Search Results (1,140)

Pediatric acute liver failure (PALF) is a rare but life-threatening condition characterized by rapid clinical deterioration and high mortality. Viral infections represent a major etiology of PALF, although the causative agent remains unidentified in a substantial proportion of cases. Human Enteroviruses (EVs) are typically associated with self-limiting illnesses; however, they may rarely cause severe systemic disease, including fulminant hepatitis, particularly in neonates and young children. We describe the case of a 4-year-old previously healthy male who presented with acute fulminant hepatitis secondary to systemic Echovirus 25 (E25) infection, with concomitant Epstein–Barr virus (EBV) co-infection of recent onset. The diagnosis was established through multiplex PCR on cerebrospinal fluid, blood, stool, and nasopharyngeal aspirate, with serotype confirmation by the Italian National Institute of Health. The patient required intensive supportive care including therapeutic plasma exchange (TPE), continuous kidney replacement therapy (CKRT), and intravenous immunoglobulins (IGIV). Despite initial clinical deterioration and placement on the liver transplant list, the patient achieved complete hepatic recovery and was discharged after fourteen days of hospitalization without requiring transplantation. This case highlights the importance of prompt virological workup including enterovirus PCR in children presenting with acute liver failure of undetermined etiology and supports the use of extracorporeal therapies as a bridge to recovery. Full article

Multiple sclerosis is an immune-driven neurological disease that affects myelinated axons in the central nervous system. However, the trigger of the (dysregulated) immune reactions is not known. According to Wilkin’s primary lesion theory, myelin-reactive T cells present in the immune repertoire hyper-react to myelin antigens that are released from idiopathic lesions within the central nervous system. However, neither the cause of the primary lesion nor the cause of the immune hyper-reactivity is known. We investigated whether these unknown activation signals may be relayed by common herpesviruses. In this concept paper, we propose the novel paradigm that the trigger of autoimmunity in MS comprises a conspiracy of three common herpesviruses: human herpesvirus-6A as a potential trigger of primary lesions due to its proven capacity to cause oligodendrogliopathy, cytomegalovirus as a trigger for the formation of effector memory cytotoxic T cells with proven capacity to induce multiple sclerosis pathology in a non-human primate MS model and Epstein-Barr Virus due to its capacity to render B cells capable to effectively present a critical myelin antigen to these effector memory cytotoxic T cells. Full article

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing a critical role in MS initiation and progression. Viral infections, especially by Epstein–Barr virus (EBV), have emerged as strong candidates and triggers of MS symptoms, through antibody-mediated molecular mimicry and B-cell dysregulation. In contrast, parasitic infections, including helminths and select protozoa, appear to exert neuroprotective effects by skewing immune responses toward regulation and tolerance. In this review, we examine antibody-driven mechanisms by which viral pathogens promote autoimmunity in MS and contrast these with parasite-induced immunoregulatory pathways that suppress pathogenic inflammation. We further discuss diagnostic and therapeutic implications, highlighting how insights from infectious immunology may inform novel strategies for MS treatment. Full article

Herpesvirus infections belong to major pathogens in the human population. This study aimed at evaluating diagnostic data for eight human herpesviruses, based on datasets derived from a large European tertiary care center. Specifically, we analyzed 118,692 herpesvirus submittals to the Diagnostic Division of the Virological Institute, University Hospital Erlangen (UKER), Germany, between July 2014 and June 2024. Our points of focus were the following: (i) the frequencies of herpesvirus diagnostic results with positivity rates, (ii) departments representing main sample submitters, (iii) the specific importance of intensive care units (ICUs), (iv) the COVID-19 pandemic period, and (v) distinct properties of sample types. Overall, we are stating the highest frequencies of diagnostic assessment for herpes simplex virus (HSV), human cytomegalovirus (HCMV), and Epstein–Barr virus (EBV) infections, pointing to their dominant relevance for clinical practice. Notably, HCMV submittals (46.6% of total), together with EBV (26.2%) and HSV (15.7), accounted for almost 90% of all herpesviral diagnostic samples during this period. Within these key groups, HCMV, EBV and HSV showed positivity rates of 14.5%, 35.0%, and 18.5%, respectively. Concerning a main input of sample submittals, two departments were predominant in our center, i.e., the Departments of Haematology–Oncology and Anaesthesiology. These included patients under multifold types of treatment associated with an increased risk of herpesvirus reactivation or primary infection. Furthermore, another high portion of submittals was noted for ICUs and external sources. In addition, a numerical, transient increase in herpesvirus diagnostic submittals, from various sources, was shown for the COVID-19 pandemic years (mostly 2021) as compared to other periods. Combined, these data underlined the importance of clinical monitoring of herpesvirus infections, particularly for high-risk patients, and the steady need of improvements in preventive measures, therapeutic options, and safe diagnostic tools. Full article

Neuroinflammation in multiple sclerosis (MS) is driven by the infiltration of myelin-reactive T cells into the central nervous system (CNS). Interferon-β (IFN-β) is one of the earliest disease-modifying treatments (DMTs) approved for MS and remains widely used in special populations (pregnant and elderly patients) owing to its favorable safety profile. However, the exact mechanism of action of this drug and reliable biomarkers of treatment response remain unclear. Transcriptomic profiling and data integration approaches offer powerful tools for investigating complex patterns of regulation and molecular mechanisms underlying therapeutic efficacy. In this study, we performed an integrative analysis of openly available transcriptomic datasets to characterize IFN-β-induced gene expression changes in MS patients. By combining data from large independent cohorts, we identified a 43-gene transcriptional signature consistently associated with IFN-β treatment across disease stages, including progressive MS. To explore the relevance of this signature, we cross-referenced the 43-gene signature with publicly available expression quantitative trait loci (eQTL) datasets to determine whether these genes could be influenced by known MS-associated risk variants highlighting Interferon-Induced Transmembrane Protein 3 (IFITM3) as a candidate molecular mediator of MS. This integrative approach provides new insights into IFN-β-driven immune modulation and supports the development of therapeutic strategies for MS. Full article

In Argentina, a high incidence of EBV-associated lymphomas was demonstrated in young children. Natural killer (NK) cells, particularly, IFN-γ-producing CD56bright NK cells, have been reported to play a key role in asymptomatic EBV infection in children, restricting viral-mediated transformation. In order to analyze NK cell characteristics in children with primary and persistent EBV infection, along with EBV+ Hodgkin lymphoma (HL) from Argentina, a cohort of EBV-infected pediatric patients was analyzed. A scarcity of CD56+ cells, as an indirect marker of NK cells, across all tonsillar samples and pediatric classical Hodgkin lymphoma cases was observed, with no significant differences according to EBV status. In primary infection, CD56+ cells showed a positive correlation with IFNγ+ cells, suggesting a role in early antiviral responses. Flow cytometry revealed an increased proportion of CD56bright NK cells in EBV-infected children, particularly in cases expressing latency II/III antigens. A significantly higher IFN-γ production was observed in CD56bright cells in children with primary infection compared with healthy carriers, along with an inverse correlation between IFN-γ production and CD56bright cells in healthy carriers. These findings suggest that NK cells may contribute to immune control predominantly during primary infection, whereas their role appears limited in healthy carriers and in EBV-associated Hodgkin lymphoma. Full article

Rapid urbanization exerts profound pressure on urban biodiversity, yet long-term assessments integrating multi-source remote sensing data remain scarce. Objective: Focusing on the Hangzhou Bay Urban Agglomeration, a rapidly developing region in China’s Yangtze River Delta, this study aims to construct a remote sensing-based Biodiversity Index (BI) and analyze its spatiotemporal evolution and underlying drivers. Six Essential Biodiversity Variables derived from satellite observations (2000–2024) were integrated using Principal Component Analysis. Spatial autocorrelation and Geodetector models were then applied to examine BI dynamics and driving factors. The regional BI declined gradually from 0.80 in 2000 to 0.72 in 2024, with the rate of decline slowing after 2020 and a partial recovery observed in Zhoushan. Marked inter-city heterogeneity exists: Huzhou retains the highest and most stable BI due to extensive forest cover, whereas Jiaxing exhibits the lowest BI and the most pronounced decline, driven by rapid expansion of construction land. Land use/cover (LULC) and fractional vegetation cover (FVC) emerge as the dominant drivers (average q-values of 0.196 and 0.208, respectively), and their interaction explains over 46% of the spatial variance in BI. Road density shows a consistently increasing influence over time. This study demonstrates the utility of remote sensing-based frameworks for monitoring urban biodiversity dynamics and provides actionable insights for evidence-based land use planning and ecological restoration. Full article

Epstein–Barr virus (EBV) lytic reactivation contributes to the pathogenesis of EBV-associated epithelial malignancies, including nasopharyngeal carcinoma and gastric carcinoma, highlighting the need for therapeutic strategies targeting viral reactivation. Capsaicin exhibits anticancer and antiviral activities; however, its effects on EBV lytic reactivation remain unclear. This study investigated the effects of capsaicin on EBV lytic reactivation in EBV-positive epithelial cancer models. Capsaicin significantly suppressed the expression of lytic genes, including BZLF1, BRLF1, BMRF1, and BLLF1, and reduced EBV virion production. Proteomic analysis revealed alterations in host cellular pathways associated with metabolism, chromatin organization, and cytoskeletal regulation, whereas metabolomic profiling demonstrated perturbations in nucleotide, amino acid, and polyamine metabolism processes involved in viral DNA replication and protein synthesis. Protein–protein interaction network analysis identified key host proteins, including HSP90AB1, MYH9, and ANXA2, implicated in metabolic reprogramming, cytoskeletal organization, and stress responses. Moreover, upstream regulators associated with EBV lytic activation, including p65, AP-1, HIF-1α, and SP1, were down-regulated following capsaicin treatment. Collectively, these findings demonstrate a multitarget inhibitory effect of capsaicin on EBV lytic reactivation and support its therapeutic potential against EBV-associated epithelial malignancies. Full article

Therapeutic vaccines are a key strategy to achieve the goal of “functional cure” of chronic viral infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human papillomavirus (HPV), and Epstein–Barr virus (EBV). Various platforms (such as viral vectors, nucleic acid vaccines, recombinant proteins, etc.) have successfully induced strong virus-specific T-cell responses in early trials, but their clinical efficacy is still limited by the immunosuppressive environment formed by the host. The core bottlenecks are severe T-cell exhaustion, viral immune escape, and various forms of local immune tolerance. Therefore, the field is moving toward combination therapies, including reduction of viral load, targeting of immune activation, and inhibition of inhibitory signaling pathways. This article summarizes the preclinical and clinical progress of therapeutic vaccines in the past decade, analyzes the major challenges in vaccine development, and discusses the future development directions in this field. Full article

Post-transplant lymphoproliferative disorder (PTLD) involving the central nervous system (CNS) is a rare but serious life-threatening complication seen in recipients of solid organ transplant. Primary CNS encompasses 5–15% of all types of PTLD diagnoses, and heart transplant recipients represent 3–5% of those reported cases. Diagnosis is often delayed due to the highly variable presentation, with some cases remaining undiagnosed for years. Multidisciplinary collaboration is crucial for early diagnosis and management. A 53-year-old woman patient presented with altered mental status. MRI revealed nodular ventriculitis and bilateral periventricular hyperdense infiltrates. CSF studies demonstrated lymphocytic pleocytosis, elevated protein, and EBV-PCR-positive results. A stereotactic brain needle biopsy confirmed the presence of EBV-positive diffuse large B-cell lymphoma, consistent with primary CNS PTLD, 14 months after her heart transplant. Despite appropriate management, the patient experienced progressive neurological decline and ultimately suffered a fatal intracerebral hemorrhage. We demonstrate the importance of the early diagnosis and variable presentation of post-heart-transplant PTLD. The importance of surveillance regardless of EBV status and close monitoring of disease progression due to potential life-threatening complications, such as fatal hemorrhages. Therefore, primary CNS-PTLD remains a challenging disease and is being increasingly recognized with improved transplant recipient survival and prolonged exposure to chronic immunosuppression. Full article

Inborn errors of immunity, including primary immunodeficiency disorders (PIDs), comprise a heterogeneous group of genetic conditions characterized by immune system dysfunction. One such rare PID is CD137 deficiency, which results from TNFRSF9 mutations. CD137, also known as 4-1BB, plays a pivotal role in immune system regulation and co-stimulation. This literature review explores CD137 deficiency and its implications, emphasizing its association with EBV-associated lymphoproliferative disease and potential therapeutic targets. We present the case of a 21-year-old female patient with CD137 deficiency who experienced recurrent infections, autoimmunity, and lymphoma. Genetic analysis revealed that the patient had a homozygous TNFRSF9 variant. The patient subsequently developed severe Epstein–Barr virus (EBV)-associated lymphoproliferative disease, which is one of the clinical manifestations associated with CD137 deficiency. Additionally, this review discusses similar cases in the literature and details the clinical manifestations and immune abnormalities associated with CD137 deficiency. Understanding the genetic complexity of CD137 deficiency and the immune system dysregulation it causes provides insights into potential therapeutic interventions for affected individuals. This review highlights the role of CD137 as a crucial regulator of immune homeostasis and a potential target for immunotherapy in autoimmune diseases and malignancies. Full article

Cutaneous hematologic neoplasms in children are relatively rare and encompass a wide range of lymphoproliferative and myeloproliferative disorders. This review explores and updates the classification, clinical presentation, diagnostic challenges, histopathology, and management of pediatric lymphomas, lymphoproliferations, and leukemias that may be seen in the skin. The most frequent of them are lymphomatoid papulosis (LyP) and mycosis fungoides (MF), and are discussed first, with a particular focus on differential diagnosis and overlaps with benign lesions—mainly pityriasis lichenoides—which raises questions regarding the delineation of these entities and their potential interconnection. It is important to underline that most cutaneous lymphoproliferations are indolent in children: primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, subcutaneous panniculitis-like T-cell lymphoproliferation (non-associated with HAVCR2 mutations), primary cutaneous marginal zone lymphoproliferative disorder, and EBV-related lymphoproliferative disorders. However, aggressive hematologic malignancies, although rarer, must not be missed; these are mostly leukemias (but not all forms) and blastic plasmacytoid dendritic cell neoplasm. We emphasize the importance of clinical–pathological correlation, with clonality studies playing a crucial role in some cases. Management strategies are briefly reviewed, ranging from skin-directed therapies like phototherapy and corticosteroids to systemic treatments for more aggressive forms of leukemia cutis and lymphomas. Full article

Type 2 diabetes is a multifactorial metabolic disease characterized by chronic hyperglycemia, insulin resistance, and persistent low-grade inflammation. All of these factors lead to dysregulation of the immune system. Of particular interest is the interaction between immune dysregulation in type 2 diabetes and oncogenic viruses such as Human papillomavirus (HPV) and Epstein–Barr virus (EBV), which play an essential role in the etiology of Head and neck cancer on the one hand and have mechanisms for escaping the immune response on the other. The aim of the present study is to perform an analysis of patients with head and neck cancer divided into two groups, with and without diabetes, aimed at studying the relationship between type 2 diabetes and the established viral status. It was found that for all viruses proven by us, the frequency of positive tests for them was higher in the group with type 2 diabetes compared to the group of patients without diabetes. The study provides new insights and suggestions for a significant association between type 2 diabetes mellitus, increased prevalence of EBV, and some low-risk HPV genotypes in patients with head and neck tumors. Continuing from our previous study, the association between EBV and HPV44, after strict statistical adjustment, highlights their potential biological and clinical significance within the oncogenic environment in the presence of type 2 diabetes. Full article

Chronic obstructive pulmonary disease remains a leading cause of death worldwide, with emphysema contributing significantly to dyspnea, exercise limitation, and mortality. Bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBVs) has emerged as a minimally invasive, reversible alternative to lung volume reduction surgery for carefully selected patients with severe emphysema who remain symptomatic despite optimal medical therapy. EBVs are one-way valves placed bronchoscopically to achieve complete lobar occlusion, inducing atelectasis of the most diseased lung segments while allowing better ventilated parenchyma to expand, thereby improving respiratory mechanics and reducing hyperinflation. Landmark randomized controlled trials demonstrated that BLVR using EBVs produces significant improvements in forced expiratory volume in one second (FEV₁), exercise capacity, and quality of life comparable to surgical lung volume reduction but with reduced morbidity and mortality. Critical to treatment success is meticulous patient selection based on emphysema distribution, absence of collateral ventilation, and appropriate physiologic parameters. Pneumothorax represents the most common serious complication, occurring in approximately 26% of patients, though paradoxically, it indicates successful lobar occlusion and predicts favorable long-term outcomes. As the most extensively studied BLVR, endobronchial valve therapy represents a cornerstone intervention for appropriately selected patients with severe emphysema. Full article

Recent research suggests a link between EBV and brain cancer, especially in high-grade gliomas, but its role has not been sufficiently elucidated. Therefore, we evaluated its occurrence in brain cancer. For this purpose, the EBV DNA and LMP-1 in tumor tissue, the level of viral load in the cerebrospinal fluid (CSF), and the serological status of patients were analyzed. We detected EBV DNA in 28.9% (42/145) of glioma samples, among which 28 were isolated from glioblastomas (GBs) and 14 from other gliomas. LMP-1 was detected in 26 (92.8%) GB samples and 5 (35.7%) samples from other gliomas. The EBV DNA load in the CSF was significantly higher in GB compared to other gliomas; anti-EBNA1, anti-EBVCA, anti-EA, and anti-Zta antibodies were detected in the serum of GB patients; and their concentration was higher in GB patients. Further research is needed to determine whether and to what extent EBV contributes to glioma development. Elucidating the role of latent EBV genes synthesized in glioblastoma is important for understanding the role of viral infection in cancer development and progression in this hitherto poorly studied area. Full article