transplantation-related complications. Serious side effects included increased liver enzymes and edema in two patients. CONCLUSION: PD-1 inhibitors are an effective salvage therapy and can provide a bridge to allo-HSCT for pediatric patients with r/r EBV-HLH. However, side effects should be monitered.

Epidemiology and treatment outcome of nasopharyngeal carcinoma in a low-incidence population - a DAHANCA analysis in Denmark 2000-2018.

INTRODUCTION: Nasopharyngeal carcinoma (NPC) is a rare disease and most studies have therefore been conducted in endemic areas. The aim of this study was to describe epidemiology and treatment outcomes of NPC in a population-based, non-endemic setting. MATERIAL AND METHODS: Patients with NPC diagnosed in Denmark from 2000 to 2018 were identified in the Danish Head and Neck Cancer Study Group (DAHANCA) database. Clinical records were reviewed to obtain missing data and confirm outcome, histological subtypes, Epstein-Barr virus (EBV)-status, prognostic factors, and treatment. RESULTS: NPC was identified in 394 patients corresponding to age-standardized incidence rates of 0.5 and 0.2 per 100,000 in men and women, respectively. The 5-year overall (OS) and disease-specific survival (DSS) were 56 and 66%. In multivariate analysis, stage, smoking, and histology affected both OS and DSS, as patients with undifferentiated carcinomas had superior outcomes. Tumor EBV-status was determined in 221 patients, of whom 160 (72%) tested positive. EBV-positivity was associated with an improved OS in univariate analysis, but not after adjustment for relevant clinical factors. INTERPRETATION: NPC is a rare malignancy in Denmark, and three in four patients have EBV-associated tumors. Tumor histology, smoking status, and stage, but not EBV-status, had independent prognostic impact on survival.

The simultaneous presence of active BK, Epstein Barr, and human cytomegalovirus infection and their correlation by host factors in patients suspected of kidney transplant rejection.

AIMS: This study aims to evaluate the presence of EBV, HCMV, and BKV genomic sequences in the plasma samples (active infection/viremia) of kidney transplant recipients suspected of rejection and to investigate host and risk factors related to the activation of these viruses in these patients. METHODS: In this cross-sectional single-center study, plasma samples were collected from 98 suspected kidney transplant rejection patients at Labafinejad Hospital, Tehran, Iran, between December 2022 and June 2023. Quantitative real-time PCR assays for HCMV, EBV, and BK were performed using GeneProof Real-time PCR kits. ROC curve analysis was used to determine the viral load cutoff point for each virus. FINDINGS: HCMV active viremia was detected in 18 (18.36%) recipients, EBV active viremia in 7 (7.14%), and BKV active viremia in 5 (5.10%). ROC results indicated viral load cutoff points of 778, 661, and 457 points for HCMV, EBV, and BKV, respectively. The duration of time after transplantation significantly differed between active viremia and no viremia groups (120.5 vs. 46 months, P = 0.014). In the BKV active viremia group, the increase in creatinine compared to baseline creatinine was significantly higher than in the no viremia group (2.7 vs. 0.8, P = 0.017). The odds ratio of HCMV active viremia in patients taking tacrolimus was 2.84 times higher, and the odds of HCMV active viremia in patients taking antithymocyte globulin was 3.01 times higher than in patients not taking these drugs. CONCLUSION: Rapid and timely diagnosis of viral active infections in kidney transplant patients is crucial for effective disease management and implementation of appropriate treatment strategies. Identifying potential risk factors, including host and treatment-related factors that influence transplantation, can facilitate the development of suitable preventive strategies.

Incidence of opportunistic viral infections in hepatitis C virus nucleic acid test negative recipients of kidneys from hepatitis C virus nucleic acid test positive donors.

BACKGROUND: In kidney transplantation, concerns have been raised regarding increased incidence of viral opportunistic infections in hepatitis C virus (HCV) nucleic acid test (NAT)-negative (-) recipients who received HCV NAT-positive (+) donor kidneys, specifically BK polyomavirus (BKPyV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The purpose of this study was to determine the incidence of these three viral opportunistic infections in HCV NAT- recipients who have undergone kidney transplantation with HCV NAT+ donor kidneys at our institution. METHODS: This was an Institutional Review Board-approved, single-center, retrospective case-control study of HCV NAT- kidney transplant recipients with HCV NAT+ donors from 2018 to 2021. The primary outcome was the cumulative incidence of viral infections of BKPyV, CMV, and/or EBV within 1 year following kidney transplantation. RESULTS: A total of 231 patients were included, 77 in the exposed (donor HCV NAT+) group and 154 in the control (donor HCV NAT-) group. The adjusted cumulative incidence of viremia within 1 year did not statistically differ between groups (77% exposed group versus 66% for the control group, hazard ratio 1.34, 95% confidence interval 0.95-1.89). In addition, no statistically significant differences were observed for secondary outcomes with the exception of CMV viremia (62% exposed versus 49% control, p = 0.021). However, there were more patients in the exposed group at high risk for CMV viremia based on serostatus (CMV Donor+/Recipient-, D+/R-). CONCLUSION: Among patients who received HCV NAT+ donor kidneys, no clear association was observed between exposure to HCV NAT+ donor kidneys and viral infections of BKPyV, CMV, or EBV.

XMEN-associated Systemic EBV-positive T-cell Lymphoma of Childhood: Report of Two Cases and Literature Review.

X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia (XMEN) is an extremely rare inborn error of immunity (IEI) caused by X-linked recessive inheritance and loss-of-function mutations in the MAGT1 gene, resulting in magnesium ion channel defects. This article reports 2 cases of systemic EBV-positive T-cell Lymphoma of childhood (SETLC) associated with XMEN, which have not been reported before. Whole exome sequencing (WES) in their family revealed previously unreported MAGT1 gene mutations (c.77T>C, p.I26T; c.956-957del: p.Ser319Tyrfs) inherited from their mothers. These mutations expand the spectrum of gene mutations in XMEN disease. The importance of genetic testing for MAGT1 mutations in the initial diagnosis of SETLC was emphasized. We also review the literature on this uncommon IEI.

Co-occurrence of Epstein-Barr virus-positive nodal T/NK-cell lymphoma and nodal T-follicular helper cell lymphoma of different clonal origins: An autopsy case report.

Nodal T-follicular helper cell lymphoma (TFHL) is a subset of T-cell lymphoma and frequently co-occurs with Epstein-Barr virus (EBV)-positive B-cell lymphoma but not with T/NK-cell lymphoma. Recently, a new entity with a worse prognosis, called EBV-positive nodal T/NK-cell lymphoma (NTNKL) has been established. Here, we report an autopsy case of synchronous multiple lymphomas, including TFHL and NTNKL. The patient was a 78-year-old female admitted with pneumonia. Although pneumonic symptoms were improved, fever, pancytopenia, and disseminated intravascular coagulation emerged, implicating lymphoma. She died on the 21st hospital day without a definitive diagnosis. The autopsy revealed the enlargement of multiple lymph nodes throughout her body. Histological analysis revealed three distinct regions in the left inguinal lymph node. The first region consists of small-sized lymphocytes with T-follicular helper phenotype and extended follicular dendritic cell meshwork, indicating TFHL. The second region included EBV-positive large B cells. The third region comprised EBV-positive large cells with cytotoxic T/NK cell phenotype, indicating NTNKL. Clonality analysis of the first and the third regions showed different patterns. Since various hematopoietic malignancies progress from common clonal hematopoiesis according to existing literature, this case may help to understand TFHL and NTNKL.

Histopathology of peritonitis due to infectious mononucleosis with background Chlamydia trachomatis infection: A case report and literature review.

Epstein-Barr virus (EBV) is a major cause of infectious mononucleosis (IM), characterized by fever, fatigue, sore throat, lymphadenopathy, atypical lymphocytosis, and elevated liver enzymes. However, ascites is a rare complication associated with IM. We present a rare case of IM with ascites and peritonitis in a patient who underwent a peritoneal biopsy. A 20-year-old woman presented with fatigue and abdominal distension. Laboratory examination revealed atypical lymphocytes in peripheral blood (54%) and elevated liver enzymes. EBV serological tests revealed a recent primary infection (EBV VCA IgM 1:160). Computed tomography revealed moderate ascites and peritonitis. Adenocarcinoma was suspected based on the ascites' cytology. Considering possible complications of IM and adenocarcinoma, a laparoscopic biopsy was performed. Histological findings of biopsy specimens from the peritoneum, omentum, and fimbria of the fallopian tube demonstrated severe inflammatory cell infiltration and focal aggregation of large EBV-encoded RNA-1 (EBER1)-positive B cells, mimicking EBV-positive polymorphous B-cell lymphoproliferative disorder. Furthermore, intracytoplasmic inclusion bodies of Chlamydia trachomatis were observed by immunohistochemistry. Real-time polymerase chain reaction detected C. trachomatis in cervical secretions. Two months after laparoscopy, ascites decreased, and the diagnosis was IM-associated peritonitis with C. trachomatis infection. IM should be considered as a differential diagnosis in young patients with ascites.