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In this narrative review, we explore the burden and risk factors of various herpesvirus infections in patients receiving chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibodies (BsAb) for the treatment of hematologic malignancies. Antiviral prophylaxis for herpes simplex/varicella zoster viruses became part of the standard of care in this patient population. Breakthrough infections may rarely occur, and the optimal duration of prophylaxis as well as the timing of recombinant zoster immunization remain to be explored. Clinically significant cytomegalovirus (CMV) infections can affect up to 10% of patients after CAR-T, depending on the CAR-T product target, post-CAR-T complications such as cytokine release syndrome and the need for glucocorticoid therapy. Surveillance and prophylactic strategies for CMV need to be developed, whereas the risk factors for and the burden of CMV infections after BsAb are not yet well-defined. Human herpes virus 6 reactivation and end organ disease such as encephalitis are rarely reported after CAR-T and have not yet been reported after BsAb; additional research is needed. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review examines the role of different viral infections in epileptogenesis, with a focus on Herpesviruses such as Human Herpesvirus 6 (HHV-6) and Epstein Barr Virus (EBV), Flaviviruses, Picornaviruses, Human Immunodeficiency Virus (HIV), Influenzavirus and Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Recent Findings: A growing literature on animal models, such as the paradigmatic Theiler's murine encephalomyelitis virus (TMEV) model, and clinical investigations in patients with epilepsy have started to elucidate cellular mechanisms implicated in seizure initiation and development of epilepsy following viral infections. A central role of neuroinflammation has emerged, with evidence of activation of the innate and adaptive immunity, dysregulation of microglial and astrocytic activity and production of multiple cytokines and other inflammatory mediators. Several chronic downstream effects result in increased blood–brain barrier permeability, direct neuronal damage, and modifications of ion channels ultimately leading to altered neuronal excitability and seizure generation. Summary: Key findings underscore the complex interplay between initial viral infection, neuroinflammation, and later development of epilepsy. Further research is needed to elucidate these mechanisms and develop targeted interventions. [ABSTRACT FROM AUTHOR]

The Epstein-Barr viwrus (EBV) is a common herpesvirus that affects more than 90% of people worldwide. Even while EBV infections are frequently asymptomatic, they can cause autoimmune diseases and a number of cancers, especially in those with impaired immune systems. The intricate relationships between EBV and other coinfecting pathogens, including as human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), and Plasmodium species, are examined in this study. We investigated the fundamental processes of these coinfections, their effects on the course of the disease, and their practical ramifications. The study reviewed how co-infections with EBV might modify immune responses, promote oncogenesis, and make treatment plans more challenging. In this review, we also discussed current therapeutic strategies, such as targeted molecular interventions, EBV vaccines, and adoptive T-cell therapy. The review underscores the need for more research to provide more focused and effective therapies that address the mutually reinforcing effects of numerous infections in disorders linked with EBV. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a chronic disorder characterized by widespread musculoskeletal pain often accompanied by fatigue, sleep disturbances, memory issues, and mood disorders. The exact cause of FM remains unknown, and diagnosis is typically based on a history of persistent widespread pain, as there are no objective biomarkers usable in diagnosis of this disorder available. The aim of this study was to identify measurable indicators specific to FM with potential as biomarkers. This study included 17 individuals diagnosed with FM and 24 apparently healthy persons. Using real-time polymerase chain reaction (qPCR), we detected the presence of human herpesvirus (HHV)-6A and B genomic sequences in DNA isolated from peripheral blood mononuclear cells (PBMCs) and buccal swabs. HHV-6-specific IgG and IgM class antibodies, along with proinflammatory cytokine levels, were measured using enzyme-linked immunosorbent assay (ELISA) and bead-based multiplex assays. Additionally, the gut microbiome was analyzed through next-generation sequencing. HHV-6B was more frequently detected in the PBMCs of FM patients. FM patients with a body mass index (BMI) of 30 or higher exhibited elevated cytokine levels compared to the control group with the same BMI range. Gut microbiome analysis revealed significant differences in both α-diversity and β-diversity between the FM and control groups, indicating a shift in species abundance in the FM group. [ABSTRACT FROM AUTHOR]

Background: Human herpesvirus 6 (HHV-6) is considered a ubiquitous virus, with many countries reporting a seroprevalence of more than 80–90% among the general population. However, this virus is unique among herpesviruses in its ability to integrate into the genetic material of the host's cells. Thus, there are three ways by which HHV-6 can cause an active infection–primary infection, reactivation of a latent acquired infection, or activation of iciHHV-6 (inherited chromosomally integrated HHV-6). Whole blood quantitative polymerase chain reaction (qPCR) is very useful in distinguishing between iciHHV-6 and primary infection/reactivation. Our aim is to assess the role of HHV-6 in the aetiology of central nervous system (CNS) infections in adults and children, to describe all HHV-6-positive cases in an attempt to determine the susceptible population and to identify potential risk factors that can be linked to HHV-6 meningoencephalitis. Methods: We performed a retrospective study involving patients that were admitted to Prof. Dr. Matei Bals National Institute of Infectious Diseases, Bucharest, Romania, with a diagnosis of meningitis or encephalitis. We only selected the clinical records of patients that had a multiplex PCR Biofire® FilmArray® meningitis/encephalitis panel. Results: We report a 5% HHV-6 positivity in the cerebrospinal fluid (CSF) of patients with CNS infections tested with a commercial multiplex PCR M/E (meningitis/encephalitis) panel. Additionally, 2% to 4% of the total study population (n = 100) had active HHV-6 infections, which denotes 40 to 80% of the HHV-6-positive samples. We did not observe any statistically significant correlation between HHV-6 positivity in the CSF and variables such as age, sex, or comorbidities, including obesity, diabetes, hypertension, immunosuppression, or oncologic disease. Therefore, no risk factors could be linked with HHV-6 positivity in the CSF. Conclusions: although multiplex qualitative PCR is highly useful for providing rapid results and identifying nearly every pathogen that can cause meningitis/encephalitis, we have to be aware of this type of test's limitations. All patients with HHV-6 detectable in their CSF via a multiplex PCR test should also undergo qPCR testing from both CSF and blood to prevent over-diagnosing HHV-6 CNS infections, to avoid unnecessary antiviral treatments, and ensure the accurate identification of the true diagnosis. [ABSTRACT FROM AUTHOR]

The Epstein-Barr viwrus (EBV) is a common herpesvirus that affects more than 90% of people worldwide. Even while EBV infections are frequently asymptomatic, they can cause autoimmune diseases and a number of cancers, especially in those with impaired immune systems. The intricate relationships between EBV and other coinfecting pathogens, including as human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), and Plasmodium species, are examined in this study. We investigated the fundamental processes of these coinfections, their effects on the course of the disease, and their practical ramifications. The study reviewed how co-infections with EBV might modify immune responses, promote oncogenesis, and make treatment plans more challenging. In this review, we also discussed current therapeutic strategies, such as targeted molecular interventions, EBV vaccines, and adoptive T-cell therapy. The review underscores the need for more research to provide more focused and effective therapies that address the mutually reinforcing effects of numerous infections in disorders linked with EBV.

Robert J Petrella1– 6 1Harvard Medical School, Boston, MA, USA; 2Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA; 3Emergency Departments, CharterCARE Health Partners, Providence and North Providence, RI, USA; 4Emergency Department, Boston VA Medical Center, Boston, MA, USA; 5Emergency Departments, Steward Health Care Systems, Boston and Methuen, MA, USA; 6Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USACorrespondence: Robert J Petrella, Email robertjpetrella@yahoo.comAbstract: Sixth Disease (roseola infantum) and its primary causative agent, HHV-6, share names that numerically concur. This article examines and answers the question of whether that correspondence is by design or coincidental by briefly reviewing the history and nomenclature of the HHV viruses and the classic febrile rashes of childhood while highlighting some clinical and microbiologic features of HHV-6 infection.Keywords: HHV-6, HHV-7, human herpesviruses, roseola infantum, sixth disease, Kawasaki disease, viral taxonomy, nomenclature, emergency medicine, historical coincidence

Alzheimer's disease (AD) is a real and current scientific and societal challenge. Alzheimer's disease is characterised by a neurodegenerative neuroinflammatory process, but the etiopathogenetic mechanisms are still unclear. The possible infectious aetiology and potential involvement of Herpes viruses as triggers for the formation of extracellular deposits of amyloid beta (Aβ) peptide (amyloid plaques) and intraneuronal aggregates of hyperphosphorylated and misfold could be a possible explanation. In fact, the possible genetic interference of Herpes viruses with the genome of the host neuronal cell or the stimulation of the infection to a continuous immune response with a consequent chronic inflammation could constitute those mechanisms underlying the development of AD, with possible implications in the understanding and management of the disease. Herpes viruses could be significantly involved in the pathogenesis of AD and in particular, their ability to reactivate in particular conditions such as immunocompromise and immunosenescence, could explain the neurological damage characteristic of AD. Our review aims to evaluate the state of the art of knowledge and perspectives regarding the potential relationship between Herpes viruses and AD, in order to be able to identify the possible etiopathogenetic mechanisms and the possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Recent studies have focused on the role of human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) in PR etiology with varying results. In our study, with the approach that the discrepancy between the results may be related to the different samples and techniques used, we aimed to clarify the etiology by examining tissue and plasma samples using molecular methods and evaluating the results together with serological parameters. Skin biopsies and plasma samples of twenty-five PR patients were tested to detect HHV-6 and HHV-7 DNA using calibrated quantitative real-time polymerase chain reaction (CQ RT-PCR). IgG and IgM antibodies against HHV-6 and HHV-7 were tested by enzyme-linked immunosorbent assay and indirect immunofluorescence. Of the patient group, 64% were positive for HHV-6 IgG without IgM positivity. HHV-6 DNA was present in seven tissue and ten plasma samples. HHV-7 positivity was 100% and 12% for IgG and IgM antibodies, respectively. HHV-7 DNA was detected in four tissue samples and one plasma sample. Patients with HHV-7 DNA-positive plasma and tissue samples had also HHV-7 IgM antibodies. In conclusion, our results seem to support the role of HHV-6/HHV-7 in the etiology of PR. To clarify the etiology of PR and avoid confusion, the collection of different biological materials simultaneously and the usage of CQ RT-PCR as a diagnostic technique are recommended. [ABSTRACT FROM AUTHOR]

HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease—this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations. [ABSTRACT FROM AUTHOR]

Study objective: to evaluate frequency of CMV, HHV-6, and EBV reactivation in children within 60 days after HSCT.Materials and methods: The study was carried out in Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology, and Transplantation of the Pavlov First Saint Petersburg State Medical University We analyzed 95 medical records of pediatric patients who underwent HSCT in 2021. Pretransplant serostatus for CMV, EBV, HHV-6 was studied, as well as the frequency and timing of virus reactivation after transplantation. In the prospective part, 35 children aged from 1 to 17 years were enrolled. The pretransplant evaluation included detection of anti-CMV, anti-HHV-6, and anti-EBV IgM and IgG by ELISA, and blood PCR for viremia. DNA of herpes viruses was identified by quantitative blood PCR on the day of HSCT, and then 10, 20, 30 and 60 days after HSCT. The number of viral DNA copies was calculated per 105 cells. Statistical analysis was carried out using SPSS Statistics 22 software package.Results: On pre-transplant evaluation, 47 of 95 pediatric patients were tested for CMV with positive result in 36 children, 27 patients were tested for EBV and 17 were positive. HHV-6 DNA was detected in 3 of 25 patientsMostly, reactivation of herpes viruses occurred in the early period up to 60 days. HHV-6 reactivation was observed on average 25±4 days after transplantation, significantly earlier than for CMV and EBV.In a prospective study, reactivation of CMV, HHV-6, and EBV was revealed in 28 (80%) patients within 60 days of transplantation, with a maximum number of patients in 20 days after HSCT.A trend toward an increase in CMV and HHV-6 concentration in blood was observed on days 10 and 20 after HSCT, with a maximum viral load of HHV-6 and minimal EBV replicative activity. Clinically significant manifestations of herpesvirus infection were diagnosed in 19 (54.3%) patients.Conclusion: High seropositivity for CMV and EBV was revealed in children before transplantation. Herpes viruses reactivation occurs early in post-transplant period, on the 20th day after HSCT, HHV-6 in forms of mono- and mixed infection predominates with a trend toward increasing viral load.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.

ABSTRACTThe aim of this study was to compare the performance of the newly developed SMG HHV-6 Q Real-Time PCR Kit (SMG assay) with the RealStar HHV-6 PCR Kit (RealStar assay). The analytical sensitivity and specificity, linearity, and precision of the SMG assay were evaluated. The clinical performance of the SMG assay was assessed and compared with that of the RealStar assay using 207 clinical specimens (HHV-6A positive, n = 51; HHV-6B positive, n = 64; HHV-6A/B negative, n = 92). The limit of detection of the SMG assay was 2.92 log10 copies/mL for HHV-6A DNA and 2.88 log10 copies/mL for HHV-6B DNA. The linear range was determined to be 3.40–9.00 log10 copies/mL for both viruses. Intra- and inter-assay variability were below 5% at concentrations ranging from 4 to 9 log10 copies/mL. No cross-reactivity was observed with the 25 microorganisms included in the specificity panel. The clinical sensitivity and specificity of the SMG and RealStar assays compared to in-house polymerase chain reaction and sequencing were as follows: SMG assay, 98.0% and 100% for HHV-6A DNA, respectively, and 96.9% and 100% for HHV-6B DNA, respectively; RealStar assay, 98.0% and 100% for HHV-6A DNA, respectively, and 90.6% and 100% for HHV-6B DNA, respectively. The correlation coefficients between viral loads measured by the two assays were 0.948 and 0.975, with mean differences of 0.62 and 0.32 log10 copies/mL for HHV-6A and HHV-6B DNA, respectively. These results demonstrate that the SMG assay is a sensitive and reliable tool for the quantitative detection and differentiation of HHV-6A and HHV-6B DNA.IMPORTANCEQuantitative real-time PCR (qPCR) that can distinguish between HHV-6A and HHV-6B DNA is recommended for diagnosis of active infection. The SMG HHV-6 Q Real-Time PCR Kit (SMG assay) is a newly developed qPCR assay that can differentiate between HHV-6A and HHV-6B DNA; however, little is known about its performance. In this study, we assessed the performance of the SMG assay and compared it with that of a commercially available qPCR assay, the RealStar HHV-6 PCR Kit (RealStar assay). The SMG assay demonstrated excellent analytical sensitivity and specificity, precision, and linearity. Furthermore, the viral loads measured by the SMG assay were highly correlated with those measured by the RealStar assay. Our results suggest that the SMG assay is a useful diagnostic tool for quantitative detection and differentiation of HHV-6A and HHV-6B DNA.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction where patients present with fever, morbilliform rash and multiorgan manifestations, which may include acute renal failure, acute respiratory distress syndrome and eosinophilic myocarditis. We present a case of a 60‐year‐old woman with acute heart failure, DRESS syndrome features and human herpesvirus 6 reactivation in the absence of a drug trigger. She was diagnosed with eosinophilic myocarditis and successfully treated with corticosteroid therapy. [ABSTRACT FROM AUTHOR]

Objective: To describe the use of cidofovir (CDV) for viral infections in immunocompromised children (IC) and provide guidance on dosing and supportive care. Data Sources: A PubMed search was conducted for literature published between 1997 and January 2022 using the following terms: cidofovir, plus children or pediatrics. Study Selection and Data Extraction: Limits were set to include human subjects less than 24 years of age receiving intravenous (IV) or intrabladder CDV for treatment of infections due to adenovirus, polyomavirus-BK (BKV), herpesviruses, or cytomegalovirus. Data Synthesis: Data were heterogeneous, with largely uncontrolled studies. Conventional dosing (CDV 5 mg/kg/dose weekly) was commonly used in 60% (31/52) of studies and modified dosing (CDV 1 mg/kg/dose 3 times/week) was used in 17% (9/52) of studies, despite being off-label. Nephrotoxicity reported across studies totaled 16% (65/403 patients), which was higher for conventional dosing 29 of 196 patients (15%) than modified dosing 1 of 27 patients (4%). Saline hyperhydration and concomitant probenecid remain the cornerstones of supportive care, while some regimens omitting probenecid are emerging to target BKV. Relevance to Patient Care and Clinical Practice: To our knowledge, this is the first comprehensive review of CDV use (indications, dosing, supportive care, response, and nephrotoxicity) in pediatric IC. Conclusions: Effective utilization of CDV in IC remains challenging. Further prospective studies are needed to determine the optimal CDV dosing; however, less aggressive dosing regimens such as modified thrice weekly dosing or low dosing once weekly omitting probenecid to enhance urinary penetration may be reasonable alternatives to conventional dosing in some IC. [ABSTRACT FROM AUTHOR]

The complexity of autoimmunity initiation has been the subject of many studies. Both genetic and environmental factors are essential in autoimmunity development. Among others, environmental factors include infectious agents. HHV-6 is a ubiquitous human pathogen with a high global prevalence. It has several properties suggestive of its contribution to autoimmunity development. HHV-6 has a broad cell tropism, the ability to establish latency with subsequent reactivation and persistence, and a range of immunomodulation capabilities. Studies have implicated HHV-6 in a plethora of autoimmune diseases—endocrine, neurological, connective tissue, and others—with some studies even proposing possible autoimmunity induction mechanisms. HHV-6 can be frequently found in autoimmunity-affected tissues and lesions; it has been found to infect autoimmune-pathology-relevant cells and influence immune responses and signaling. This review highlights some of the most well-known autoimmune conditions to which HHV-6 has been linked, like multiple sclerosis and autoimmune thyroiditis, and summarizes the data on HHV-6 involvement in autoimmunity development. [ABSTRACT FROM AUTHOR]

Background and Aims: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). MS results from an inflammatory process leading to the loss of neural tissue and increased disability over time. The role of Epstein Barr Virus (EBV), as one of the most common global viruses, in MS development has been the subject of several studies. However, many related questions are still unanswered. This study aimed to review the connection between MS and EBV and provide a quick outline of MS prevention using EBV vaccination. Methods: For this narrative review, an extensive literature search using specific terms was conducted across online databases, including PubMed/Medline, Scopus, Web of Science, and Google Scholar, to identify pertinent studies. Results: Several studies proved that almost 100% of people with MS showed a history of EBV infection, and there was an association between high titers of EBV antibodies and an increased risk of MS development. Various hypotheses are proposed for how EBV may contribute to MS directly and indirectly: (1) Molecular Mimicry, (2) Mistaken Self, (3) Bystander Damage, and (4) Autoreactive B cells infected with EBV. Conclusion: Given the infectious nature of EBV and its ability to elude the immune system, EBV emerges as a strong candidate for being the underlying cause of MS. The development of an EBV vaccine holds promise for preventing MS; however, overcoming the challenge of creating a safe and efficacious vaccine presents a significant obstacle. [ABSTRACT FROM AUTHOR]

A comparison of the presence frequency of herpes viruses HSV1/2, VZV, HHV-6, HHV-7, EBV, CMV was conducted in 430 patients with classical trigeminal neuralgia (TN) using RT PCR method. In the venous blood of patients with paroxysmal pain syndrome (TNP) and persistent background pain (TNB), herpes viruses were detected in 36.3% (97/267) and 80.4% (131/163) cases, respectively. The effectiveness of microvascular decompression and long-term outcomes were assessed depending on the presence of herpes viruses. Pain syndrome completely regressed in 404 out of 430 patients (93.9%), partially in 25 patients (5.8%), and persisted in 1 patient (0.2%). In TNB group, pain recurrence and partial regression were observed more frequently (20.2% (34/163) and 12.8% (21/163), respectively) if compared to TNP group (1.8% (5/267) and 1.5% (4/267), respectively). Complete pain regression in TNB group was less than in TNP group: 86.5% (141/163) and 98% (263/267), respectively. The presence of herpes viruses in patients with TN, a higher frequency of detection of herpes viruses, as well as a higher percentage of patients with recurrence of pain in TNB versus TNP group suggest a potential role of herpes viruses in the development of pain syndrome. Thus, studying herpes viruses in the blood could be recommended for improving the diagnostics and therapy of patients with classical TN [ABSTRACT FROM AUTHOR]

Background: Human herpes virus-6 (HHV-6) is a ubiquitous virus known as an etiological agent of exanthem subitum. HHV-6-encephalitis in immunocompetent children is a rare complication of the primary infection. There are a lack of data on the prevalence of HHV-6-encephalitis in Russia. The aim of our study was to analyze the prevalence of HHV-6 DNA in the cerebrospinal fluid (CSF) of immunocompetent children with suspected acute meningoencephalitis. Materials and Methods: A total of 712 CSF samples were tested using qualitative PCR over 12 years at N.F. Filatov Children’s City Clinical Hospital No.5, Saint-Petersburg, Russia. Results: HHV-6 DNA was detected in 20 (2.8%) of the samples. Retrospectively, we analyzed the medical records of 15 cases. There were seven boys and eight girls from 1 month to 7 years old; the mean age was 22.3 ± 5.6 months. Most HHV-6 DNA-positive cases were due to the primary form of HHV-6 infection. There were, in total, four cases of HHV-6-meningoencephalitis. All the children had a complete recovery, without neurological deficits or death. Conclusions: HHV-6 encephalitis is a very rare disease in immunocompetent children (four cases among 712 samples over 12 years). Additional studies are needed to develop accurate diagnostic criteria and therapeutic approaches.

Abstract Background and Aims Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS). MS results from an inflammatory process leading to the loss of neural tissue and increased disability over time. The role of Epstein Barr Virus (EBV), as one of the most common global viruses, in MS development has been the subject of several studies. However, many related questions are still unanswered. This study aimed to review the connection between MS and EBV and provide a quick outline of MS prevention using EBV vaccination. Methods For this narrative review, an extensive literature search using specific terms was conducted across online databases, including PubMed/Medline, Scopus, Web of Science, and Google Scholar, to identify pertinent studies. Results Several studies proved that almost 100% of people with MS showed a history of EBV infection, and there was an association between high titers of EBV antibodies and an increased risk of MS development. Various hypotheses are proposed for how EBV may contribute to MS directly and indirectly: (1) Molecular Mimicry, (2) Mistaken Self, (3) Bystander Damage, and (4) Autoreactive B cells infected with EBV. Conclusion Given the infectious nature of EBV and its ability to elude the immune system, EBV emerges as a strong candidate for being the underlying cause of MS. The development of an EBV vaccine holds promise for preventing MS; however, overcoming the challenge of creating a safe and efficacious vaccine presents a significant obstacle.

Human herpesvirus 6 (HHV-6) is one of the most prevalent childhood viruses. HHV-6 reactivation in allogeneic hematopoietic cell transplant recipients and solid organ transplant recipients is well described in medical literature. We present a case of HHV-6 reactivation causing encephalitis, which is rare in immunocompetent adults.

Purpose: Fever is a common cause for hospitalization among the pediatric population. The spectrum of causative agents is diverse. Human herpesvirus 6 (HHV-6) is a ubiquitous virus that often causes hospitalization of children in western countries. Previously, we investigated the cause of fever of 600 febrile hospitalized children in Gabon, and in 91 cases the causative pathogen was not determined. In this study, we assessed HHV-6 infection as potential cause of hospitalization in this group. Methods: Blood samples were assessed for HHV-6 using real-time quantitative PCR. Three groups were investigated: (1) group of interest: 91 hospitalized children with febrile illness without a diagnosed causing pathogen; (2) hospitalized control: 91 age-matched children hospitalized with febrile illness with a potentially disease-causing pathogen identified; both groups were recruited at the Albert Schweitzer Hospital in Lambaréné, Gabon and (3) healthy control: 91 healthy children from the same area. Results: Samples from 273 children were assessed. Age range was two months to 14 years, median (IQR) age was 36 (12–71) months; 52% were female. HHV-6 was detected in 64% (58/91), 41% (37/91), and 26% (24/91) of the samples from groups 1, 2, and 3, respectively; with statistically significant odds of being infected with HHV-6 in group 1 (OR = 4.62, 95% CI [2.46, 8.90]). Only HHV-6B was detected. Conclusions: Although tropical diseases account for a large proportion of children's hospitalizations, considering common childhood diseases such as HHV-6 when diagnosing febrile illnesses in pediatric populations in tropical countries is of importance. [ABSTRACT FROM AUTHOR]

Although hematopoietic stem cell transplantation (HSCT) and other cellular therapies have significantly improved outcomes in the management of multiple hematological and nonhematological malignancies, the resulting impairment in humoral and cellular response increases the risk for opportunistic infection as an undesirable side effect. With their ability to establish latent infection and reactivate when the host immune system is at its weakest point, the Herpesviridae family constitutes a significant proportion of these opportunistic pathogens. Despite recent advancements in preventing and managing herpesvirus infections, they continue to be a common cause of significant morbidity and mortality in transplanted patients. Herein, we aim to provide and update on herpesvirus other than cytomegalovirus (CMV) affecting recipients of HSCT and other cellular therapies. [ABSTRACT FROM AUTHOR]

Background: Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease- modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler's murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro. Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide. Methods: A total of 11 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 8 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L). Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (6.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = .221; p = .28) and 6 months later (r = .24; p = .17). We found that higher EBNA-1 titers (p = .1) and a higher age (p = .4) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23. AU and >42.8 years (P5 values) were NEDA-3. Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response. [ABSTRACT FROM AUTHOR]

Objective. To assess the impact of CMV and HHV-6 reactivation on the course of early post-transplant period in patients with hematologic malignancies. Materials. Retrospective analysis of medical records of 339 patients with hematologic malignancies who received hematopoietic stem cell transplantation (HSCT) was performed, and markers of CMV and HHV-6 infections were detected (specific IgG, EIA). Blood and other materials from HSCT recipients were tested (PCR) for viral DNA in early post-transplant period (up to Day 100). Results. Reactivation of viral infections after HSCT was discovered in 177 patients (52,2 %): CMV-infection was detected in 23 %, HHV-6 in 17,4 %, CMV+HHV-6 in 11,6 % of HSCT recipients. CMV DNA was predominantly identified in blood, while HHV-6 DNA was more frequently discovered in GIT mucosa and bone marrow. 40 % of 99 patients with HHV-6 reactivation had concomitant CMV+HHV-6 reactivation. In this group, the clinical manifestation of infections was registered significantly more frequently. Febrile neutropenia was more frequent in HSCT recipients with CMV reactivation, sepsis and graft hypofunction were diagnosed more frequently in presence of HHV-6 and predominantly HHV-6+CMV infections. The direct correlation (using Spearman’s method) between CMV and HHV-6 reactivation and terms of leukopoiesis recovery, engraftment terms, and transplant hypofunction was revealed. An impact of herpetic infections reactivation on the graft hypofunction and late recovery of leukopoiesis was confirmed using the logistic regression; its impact on the chimerism was revealed. In 72 % of cases, the graft failure in early post-transplant period occurred in patients with herpetic infections reactivation. Conclusion. HHV-6 and CMV reactivation in the early period after HSCT correlates with terms of leukopoiesis recovery, contributes to development of complications, and is an additional factor aggravating the course of the post-transplant period.

Nascent nucleocapsids of herpesviruses acquire a primary envelope during their nuclear export by budding through the inner nuclear membrane into the perinuclear space between the inner and outer nuclear membranes. This process is mediated by a conserved viral heterodimeric complex designated the nuclear egress complex, which consists of the nuclear matrix protein and the nuclear membrane protein. In addition to its essential roles during nuclear egress, the nuclear matrix protein has been shown to interact with intracellular signaling pathway molecules including NF-kB and IFN-ß to affect viral or cellular gene expression. The human herpesvirus 6A (HHV-6A) U37 gene encodes a nuclear matrix protein, the role of which has not been analyzed. Here, we show that HHV-6A U37 activates the heat shock element promoter and induces the accumulation of the molecular chaperone Hsp90. Mechanistically, HHV-6A U37 interacts with heat shock transcription factor 1 (HSF1) and induces its phosphorylation at Ser-326. We report that pharmacological inhibition of HSF1, Hsp70, or Hsp90 decreases viral protein accumulation and viral replication. Taken together, our results lead us to propose a model in which HHV-6A U37 activates the heat shock response to support viral gene expression and replication. IMPORTANCE: Human herpesvirus 6A (HHV-6A) is a dsDNA virus belonging to the Roseolovirus genus within the Betaherpesvirinae subfamily. It is frequently found in patients with neuroinflammatory disease, although its pathogenetic role, if any, awaits elucidation. The heat shock response is important for cell survival under stressful conditions that disrupt homeostasis. Our results indicate that HHV-6A U37 activates the heat shock element promoter and leads to the accumulation of heat shock proteins. Next, we show that the heat shock response is important for viral replication. Overall, our findings provide new insights into the function of HHV-6A U37 in host cell signaling and identify potential cellular targets involved in HHV-6A pathogenesis and replication. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a silent global health problem that can lead to suicide. MDD development is suggested to result from numerous risk factors, including genetic factors. A precise tool for MDD diagnosis is currently not available. Recently, inflammatory processes have been identified as being strongly involved in MDD development and the reactivation of human herpesvirus type 6 (HHV-6), upregulating cytokines such as TNF-α, which are associated with MDD. Therefore, this study aimed to determine the association of HHV-6 with genetic factors, especially TNF-α mutation, in MDD patients and their relatives compared to healthy controls. The Patient Health Questionnaire (PHQ-9) was used to evaluate MDD status, and 471 oral buccal samples were investigated for HHV-6 infection and viral copy number by qPCR. TNF-α (-308G/A) gene mutation and the cytokines TNF-α, IL-6, and IL-10 were analyzed by high-resolution melting (HRM) analysis and enzyme-linked immunosorbent assay (ELISA). Whole-exome sequencing of buccal samples was performed to analyze for genetic factors. The results showed significantly higher HHV-6 positivities and viral loads in MDD patients (15/59 (25.67%) and 14,473 ± 16,948 copies/µL DNA) and their relatives (blood relatives 17/36 (47.22%) and 8146 ± 5656 copies/µL DNA); non-blood relatives 7/16 (43.75%) and 20,721 ± 12,458 copies/µL DNA) compared to the healthy population (51/360 (14.17%) and 6303 ± 5791 copies/µL DNA). The TNF-α (-308G/A) mutation showed no significant difference. Surprisingly, 12/26 (46.15%) participants with the TNF-α (-308G/A) mutation showed HHV-6 positivities at higher rates than those with wild-type TNF-α (-308G) (70/267 (26.22%)). HHV-6-positive participants with TNF-α (-308G/A) showed higher levels of TNF-α, IL-6, and IL-10 than those of negative control. Exome analysis revealed that common mutations in immune genes were associated with depression. Therefore, this study unveiled the novel association of inflammatory gene TNF-α (-308G/A) mutations with HHV-6 reactivation, which could represent a combined risk factor for MDD. This result could induce further research on MDD development and clinical applications. [ABSTRACT FROM AUTHOR]

Background: Human herpes virus-6 (HHV-6) is a ubiquitous virus known as an etiological agent of exanthem subitum. HHV-6-encephalitis in immunocompetent children is a rare complication of the primary infection. There are a lack of data on the prevalence of HHV-6-encephalitis in Russia. The aim of our study was to analyze the prevalence of HHV-6 DNA in the cerebrospinal fluid (CSF) of immunocompetent children with suspected acute meningoencephalitis. Materials and Methods: A total of 712 CSF samples were tested using qualitative PCR over 12 years at N.F. Filatov Children's City Clinical Hospital No.5, Saint-Petersburg, Russia. Results: HHV-6 DNA was detected in 20 (2.8%) of the samples. Retrospectively, we analyzed the medical records of 15 cases. There were seven boys and eight girls from 1 month to 7 years old; the mean age was 22.3 ± 5.6 months. Most HHV-6 DNA-positive cases were due to the primary form of HHV-6 infection. There were, in total, four cases of HHV-6-meningoencephalitis. All the children had a complete recovery, without neurological deficits or death. Conclusions: HHV-6 encephalitis is a very rare disease in immunocompetent children (four cases among 712 samples over 12 years). Additional studies are needed to develop accurate diagnostic criteria and therapeutic approaches. [ABSTRACT FROM AUTHOR]

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Nonpharmaceutical interventions (NPIs) to control COVID‐19 have decreased the incidence of many pediatric infectious diseases. The epidemiology of β‐ and γ‐herpesvirus infections might have been affected by NPIs. The aim of this study was to elucidate changes in trends in β‐ and γ‐herpesvirus infections and complex febrile seizures (cFS) of viral etiology before and during the COVID‐19 pandemic. Between April 2017 and March 2021, febrile children aged ≤5 years were enrolled. Detection of EBV, CMV, HHV‐6B, and HHV‐7 DNA in serum was performed using real‐time PCR. The epidemiology of viral infections and cFS were compared between the prepandemic and pandemic periods. During the observation period, 1432 serum samples were collected. The mean number of febrile children decreased during the pandemic period, but the number of patients with HHV‐6B infection increased from 35 (9.3% of all febrile children) per year before the pandemic to 43 (15.5%) during the pandemic. The change in the proportion of patients with primary HHV‐6B infection was 6.50% (95% confidence interval [CI], 2.05%–11.3%; p = 0.0047). The mean number of patients with cFS decreased during the pandemic period, but the number of patients with HHV‐6B–associated cFS was stable throughout the observation period. Therefore, the change in proportion of patients with cFS caused by primary HHV‐6B infection was 49.5% (95% CI, 12.2%–60.5%; p = 0.0048). The disease burden of primary HHV‐6B infection among patients in the emergency room remained unchanged, with a significant increase in the relative proportion after the COVID‐19 pandemic began. [ABSTRACT FROM AUTHOR]

In this article, we discuss a recently published article that demonstrated a novel way of identifying viral pathogens reactivating in human cells to be used as cellular therapy, in this instance chimeric antigen receptor (CAR) T cells. The authors used search engines and databases to identify viruses able to reactivate in T cells and then tested this initially in T‐cell cultures, specifically human herpesvirus 6. This virus was then shown to reactivate infrequently in vitro and in vivo in CAR T cells as a consequence of T‐cell activation. The methodology may be most clinically useful for more frequently reactivating viruses in other types of cellular therapy such as allogenic CAR T cells or induced pluripotent stem cells. [ABSTRACT FROM AUTHOR]

The role of viral infection in bronchial asthma (BA) is well-known being reflected particularly in GINA. An effect of pneumotropic intracellular persistent herpesviruses on the course of BA is of particular interest. The most common viruses of this group are cytomegalovirus (CMV), EpsteinBarr virus (EBV), and human herpesvirus 6 (HHV-6). The CMV role has been discussed in our previous publications allowing us to focus here on EBV and HHV-6. We examined 167 children with BA that was diagnosed and clinically assessed in accordance with the current national clinical guidelines. Patients with controlled asthma (70 patients), partially controlled and uncontrolled asthma (97 patients) were stratified into several groups. The detection of EBV and HHV-6 DNA was carried out in throat swabs by PCR; the level of total and virus-specific IgA, IgM, IgG, IgE as well as serum level of IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-8 and TNF was assessed by enzyme linked immunosorbent assay; lymphocyte subpopulations were analyzed by flow cytometry. The dose of topic GCS was taken into account with reference to the fluticosone equivalent; the function of external respiration was studied by spirometry. It was revealed that EBV DNA was found in 14.2% of cases, whereas HHV-6 in 19.0% of cases, but 14.4% and 52.4% of patients, respectively, shed no pathogen-linked DNA. At the same time, patients with uncontrolled BA are significantly more likely to shed the pathogen DNA, so that EBV is released in 17.1% vs 4.5% of patients with controlled BA, HHV-6 in 19.5% vs 13.6%. On the contrary, children with controlled BA were significantly more often (63.6% vs 51.2%) negative for viral DNA shedding. Moreover, virus shedding was paralleled with higher levels of IL-5: it was as high as 0.91 pg/ml and 0.29 pg/ml for EBV and HHV-6, respectively; those shedding DNA of both pathogens vs no shedding had IL-5 at level of 0.25 pg/ml vs 0.11 pg/ml. Similar pattern was observed for higher total IgE: 184.5 IU for EBV, 113.1 IU for HHV-6, and 371.7 IU shedding both viruses vs 95.2 IU in without DNA pathogen shedding; lower level of FEV1: EBV 96.6%, HHV-6 98.8%, and 106.2% in patients shedding both viruses vs 109.8% in patients not shedding the pathogen DNA. Patients shedding EBV DNA require higher doses of topic GCS to achieve disease control: EBV 325.0 mg, HHV-6 186.4 mg; shedding both viruses 328.1 mg of topic GCS vs 198.6 mg in patients without pathogen DNA shedding. Thus, activation of both EBV and HHV-6 worsens BA control and aggravates its course, but EBV persistence has a more pronounced effect on the course and control of the disease.

Objective: to study the clinical manifestations of herpetic stromal keratitis with ulceration associated with EBV and HHV-6 reactivation.Patients and methods. 172 patients with anterior ophthalmic herpes were under observation, of which 43 patients had herpetic stromal keratitis with ulceration with an average duration of complaints of more than 60 days. Tear, saliva, blood and urine samples were used as a material for PCR (qualitative and quantitative) for the presence of HSV, VZV, CMV, EBV, HHV-6, HHV-7 DNA. Local therapy of the acute period included instillation of antiviral, anti-inflammatory agents and lubricants. Systemic antiherpetic therapy included oral use of selective nucleoside analogues: valacyclovir and famciclovir in increased daily dosages.Results. 87 cumulative positive results were obtained, of which the proportion of EBV and HHV-6 DNA detection was 23 % and 28 %. Complex local therapy with the inclusion of heparin-containing lubricant and a drug containing 5 % dexpanthenol (“Corneregel”) combined with systemic therapy with nucleoside analogues in increased daily dosages led to complete relief of objective symptoms within 14 to 28 days.Conclusions. EBV and HHV-6 were detected in more than 50 % of cases, which determines systemic antiviral therapy in increased daily dosages and a prolonged course. The pathogenesis of ulcerative defects may be associated with the direct reactivation of HHV-6 and EBV, which requires the use of active reparative therapy from the first days of curation. The phenomenon of a transient viral “surge” detected by PCR during disease course can be observed by adequate systemic therapy and is a normal laboratory pattern indicating the correct tactics.

BackgroundEpstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler’s murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro.Objective1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide.MethodsA total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L).ResultsAntiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3.ConclusionTreatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

The human betaherpesviruses including human cytomegalovirus (HCMV), human herpesvirus (HHV)-6a and HHV-6b, and HHV-7 infect and establish latency in CD34+ hematopoietic stem and progenitor cells (HPCs). The diverse repertoire of HPCs in humans and the complex interactions between these viruses and host HPCs regulate the viral lifecycle, including latency. Precise manipulation of host and viral factors contribute to preferential maintenance of the viral genome, increased host cell survival, and specific manipulation of the cellular environment including suppression of neighboring cells and immune control. The dynamic control of these processes by the virus regulate inter- and intra-host signals critical to the establishment of chronic infection. Regulation occurs through direct viral protein interactions and cellular signaling, miRNA regulation, and viral mimics of cellular receptors and ligands, all leading to control of cell proliferation, survival, and differentiation. Hematopoietic stem cells have unique biological properties and the tandem control of virus and host make this a unique environment for chronic herpesvirus infection in the bone marrow. This review highlights the elegant complexities of the betaherpesvirus latency and HPC virus-host interactions. [ABSTRACT FROM AUTHOR]

The complexity of autoimmunity initiation has been the subject of many studies. Both genetic and environmental factors are essential in autoimmunity development. Among others, environmental factors include infectious agents. HHV-6 is a ubiquitous human pathogen with a high global prevalence. It has several properties suggestive of its contribution to autoimmunity development. HHV-6 has a broad cell tropism, the ability to establish latency with subsequent reactivation and persistence, and a range of immunomodulation capabilities. Studies have implicated HHV-6 in a plethora of autoimmune diseases—endocrine, neurological, connective tissue, and others—with some studies even proposing possible autoimmunity induction mechanisms. HHV-6 can be frequently found in autoimmunity-affected tissues and lesions; it has been found to infect autoimmune-pathology-relevant cells and influence immune responses and signaling. This review highlights some of the most well-known autoimmune conditions to which HHV-6 has been linked, like multiple sclerosis and autoimmune thyroiditis, and summarizes the data on HHV-6 involvement in autoimmunity development.

The human betaherpesviruses including human cytomegalovirus (HCMV), human herpesvirus (HHV)-6a and HHV-6b, and HHV-7 infect and establish latency in CD34+ hematopoietic stem and progenitor cells (HPCs). The diverse repertoire of HPCs in humans and the complex interactions between these viruses and host HPCs regulate the viral lifecycle, including latency. Precise manipulation of host and viral factors contribute to preferential maintenance of the viral genome, increased host cell survival, and specific manipulation of the cellular environment including suppression of neighboring cells and immune control. The dynamic control of these processes by the virus regulate inter- and intra-host signals critical to the establishment of chronic infection. Regulation occurs through direct viral protein interactions and cellular signaling, miRNA regulation, and viral mimics of cellular receptors and ligands, all leading to control of cell proliferation, survival, and differentiation. Hematopoietic stem cells have unique biological properties and the tandem control of virus and host make this a unique environment for chronic herpesvirus infection in the bone marrow. This review highlights the elegant complexities of the betaherpesvirus latency and HPC virus-host interactions.

Drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome (DRESS/DIHS) is one type of severe cutaneous adverse reaction (SCAR). It is featured by fever, widespread skin lesions, protracted clinical course, internal organ involvement, and possibly long-term autoimmune sequelae. The presence of high-risk human leukocyte antigen (HLA) alleles, hypersensitivity reaction after culprit drug ingestion, and human herpesvirus reactivation may all contribute to its complex clinical manifestations. Some recent studies focusing on the roles of involved cytokines/chemokines and T cells co-signaling pathways in DRESS/DIHS were conducted. In addition, some predictors of disease severity and prognosis were also reported. In this review, we provided an update on the current understanding of the pathogenesis, potential biomarkers, and the relevant therapeutic rationales of DRESS/DIHS.

Inherited chromosomally integrated human herpesvirus 6 (iciHHV-6) is a condition in which the complete HHV-6 genome is integrated into the chromosomes of the host germ cell and is vertically transmitted. The aims of this study were to identify iciHHV-6 prevalence in hospitalized patients and clinical features in individuals carrying this integration. HHV-6 PCR on hair follicles was used to confirm iciHHV-6 status when the blood viral load was more than 5 Log10 copies/mL. From January 2012 to June 2022, HHV-6 DNAemia was investigated in 2019 patients. In particular, 49 had a viral load higher than 6 Log10 copies/mL and HHV-6 DNA in hair follicles was positive. A viral load between 5.0 and 5.9 Log10 copies/mL was observed in 10 patients: 6 infants with acute HHV-6 infection and 4 patients with leukopenia and HHV-6 integration. Therefore, the iciHHV-6 prevalence in our population was 2.6% (53/2019). Adult patients with integration presented hematological (24%), autoimmune (11%), autoimmune neurological (19%), not-autoimmune neurological (22%), and other diseases (19%), whereas 5% had no clinically relevant disease. Although in our study population a high percentage of iciHHV-6 adult hospitalized patients presented a specific pathology, it is still unknown whether the integration is responsible for, or contributes to, the disease development. [ABSTRACT FROM AUTHOR]

Skin rash is one of the most common complications during childhood. Viral agents play an essential role in the development of such symptoms. Present study aims to determine the prevalence and genetic variability of Human Herpesvirus 6 and 7 (HHV‐6 and HHV‐7) infections and their subtypes in children under 5 years of age with skin rash and negative for rubella and measles. We used serum and throat swap samples from 196 children with skin rash and fever. ELISA and IFA tests were performed to detect antibodies against HHV6/7. Sequencing was performed using Sanger sequencing, and BioEdit and MEGA10 software were used for sequence analysis. According to the results, 66% and 40% of cases were positive for HHV‐6 IgM and HHV‐7 IgM, respectively. According to the molecular analysis, HHV‐6 Nested‐PCR was positive in 18% of cases, however, HHV‐7 Nested‐PCR was positive in 7.7% of cases. On the other hand, HHV‐6 IgG and HHV‐7 IgG were positive in 91% and 55% of study cases, respectively. For HHV‐6, we found some genetic variabilities resulting in antigenic changes compared to reference strains. HHV‐7 isolates showed no genetic differentiation and had a stable gene sequence. Based on the results, the detection of some cases of HHV6/7 primary infection and the presence of specific symptoms of roseola in the study population needs continuous evaluation of HHV6/7 frequency and distribution, also genetic variabilities of HHV6. This can pave the way for investigating HHV6 immune evasion and vaccine research and studying the relationship between viral genetic variations and other factors like disease severity. Furthermore, it is necessary to determine the relation between HHV6 genetic changes and latent infection to be considered in possible future vaccines and antiviral drug development. [ABSTRACT FROM AUTHOR]

A novel syndrome called long-haul COVID or long COVID is increasingly recognized in a significant percentage of individuals within a few months after infection with SARS-CoV-2. This disorder is characterized by a wide range of persisting, returning or even new but related symptoms that involve different tissues and organs, including respiratory, cardiac, vascular, gastrointestinal, musculo-skeletal, neurological, endocrine and systemic. Some overlapping symptomatologies exist between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Very much like with long ME/CFS, infections with herpes family viruses, immune dysregulation, and the persistence of inflammation have been reported as the most common pattern for the development of long COVID. This review describes several factors and determinants of long COVID that have been proposed, elaborating mainly on viral persistence, reactivation of latent viruses such as Epstein–Barr virus and human herpesvirus 6 which are also associated with the pathology of ME/CFS, viral superantigen activation of the immune system, disturbance in the gut microbiome, and multiple tissue damage and autoimmunity. Based on these factors, we propose diagnostic strategies such as the measurement of IgG and IgM antibodies against SARS-CoV-2, EBV, HHV-6, viral superantigens, gut microbiota, and biomarkers of autoimmunity to better understand and manage this multi-factorial disorder that continues to affect millions of people in the world. [ABSTRACT FROM AUTHOR]

Tissue fibrosis can affect every type of tissue or organ, often leading to organ malfunction; however, the mechanisms involved in this process are not yet clarified. A role has been hypothesized for Human Cytomegalovirus (HCMV) and Human Herpesvirus 6 (HHV-6) infections as triggers of systemic sclerosis (SSc), a severe autoimmune disease causing progressive tissue fibrosis, since both viruses and antiviral immune responses toward them have been detected in patients. Moreover, HCMV or HHV-6A infection was reported to increase the expression of fibrosis-associated transcriptional factors and miRNAs in human dermal fibroblasts. However, it is unlikely that they have separate effects in the infected host, as both viruses are highly prevalent in the human population. Thus, our study aimed to investigate, by quantitative real-time PCR microarray, the impact of HCMV/HHV-6A coinfection on the expression of pro-fibrotic miRNAs in coinfected cells, compared to the effect of single viruses. The results showed a possible synergistic effect of the two viruses on pro-fibrotic miRNA expression, thus suggesting that HCMV and HHV-6 may enhance each other and cooperate at inducing enhanced miRNA-driven fibrosis. These data may also suggest a possible use of virus-induced miRNAs as novel diagnostic or prognostic biomarkers for SSc and its clinical treatment. [ABSTRACT FROM AUTHOR]

Human herpesvirus-6 (HHV-6) infection can rarely cause life-threatening conditions, such as encephalitis, in otherwise healthy children, with unclear pathogenesis. We studied a child who presented with acute HHV-6 encephalitis at the age of 10 months and who was homozygous for a novel missense mutation in IRAK4, encoding interleukin-1 receptor-associated kinase 4, identified by whole-exome sequencing. We tested the damaging impact of this mutation in silico by molecular dynamics simulations and in vitro by biochemical and functional experiments utilizing cell lines and patient's cells. We found that the mutation is severely hypomorphic, impairing both the expression and function of IRAK-4. Patient's leukocytes had barely detectable levels of IRAK-4 and diminished anti-viral immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors. Overall, these findings suggest that acute HHV-6 encephalitis can result from inborn errors of immunity to virus. This study represents the first report of isolated acute HHV-6 infection causing encephalitis in an inherited primary immunodeficiency, notably autosomal recessive (AR) partial IRAK-4 deficiency, and the first report of AR IRAK-4 deficiency presenting with a severe viral disease, notably HHV-6 encephalitis upon an acute infection, thereby expanding the clinical spectrum of IRAK-4 deficiency. [ABSTRACT FROM AUTHOR]

Drug-induced hypersensitivity syndrome (DIHS) is one of the severe drug eruptions accompanied by fever and multiple organ dysfunction, and it is induced by a relatively limited range of drugs, including anticonvulsants. A distinctive feature of this condition is its association with the reactivation of herpes viruses, particularly human herpesvirus 6. The pathogenesis involves two key factors: drug allergy and herpesvirus reactivation. DIHS is often challenging to diagnose in its early stages, and its clinical course varies widely, ranging from relatively mild to life-threatening cases. Additionally, unexpected complications, such as autoimmune diseases, may occur during the convalescent phase. As a result, diagnosing, treating, and predicting the prognosis of DIHS remain complex issues. In response to these challenges, the Ministry of Health, Labour and Welfare Study Group on Severe Erythema Multiforme has taken the lead in developing new guidelines for the management of DIHS. These guidelines aim to support clinical practice by providing up-to-date, evidence-based information on the diagnosis, treatment, and prognosis of DIHS., (© 2025 Japanese Dermatological Association.)

Abstract Background This is an update on the existing evidence regarding a relationship between infection with human herpesvirus 6 (HHV-6) and multiple sclerosis (MS) in order to contribute on the attempt to define the nature and strength of that relationship. Results Study quality was assessed using the criteria proposed by Moore and Wolfson and by the classification criteria used by the Canadian Task Force on the Periodic Health Examination. Studies were categorized both by experimental technique and by quality (high [A], intermediate [B], and low [C]) as determined by the Moore and Wolfson criteria. Overall, 27 (90%) of 30 studies, 18 (86%) of which were classified as A quality, reached a statistically significant result. According to the Canadian Task Force classification, all studies were categorized as evidence of qualityII-1. Limitations of the available experimental techniques and perspectives for future research are discussed. Conclusions The current review continues to emphasize the need for further, objective, evidence-based examination of the relationship between HHV-6 infection and multiple sclerosis.

Viral encephalitis can lead to encephalopathy, epileptic activity, focal neurological deficits, and death. Prompt recognition and a high index of clinical suspicion can lead to early initiation of appropriate management. We describe an interesting case of a 61-year-old presenting with fever and altered mental status, diagnosed with numerous episodes of viral encephalitis caused by divergent and recurrent viruses. On his initial presentation, lumbar puncture revealed lymphocytic pleocytosis and positivity for Human Herpesvirus 6 (HHV-6), and he was treated with ganciclovir. On subsequent admissions, he was diagnosed with recurrent HHV-6 encephalitis as well as Herpes Simplex Virus 1 encephalitis and treated with ganciclovir, foscarnet and acyclovir. Despite prolonged courses of treatment and resolution of symptoms, he continued to have persistently high plasma viral loads of HHV-6, consistent with probable chromosomal integration. In this report, we emphasize the clinical pearl of chromosomally integrated HHV-6 that can present in a patient with persistently high plasma viral loads of HHV-6, that are non-responsive to treatment. Individuals with chromosomally integrated HHV-6 may be more susceptible to other viral infections.