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.

Multifocal Epstein-Barr Virus-Positive Mucocutaneous Ulcers in a Patient With Crohn's Disease.

Epstein-Barr Virus-positive mucocutaneous ulcer (EBVMCU) is a rare and new category of mature B-cell neoplasms commonly linked to immunosuppression. It often has a benign course and regresses spontaneously after discontinuation or dose reduction of immunosuppressive agents. We report the case of a 48-year-old woman on long-term azathioprine therapy for rectosigmoid Crohn's disease. In contrast to the prevalent sites typically associated with EBVMCU, such as the oral mucosa and skin, this patient was found to have locations in the gastrointestinal tract and upper neck. These areas tested positive for histopathology consistent with EBVMCU and were excised due to bowel perforation and concern for malignancy.

Epstein-Barr Virus-Associated Aggressive Natural Killer Cell Leukemia: Challenges and Emerging Therapies.

A 24-year-old Ecuadorian female, previously diagnosed with acute fatty liver (AFL) during pregnancy, developed constitutional symptoms, jaundice, and abdominal pain in a subsequent pregnancy, prompting investigations that suggested a recurrence of AFL. She underwent an elective abortion, which resulted in the resolution of her abdominal pain, and a liver biopsy, which showed granulomatous inflammation and lymphocytic infiltration. She later presented with abdominal distention, productive cough, and persistent constitutional symptoms and jaundice. Extensive laboratory and imaging studies indicated sepsis, acute liver injury, and disseminated intravascular coagulopathy. Her serum Epstein-Barr virus (EBV) level was elevated. Special staining of her previous liver biopsy revealed EBV-positive natural killer (NK) cells. A bone marrow biopsy also revealed EBV-positive NK cells. She was diagnosed with aggressive NK cell leukemia (ANKL) with or without chronic active EBV (CAEBV). Treatment included dexamethasone, atovaquone, bortezomib, and ganciclovir, with plans for a stem cell transplant. However, her course was complicated by infections and multi-organ failure, resulting in her passing. This case highlights the rarity and challenges in managing EBV-associated ANKL, emphasizing the need for early detection and improved treatment options, with stem cell transplantation offering the best prognosis.

Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder.

Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P < 0.001). The enhanced efficacy of IL-15/IL-15Rα-NKG2D CAR T cells was probably due to the IL-15/IL-15Rα signaling improved homing and persistence of NKG2D CAR-T cells in vivo, and increased the production of IFN-γ, Perforin, and Granulysin. In conclusion, NKG2D CAR-T cells co-expressing IL-15/IL-15Rα promoted the central memory CAR T cell proliferation and improved the homing and persistence of CAR T cells in vivo, resulting in enhanced anti-tumor and anti-viral effects in treating EBV-PTLD.

Genetics of Acquired Cytokine Storm Syndromes : Secondary HLH Genetics.

Secondary hemophagocytic lymphohistiocytosis (sHLH) has historically been defined as a cytokine storm syndrome (CSS) occurring in the setting of triggers leading to strong and dysregulated immunological activation, without known genetic predilection. However, recent studies have suggested that existing underlying genetic factors may synergize with particular diseases and/or environmental triggers (including infection, autoimmune/autoinflammatory disorder, certain biologic therapies, or malignant transformation), leading to sHLH. With the recent advances in genetic testing technology, more patients are examined for genetic variations in primary HLH (pHLH)-associated genes, including through whole exome and whole genome sequencing. This expanding genetic and genomic evidence has revealed HLH as a more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Rather than a simple, binary definition of pHLH and sHLH, HLH represents a spectrum of diseases, from a severe complication of common infections (EBV, influenza) to early onset familial diseases that can only be cured by transplantation.

[Infectious mononucleosis : an atypical cause of acute alithiasic cholecystitis]. / La mononucléose infectieuse : une cause atypique de cholécystite aiguë alithiasique.

The Epstein-Barr virus (also known as EBV), responsible for infectious mononucleosis, is a virus that infects the majority of the world's population. Infection occurs in several forms, most often asymptomatic, or as a fever accompanied by pharyngitis and lymphadenopathies. A rare complication of infectious mononucleosis is acute acalculous cholecystitis, an inflammation of the gallbladder characterized by ischaemia and severe cholestasis. The diagnosis of this pathology is made by imaging, but determining the cause may be tricky. We present here the case of acute acalculous cholecystitis in a 21-year-old woman. This case highlights a rare complication of EBV infection that is probably under-diagnosed, and demonstrates the usefulness of interpreting liver tests and leukocyte count in association with imaging findings.

Le virus d'Epstein-Barr (aussi appelé EBV), responsable de la mononucléose infectieuse, est un virus qui infecte la majorité de la population mondiale. L'infection se présente sous plusieurs formes, soit, le plus souvent, asymptomatique, soit avec une fièvre accompagnée d'une pharyngite et de lymphadénopathies. Une des rares complications de la mononucléose infectieuse est la cholécystite aiguë alithiasique, une inflammation de la vésicule biliaire, caractérisée par une ischémie et une cholestase importante. Le diagnostic de cette pathologie est réalisé par imagerie et la détermination de la cause peut s'avérer compliquée. Nous présentons ici le cas clinique d'une cholécystite aiguë alithiasique chez une jeune femme de 21 ans. Ce cas nous permet de mettre en lumière une complication rare de l'infection par l'EBV, probablement sous-diagnostiquée, et démontre l'utilité d'interpréter les tests hépatiques ainsi que la formule leucocytaire en relation avec les résultats d'une imagerie.

Serum Concentrations of Chemokines CCL20, CXCL8 and CXCL10 in Relapsing-Remitting Multiple Sclerosis and Their Association with Presence of Antibodies against Epstein-Barr Virus.

Epstein-Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein-Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS.

Association of Epstein-Barr virus (EBV) with nasopharyngeal carcinoma: Experience from a North Indian tertiary care hospital.

INTRODUCTION: Nasopharyngeal carcinoma (NPC), arising from nasopharyngeal epithelium is caused by Epstein-Barr virus (EBV). It is common in South China, South East Asia and North East India. The aim and objectives of this study were to determine the prevalence of EBV in formalin-fixed paraffin-embedded (FFPE) tissue sections of clinically suspected NPC patients, correlate the results of polymerase chain reaction (PCR) with histopathology findings, and to determine the utility of tissue EBV DNA as a diagnostic bio-marker. MATERIALS AND METHODS: 31 FFPE tissue samples were collected from clinically suspected NPC patients from April 2018-December 2019. Histopathological diagnosis was done by examination of Hematoxylin and Eosin stained slides. Presence of EBV was detected by EBNA-1 PCR. IHC was performed using EBV Latent Membrane Protein 1. RESULTS: Of the 31 clinically suspected NPC cases, 15 (48.4 %) were histopathological confirmed NPC. Of these15, 13 (86.6 %) were non-keratinising undifferentiated NPC, and one each were keratinising NPC and non-keratinising differentiated NPC respectively. EBV EBNA1 PCR was positive in 35.5 % (11/31) of clinically suspected NPC cases. Of the 11 PCR positive cases, 9 (81.8 %) were histopathological confirmed NPC. Of the 31 clinically suspected NPC cases, IHC was indicated in 23 biopsies. Of which, 12 (52.2 %) were positive for LMP1 in the abnormal cells. Of the 12 IHC positive samples, 10 were NPC cases. CONCLUSION: EBV DNA as an indicator towards NPC among clinically suspected cases had a sensitivity of 60 % and specificity of 87.5 %. In this study, addition of EBV DNA detection by PCR from FFPE tissue sections could confirm EBV association in 20 % of cases where it was not detected by EBV LMP1 IHC, thus helped in increasing the detection of EBV positivity in NPC cases. Early diagnosis of NPC will improve the cure rate and hence reduce the morbidity and mortality rates.

Nodal T-Follicular Helper Cell Lymphoma, Angioimmunoblastic-Type, Diagnosed in a Patient with Psoriasis Following COVID-19 Vaccination under Adalimumab Treatment: A Causal Association?

Biologics have expanded the armamentarium for psoriasis, but there has been a growing concern about the risk of lymphoma in patients under tumour necrosis factor (TNF)-α inhibitor and methotrexate. Besides, the mRNA-based coronavirus disease 2019 (COVID-19) vaccination was known to stimulate the proliferation of T-follicular helper cells. We report a case of a patient with psoriasis under adalimumab developing nodal T-follicular helper cell lymphoma, angioimmunoblastic-type following the mRNA-1273 COVID-19 vaccine. We suspect that adalimumab, methotrexate, Epstein-Barr virus (EBV) reactivation, previous reactive lymphoid hyperplasia and psoriasis per se predispose our patient to a lymphoma-prone condition, and the two doses of the mRNA vaccine act as the last straw.

A magnetic resonance imaging-based lymph node regression grading scheme for nasopharyngeal carcinoma after radiotherapy.

Background: Among patients with nasopharyngeal carcinoma (NPC), there is no established method to distinguish between patients with residual disease that may eventually progress and those who have achieved cured. We thus aimed to assess the prognostic value of magnetic resonance imaging (MRI)-based lymph node regression grade (LRG) in the risk stratification of patients with NPC following radiotherapy (RT). Methods: This study retrospectively enrolled 387 patients newly diagnosed with NPC between January 2010 and January 2013. A four-category MRI-LRG system based on the areal analysis of RT-induced fibrosis and residual tumor was established. Univariate analysis was performed using the Kaplan-Meier method, and comparisons were conducted via the log-rank test. Multivariate analyses were conducted using Cox regression models to calculate the hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted P values. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. Results: The sum of MRI-LRG scores (LRG-sum) was an independent prognostic factor for progression-free survival (PFS) (HR 2.50, 95% CI: 1.28-4.90; P<0.001). LRG-sum ≤9 and >9 showed a poorer 5-year PFS rate than did LRG-sum ≤2 (66.1%, 42.9%, and 77.6%, respectively; P<0.001). A survival clustering analysis-based decision tree model showed more complex interactions among LRG-sum and pretreatment and post-RT Epstein-Barr virus (EBV) DNA, yielding four patient clusters with differentiated disease progression risks (5-year PFS rates of 89.5%, 76.4%, 57.6%, and 27.8%, respectively), which showed better risk stratification than did post-RT EBV DNA alone (P<0.001). Conclusions: The MRI-LRG system adds prognostic information and is a potentially reliable, noninvasive means to stratify treatment modalities for patients with NPC.

Modified SMILE (mSMILE) is active in the treatment of pediatric Epstein-Barr virus-associated natural killer/T-cell lymphoma: a single center experience, case series.

Background: The Epstein-Barr virus-associated natural killer (NK) and T-cell lymphoma (EBV + NK/T cell lymphoma) is a severe illness mainly affecting children and young adults, often resulting in a poor prognosis. To date, there is no consensus on an established treatment strategy. This study aims to evaluate the efficacy and safety of the mSMILE (modified steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) chemotherapy regimen in treating EBV+ NK/T-cell lymphoma and to provide insights into potential treatment outcomes. Methods: In this study, we conducted a retrospective analysis of the clinical data and treatment outcomes for patients with EBV + NK/T cell lymphoma treated at Children's Hospital of Nanjing Medical University between July 2017 and January 2022. These patients received at least two cycles of the mSMILE chemotherapy, in which a single dose of pegaspargase was substituted for 7 doses of L-asparaginase per cycle. Results: Eight patients were included in the study: one with extranodal NK/T-cell lymphoma, one with primary nodal NK/T-cell lymphoma, and six with Systemic EBV+ NK/T cell lymphoma of childhood. The results showed that five patients achieved complete remission, two achieved partial remission, and one showed progressive disease, resulting in a complete remission rate of 62.5% and an overall response rate of 87.5%. The 3-year overall survival (OS) and event-free survival (EFS) rates were 87.5% and 75%, respectively. The most common adverse reactions associated with chemotherapy were hematologic toxicities of stages III to IV. Nonhematologic adverse reactions mainly included impaired liver function, infections, and oral mucositis, which were resolved with aggressive anti-infective therapy. Conclusions: Based on our clinical experience, the mSMILE appears to be a safe and effective treatment option for EBV + NK/T-cell lymphoma, meriting further investigation in late-phase clinical trials.

Role of 14-3-3 protein family in the pathobiology of EBV in immortalized B cells and Alzheimer's disease.

Background and Aims: Several studies have revealed that Epstein-Barr virus (EBV) infection raised the likelihood of developing Alzheimer's disease (AD) via infecting B lymphocytes. The purpose of the current investigation was to assess the possible association between EBV infection and AD. Methods: The microarray datasets GSE49628, GSE126379, GSE122063, and GSE132903 were utilized to extract DEGs by using the GEO2R tool of the GEO platform. The STRING tool was used to determine the interaction between the DEGs, and Cytoscape was used to visualize the results. The DEGs that were found underwent function analysis, including pathway and GO, using the DAVID 2021 and ClueGo/CluePedia. By using MNC, MCC, Degree, and Radiality of cytoHubba, we identified seven common key genes. Gene co-expression analysis was performed through the GeneMANIA web tool. Furthermore, expression analysis of key genes was performed through GTEx software, which have been identified in various human brain regions. The miRNA-gene interaction was performed through the miRNet v 2.0 tool. DsigDB on the Enrichr platform was utilized to extract therapeutic drugs connected to key genes. Results: In GEO2R analysis of datasets with |log2FC|≥ 0.5 and p-value <0.05, 8386, 10,434, 7408, and 759 genes were identified. A total of 141 common DEGs were identified by combining the extracted genes of different datasets. A total of 141 nodes and 207 edges were found during the PPI analysis. The DEG GO analysis with substantial alterations disclosed that they are associated to molecular functions and biological processes, such as positive regulation of neuron death, autophagy regulation of mitochondrion, response of cell to insulin stimulus, calcium signaling regulation, organelle transport along microtubules, protein kinase activity, and phosphoserine binding. Kyoto Encyclopedia of Genes and Genomes analysis discovered the correlation between the DEGs in pathways of neurodegeneration: multiple disease, cell cycle, and cGMP-PKG signaling pathway. Finally, YWHAH, YWHAG, YWHAB, YWHAZ, MAP2K1, PPP2CA, and TUBB genes were identified that are strongly linked to EBV and AD. Three miRNAs, i.e., hsa-mir-15a-5p, hsa-let-7a-5p, and hsa-mir-7-5p, were identified to regulate most of hub genes that are associated with EBV and AD. Further top 10 significant therapeutic drugs were predicted. Conclusion: We have discovered new biomarkers and therapeutic targets for AD, as well as the possible biological mechanisms whereby infection with EBV may be involved in AD susceptibility for the first time.

Cephalic and ocular manifestations of EBV-associated plasmablastic lymphoma: Clinical and radiological response to bortezomib, EPOCH, and intrathecal methotrexate.

Plasmablastic lymphoma (PBL) is a rare and aggressive type of lymphoma, particularly affecting HIV-positive and immunocompromised individuals, with a median diagnosis age of 49 years. Cases of this malignancy in HIV-negative individuals are less common and rarely involve the bone marrow. While traditional chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) were previously utilized in the management of such malignancy, the National Comprehensive Cancer Network currently recommends more intensive approaches. We present a rare stage IV Epstein-Barr virus (EBV)-positive PBL with a nasal cavity tumor extending into the left orbital sinus and encapsulating segments of the optic nerve in a 38-year-old young immunocompetent adult, without a significant past medical history. Treatment consisted of 6 cycles of Bortezomib in combination with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and intrathecal methotrexate which exhibited significant clinical and radiological improvement suggesting the potential efficacy of this regimen. Vision returned to baseline, the mass size reduced significantly, and headaches improved. Given this outcome, it is highly encouraged to emphasize the need for further exploration of this treatment in larger clinical trials.

EBV + B cell-derived exosomes promote EBV-associated T/NK-cell lymphoproliferative disease immune evasion by STAT3/IL-10/PD-L1 pathway.

EBV-associated T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs) are characterized by the clonal proliferation of EBV-positive ( +) T/NK cells. EBV is typically latent in B cells and the mechanism by which the EBV genome invades T/NK cells remains unknown. Recent studies have demonstrated that exosomes derived from EBV + B cells play a pivotal role in immunosuppressive microenvironment remodeling. Moreover, the existence of an immunosuppressive microenvironment is known to be critical in the development of EBV-T/NK-LPDs. Hence, we hypothesized that exosomes derived from EBV + B cells might promote the development of EBV-T/NK-LPDs by stimulating immune evasion. In this study, we utilized paraffin sections to clarify the STAT3/IL-10/PD-L1-associated immunosuppressive microenvironment in EBV-T/NK-LPDs. Further, we extracted exosomes from BL2009 (EBV + B cell lymphoma) and CA46 (EBV- B cell lymphoma) cell lines to co-culture with cutaneous T-cell lymphoma (CTCL) cell lines, to verify the changes in the above immune evasion pathway. The paraffin sections of EBV-T/NK-LPDs showed high-expression levels of IL-10/PD-L1, which might be related to the phosphorylation of STAT3. Exosomes derived from EBV + B cells could significantly activate the STAT3/IL-10/PD-L1 pathway. After being treated with C188-9, EBV + B cell-derived exosomes were no longer able to stimulate the expression of IL-10/PD-L1 in CTCL cells. EBV-T/NK-LPDs have a STAT3/IL-10/PD-L1 overactivation-associated immunosuppressive microenvironment. Our study elucidated part of this mechanism. Exosomes derived from EBV + B could induce phosphorylation of STAT3 in CTCL cells, leading to the overexpression of IL-10/PD-L1. Our findings might shed light on new directions for understanding immune evasion in EBV-T/NK-LPDs.

Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites.

Introduction: Intra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells. Methods: B lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry. Results: Antibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients' sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells. Discussion: These studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

A Case of Adrenal Insufficiency Secondary to Bilateral Adrenal Hemorrhage in a Patient With Antiphospholipid Antibody Syndrome and Epstein-Barr Virus Infection.

Bilateral adrenal hemorrhage (AH) is linked to various causes, including bacterial and viral infections, coagulopathies, and postoperative states. Symptoms can range from mild adrenal insufficiency to shock from Waterhouse-Friedrichsen syndrome. We present a case of a 47-year-old male with antiphospholipid antibody syndrome (APS) on warfarin who presented to the emergency department (ED) with bilateral flank pain and was found to have bilateral AH. On exam, he was hypertensive, mildly tachycardic, and in severe pain. The abdomen was tender over the bilateral flank and costovertebral regions. Labs showed thrombocytopenia but normal international normalized ratio (INR) and fibrinogen. The CT and MRI confirmed bilateral AH. Further investigations revealed low ante meridiem (AM) cortisol and elevated adrenocorticotropic hormone (ACTH). The antinuclear antibody (ANA) test was negative, but the antiphospholipid antibody panel was positive. In addition, the patient had a positive Epstein-Barr virus (EBV) nuclear antigen with a significant IgM titer. He was treated with low-dose steroids and was placed on a prophylactic dose of enoxaparin with the resolution of symptoms. At discharge, he was advised to follow up with a hematologist in six weeks to restart full-dose anticoagulation, allowing time for the bleeding to resolve. This case highlights EBV infection as a possible trigger of adrenal insufficiency from adrenal bleeding in a patient with preexisting coagulopathy, necessitating prompt recognition and treatment.

Hemophagocytic Lymphohistiocytosis (HLH) in an Elderly Male With Epstein-Barr Virus (EBV) Viremia.

This is a case of a 75-year-old male with a complicated past medical history who presented initially with weakness, fevers, exertional dyspnea, cough, and confusion. His initial workup revealed elevated aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, and D-dimer. Right upper quadrant (RUQ) ultrasound revealed a partially contracted gallbladder with gallstones, so he underwent laparoscopic cholecystectomy. Due to worsening hyperbilirubinemia and anemia, he later underwent a liver biopsy which showed Epstein-Barr virus (EBV)-positive lymphoid infiltration. He developed anemia, thrombocytopenia, and low fibrinogen. He met the criteria for hemophagocytic lymphohistiocytosis (HLH) with 6/8 HLH-2004 criteria and an H score of 230 with a 96-98% probability of HLH. The patient was promptly treated with steroids, rituximab, and etoposide; however, the patient's health continued to deteriorate, and he expired. This case highlights the challenges of early diagnosis of HLH in the elderly patient population due to large differentials, confounding comorbidities, and the rarity of the diagnosis in this age range.

Transition From Epstein-Barr Virus (EBV)-Positive Rectal Hodgkin Lymphoma to Diffuse Large B-Cell Lymphoma in the Lung.

We report a distinctive case of sequential lymphomas in a 72-year-old male, initially diagnosed with Epstein-Barr virus (EBV)-positive rectal classic Hodgkin lymphoma (cHL), followed by the development of diffuse large B cell lymphoma (DLBCL) in the lung. This rare progression underscores the complexity of lymphomas associated with EBV infection and their unpredictable clinical courses. The patient's journey began with symptoms of intractable diarrhea, low appetite, and significant weight loss, leading to the diagnosis of stage 4B cHL, managed initially with brentuximab/doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy. Despite a partial response, surveillance identified a transition to DLBCL, marked by new pulmonary lesions. This case highlights the clinical and diagnostic challenges in managing sequential lymphomas, emphasizing the role of EBV in lymphomagenesis and the potential for clonal evolution from a common precursor cell. The therapeutic approach evolved from targeted chemotherapy to consideration of advanced treatments such as autologous stem cell transplant and chimeric antigen receptor (CAR) T-cell therapy, reflecting the aggressive nature and poor prognosis of the disease. This case contributes to our understanding of the EBV's impact on lymphoma progression and underscores the need for vigilant monitoring and adaptive treatment strategies in similar clinical scenarios.

Epstein-Barr virus-positive mucocutaneous ulcer resulting in severe methotrexate intoxication: a case report.

BACKGROUND: Epstein-Barr virus-positive mucocutaneous ulcer is one of the mature B-cell lymphoproliferative diseases occurring in patients with immune dysfunction including those with immunosuppressive treatment such as methotrexate. CASE PRESENTATION: A Japanese elderly man in his 80s with rheumatoid arthritis on methotrexate was admitted to our hospital complaining persistent pharyngeal pain. Laboratory tests revealed severe pancytopenia, elevated C-reactive protein, and increased creatinine levels. An otolaryngological examination showed ulceration of the right tonsil, from which diagnostic biopsy was performed. The diagnosis of Epstein-Barr virus-positive mucocutaneous ulcer was made and bone marrow aspiration revealed hypocellularity and megaloblastic changes. Pancytopenia was improved after discontinuing methotrexate, and repeated bone marrow aspiration test revealed recovery of normal cellularity and disappearance of dysplasia, confirming the diagnosis of methotrexate intoxication. Tonsil ulcer was improved only with discontinuation of methotrexate, which strongly supported the diagnosis of EBV-MCU. CONCLUSION: Our case suggested that even this best prognosis form of lymphoproliferative disease could lead to fatal complications if not appropriately managed.