Case report: Non-EBV associated cerebral vasculitis and cerebral hemorrhage in X-linked lymphoproliferative disease.

X-linked lymphoproliferative disease (XLP) is a rare genetic disorder characterized by immune dysregulation. The three most common clinical phenotypes are EBV-associated infectious mononucleosis (FIM), abnormal gammaglobulinemia, and lymphoma. We present a rare case of XLP1 with neurovasculitis, which is non-EBV-related and involves multiple systems, a condition rarely seen in children. The patient initially presented with an unsteady gait, which progressively evolved into language and consciousness disorders. Additionally, CT scans revealed multiple nodules in the lungs. Subsequent genetic testing and brain tissue biopsy confirmed the diagnosis: XLP1-related cerebral vasculitis and cerebral hemorrhage. Tragically, during the diagnostic process, the child experienced a sudden cerebral hemorrhage and herniation, ultimately resulting in fatality. This case offers a comprehensive insight into XLP1-related cerebral vasculitis and cerebral hemorrhage, underscoring the significance of early diagnosis and prompt treatment, while also imparting valuable clinical experience and lessons to the medical community.

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds, one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A-the gene responsible for XLP1-was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients' background, indicating the key features of EBV-HLH.

A differential diagnosis method for systemic CAEBV and the prospect of EBV-related immune cell markers via flow cytometry.

Chronic active Epstein-Barr virus (CAEBV) infection of the T-cell or Natural killer (NK)-cell type, systemic form (systemic CAEBV or sCAEBV) was defined by the WHO in 2017 as an EBV-related lymphoproliferative disorder and is listed as an EBV-positive T-cell and NK-cell proliferation. The clinical manifestations and prognoses are heterogeneous. This makes systemic CAEBV indistinguishable from other EBV-positive T-cell and NK-cell proliferations. Early diagnosis of systemic CAEBV and early hematopoietic stem cell transplantation can improve patient prognosis. At present, the diagnosis of systemic CAEBV relies mainly on age, clinical manifestations, and cell lineage, incurring missed diagnosis, misdiagnosis, long diagnosis time, and inability to identify high-risk systemic CAEBV early. The diagnostic methods for systemic CAEBV are complicated and lack systematic description. The recent development of diagnostic procedures, including molecular biological and immunological techniques such as flow cytometry, has provided us with the ability to better understand the proliferation of other EBV-positive T cells and NK cells, but there is no definitive review of their value in diagnosing systemic CAEBV. This article summarizes the recent progress in systemic CAEBV differential diagnosis and the prospects of flow cytometry.

Allogeneic Hematopoietic Cell Transplantation Ameliorated Asymptomatic Granulomatous and Lymphocytic Interstitial Lung Disease in a Patient With XIAP Deficiency.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is an inborn error of immunity (IEI). Allogeneic hematopoietic cell transplantation (HCT) is currently the only curative therapy available for XIAP deficiency. Granulomatous and lymphocytic interstitial lung disease (GLILD) is a common immune-related lung complication of IEIs. We present a 6-year-old boy with XIAP deficiency and GLILD. Computed tomography showed lung nodes but no symptoms. Before HCT, GLILD was not managed with immunosuppressive therapy, because he was asymptomatic. The HCT procedure was subsequently performed. The post-HCT course was uneventful; follow-up computed tomography on day 46 showed nodules had disappeared. HCT could potentially ameliorate GLILD like other inflammatory processes associated with the underlying IEIs.

Severe mosquito bite allergy complicated by bacterial infection in a 7-year-old child: a case report and brief review of the literature.

INTRODUCTION: SMBA is a cutaneous form of CAEBV that predominantly affects adolescents and children from East Asian countries. It is characterized by local skin erythema, bullae, ulcers, necrosis, and scarring following a mosquito bite. Affected patients may experience IM-like systemic inflammatory reactions. SMBA mainly involves NK cells and has the potential to progress to NK/T-cell lymphoma or invasive NK-cell leukemia. CASE REPORT: A 7-year-old female was admitted to the hospital owing to recurring fever, skin allergies, and multifocal severe ulcerative necrotic skin lesions affecting both lower limbs. The authors primarily suspected bacterial infection, and debridement was insufficient to manage it. Pathological examination of residual skin tissues around the necrotic lesion revealed EBER-positive T cells. Eventually, the patient was diagnosed with SMBA complicated by bacterial infection based on diagnostic criteria and pathology findings. The patient responded well to timely antiviral and antibacterial treatment, with no deterioration during regular follow-up visits. CONCLUSIONS: SMBA is a subtype of CAEBV that is characterized by severe skin ulceration and is easily missed or misdiagnosed. Based on its mosquito bite history, pathological characteristics, and laboratory indicators, SMBA could expand new diagnostic and therapeutic approaches to the ulcerative skin diseases.

Unusual Presentation of SET::NUP214-Associated Concomitant Hematological Neoplasm in a Child-Diagnostic and Treatment Struggle.

Simultaneous multilineage hematologic malignancies are uncommon and associated with poorer prognosis than single-lineage leukemia or lymphoma. Here, we describe a concomitant malignant neoplasm in a 4-year-old boy. The child presented with massive lymphoproliferative syndrome, nasal breathing difficulties, and snoring. Morphological, immunocytochemical, and flow cytometry diagnostics showed coexistence of acute myeloid leukemia (AML) and peripheral T-cell lymphoma (PTCL). Molecular examination revealed a rare t(9;9)(q34;q34)/SET::NUP214 translocation as well as common TCR clonal rearrangements in both the bone marrow and lymph nodes. The disease showed primary refractoriness to both lymphoid and myeloid high-dose chemotherapy as well as combined targeted therapy (trametinib + ruxolitinib). Hence, HSCT was performed, and the patient has since been in complete remission for over a year. This observation highlights the importance of molecular techniques for determining the united nature of complex SET::NUP214-positive malignant neoplasms arising from precursor cells with high lineage plasticity.

No Additional Risk of Ampicillin Rash Among Pediatric Liver Transplant Recipients With Concurrent Epstein-Barr Virus Infection.

BACKGROUND: Epstein-Barr virus (EBV) infection frequently develops in children undergoing liver transplantation (LT) because of mandated immunosuppressive therapy. There is a risk of ampicillin rash when penicillin derivatives are used in patients with EBV-associated infectious mononucleosis. Hence, the administration of penicillin derivatives may raise concerns about ampicillin rash in patients with high EBV loads. However, no studies confirmed the risk of administering penicillin derivatives to EBV-infected children after LT. METHODS: This retrospective study was conducted at the largest pediatric transplantation center in Japan. We investigated all pediatric liver transplant recipients who received penicillin derivatives within 2 years of LT between 2014 and 2020. We separated the cohort into EBV-positive and EBV-negative groups to assess the frequency of ampicillin and antibiotic-associated rash. RESULTS: Two hundred eighty-six liver transplant recipients were enrolled. There were 111 recipients in the EBV-positive group and 175 recipients in the EBV-negative group. In the EBV-positive group, 49 patients had high EBV DNA loads (≥1000 copies/µg DNA). None of the patients in either group developed ampicillin rash, and the frequency of antibiotic-associated rash did not differ [8/111 (7.2%) vs. 10/175 (5.7%), P = 0.797]. Additional subgroup analysis revealed no difference in the frequency of antibiotic-associated rashes regardless of the presence or absence of high EBV loads. CONCLUSIONS: In this study, ampicillin rash was not observed, and antibiotic-associated rash was not associated with concurrent EBV infection. Penicillin derivatives can be used safely, even in liver transplant recipients with persistent asymptomatic EBV infection.

Deciphering molecular complexity of HCV-associated lymphoproliferation.

Recent clinical studies demonstrated the achievement of lymphoma responses in patients with Hepatitis C virus-associated indolent lymphoproliferative disorders (LPD) receiving direct-acting antivirals (DAAs) as their sole treatment. However, the molecular mechanisms underlying LPD responses to DAAs are still poorly understood. In their paper the authors provide new molecular insights on this issue, reporting intraclonal diversification and persistence of B-cell clones in most cases, despite viral eradication and beneficial clinical outcome. These provocative data suggest that the achievement of molecular response is probably not required for a 'functional cure' of these patients. Further comprehensive immunogenetic and mutational studies would be fundamental to dissect this biological puzzle and, ultimately, to refine improved treatment strategies in this setting. Commentary on: Mazzaro et al. Persistence of monoclonal B-cell expansion and intraclonal diversification despite virus eradication in patients affected by hepatitis C virus-associated lymphoproliferative disorders. Br J Haematol 2023;203:237-243.

Unpacking the CNS Manifestations of Epstein-Barr Virus: An Imaging Perspective.

Epstein-Barr virus is a ubiquitous herpesvirus that may cause both infective (encephalitis, meningitis, and so forth) and postinfection inflammatory (such as Guillain-Barré syndrome, acute disseminated encephalomyelitis) manifestations in the CNS. Diagnosis of Epstein-Barr virus-related CNS pathologies is often complicated due to a nonspecific clinical presentation and overlap with other infectious and noninfectious causes, both clinically and on imaging. The Epstein-Barr virus is also implicated in several lymphoproliferative disorders in both immunocompromised and immunocompetent hosts. MR imaging is preferred for evaluating the extent of involvement and monitoring therapy response, given its high sensitivity and specificity, though imaging findings may be nonspecific. Herein, we review the imaging spectrum of Epstein-Barr virus-associated CNS disorders.

Methotrexate-associated lymphoproliferative disorder presenting as an ulcer with tendon exposure on the dorsum of the hand: a case report and literature review.

INTRODUCTION: MTX-LPD is a complication that occurs during MTX treatment. Skin lesions in MTX-LPD are often subcutaneous nodules with occasional necrosis and ulceration. Although MTX-LPD regression is frequently observed upon discontinuation of oral MTX treatment, delayed diagnosis of MTX-LPD with associated ulceration may lead to ulcer enlargement and the need for surgical procedures such as skin grafts. CASE REPORT: A 74-year-old female was diagnosed with RA and administered MTX for 3 years and 8 months. The patient presented with a 2-month-old ulcer on the dorsum of the hand. The ulcer size was 6.5 cm × 5 cm, and it was surrounded by an embankment tumor measuring 7 cm × 6 cm. Although a definitive diagnosis could not be made based on the biopsy specimen, excision of the ulcer-containing mass confirmed MTX-LPD diagnosis. MTX was discontinued, and free-flap reconstruction was performed 3 weeks after the first surgery. The postoperative period was uneventful, and MTX-LPD recurrence was not observed 10 months after the second surgery. CONCLUSION: Although MTX-LPD with ulceration is rare, it should be considered in cases of refractory ulcers in patients with RA. The discontinuation of MTX based on early MTX-LPD diagnosis is critical to avoid surgical procedures such as skin grafts and flap reconstruction.

Slowly Expanding 18 F-FDG PET-Positive Irregular Opacities in the Lung Due to Diffuse Lymphoid Hyperplasia Preceding Rheumatoid Arthritis.

ABSTRACT: Pulmonary diffuse lymphoid hyperplasia (DLH), a nonneoplastic lymphoproliferative disorder (LPD), is extremely rare, and no PET/CT findings have been reported for pulmonary DLH. We observed slowly expanding irregular opacities with 18 F-FDG accumulation (SUV max , 3.64) in the right lower lobe of a 51-year-old asymptomatic man. The patient underwent video-assisted thoracoscopic biopsy on suspicion of malignant lesions. Histologically, no neoplastic cells were present, and the lesion was consistent with DLH. Six months later, the patient developed rheumatoid arthritis. DLH should be considered in the differentiation of PET-positive irregular opacities, even in the absence of known immune abnormalities.

Epstein-Barr virus-positive CD30+ B-cell lymphoproliferative disease with histologic features resembling grade III lymphomatoid granulomatosis induced by methotrexate.

Methotrexate (MTX) is a first-line systemic medication used to treat rheumatoid arthritis because of its immunomodulatory effects. However, MTX has also been linked to the development of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis. We describe a patient with long-standing rheumatoid arthritis treated with MTX who developed cutaneous Epstein-Barr virus (EBV)-positive B cell lymphoproliferative disease resembling grade III lymphomatoid granulomatosis localized to the right leg. The lymphomatoid process resolved with withdrawal of the MTX. The pathogenesis of iatrogenic lymphoproliferative disorder was most likely triggered by the rheumatoid inflammation and the immunosuppressing effects of MTX, which led to EBV reactivation. We recommend a trial of MTX discontinuation prior to considering chemotherapy in patients with rheumatoid arthritis treated with MTX who develop EBV-positive B cell lymphoproliferative disease resembling a high grade B-cell lymphoma.

Arrhythmogenic Cardiotoxicity Associated With Contemporary Treatments of Lymphoproliferative Disorders.

Background There are limited data on risk of arrhythmias among patients with lymphoproliferative disorders. We designed this study to determine the risk of atrial and ventricular arrhythmia during treatment of lymphoma in a real-world setting. Methods and Results The study population comprised 2064 patients included in the University of Rochester Medical Center Lymphoma Database from January 2013 to August 2019. Cardiac arrhythmias-atrial fibrillation/flutter, supraventricular tachycardia, ventricular arrhythmia, and bradyarrhythmia-were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes. Multivariate Cox regression analysis was used to assess the risk of arrhythmic events with treatments categorized as Bruton tyrosine kinase inhibitor (BTKi), mainly ibrutinib/non-BTKi treatment versus no treatment. Median age was 64 (54-72) years, and 42% were women. The overall rate of any arrhythmia at 5 years following the initiation of BTKi was (61%) compared with (18%) without treatment. Atrial fibrillation/flutter was the most common type of arrhythmia accounting for 41%. Multivariate analysis showed that BTKi treatment was associated with a 4.3-fold (P<0.001) increased risk for arrhythmic event (P<0.001) compared with no treatment, whereas non-BTKi treatment was associated with a 2-fold (P<0.001) risk increase. Among subgroups, patients without a history of prior arrhythmia exhibited a pronounced increase in the risk for the development of arrhythmogenic cardiotoxicity (3.2-fold; P<0.001). Conclusions Our study identifies a high burden of arrhythmic events after initiation of treatment, which is most pronounced among patients treated with the BTKi ibrutinib. Patients undergoing treatments for lymphoma may benefit from prospective focused cardiovascular monitoring prior, during, and after treatment regardless of arrhythmia history.

Virological Markers in Epstein-Barr Virus-Associated Diseases.

Epstein-Barr virus (EBV) is an oncogenic virus infecting more than 95% of the world's population. After primary infection-responsible for infectious mononucleosis in young adults-the virus persists lifelong in the infected host, especially in memory B cells. Viral persistence is usually without clinical consequences, although it can lead to EBV-associated cancers such as lymphoma or carcinoma. Recent reports also suggest a link between EBV infection and multiple sclerosis. In the absence of vaccines, research efforts have focused on virological markers applicable in clinical practice for the management of patients with EBV-associated diseases. Nasopharyngeal carcinoma is an EBV-associated malignancy for which serological and molecular markers are widely used in clinical practice. Measuring blood EBV DNA load is additionally, useful for preventing lymphoproliferative disorders in transplant patients, with this marker also being explored in various other EBV-associated lymphomas. New technologies based on next-generation sequencing offer the opportunity to explore other biomarkers such as the EBV DNA methylome, strain diversity, or viral miRNA. Here, we review the clinical utility of different virological markers in EBV-associated diseases. Indeed, evaluating existing or new markers in EBV-associated malignancies or immune-mediated inflammatory diseases triggered by EBV infection continues to be a challenge.

αß and γδ T-cell responses to Epstein-Barr Virus: insights in immunocompetence, immune failure and therapeutic augmentation in transplant patients.

Epstein-Barr Virus (EBV) is a human gamma herpes virus, which causes several diseases in immunocompetent (mononucleosis, chronic fatigue syndrome, gastric cancer, endemic Burkitt's lymphoma, head and neck cancer) and immunosuppressed (post-transplant lymphoproliferative disease, EBV-associated soft tissue tumors) patients. It elicits a complex humoral and cellular immune response with both innate and adaptive immune components. Substantial progress has been made in understanding the interplay of immune cells in EBV-associated diseases in recent years, and several therapeutic approaches have been developed to augment cellular immunity toward EBV for control of EBV-associated malignancy. This review will focus on recent developments in immunosuppressed transplant recipients.

Rare diseases presenting with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. HLH is caused by a variety of factors and is classified into primary and secondary HLH. Familial HLH (FHL) types 1-5, X-linked lymphoproliferative syndrome types 1 and 2, and FHL syndrome with hypopigmentation are all examples of primary HLH. Secondary HLH, on the other hand, is linked to infections, malignant tumors, autoimmune diseases, and other diseases. The causes of HLH vary, and finding the underlying disease is critical for diagnosis and treatment. The majority of HLH is caused by the aforementioned conditions; however, approximately 10% of cases are caused by rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Novel IEI, such as RhoG, MAP kinase activating death domain, TIM3, and ZNFX1 deficiencies, have recently been identified as causes of HLH. IEM patients are rarely associated with HLH. Surprisingly, children with lysinuric protein intolerance and lysosomal acid lipase deficiency (Wolman disease) frequently develop HLH. This review focuses on the most recent knowledge of HLH caused by rare diseases such as IEI and IEM.

Successful Treatment of Central Nervous System Involvement in Posttransplant EBV-related Lymphoproliferative Disease With Intrathecal Rituximab Therapy.

The posttransplant lymphoproliferative disease is a severe cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Central Nervous System involvement in EBV-related PTLD is rare, and there is no standard treatment recommendation. We present our patient and discuss other previously reported cases of EBV-associated PTLD with CNS involvement.