Search Results (1,084)

[Background] Herpesvirus infections can induce diverse visual impairments with permanent sequelae, yet systematic data on their clinical spectrum and outcomes remain scarce. [Methods] We conducted a single-center retrospective cohort study at the Department of Neurology, Beijing Tongren Hospital, Capital Medical University. Thirteen consecutive patients (19 affected eyes) with herpesvirus-related visual impairment admitted between January 2016 and January 2025 were enrolled. Demographic data, clinical manifestations, etiological tests (polymerase chain reaction [PCR], metagenomic next-generation sequencing [mNGS], serology), neuroimaging, treatment regimens, and visual outcomes were analyzed. [Results] The cohort had a mean age of 50.4 years (range 31–66), with male predominance (84.6%, 11/13). Varicella zoster virus (VZV) was the leading pathogen (76.9%, 10/13), followed by herpes simplex virus type 1 (HSV-1), Epstein–Barr virus (EBV), and pseudorabies virus (PRV). Eight patients (61.5%) developed optic neuritis (ON) secondary to VZV infection, and five patients (38.5%) suffered from acute retinal necrosis (ARN), which was caused by VZV (n = 2), HSV-1 (n = 2), and PRV (n = 1). Bilateral involvement occurred in 46.2% (6/13) of patients. ARN was associated with the most severe visual loss. At the disease nadir, 46.2% of patients (6/13) presented with no light perception (NLP). Notably, five of these six NLP cases were diagnosed with ARN. Etiological confirmation was achieved in only 38.5% (5/13) of cases. mNGS of cerebrospinal and vitreous fluid, alongside aqueous humor PCR, are pivotal for diagnosing HSV-1/EBV mixed infections and rare PRV infection. All patients received antiviral therapy, 11 of whom (84.6%) were treated with intravenous antiviral agents. Glucocorticoids were administered as combination therapy to all patients. However, only one of eight VZV–ON eyes showed genuine visual improvement. In VZV–ARN, the initially involved eyes stayed NLP at final follow-up, while the fellow eyes recovered vision. Still, all non-VZV ARN patients had persistent bilateral NLP during follow-up. [Conclusions] Herpesvirus-associated visual impairment is dominated by VZV, manifests as ON or ARN, and carries a high risk of severe permanent vision loss—particularly in ARN. The emergence of zoonotic PRV underscores the need for heightened clinical vigilance. Diagnostic delays and insufficient interdisciplinary collaboration contribute substantially to poor outcomes. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and one of the most common hematological neoplasia. Entropy is a statistical measure of randomness that characterizes the texture of an input image and measures tissue complexity. Methods: Image processing and computer vision analysis were performed on a series of 114 diagnostic DLBCL cases and 44 reactive lymphoid tissues stained with hematoxylin and eosin (H&E). Histological entropy was measured to differentiate between reactive lymphoid tissue and DLBCL and predict clinical evolution. At protein level, immunohistochemistry analyzed Ki67, LMO2, MYC, MDM2, CDK6, E2F1, BCL2, CASP8, MYOB, TP53, cPARP, cCASP3, ISY1, TNFAIP8, CSF1R, CD163, PD-L1 and IL-10 markers. Gene expression analysis using the NanoString nCounter PanCancer Immune Profiling Panel was performed in 29 cases. Results: In comparison with reactive lymphoid tissue, DLBCL was characterized by lower entropy (7.32 ± 0.16 vs. 6.82 ± 0.44, respectively; p < 0.001). Within the DLBCL diagnostic category, higher entropy was associated with poor overall survival and death events within the first 2 years (hazard-risk = 2.4, p = 0.004) and lower entropy with a moderate and more favorable outcome (hazard-risk = 0.4, p = 0.004). High entropy was also correlated with ECOG performance status ≥ 2, lower protein expression of apoptosis markers of cPARP and cCASP3, and upregulation of specific immuno-oncology genes such as STAT3, BTK, CASP8, CD47, VCAM1, and MYD88. The prognostic value of entropy was independent of the international prognostic index (IPI), Epstein–Barr virus (EBER), and cell of origin (Hans). Conclusions: The histological evaluation of entropy is useful for the differential diagnosis of reactive lymphoid tissue and DLBCL and is a predictive factor of DLBCL prognosis. Full article

Epstein–Barr virus (EBV) is a highly prevalent oncogenic virus that establishes persistent infection in most of the human population and is strongly associated with several lymphoid and epithelial malignancies, particularly nasopharyngeal carcinoma, gastric carcinoma, and lymphoepithelial carcinoma. This review summarizes current knowledge on the relationship between EBV infection and apoptosis regulation in epithelial cancers, with emphasis on how viral persistence may contribute to tumor cell survival and therapeutic resistance. The manuscript reviews evidence on EBV genome organization, latent and lytic infection programs, the epidemiology of EBV-associated epithelial tumors, and the main intrinsic and extrinsic apoptotic pathways. It then discusses how viral proteins, including latent membrane proteins, Epstein–Barr nuclear antigen 1 (EBNA1), BHRF1, and BARF1, as well as EBV-encoded microRNAs, modulate key apoptotic regulators such as p53, Bcl-2 family members, death receptor pathways, and caspases. Current evidence indicates that EBV can promote apoptosis resistance through coordinated effects on mitochondrial and death receptor-mediated cell death. Understanding these mechanisms may help clarify the contribution of EBV to epithelial oncogenesis and support therapeutic strategies aimed at restoring apoptotic sensitivity in EBV-associated tumors. Full article

Gammaherpesviruses (GHVs) represent a global clinical burden as the causative agents of Kaposi’s sarcoma and mononucleosis, among other diseases. Kaposi’s sarcoma-associated herpesvirus (KSHV) and Epstein–Barr virus (EBV) are the most studied human GHVs, and murine gammaherpesvirus 68 (MHV-68) is a recognized experimental model. GHVs are defined by their modulation of the host cell to establish lifelong latent infections and increase host dysregulation during periodic reactivation. Due to their ubiquitous changes in host cells, systems-level techniques are well-suited to study GHV infections at all stages of the central dogma: genomics, transcriptomics, and proteomics. Furthermore, metabolomics can reveal the final metabolic changes across numerous host cellular pathways. This review assesses the current knowledge on GHV infections gained through omics techniques. We also identify gaps and propose future directions, including the development of new therapeutic strategies. Early omics techniques have characterized large swaths of infection for EBV, KSHV, and MHV-68, revealing conserved genes, homologous transcripts, and proteins. Modern omics techniques have enabled higher-resolution studies, yielding insights into heterogeneity in viral-host gene, transcript, and protein modulation strategies across geographical populations, viral subtypes, inter- and intra-patient infections, and latent and lytic states. The metabolome during GHV infections remains the least understood, but current studies have identified essential modulations of nucleotide, amino acid, and lipid synthesis by EBV, KSHV, and MHV-68. Importantly, the application of integrative omics methods to GHV infections remains a promising direction of study as the increased resolution of modern techniques meets the need for greater understanding of differences in each GHV infection. Full article

Background/Objectives: Pediatric acute-onset neuropsychiatric syndrome (PANS) describes the rapid onset of obsessive–compulsive symptoms or severe food restriction, accompanied by neuropsychiatric or somatic features that are not better explained by another disorder. PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) is a related, more narrowly defined construct in which symptoms are temporally associated with group A Streptococcus infection. This review examines clinical symptoms, infectious associations, proposed immune mechanisms, biomarker limitations, and treatment strategies for infection-associated PANS/PANDAS. Methods: A structured narrative search of PubMed/MEDLINE, Embase, the Cochrane Library, Google Scholar/publisher-indexed literature, ClinicalTrials.gov, and reference lists was performed up to 16 June 2026. Original cohorts, case series, systematic reviews, narrative reviews, consensus guidance, mechanistic studies, and registered prospective studies were prioritized. The review was not designed as a PRISMA-ScR scoping review; however, the methods were expanded to improve transparency and align with SANRA principles. Results: Group A Streptococcus remains the best characterized infectious association, although prospective studies have not uniformly demonstrated a consistent temporal relationship between streptococcal infection and neuropsychiatric exacerbations. Parent-reported surveys and case-based literature also describe temporal associations with Mycoplasma pneumoniae, influenza-like illnesses, upper respiratory infections, Borrelia burgdorferi, Epstein–Barr virus, and SARS-CoV-2. Proposed mechanisms include molecular mimicry, anti-D1R and anti-D2R antibodies, other antineuronal antibodies, calcium/calmodulin-dependent protein kinase II signaling, blood–brain barrier vulnerability, cytokine and Th17 effects, neuroinflammatory amplification, basal ganglia/CSTC circuit dysfunction, and gut–oral–brain immune interactions. None currently provides a definitive diagnostic biomarker. Conclusions: Infection-associated PANS is best approached as a clinically defined, heterogeneous neuroimmune presentation that requires rigorous differential diagnosis, multidisciplinary care, cautious treatment escalation, prospective biomarker validation, and large, multicenter treatment trials. Full article

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma endemic in children in regions of sub-Saharan Africa, where its incidence geographically overlaps holoendemic Plasmodium falciparum malaria and poorly controlled childhood Epstein–Barr virus (EBV) infection. Despite decades of research, the precise mechanistic synergy between these two pathogens remains incompletely defined. This review synthesizes current epidemiological, immunological, and molecular evidence to propose an integrated model for the etiology of endemic BL. We outline a paradoxical, dual-edged relationship wherein EBV infection during infancy may provide a short-term child survival advantage against severe malaria while simultaneously increasing the long-term oncogenic risk in B-cells infected by EBV. P. falciparum infection triggers polyclonal B-cell activation, increasing the probability of an activation-induced cytidine deaminase (AID)-mediated c-MYC translocation in proportion to the recurrent parasite burden. Concurrently, EBV expands within this B-cell pool and modulates the host immune response, potentially through viral interleukin-10 (vIL-10), to prevent lethal malarial inflammation. At the cellular level, EBV provides a critical “second hit” when it establishes latency I infection that rescues c-MYC-translocated B-cells from apoptosis. This framework explains why BL manifests as a “tumor of malaria survivors,” peaking in incidence years after the highest-risk period for malaria mortality. Ultimately, this model underscores that malaria control is a critical form of cancer control and highlights key future directions for validating these pathways in prospective clinical studies. Full article

Systemic chronic active Epstein–Barr virus disease (sCAEBV) is a rare and potentially fatal disorder characterized by inflammatory manifestations and organ infiltration by EBV-infected T- or NK-cells. Although [¹⁸F]FDG PET/CT has limited utility for assessing the disease activity of sCAEBV, [¹¹C]acetate PET/CT has not previously been evaluated in this setting. We therefore conducted this exploratory retrospective study to assess the utility of sequentially performed [¹¹C]acetate and [¹⁸F]FDG PET/CT in sCAEBV. Five patients diagnosed with sCAEBV according to the criteria of the Research Group on Measures against Intractable Diseases, Ministry of Health, Labour and Welfare of Japan (consistent with the 2017 WHO classification) and assessed between July 2017 and December 2018 were included; patients younger than 20 years were excluded. Each patient underwent both [¹¹C]acetate and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) on the same day. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the liver and spleen and the liver-to-spleen ratio (LSR) were correlated with laboratory parameters, including alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), using Spearman’s rank correlation coefficient. The LSR was compared between active and inactive cases using the Mann–Whitney U test. Twenty-one lymph node regions were assessed in each patient, and the SUVmax of detected lesions was measured. The detection rate of lymph node lesions between the two tracers was compared using McNemar’s test, and the SUVmax of lymph node lesions was compared between the two tracers and between active and inactive cases using the Mann–Whitney U test. All statistical analyses were performed using R version 4.5.3 (R Foundation for Statistical Computing, Vienna, Austria), and a p-value < 0.05 was considered statistically significant. Five patients (three men and two women; mean age 31.8 years, range 21–39 years) were included. [¹¹C]acetate PET/CT showed significant negative correlations between spleen SUV and liver enzymes (AST, ALT, and LDH), and significant positive correlations between the LSR and all five liver enzymes tested (AST, ALT, LDH, γGTP, and ALP) (Spearman’s rank correlation coefficient; p < 0.05 for all). No significant correlations were observed with [¹⁸F]FDG PET/CT. The LSR on [¹¹C]acetate PET/CT was numerically higher in active cases than in inactive cases, though this difference was not statistically significant (0.88 ± 0.02 vs. 0.61 ± 0.02; p = 0.20, Mann–Whitney U test). Lymph node lesion detectability did not differ significantly between the two tracers (16 vs. 12 regions; p = 0.13, McNemar’s test). In this pilot study, [¹¹C]acetate PET/CT spleen SUV showed significant negative correlations with liver enzymes (AST, ALT, and LDH), and the LSR showed significant positive correlations with all measured liver enzymes, suggesting that [¹¹C]acetate PET/CT reflects both hepatic and splenic involvement in sCAEBV. [¹¹C]acetate PET/CT may therefore serve as a novel imaging biomarker for assessing disease activity in sCAEBV, warranting further investigation in larger cohorts. Full article

Background: Gastric adenocarcinomas constitute a histologically and genomically heterogeneous group of cancers. The genomic classification of gastric cancers in four groups by The Cancer Genome Atlas (TCGA) has defined a framework for pathogenic discoveries. One of the groups is associated with infection by the gamma herpes virus Epstein–Barr virus (EBV) and represents a distinct subset of gastric cancers with potential therapeutic opportunities. Methods: The EBV-associated cancers from the TCGA gastric cancer cohort were analyzed to determine specific mutational and mRNA expression profiles that set these cancers apart from other gastric cancer subtypes. The cBioportal for Cancer Genomics site was used for downloading and analyzing the primary data. Results: EBV-associated cancers represented about 7% of the cohort. Mutations in the catalytic alpha subunit of PI3K kinase, PIK3CA, and the epigenetic modifiers ARID1A and BCOR were common. PIK3CA mutations were observed in 80% of EBV-associated cancers and frequently affected the hotspot codons E542 and E545. The few cases without PIK3CA mutations displayed frequent alterations in ERBB2 or in the regulatory unit of PI3K. EBV-associated cancers did not display excess cytidine to thymine (C>T) transitions compared with other gastric cancer genomic subtypes, as would be expected from the high genome methylation caused by the virus. In contrast, an increased rate of T to G (T>G) transversions was observed in EBV-associated cancers. Translesion polymerase eta (POLH), which produces a signature characterized by a preponderance of T>G, was up-regulated in EBV-associated gastric cancers and may be a contributing factor in this increase, up-regulated by wild-type p53 and over-expression of transcription factor IRF1. Conclusions: The data presented here suggest that mutagenesis in the EBV-associated gastric cancers is not a direct consequence of the virus-derived hypermethylation. Up-regulation of kinase PI3K and its pathway is a prerequisite for EBV transformation, and epigenetic alterations are frequently present, suggesting therapeutic avenues. Full article

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

The diversity and abundance of the brain virome is an active field of investigation. However, how the brain virome relates to the presence of viruses outside of the nervous system remains unclear. The rationale for this study is that analyses across multiple biologically linked compartments within the same individuals provide an important opportunity to evaluate virome discordance and viral burden. To characterize viral prevalence and burden across anatomical compartments, we applied the targeted viral enrichment method ViroFind to matched postmortem brain (n = 66), cerebrospinal fluid (CSF; n = 24), and peripheral samples (spleen, peripheral blood mononuclear cells, and lymph nodes; n = 66) from individuals with and without human immunodeficiency virus (HIV) infection and substance use disorder (SUD) in the National NeuroAIDS Tissue Consortium. We detected nucleic acids from 27 viruses representing 12 taxa. Several viruses, including adenovirus, torque teno virus, Epstein–Barr virus, human herpesvirus 6 and 7, cytomegalovirus, parvovirus, and JC polyomavirus, showed significant inter-compartment differences in prevalence or burden. CSF exhibited lower overall viral diversity than brain or peripheral samples, whereas peripheral samples showed the highest viral burden. CNS viral detection was more likely when the same virus was also detected in the periphery. We also detected HBV and HCV in CNS samples despite them not being classically regarded as neurotropic. Broader virome profiling showed greater peripheral viral burden and diversity in HIV-positive than HIV-negative individuals, whereas SUD was not associated with overall viral burden differences. These findings highlight important cross-compartment differences in viral detection, including occurrence of occult HBV infection within the CNS, and support the value of CNS–periphery comparisons in virome studies. These findings can contribute to improved diagnosis and management of viral infections. 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

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

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